VBCC Oct 2013

OCTOber 2013 VOL 4 NO 8

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM www.ValueBasedCancerCare.com VBCC Perspective

Cancer Prehabilitation May Reduce Healthcare Costs and Improve Outcomes

By Julie Silver, MD Associate Professor, Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston

P

rehabilitation (or “prehab”) has a long history as an important part of the rehabilitation care continuum. For example, patients who are electing to have a total hip or knee arthroplasty may have preoperative assessments and interventions that are sometimes grouped together and called “joint camp.” Prehabilitation has also

been gaining traction in the oncology community, because of the potential it may have to improve cancer care. In general, prehabilitation is used in anticipation of an upcoming stressor to improve outcomes; it typically should not delay the start of cancer treatment but rather use the available time between diagnosis and surgery or Continued on page 23

ESMO Annual Congress

MPDL3280A: Responses Better in Smokers than in Nonsmokers in Advanced Lung Cancer

First ever therapy to show advantage for patients who smoke

By Phoebe Starr Amsterdam, The Netherlands—For the first time, a therapy for non–smallcell lung cancer (NSCLC) has achieved responses in smokers better than in nonsmokers. The antibody MPDL3280A also achieved good responses in squamous and adenoma histologic types of NSCLC. These results of a phase 1 study in ©2013 Engage Healthcare Communications, LLC

patients with metastatic NSCLC were so encouraging that experts suggested bypassing phase 2 studies and going on to phase 3 clinical trials directly.

Recruitment for this human monoclonal antibody is ongoing for phase 2 and 3 trials in NSCLC. “We are at the beginning of a new

Continued on page 6

IOM Cites Looming Cancer Care Crisis, Recommends Course-Correcting Strategies

By Charles Bankhead

A

Patricia A. Ganz, MD

n evolving crisis in cancer care will reach a critical mass over the next 15 to 20 years without a transition to a more patient-centered, evidence-based delivery system, warn the authors of a report from the Institute of Medicine (IOM).

A conflagration of factors will stretch

cancer care to the breaking point, including the rapidly aging patient population, a growing case volume that will overwhelm the oncology workforce, and the rising cost of care. The 315page report, “Delivering High-Quality Cancer Care: Charting a New Course Continued on page 14

Growing Pressures on Oncolytics to Demonstrate Value

Doug Long

Oncology trends through the lens of IMS Health

By Caroline Helwick Hollywood, FL—Oncology growth for the next couple of years will be driven by several strong trends, according to Doug Long, Vice President of Industry Relations, IMS Health, who described these trends at the 3rd Annual Conference of the Association for Value-Based Cancer Care.

IMS analyses of the oncology landscape indicate the following trends:

• A continual increase in all tumor types, with high unmet needs for many of them • A strong cancer drug pipeline, with more than 470 new chemical entities in phase 2 trials or later development • Fierce competition as a result of the robust pipeline, which includes Continued on page 29

inside FROM THE EDITOR . . . . . . . . . . . 4 Is cancer care in crisis? The IOM Report FDA UPDATE . . . . . . . . . . . . . . . . . .

Perjeta first drug approved for neo­ adjuvant breast cancer therapy

4

IN THE LITERATURE . . . . . . . . . . . . 20 PD-1 inhibitor lambrolizumab: durable responses in advanced melanoma 3RD CONFERENCE . . .

Community oncology practices

29

VALUE PROPOSITIONS . . . . . . . . . 5 Value-based care will change medicine

PERSONALIZED MEDICINE . . . . . 42 Genomics of acute myeloid leukemia

6

DRUG UPDATE . . . . . . . . . . . . . . . 44 Revlimid for relapsed/progressing MCL

ESMO ANNUAL CONGRESS . . . . .

The state of cancer globally in 2013

ECONOMICS OF CANCER CARE . 14 Outpatient vs community-based care

EMERGING THERAPIES . . . . . . . . 46 Idelalisib, ibrutinib show promise

AN 8-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

™

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 CareTM, is to provide our 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 explore a specific topic to be considered when developing value-based strategies.

IN MULTIPLE MYELOMA

Value-BasedCare FEBRUARY 2013

™

1st IN A SERIES

Treating Newly Diagnosed Multiple Myeloma: Data on Safety, EfďŹ cacy, and Dosing Regimens

Topics to include: Safety and Efficacy of Front-Line Treatment Assessing the Value of Complete Response Pharmacoeconomic Analysis of Treatment Options Therapeutic Decision Making Based on Cytogenetics Assessing the Value of Progression-Free Survival Data Safety and Efficacy of Therapies in the Relapsed Setting Using Alternate Routes of Drug Administration Cost-Effective Use of Imaging Techniques

Introduction The therapeutic paradigm for multiple myeloma (MM) continues to evolve, due to advances in our understanding of the molecular and genetic basis of the disease.1 Newly diagnosed patients typically undergo multidrug therapy that includes novel, targeted agents, often followed by consolidation with autologous stem cell transplantation (ASCT) and maintenance therapy.1,2 This therapeutic model has altered the value equation in newly diagnosed MM, because survival and life quality have increased along with cost of treatment.1 Enhanced survival, through the use of novel therapies, requires us to balance both short- and long-term outcomes. Over its clinical course, MM has one of the highest direct costs of any cancer.1 For example, in a 2007 analysis, the direct costs associated with a course of treatment with a novel agent plus a steroid (taking into account the drugs themselves, as well as prophylaxis and management of toxicities) ranged from approximately $47,000 to $72,000.1,3 Simple assessment of cost, however, is not sufďŹ cient, because value comprises not only expenses but also outcome over the increasingly prolonged survival time for MM. For example, in the VISTA trial (N=682), newly diagnosed, transplant-ineligible patients who were randomized to either triple therapy with bortezomib/melphalan/prednisone (VMP) or double therapy with melphalan/prednisone (MP) were followed for life quality over nine 6-week cycles.4 The study found that, through cycle 4, health-related quality of life (HRQoL) was lower with VMP than with MP, due to decreased treatment tolerability. However, from cycle 5 through the end of therapy, HRQoL with VMP was not compromised relative to MP, and recovered to the point where HRQoL was comparable for the 2 treatments.4 This investigation also demonstrated the link between antimyeloma efďŹ cacy and HRQoL. Among responders to therapy, HRQoL increased from the time of response to the end of treatment.4 Responders were more common in the VMP group than in the MP group in this trial, in which response rates were 71% and 35%, respectively (P<.001).5 In addition, 5-year overall survival (OS) was prolonged with VMP versus MP,6 another beneďŹ t to consider in the value equation.

Pharmacoeconomic analysis of initial treatment with melphalan/prednisone/lenalidomide (MPR) followed by lenalidomide maintenance (MPR-R) reported that this regimen, although more expensive than MPR or MP without maintenance, yielded greater cost-effectiveness.7 Although MPR-R increased progression-free survival (PFS) compared with regimens without maintenance, no This newsletter has been supported by funding from Millennium: The Takeda Oncology Company

beneďŹ t in OS has yet been reported with MPR-R, so the observation of cost-effectiveness remains provisional.7 In todayâ&#x20AC;&#x2122;s healthcare environment, when evidence changes the value equation, it changes practice. Therefore, it is critical to be aware of current and emerging data on the tolerability and efďŹ cacy of novel agents, which will inďŹ&#x201A;uence therapeutic strategies.

Tolerability: The Role of Optimized Dosing and Novel Drugs For newly diagnosed MM, current recommendations for care typically include the use of bortezomib, lenalidomide, or thalidomide in multidrug regimens, either for pre-ASCT induction or, in transplant-ineligible patients, as an initial course of therapy.2 All

OVERVIEW 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 provide our 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-ef

topic to be considered when developing value-based

newly diagnosed MM.

STAKEHOLDERSâ&#x20AC;&#x2122; PERSPECTIVES Assessing the Value of Novel Therapies for Multiple Myeloma ............................................. 5

By William J. Cardarelli, PharmD Atrius Health, Harvard Vanguard Medical Associates

Clinical and Economic Challenges in the Treatment of Multiple Myeloma........................ 6

By Kevin B. Knopf MD, MPH California PaciďŹ c Medical Center

An ofďŹ cial publication of

TO VIEW THE SERIES ONLINE PLEASE LOG ON TO:

www.valuebasedcancer.com/myeloma AVBCC100Ksize21213

In This Issue FROM THE EDITOR

Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Vice President/Director of Sales & Marketing Joe Chanley joe@greenhillhc.com Publisher Cristopher Pires cris@engagehc.com Editorial Director Dalia Buffery dalia@engagehc.com 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 Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede 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 Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma 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 9 times a year by Engage Healthcare Communica­tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2013 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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ECONOMICS OF CANCER CARE

Is cancer care in crisis?

IOM cites looming cancer care crisis More….

FDA UPDATE

Perjeta first drug ever approved for neoadjuvant breast cancer therapy

IN THE LITERATURE

VALUE PROPOSITIONS

Molecular test identifies patients at risk for early and late breast cancer recurrence More….

VBCC PERSPECTIVE

Seeking value in oncology care Medication nonadherence More….

Value-based care will change the face of medicine Oncologists urged to adopt value-based care More….

Cancer prehabilitation may reduce healthcare costs

3RD CONFERENCE

PERSONALIZED MEDICINE

ESMO ANNUAL CONGRESS

The global state of cancer in 2013 Second-generation ALK inhibitor regresses CNS metastases in lung cancer More….

BREAST CANCER SYMPOSIUM

Current patterns and costs of treating patients with metastatic breast cancer More….

Genomics of acute myeloid leukemia explored More….

DRUG UPDATE

Revlimid gets new indication for relapsed/ progressing MCL

EMERGING THERAPIES

Idelalisib, ibrutinib promising for B-cell cancers

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 Manager, 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

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 CareFirst BlueCross BlueShield Baltimore, MD

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

Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS Chief Executive Officer, OncoMed Great Neck, NY

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.

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

OCTOber 2013

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From the Editor

Is the US Cancer Care System in Crisis? The IOM Report

By Craig Deligdish, MD

Hematologist/Oncologist, Oncology Resource Networks, Orlando, FL, and Editor-in-Chief, Value-Based Cancer Care

O

n September 10, 2013, the Institute of Medicine (IOM), part of the National Academy of Sciences, published a 315-page report, titled “Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis” (see article, page 1). The incredible effort necessary to generate this report was based in part on the 1999 effort by the IOM, titled “Insuring Quality Cancer Care.”

The new report calls for improvements in the use of evidence-based guidelines, electronic data, and quality monitoring, with a focus on providing high-quality care at the end of life and a commitment to improving cancer treatment for all populations of patients.

The Committee on Improving the Quality of Cancer Care was made up of a team of well-respected oncologists and other researchers, and was assisted by policy experts, leaders of professional organizations, and community oncologists. Clearly, there is room for improvement in our cancer delivery system. As noted in the report, several studies have suggested that cancer care could be more patient-centered.

Attempts to better coordinate care, to deliver evidence-based care, and to

enhance palliative and end-of-life care can all be improved.

However, the report’s title is misleading, stating that there is a “crisis” in the cancer delivery system. A crisis is defined by the Oxford Dictionary as “a time of intense difficulty, trouble, or danger” and as “a difficult or dangerous situation that needs serious attention” in the Merriam-Webster Dictionary. We all agree that the number of patients diagnosed with cancer has significantly increased during the past 20 years, and will continue to increase, with a rising number of cancer survivors. Workforce shortages resulting from an aging physician population and the limited training of new oncologists will exacerbate this problem. The cost of cancer care continues to rise at rates that exceed the gross domestic product and the cost of treating other diseases, and the cost of healthcare in the United States is significantly greater than in other industrialized countries.

There are certainly opportunities to improve the commitment of the oncology community to evidence-based treatment, and there are huge opportunities to develop and apply systems that collect and disseminate outcomes data to ensure best practices. However, classifying our country’s cancer delivery system as being in crisis is a less-than-ac-

curate portrayal of the current state of cancer care and is potentially detrimental to our patients, their families, and to the providers who strive to improve the care that patients with cancer receive on a daily basis. Although there are tremendous opportunities in all aspects of our cancer delivery system, to suggest that the delivery system is in crisis could be construed as overreaching and alarmist.

Significant Progress in Cancer Diagnosis and Treatment During the past 20 years, there have been tremendous strides made in the diagnosis and treatment of patients with cancer. Mortality rates, overall survival, and quality of life have dramatically improved for many patients with cancer. The number and variety of treatments for diseases that were in some cases untreatable have increased substantially. In addition, the toxicity of many treatments has been dramatically reduced by improvements in the development and the availability of supportive care agents to the point that many patients with cancer who are undergoing treatment today can do so without having their treatment interfere with their daily lives.

There has been improvement in screening rates, and there is clearly much greater focus on palliative care

and on hospice care than in 1999. There are many more resources available in numerous parts of the country for the underserved population to receive treatment for cancer. The Affordable Care Act has provided significant support to make care available to the entire US population. Other aspects of the law preclude penalties for preexisting illness and provide funding for healthcare innovation, programs that enhance patient engagement, and initiatives that address payment methodology.

Although the new IOM report summarizes these accomplishments, they can be lost in the report’s title, recommendations, and summaries, as well as in the sound bites that follow the publication of a report such as this one.

The IOM should be commended for its attempts to define high-quality cancer care and for its focus on addressing the cost of cancer care. We may have a long way to go and a tough road to hoe before we win the “war on cancer.” Academic, hospital-based, and community oncologists, as well as all providers of care to patients with cancer, have made dramatic contributions and will continue to do so in the hope of eradicating this disease. I and others remain hopeful that the lessons of the IOM’s 1999 report, and those in the 2013 report, will be efficiently adopted, implemented, and executed. n

their cancer metastasize, or who are at high risk of dying from breast cancer.

Pertuzumab is indicated for use in combination with trastuzumab (Herceptin) and other chemotherapy before surgery and, depending on the treatment regimen used, may be followed by chemotherapy after surgery.

After surgery, patients should continue to receive trastuzumab to complete 1 year of treatment.

This approval opens a new path for the FDA to approve therapies for early-stage breast cancer. “We are seeing a significant shift in the treatment paradigm for early-stage breast cancer,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the Center for Drug Evaluation and Research.

“By making effective therapies available to high-risk patients in the earliest disease setting, we may delay or pre-

vent cancer recurrences.’’

“This is a historic moment,” said Mikkael A. Sekeres, MD, Associate Professor at the Cleveland Clinic who served as the chairman of the FDA’s advisory committee, which voted unanimously to approve the drug.

In May 2012, the FDA issued a draft guidance about the use of pathologic complete response (pCR) as a new end point to support the accelerated approval of a drug for the neoadjuvant treatment of high-risk, early-stage breast cancer. The accelerated approval of pertuzumab for neoadjuvant treatment is based on a study specifically designed to measure pCR. The study included 417 patients with breast cancer who were randomly assigned to receive 1 of 4 neoadjuvant treatment regimens—trastuzumab plus docetaxel, pertuzumab plus trastuzumab and docetaxel, pertuzumab plus trastu-

zumab, or pertuzumab plus docetaxel.

Approximately 39% of the patients receiving pertuzumab plus trastuzumab and docetaxel achieved pCR compared with approximately 21% of those who received trastuzumab plus docetaxel, a significant difference.

The confirmatory trial for this accelerated approval is being conducted in 4800 patients with HER2-positive breast cancer who had previous breast cancer surgery and are at high risk of recurrence. The results are expected in 2016.

The most common side effects reported with pertuzu­mab plus trastuzumab and docetaxel were hair loss, diarrhea, nausea, and a decrease in white blood cells. Other significant side effects included decreased cardiac function, infusion-related reactions, hypersensitivity reactions, and anaphylaxis. September 30, 2013 n

FDA Update Perjeta First Drug Ever Approved for Neoadjuvant Breast Cancer Therapy

The US Food and Drug Adminis­ tration (FDA) granted accelerated approval to pertuzumab (Perjeta; Gen­ entech) as part of a treatment regimen for the neoadjuvant setting (ie, before surgery) for patients with HER2positive early-stage breast cancer. This is the first time that the FDA approved a drug for the neoadjuvant treatment of patients with breast cancer.

Pertuzumab received FDA approval in 2012 for the treatment of patients with advanced or metastatic HER2positive breast cancer. This new indication is for patients with HER2positive, locally advanced, inflammatory or early-stage breast cancer (ie, tumor size of >2 cm in diameter or with positive lymph nodes) who are at high risk for recurrence, of having

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Advance Care Planning

VALUE PROPOSITIONS Value-Based Care Will Change the Face of Medicine

In a recent guest blog on the Harvard Business Review website, Toby Cosgrove, MD, President and CEO of the Cleveland Clinic in Ohio, suggested that value-based care represents a life-saving “breakthrough,” not unlike penicillin or decoding the human genome, by focusing on lowering costs and improving quality of care and outcomes as its main goals. According to Dr Cosgrove, value-based care “is being slowed by criticism, misunderstanding, and reluctance to do things differently,” but it is inevitable, and it will change the way medicine is being practiced in this country.

Value-based care “will eventually affect every patient across the United States. Not everyone, however, is on board yet, because part of the value-based equation is that hospitals will be paid less to deliver better care.

That’s quite a challenge, but one that the Cleveland Clinic is embracing as an opportunity to do better. Others must, too,” says Dr Cosgrove.

Value-based care, Dr Cosgrove notes, is moving away from a fee-forservice reimbursement model to a system that rewards quality and patient outcomes. “No longer will health care be about how many patients you can see, how many tests and procedures you can order, or how much you can charge for these things. Instead, it will be about costs and patient outcomes: quicker recoveries, fewer readmissions...lower medical errors….In other words, it will be about value. And that is good.”

He predicts that as medicine is increasingly becoming a data-driven science, there will be further consolidation from community hospitals to large hospitals that are driven by physicians “based on what is best for the patient.” Reducing waste and unnecessary procedures or tests are keys to lowering costs without compromising quality.

“A key part of the cost solution is to educate all caregivers, including doctors, about what items cost,” Dr Cosgrove says. Although he is not focused specifically on cancer care, many cancer centers and networks are hard at work to find ways to incorporate value-based care in their cancer care delivery and consider cost-effective alternatives where such alternatives are available. Harvard Business Review Blog Network; September 24, 2013

of Clinical Oncology listed its “top 5 opportunities” to reduce costs and improve care, only 2 of the things listed there were related to drug therapy; the other 3 were related to different areas of cancer care. Clearly, Dr Pfister insists, “Any strategy moving forward for cost containment of these drugs needs to be considered in this broader sense” of all the aspects of cancer care.

Dr Pfister urges oncologists to take matters into their hands and begin to consider costs as part of the entire picture of patient care. “The mandate for demonstrating value in the care we provide is only increasing; we have the scientific tools to help us with these determinations. The best way forward may be controversial, but as oncologists advocating for our patients, we have a responsibility to better understand these issues, explain their implications to our patients, and work with our professional societies and other stakeholders to be part of the solution.” J Clin Oncol. 2013;31: 3487-3489. Epub 2013 Sept 3

New Molecular Markers Can Identify Early Breast Cancer that Will Spread to the Brain

Researchers have identified new molecular markers—microribonucleic acids (RNAs)—that, combined with their target genes, are believed to be able to identify which breast cancer will metastasize to the brain. “Survival rates are low once breast cancer metastasized to the brain,” said Seema Sethi, MD, lead investigator of a study presented at the 2013 American Society for Clinical Pathology (ASCP) annual meeting, and a resident at Wayne State University and Detroit Medical Center. This discovery is a new step in the evolving field of personalized medicine.

Dr Sethi and her team believe that the RNAs and their target genes could identify at the initial diagnosis of breast cancer whether the tumor will metastasize to the brain or not, which would guide the course of therapy early on and could lead to new preventive therapies. The researchers found that several microRNAs were significantly mutated in patients whose cancer had spread to the brain, as well as several target genes that were involved in this process. ASCP annual meeting; Chicago; September 20, 2013

Mandate to Demonstrate Value in Cancer Care Is Growing: Oncologists Urged to Be Part of the Solution

The cost of cancer care has become a frequent topic of conversation in oncology conferences and publications, as well as among other stakeholders, including patients and payers. In a recent editorial published in the Journal of Clinical Oncology, David G. Pfister, MD, Chief, Head and Neck Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, joined the discussion, acknowledging previous discussions related to the cost of cancer drugs and the notion that the status quo in drug pricing allows for arbitrary setting of a price for a drug that is not necessarily based on a demonstration of true value. However, Dr Pfister insists, although the high costs of cancer drugs are unsustainable, cancer drugs are not the only drivers of the rising costs in oncology. The need to demonstrate value does not apply to cancer drugs only, he says. Drug costs are only part of the problem.

“The cost of cancer care is driven by many factors, of which the price of anticancer drugs is but one; similarly, drug choice and efficacy impact on other resource use (eg, symptom/supportive care measures; inpatient facility use).” Dr Pfister notes that when the American Society of

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New Approach to Treating Medulloblastoma Developed at NCI-Designated Cancer Center

A team of researchers at Sanford-Burnham Medical Research Institute, led by Robert Wechsler-Reya, PhD, Professor at Sanford-Burnham’s National Cancer Institute (NCI)-Designated Cancer Center and Director of the Tumor Initiation and Maintenance Program, discovered that they can block the rapid growth of cancerous brain cells by using small-molecule inhibitors. “By targeting fast-growing TPCs [tumor-propagating cells] with cell-cycle inhibitors, we have developed a new route to assault medulloblastoma. In this study, we have shown that cell-cycle inhibitors essentially block medulloblastoma tumor progression by halting TPC expansion, and have opened the window to preventing cancer recurrence,” said Dr Wechsler-Reya. Sanford-Burnham Medical Research Institute; September 25, 2013

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ESMO Annual Congress

The State of Cancer Globally in 2013

Radical solutions to global disparities in oncology are needed, calling on industry to step up

By Audrey Andrews Amsterdam, The Netherlands—Although much progress has been made in cancer care over the past couple of dec­ ades, a report presented at the 2013 European Cancer Congress emphasizes that on a global scale, the impact is far from equitable.

“Many parts of the world are already unable to cope with the current situation and are totally unprepared for the future growth of the cancer problem,” said Peter Boyle, PhD, DSc, President, International Prevention Research Institute, and Director, Strathclyde Institute for Global Public Health, Lyon, France.

A report called “The State of Oncology 2013,” spearheaded by Dr Boyle, with an educational grant from Roche, intends to inform the scientific and lay communities and their political representatives about the status of oncology around the world.

Dr Boyle called for a “radical solution” to the problem—asking the private sector, primarily the pharmaceutical and medical device industry, to lead the charge.

Global Burden Increasing Dr Boyle and colleagues estimate that by 2030, the global incidence of cancer will reach 26.4 million, and cancer deaths will be 17 million. More than 50% of cases and 66% of cancer deaths will increase in low- and me-

The estimated cost of achieving parity around the world for patients with cancer is $250 billion.

“Global funds…are totally inadequate for dealing with cancer. We need a new model and, to my mind, this should be driven by the private sector.”

—Peter Boyle, PhD, DSc

dium-income countries, with 30% increase over time compared with only 4% increase in high-income countries, Dr Boyle said.

The steady rise in population, the aging of the population around the world, and the increase in smoking among the poor will influence the burden of care. All will combine to increase the cancer burden, with lowand medium-income countries most affected.

“It is bad to have cancer, and worse

to have cancer if you are poor. The gap between rich and poor, highly educated and little educated…is substantial and is set to continue to grow. Steady progress continues to be made in oncology, but not all patients have had the benefit of this progress,” Dr Boyle said at a press briefing.

Resources Lacking In lower-resource countries, the high mortality rate from cancer is largely due to advanced disease at presentation and the lack of appropriate diagnostic and treatment modalities and facilities.

“For instance, there is often just 1 radiotherapy machine for an entire country, and it is usually outdated and even broken,” Dr Boyle said. In Africa, the actual supply of radiotherapy machines is 20% of the country’s need, and in the Asia-Pacific region, there is a need for 4000 radiotherapy machines, although just 1200 or so exist.

“It is clear that accessible, affordable, and suitable radiotherapy technologies are needed,” he said.

Beyond clinical services, the availability of basic medications for symptom control remains an enormous challenge. “Patients in the final stages of cancer are frequently in terrible pain, with only paracetamol (a mild analgesic) available in many places,” Dr Boyle noted.

Need for Radical Solutions Radical solutions are the only reasonable response to these dire predictions, Dr Boyle and colleagues maintain. “Current models are broken. We need a new model of financing to cope with this situation and those to come,” he said.

The estimated cost of achieving parity around the world for patients with cancer is $250 billion. Since “no source of philanthropy, government, or institution can afford this investment,” Dr Boyle said, the report is proposing a private–public partnership. “Global funds, such as those funding HIV/ AIDs efforts, are totally inadequate for dealing with cancer. We need a new model and, to my mind, this should be driven by the private sector.”

Dr Boyle acknowledged that the pivotal question will be “what’s in this for industry,” but he believes that industry will see the need to seek “the greater good.”

“I think there may be enough support to make this work,” he said, adding that his group is in “serious discussions” with some members of that community “and we hope to make a big announcement in the fall of 2014.”

The commitment should have as its “metric” the right of every patient with cancer to have the most appropriate treatment and care, Dr Boyle said. n

MPDL3280A: Responses Better in Smokers than Nonsmokers... Continued from cover era. After 30 years of research in immunotherapy for lung cancer, we have one that works, and it works in smokers,” said lead investigator Jean-Charles Soria, MD, PhD, of the Department of Medicine, Institut Gustav Roussy, Villejuif, France. “In this study, smokers responded much better than nonsmokers. This is great news for lung cancer patients—the majority are current or former smokers. The data are preliminary, but the trends are extremely promising,” Dr Soria added.

Study Results The study results were based on 85 patients (53 evaluable for efficacy) with NSCLC. Patients received an intravenous infusion of MPDL3280A every 3 weeks for a median duration of 106 days (range, 1-450 days). The median duration of therapy was 48 weeks.

Of the 85 patients, 55% were heavily

6

pretreated with at least 3 previous therapies, and 81% were smokers or previ-

mild. No dose-limiting toxicities were identified in this trial, nor were any

“We are at the beginning of a new era. After 30 years of research in immunotherapy for lung cancer, we have one that works, and it works in smokers. In this study, smokers responded much better than nonsmokers….The data are preliminary, but the trends are extremely promising.”

—Jean-Charles Soria, MD, PhD

ous smokers; 19% were never smokers.

MPDL3280A was considered safe.

The majority of adverse events were

Value-Based Cancer Care

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OCTOber 2013

grade 3 to 5 adverse events reported.

The objective response rate (ORR) was 21% in the overall population and

23% in patients with NSCLC; 17% of responders were stable over 24 weeks.

The 24-week progression-free survival rate was 44% in squamous-cell NSCLC and 46% in non–squamous-cell NSCLC. PD-L1 expression (the target of MPDL3280A) was directly correlated with response, with the best response seen in those with the highest expression of PD-L1 on immunohistochemistry (IHC) 3. Those with IHC 3 also had less progressive disease. Although based on very small numbers of patients, the ORR was 46% in patients with PD-L1 IHC 2 and IHC 3, and 86% in those with IHC 3.

Responses were sustained over time in all but 1 patient, Dr Soria said.

Smoking status was a predictor of response; former or current smokers had an ORR of 26% compared with 10% in never smokers. n

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ESMO Annual Congress

Kadcyla Prolongs Survival in Advanced HER2Positive Breast Cancer Novel data point to a potential new standard of care

By Phoebe Starr Amsterdam, The Netherlands—The antibody-conjugate ado-trastuzumab emtansine (Kadcyla), also known as T-DM1, prolonged progression-free survival (PFS) in advanced HER2positive breast cancer in a heavily pretreated population, according to the final results of the phase 3 clinical trial

TH3RESA. The study included cancer that progressed with ≥2 previous HER2-directed therapies—trastuzumab (Herceptin) and lapatinib (Tykerb).

“In TH3RESA, T-DM1 achieved a significant improvement in PFS, and the effect was clear and consistent across subgroups….

T-DM1 should become the new standard of care for second-line treatment.”

at a glance ➤ New data from the phase 3 trial TH3RESA extends the results of EMILIA, in which T-DM1 extended PFS in patients with HER2-positive advanced breast cancer who had received trastuzumab and a taxane ➤ In this new trial, T-DM1 achieved a significant improvement in PFS—6.2 months versus 3.3 months in the control arm, and the effect was clear and consistent across subgroups ➤ Adverse events of grade ≥3 were 43.5% in the control arm versus 32.3% in the T-DM1 arm ➤ “T-DM1 should become the new standard of care for second-line treatment,” according to Dr Wildiers

HER2-positive advanced breast cancer,” said Hans Wildiers, MD, PhD, Department of Medical Oncology/ Multidisciplinary Breast Centre, Uni­

—Hans Wildiers, MD, PhD

TH3RESA extends the results of the EMILIA trial, in which T-DM1 extended PFS versus capecitabine (Xeloda)/ lapatinib in HER2-positive advanced breast cancer in women previously receiving trastuzumab and a taxane.

T-DM1 was granted US Food and Drug Administration approval for patients with previously treated progressive metastatic HER2-positive breast cancer based on the results from EMILIA. “In TH3RESA, T-DM1 achieved a significant improvement in PFS, and the effect was clear and consistent across subgroups. These data affirm the results of EMILIA, demonstrating a consistent PFS benefit of T-DM1 in patients with previously treated

versity Hospitals Leuven, Belgium. Dr Wildiers presented these results at the 2013 European Cancer Congress.

“T-DM1 should become the new standard of care for second-line treatment,” he stated.

Positive Data from TH3RESA TH3RESA enrolled 602 patients with advanced breast cancer who were previously treated with at least 2 HER2directed therapies, and randomized them in a 2:1 ratio to T-DM1 or to physician’s choice of chemotherapy (83% received trastuzumab-based regimens and 17% received chemotherapy).

Treatment was continued until disease progression. Patients were allowed to

Second-Generation ALK Inhibitor Regresses Brain Metastases in Patients with Lung Cancer Amsterdam, The Netherlands—The novel ALK/EGFR inhibitor known as AP26113 achieved good responses in reducing brain metastases in patients with crizotinib (Xalkori)-resistant and crizotinib-naïve non–small-cell lung cancer (NSCLC), as well as radiographic regression of central nervous system (CNS) metastases. These results of the first-in-human phase 1/2 dose-finding study of AP26113 were presented at the 2013 European Cancer Congress by David R. Camidge, MD, PhD, Director, Thoracic Oncology Clinical Program, University of Colorado Denver, Aurora.

“ALK-positive NSCLC came to prominence because of the marked activity of crizotinib. However, most,

8

“ALK-positive NSCLC came to prominence because of the marked activity of crizotinib….80% [of the patients] remain on therapy after 6 months, and we see marked responses in CNS metastases.”

—David R. Camidge, MD, PhD

if not all, patients will become resistant to crizotinib,” Dr Camidge said.

Of the patients with ALK-positive NSCLC who develop crizotinib resis-

Value-Based Cancer Care

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OCTOber 2013

tance, 50% showed resistance in the brain, suggesting that crizotinib has an inadequate CNS exposure: systemic disease progression typically occurs

cross over to T-DM1 at progression.

The median PFS was 6.2 months for T-DM1 versus 3.3 months in the control arm, representing almost a doubling of PFS. The PFS difference between groups was significant (P <.001).

A prespecified subgroup analysis showed similar PFS results favoring T-DM1 across all subgroups, including age, geographic area, race, performance status, tumor characteristics, and visceral disease.

Dr Wildiers also presented the first interim analysis of overall survival (OS) from TH3RESA—the median OS was 40.9 months in the control arm and was “not yet reached” for T-DM1.

Longer-term follow-up will determine if there is a survival advantage with this drug.

No new safety signals for T-DM1 were reported in TH3RESA. Adverse events of grade ≥3 were more frequent in the control arm—43.5% versus 32.3% in the T-DM1 arm. Adverse events leading to discontinuation of therapy occurred in 10.9% of controls versus 6.7% of the T-DM1 group. The rate of cardiac events was low in both arms—left-ventricular ejection fraction <50 was reported in 1.1% and 1.5% of the patients, respectively.

First-line therapy with T-DM1 is being evaluated in an ongoing phase 3 clinical trial in advanced HER2positive breast cancer. n

at a glance ➤ The novel ALK/EGFR inhibitor AP26113 achieved good responses in reducing brain metastases in patients with NSCLC ➤ ALK-positive NSCLC came to prominence because of the marked activity of crizotinib ➤ In a phase 2 study, of the 10 patients with brain metastases, 8 had radiographic evidence of regression, and this improvement lasted from 8 to 40 weeks ➤ More experience is needed to determine if this novel ALK inhibitor will provide improvement for patients with crizotinib resistance

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Breast Cancer Symposium

For Oncologists, Some Food for Thought in the New Era of Healthcare Reform Factoring in cost considerations and payment reform

By Audrey Andrews San Francisco, CA—At the 2013 Breast Cancer Symposium, Lawrence N. Shulman, MD, Senior Vice President for Medical Affairs, Dana-Farber Cancer Institute, Boston, told oncologists that in the current era of healthcare reform, they will need to think beyond treatment outcomes, toxicities, and personal preferences.

Dr Shulman told oncologists they will need to “factor in” cost considerations and payment reform. “Ideally, our treatment decisions would be the same, but several factors cause us to rethink our approaches to cancer care,” he said.

Guidelines versus Pathways For one thing, guidelines will no longer suffice. Guidelines are focused on a particular decision point in care, whereas pathways describe an entire course of treatment that may include preoperative imaging, preoperative systemic imaging options, surgical choices, nodal sampling options, radiation therapy guidelines, chemotherapy options, and posttreatment surveillance plans.

“It is important in the development of a pathway to think broadly about all aspects of care. In particular, you are specifying not only what should be done, but also what should not be done,” Dr Shulman said.

For example, routine cardiac mon-

The lack of evidence contributes to variation in care and variation in the cost of care. “We must include issues of utilization and cost as we plan cancer care, and must do this prospectively rather than patient by patient.”

—Lawrence N. Shulman, MD

itoring for left-ventricular ejection fraction by a multigated acquisition scan or echocardiogram is a common practice for patients with breast cancer who are about to receive anthracycline therapy, but in the absence of symp-

toms or a history of cardiac disease, its use is not supported by the evidence, Dr Shulman pointed out.

He emphasized that pathways must include total cost of care, with careful consideration as to what is “really needed.” Pathway developers will need “to make some tough choices,” Dr Shulman suggested. Although efficacy and toxicity of regimens should be the first 2 priorities in decision-making, when these outcomes are equal between regimens, “the less expensive regimen or test should be chosen,” he advised.

Evidence in Clinical Practice Too frequently, the evidence to back a physician’s management decision may be lacking. “Much of what we do day-to-day in the clinic has only weak evidence to tell us the best treatment choices,” Dr Shulman said. In the absence of phase 3 prospective randomized clinical trial data, he said oncologists should avoid “shooting from the hip” and should try to “reason out the best we can, in the theoretical.”

The lack of evidence contributes to variation in care and variation in the cost of care, he said. “We must include issues of utilization and cost as we plan cancer care, and must do this prospectively rather than patient by patient,” Dr Shulman emphasized.

He added that it is a mistake when

at a glance ➤ Oncology guidelines are focused on a particular decision point in care, whereas pathways describe an entire treatment course ➤ In developing a pathway, physicians must think broadly about all aspects of care, including what should, and should not, be done ➤ Often, the evidence to back a physician’s management decision is lacking ➤ Much of what is done today in the clinic has only weak evidence to guide the best treatment choices ➤ The lack of evidence contributes to variations in care and in the cost of care ➤ Oncologists must keep treatment patient-centered and include utilization and cost to provide the most effective care treatment choices are not patient-centered. “We all try, but sometimes the system makes this very difficult. We need to keep the patient front and center.” n

ESMO Annual Congress

Second-Generation ALK Inhibitor Regresses... later in the course of the disease.

The phase 1 study was a 3 × 3 doseescalation study that included up to 60 patients with different types of advanced malignancies.

The phase 2 study had 5 cohorts—4 groups with NSCLC (N = 85 total) and 1 group with other ALK-positive cancers (N = 20).

The identified dose of 180 mg daily was initially used in the phase 2 study, but some patients developed pulmonary symptoms at that level, which resolved with steroids that were tapered

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No. 8

over 1 week.

Because of the pulmonary symptoms with the higher dose, a step-up approach will be used in future studies, starting with 90 mg daily for the first week, moving to 180 mg daily, Dr Camidge said.

Other adverse events included gastrointestinal disturbances, which were mainly mild; 12% of the patients had elevated liver enzymes. Treatmentemergent grade ≥3 adverse events were reported in 2% to 4% of the patients across all dose levels.

The objective response rate (ORR) was 65%. The ORR rate was 61% in patients previously treated with crizotinib and 100% in all 4 crizotinib-naïve patients (1 had a complete response).

Of the 10 patients with CNS metastases, 8 had radiographic evidence of regression, which lasted from 8 to 40 weeks.

Responses were seen in some patients whose tumors expressed the T290M mutation. Among 12 patients with the T790M mutation, 5 had stable disease, 4 had progressive disease, and

OCTOber 2013

I

Continued from page 8 3 discontinued the study before going on treatment.

These data are preliminary, Dr Camidge emphasized, noting that of the patients in this study, “80% remain on therapy after 6 months, and we see marked responses in CNS metastases.”

More experience is needed to determine if this novel ALK inhibitor will be an improvement on crizotinib. At least 2 other second-generation ALK inhibitors are in development, and these drugs also show radiographic regression in CNS metastases.—PS n

www.ValueBasedCancerCare.com

9

Breast Cancer Symposium

Role of Radiation and Imaging in DCIS Explained

By Phoebe Starr

San Francisco, CA—Management of ductal carcinoma in situ (DCIS) was the focus of 2 studies highlighted at a press conference before the 2013 Breast Cancer Symposium. These studies showed that: • Radiation to the breast as part of treatment of patients with DCIS does not increase cardiovascular toxicity, including the risk for cardiovascular disease (CVD) and death from CVD or from other causes • Perioperative magnetic resonance imaging (MRI) does not reduce the risk of locoregional recurrence or contralateral breast cancer in patients with DCIS who are undergoing surgery as part of their treatment program.

Women and their physicians can gain reassurance from the first study that radiation for DCIS does not increase cardiotoxicity, and the second study indicates that MRI should not be part of routine presurgical or surgical planning in this patient population.

Radiation Does Not Increase CVD Risk in DCIS DCIS is a precancerous lesion that, if left untreated, may progress to invasive cancer in a small percentage of patients. At present there is no way to identify which patients with DCIS are at risk of progression, so DCIS is typically treated with surgery plus or

minus radiation to reduce the risk of locoregional recurrence.

Concern has been raised about increased cardiotoxicity with radiation to the breast area, and modern protocols have been adjusted to reduce exposure to the breast, as well as radiation dose. The risk of CVD was not increased in women with DCIS who received radiotherapy in a large population-based study compared with women who had surgery alone and with women in the general population.

“Our findings indicate that MRI is not necessary for every patient with DCIS.” —Melissa L. Pilewskie, MD This is the first large study to evaluate long-term effects of radiotherapy for DCIS on the incidence of CVD and associated deaths, said lead investigator Naomi B. Boekel, MSc, a PhD candidate at the Netherlands Can­ cer Institute, Amsterdam. However, longer follow-up is needed to confirm the cardiovascular safety of radiation in patients with DCIS. Ms Boekel said that 5 or 10 more years of follow-up should be sufficient.

The study included 10,468 women

diagnosed with DCIS younger than 75 years of age between 1989 and 2004.

Approximately 71% had surgery only, and 28% underwent surgery and radiotherapy. DCIS survivors had similar death rates, as well as a 30% lower risk of dying from CVD compared with the general population. Patients treated with surgery alone had a similar risk for CVD as those undergoing surgery and radiotherapy; no difference in risk was observed between patients who received left-sided radiotherapy or right-sided radiotherapy (which does not include the heart in the radiation field); in these subgroups, the incidence of CVD was 7% versus 8%, respectively.

It is not clear why DCIS survivors had a slightly lower risk of CVD compared with the general population, but Ms Boekel suggested that cancer survivors may be more concerned about a healthy lifestyle than the general population.

Perioperative MRI Often Unnecessary Perioperative MRI may not be necessary in all patients undergoing surgery for DCIS, according to results of the second study. The risk of loco­ regional recurrence or contralateral breast cancer was not lower in women who underwent MRI around the time of surgery, according to this retrospective study.

Although no official guidelines for MRI in DCIS are available, many medical centers routinely order perioperative MRI with the hope of improving outcomes by finding additional cancers not detected by mammograms or other imaging studies. “Our findings indicate that MRI is not necessary for every patient with DCIS,” stated lead investigator Melissa L. Pilewskie, MD, Surgical Breast Oncologist, Memorial Sloan-Kettering Cancer Center (MSKCC), New York. Dr Pilewskie noted that perioperative MRI may be useful in specific patients with DCIS, such as those with a palpable mass and nipple discharge not found on mammography screening.

The study included 2321 women who underwent a lumpectomy between 1997 and 2010 at MSKCC; 596 had an MRI before or immediately after surgery and 1725 did not. At a median follow-up of 59 months, 5-year locoregional recurrence rates were 8.5% in those who had an MRI versus 7.2% for those who did not.

In addition, no significant differences were seen in the 5-year rates of contralateral breast cancer. The rates were still similar at 8 years.

MRIs are typically ordered for women who have risk factors for breast cancer, such as younger age or family history. Dr Pilewskie said that this may explain the higher recurrence rates in these women. n

Current Patterns and Costs of Treating Patients with Metastatic Breast Cancer Study examines use and cost of drugs by treatment line

By Audrey Andrews San Francisco, CA—In a population of patients with metastatic breast cancer and Medicare Part D claims, the mean lifetime cost of treatment was approximately $102,000, according to a study presented at the 2013 Breast Cancer Symposium by Hope S. Rugo, MD, Director, Breast Oncology Clinical Trials Program, University of California, San Francisco.

The injectable endocrine agent fulvestrant (Faslodex) was the most frequently used first- and second-line therapy, and anastrozole (Arimidex) was the second choice; in the thirdline setting, fulvestrant and anastrozole were equally used.

10

Metastatic breast cancer treatment is costly, requiring systemic therapy that often includes combinations of chemotherapies, hormonal therapies, and molecular targeted therapies. A previous analysis of the Surveillance, Epidemiology and End Results (SEER)Medicare database from 2001 to 2008 showed that fulvestrant was the most common first-line agent, vin­orelbine (Navelbine) was used most in the second line, and trastuzumab (Herceptin) was the preferred third-line agent, but that analysis did not include Part D claims; therefore, oral therapies were not included.

The current study updates the pre-

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OCTOber 2013

“The inclusion of Part D claims provides increased understanding of treatment patterns and costs among patients with metastatic breast cancer.”

—Hope S. Rugo, MD

vious analysis with data through 2009, and examines patterns of care and associated costs in a subgroup of women with Part D enrollment.

“The inclusion of Part D claims provides increased understanding of treatment patterns and costs among patients with metastatic breast cancer,” Dr Rugo noted.

The SEER-Medicare database includes linked data from 2001 to 2007 SEER cancer registries and 2001 to 2009 Medicare enrollment and claims files.

Along with examining these data, the investigators also calculated healthcare costs, including those related to inpatient and outpatient care, skilled nursing facility stays, home healthcare, and durable medical equipment.

The cost of injectable agents was Continued on page 12

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A Global Collaboration dedicated to improving the lives of patients with B-Cell Malignancies

Š Pharmacyclics, Inc. 2013 Š Janssen Biotech, Inc. 2013 08/13 K08BR13002C

Breast Cancer Symposium

Comparative Effectiveness Research Should Reap Benefits for Oncology Care Unsustainable costs major driver of real-world value-based care

By Audrey Andrews San Francisco, CA—Comparative effectiveness research (CER) is an important construct for identifying and summarizing the evidence on the effectiveness, safety, and overall value of alternative strategies in oncology care, said Gary H. Lyman, MD, MPH, Professor of Medicine, Duke University and the Duke Cancer Research Institute, Durham, NC, during the 2013 Breast Cancer Symposium.

“The big challenge is deciding what treatment works in whom, under what circumstances, and whether we can afford it,” Dr Lyman said.

“The rapid rise in healthcare costs, along with the emergence of exciting but costly technologies, has focused attention on the need for rigorous evaluation of benefits, harms, and overall value in a real-world patient setting—which is the aim of CER.”

How Is Cost Driving CER? The major driver of CER is the unsustainable rise in healthcare costs. “The rapid rise in healthcare costs, along with the emergence of exciting but costly technologies, has focused attention on the need for rigorous evaluation of benefits, harms, and overall value in a real-world patient setting—which is the aim of CER,” Dr Lyman said.

He indicated, however, that the problem of rising costs is complex, and CER must try to examine the various contributors.

It has been argued by some, including the American Society of Clinical Oncology (ASCO), that inappropriate overuse of expensive cancer interventions is a major driver of escalating healthcare costs, with the fee-for-service payment system providing perverse in-

—Gary H. Lyman, MD, MPH

centives for the use of expensive new drugs, even before the drugs receive specific label indications, according to Dr Lyman.

However, a recent study (Conti RM,

et al. J Clin Oncol. 2013;31:1134-1139) showed that most patent-protected cancer therapies are used according to label indications, and most off-label use was compliant with guideline recommendations or compendia, he noted.

“The primary drivers of healthcare costs appear to be less that of overuse or misuse of expensive new drugs and technologies and more related to rising prices and required payments,” Dr Lyman said.

“Meaningful control of healthcare spending in cancer may need to focus more attention in other areas, such as the actual price of drugs, escalating insurance premiums, and market concentration through aggressive efforts on the part of the healthcare system,” he suggested.

Multiple Approaches to CER Are Needed Although CER largely focuses on treatment, in breast cancer it has also been applied to disease prevention and screening, staging, prognostic and predictive biomarker determination, and supportive care. CER is also gaining attention as a way to improve the regulatory approval process.

Certainly, CER has been performed for years via randomized controlled trials. These remain the gold standard, but what has changed is the awareness that all the important questions in oncology cannot be answered by random-

ized controlled trials, Dr Lyman said.

Additional methodological tools, when properly used and interpreted, can help identify the most effective, safe, and valuable approaches, including quality-of-life studies, clinical decision simulation studies, and cost-effectiveness and cost-utility analyses.

“These may provide reasonable, valid, and more generalizable estimates of comparative effectiveness, safety, and cost and may also generate hypotheses that form the basis of future confirmatory randomized controlled trials,” Dr Lyman said.

ASCO Initiatives Among new initiatives to provide more rapid evaluation of promising therapies without compromising safety is the ASCO Initiative for Defining and Measuring Clinical Value, which will examine, according to Lyman: • The clinical benefit of given treat­ ments • Short-term and long-term toxicity • Direct and indirect costs, and value (ie, patient outcomes divided by costs of delivery) • Value benchmarks, which will utilize quality-adjusted life-years, weighted values, and hard and soft thresholds.

“We thought, who better to talk about cost and value than the persons providing the care? We thought it important that ASCO be involved in these processes,” he emphasized. n

Current Patterns and Costs of Treating Patients with... included as part of inpatient and outpatient costs. The cost of oral medica-

773 had Medicare Part D coverage. In the overall sample, first-line therapy

Table Mean Lifetime Medical Costs in Patients with Part D Coverage First-line Second-line Third-line Agent setting cost, $ setting cost, $ setting cost, $ Anastrozole

103,277

105,753

109,873

Fulvestrant

96,000

111,000

99,902

Letrozole

81,177

108,000

70,912

Tamoxifen

89,660

107,219

100,946

Taxane

96,126

Vinorelbine

155,000

Not used

tions was not included in total costs.

There were 7905 patients with metastatic breast cancer identified, and

12

Not used

Not used

134,475

was identified for 82% of patients, of whom 48% went on to receive second-line treatment, and 26% received

Value-Based Cancer Care

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OCTOber 2013

third-line therapies. Fulvestrant was the most common first-line therapy, received by 19% of patients on firstline treatment, and vinorelbine was the most common second-line (18%) and third-line (16%) drug. The total mean per-patient cost was $127,000, which was higher than the $113,000 determined from the previous analysis from 2001 to 2007.

Part D Subgroup For the subgroup of 681 patients with Part D coverage and a diagnosis of metastatic breast cancer in 2007, first-line therapy was identified for 88% of patients. Of those receiving first-line therapy, 63% went on to receive second-line treatment and 45%

Continued from page 10

had a third-line drug. For this group, fulvestrant was the most common first-line and second-line therapy, and anastrozole was the second most common in both of these settings, with letrozole third. In the third line, anastrozole and fulvestrant were used equally. In all settings, tamoxifen was infrequently used.

The mean lifetime healthcare cost for the patients with Part D benefits was $102,000 overall, nearly $70,000 of which were physician and hospital costs. By line of therapy (Table), the costliest drug in the first-line setting was anastrozole ($103,277), and vin­ orelbine was most expensive in the second-line ($155,000) and third-line ($134,475) settings. n

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In the Literature Large-Scale Oncology Pathways Program Reduces Drug and Hospitalization Costs

The cost of cancer care continues to rise, and especially the cost of cancer drugs. Since their introduction in the 1990s, clinical pathways have demonstrated an improvement in the quality of care, while lowering costs in numerous clinical settings. Data, however, are limited regarding the role of clinical pathways in cancer care. CareFirst BlueCross BlueShield in partnership with P4 Pathways implemented a multistate oncology pathways program in 2008. A new study evaluated the effectiveness of the program for treatment compliance, the impact of compliance on outcomes, and its ability to curb expected increases in drug and hospitalization costs (Kreys ED, et al. J Oncol Pract. 2013;9:e241-e247).

In this retrospective, single-group, pretest–posttest, researchers looked at data representing 1 year before and 2 years after the program’s initiation from a CareFirst claims database.

The study included participating sites with ≥1 claims for breast, lung, or colorectal cancer treatment from each of the 3 years of the study. Compliance was defined as the site attainment of prespecified annual thresholds for the use of chemotherapy and supportive care.

Savings were determined by comparing per-patient charges in drug and hospital costs through year 2 of the pathways program, with the projected annual expenditure increases of 12% and 7%, respectively. Overall, 46 sites representing 193 physicians, 4713 patients, and 78,821 claims met the study inclusion criteria.

The results show that 83% of the sites met the unadjusted compliance rate of 65% chemotherapy benchmark after 1 year of the pathways program.

For year 2, when chemotherapy compliance criteria became more stringent with the 80% benchmark, only 54% of the sites could be considered compliant; supportive care compliance was 74% for both years.

The total drug costs for the 3 years were $30.5 million for the 1 year prepathways, $33.1 million for year 1 on pathways, and $27.0 million for year 2 on pathways. Chemotherapy was responsible for 86% of the total drug costs.

Actual overall drug costs were reduced by $35 million from 1 year prepathways to year 2 on pathways.

Per-patient drug costs increased only slightly, from $16,494 in year 1 prepathways to $16,906 in year 2 on pathways (95% confidence interval [CI], −1076.36 to 1900.50; P = .587).

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In addition, per-patient costs for hospitalizations significantly decreased by 57% in the 3 years, from $2502 to $1064 (95% CI, −2419.16 to −455.73; P = .004). A 1.5% decrease in per-patient chemotherapy costs and a significant 30% increase in supportive care costs resulted in a small 2.5% increase in

overall per-patient drug costs. Because supportive care comprised a small portion of total drug expenditures, changes in supportive care costs had a relatively small overall impact.

Of note, in sharp contrast to the projected cost increases in cancer care nationwide, the implementation of

this large-scale pathways program resulted in $10.3 million in savings by participant sites ($7 million from drugs and $3.3 million from hospitalizations), or by $30.9 million when extrapolated to the entire health plan.

These findings demonstrate that an Continued on page 20

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Economics of Cancer Care

IOM Cites Looming Cancer Care Crisis... for a System in Crisis,” enumerates a laundry list of reasons for the crisis but also offers suggestions for improving cancer care and avoiding a socioeconomic and professional meltdown.

“As a nation, we need to chart a new course for cancer care,” said Patricia A. Ganz, MD, Distinguished University Professor of Medicine and Public Health, University of California, Los Angeles, and Chair of the committee that wrote the IOM report. “Changes are needed across the board, from how we communicate with patients, to how we translate research into practice, to how we coordinate care and measure its quality.”

The report identifies key stressors that will meld into a crisis. The number of adults aged ≥65 years, which is the fastest growing segment of the US population, is expected to double between 2010 and 2030. This population will account for the most new cancer diagnoses, which are projected to increase by 45% by 2030, from 1.6 million to 2.3 million annually.

Growing Caseload and Treatment Complexity Oncology providers will be unable to keep pace with the growing caseload, because training programs lack the capacity that the rapid expansion requires to meet the growing demand for cancer care. A study commissioned by the American Society of Clinical Oncology (ASCO) found that the oncology workforce will have 2500 to 4100 fewer oncologists than needed to keep pace with the demand for services by the start of the next decade.

Advances in the understanding of the molecular and cellular biology of cancer have led to increased aware-

at a glance ➤ The costs of oncology care have been rising faster than in any other area of medicine, from $72 billion in 2004 to $15 billion in 2010; a 39% increase, to $173 billion, is expected by 2020 ➤ Clinicians must now master more cancer-related information as a result of molecular and cellular advances in oncology ➤ The IOM objective is to improve the affordability of cancer care through the restructuring of the payment system and through the elimination of waste

14

ness of the complexity of cancer and cancer therapy, frequently resulting in the development of new therapies that address abnormalities and genetic mutations in small subsets of patients.

Clinicians are often challenged to re-

“As a nation, we need to chart a new course for cancer care. Changes are needed across the board, from how we communicate with patients, to how we translate research into practice, to how we coordinate care and measure its quality.”

—Patricia A. Ganz, MD

main abreast of these developments, or to formulate therapeutic strategies that incorporate the rapidly expanding knowledge base. As a consequence, de­­ cisions about cancer care are often not sufficiently evidence-based, according to the IOM. The IOM committee found that only a minority of clinicians involved in cancer care follow ASCO and other professional organizations’ guideline recommendations. The reasons for nonadherence fell into 3 general categories—some physicians believe that their experience is more valuable than guidelines in clinical decision-making, others think their patients differ from those covered by the guidelines, and still others are unaware of the guidelines’ recommendations.

The IOM committee also found clinicians’ performance lacking in some specific areas. For example, a substantial proportion of oncologists demonstrated a lack of proficiency in the use of palliative care when the therapeutic options for a patient have been exhausted.

Communication with patients is another area for improvement. Too often,

Value-Based Cancer Care

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OCTOber 2013

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clinicians do not discuss with patients the advantages and disadvantages of different or competing treatment options. In many instances, clinicians do not explain the goals of treatment or how a particular type of treatment may affect a patient’s quality of life.

The IOM committee also identified several recent studies showing that 65% to 80% of patients with poor prognoses erroneously believed that they had a curable condition, indicating providers’ discomfort with delivering bad news.

Burgeoning Costs a Key Stressor The burgeoning cost of cancer care constitutes another key stressor in the crisis framework. According to Dr Ganz and colleagues, the cost of cancer care has risen faster than that of other areas of medicine. The estimated total cost of cancer care increased from $72 billion in 2004 to $125 billion in 2010, and is expected to increase by another 39% by the year 2030, reaching an estimated total annual cost of $173 billion.

Further adding to the stress are the ongoing financial struggles of Medicare, the largest single healthcare insurer for people aged ≥65 years.

Despite identifying several shortcomings in oncologists’ performance, Dr Ganz emphasized that the reason for the approaching crisis is multifactorial. “Most clinicians caring for cancer patients are trying to provide optimal care, but they’re finding it increasingly difficult because of a range of barriers,” she said.

Future Strategies The committee identified 6 focal areas for the development of evidence-based strategies to address the stressors pushing cancer care toward a state of crisis and to improve the delivery and control the cost of care. Listed by priority, the areas are: • Support for informed decision-making. Multidisciplinary cancer care teams should engage patients and families and provide understandable information about the patient’s prognosis and the benefits, potential harms, and costs of treatment.

The goal should be to guide patients toward decisions that are consistent with their needs, values, and preferences • Development of an adequately staffed, trained, and coordinated workforce. New models of teambased care are encouraged to promote care coordination and to address challenges and stressors identified in the study. High-quality

cancer care requires a workforce with an adequate number of clinicians who have appropriate training in core competencies • Evidence-based cancer care. Too many medical decisions lack evidentiary support. Moving forward, clinical research should include efforts to accumulate the evidence that patients and clinical care teams need to make informed decisions about treatment • Intelligent information technology systems. High-quality cancer care requires information technology systems that “learn” from real-time analysis of data on patients with cancer in a variety of care settings • Translation of evidence into clinical practice and quality assessment and improvement. Clinicians should have ready access to evi­ dence-based tools and initiatives that can be incorporated into clinical practice, quality assessment, and performance improvement • Access to affordable cancer care.

The committee called on the US Department of Health & Human Services to develop a national strategy that leverages existing community interventions to address disparities in cancer care and provide accessible and affordable cancer care.

Value-Based Care, New Reimbursement Models The overall objective is to improve the affordability of cancer care through the restructuring of the payment system and the elimination of waste.

Professional organizations should rapidly and publicly disseminate evidence-based information about valuable cancer care practices, as well as practices that are unnecessary or that may involve more harm than benefits.

Payers need to develop their payment policies based on the evidence-based conclusions of these organizations. New models of reimbursement should be developed to offer cancer care teams the incentive to provide evidence-based care that is also in alignment with patients’ needs, values, and preferences. If assessments of specific reimbursement models show increased quality and value, payers should quickly move away from the traditional fee-for-service model to the newer payment model.

The study and report were sponsored by the National Cancer Institute and the Centers for Disease Control and Prevention in collaboration with multiple professional and nonprofit organizations devoted to cancer care. n

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No. 8

Economics of Cancer Care

Costs to Medicare Nearly Twice as High for Hospital Outpatient versus Community-Based Oncology Services

By Neil Canavan

A

new analysis of Medicare claims between 2009 and 2011 has revealed that patients with cancer receiving chemotherapy in hospital outpatient settings are billed at rates that are 25% to 47% higher than for equivalent oncology services rendered at community-based physicians’ offices.

The results of this analysis, contained in a report sponsored by the US Oncology Network and the Community Oncology Alliance and performed by the Moran Company, suggest that Medicare patients with cancer routinely receive more lines of chemotherapy treatments, often with more expensive chemotherapy drugs, compared with patients treated in a community-based setting. Such treatment practices account for the higher costs overall, even though recent changes to Medicaid’s Hospital Outpatient Prospective Payment System (OPPS) lowered unit payment rates during the study period.

Other key findings from this report for the years 2009 to 2011 include: • The number of chemotherapy treatment days per Medicare beneficiary ranged from 9% to 14% greater in hospital outpatient settings compared with community-based settings • Hospital chemotherapy expenses ranged from 25% to 47% higher on a per-beneficiary basis than costs observed in a physician office setting; rates were 25.4% higher in 2009, 46.8% higher in 2010, and 33.3% higher in 2011 • On a per–chemotherapy day basis, hospital outpatient compared with physician office spending was 24.3% higher in 2009, 40.1% higher in 2010, and 29.4% higher in 2011 • On a per-beneficiary basis, spending on hospital outpatient chemotherapy administration was 42% higher in 2009, 67.8% higher in 2010, and 51.1% higher in 2011 than the same procedures in a community setting.

Although the specific reasons for these disparities were not investigated, the analysts suggest that subtle differences in the payment mechanisms of OPPS and the community-based Medicare Physician Fee Schedule are to blame. These differences include variations in coding, in the type of data and related methods used to calculate payments under each system, differences in how beneficiary cost-sharing is determined, and differing rates at which payments are updated.

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No. 8

Table 1 Differences in Drug Costs by Care Setting, 2009-2011 2009 Drug cost

Community, $

2010 Hospital, $

Community, $

2011 Hospital, $

Community, $

Hospital, $

Per line

1058.08

1609.07

1059.07

1809.20

1112.28

1720.53

Per day

1494.91

1857.96

1489.93

2087.90

1550.11

2006.38

Per beneficiary

9779.27

12,262.78

9359.79

13,738.73

9966.34

13,286.42

Source: The Moran Company. Cost differences in cancer care across settings. August 2013.

Table 2 MPFS Payments versus OPPS Payments for Select Chemotherapy Services, 2009-2011 2009

2010

HCPCS code

MPFS total payments

OPPS total payments

Chemotherapy IV push single drug

96409

$24,990,980

Chemotherapy IV infusion 1 hr

96413

Refill/maintain portable pump

96521

Description

Total payments

OPPS total payments

MPFS total payments

OPPS total payments

$28,748,443

$25,389,381 $29,392,027

$29,055,448

$33,083,566

$259,409,396

$330,546,462

$236,706,968 $363,926,994

$235,393,684

$330,906,232

$7,429,373

$10,999,670

$6,713,847 $6,749,618

$6,824,527

$6,581,264

$441,523,307

$527,148,684

$398,848,415 $549,518,551

$403,848,403

$515,761,837

Percentage of MPFS

119%

MPFS total payments

2011

138%

128%

HCPCS indicates Healthcare Common Procedure Coding System; IV, intravenous; MPFS, Medicare Physician Fee Schedule; OPPS, Outpatient Prospective Payment System.

Source: The Moran Company. Cost differences in cancer care across settings. August 2013.

Although these variations between payment methodologies may appear minor, the cumulative effect is overpayment to hospital outpatient programs to the tune of millions of dollars annually. Furthermore, the authors predict that should current reimbursement practices remain in place, this disparity will only worsen over time.

“Cancer care will cost more than it should until current government policies favoring hospital-based care are ended.”

—Barry D. Brooks, MD “Medicare data again confirm that outpatient cancer care in hospital outpatient departments costs significantly more than the same care in community cancer clinics,” said Barry D. Brooks, MD, Vice Chairman of the Pharmacy and Therapeutics Committee, in a statement issued by The US Oncology Network. “Medicare policies create perverse incentives for hospitals to acquire community prac-

tices and bill Medicare at a higher rate.

Unfortunately, for patients fighting cancer and for taxpayers, cancer care will cost more than it should until current government policies favoring hospital-based care are ended.”

A previous Moran analysis (published in the spring of 2013) showed that between 2003 and 2011, community-based cancer care declined by 20%. As a result, Medicare beneficiaries now receive nearly 33% of their outpatient chemotherapy services in the hospital outpatient setting.

Cancer Care Costs: Hospital versus Community Setting For this analysis, 2 data sets based on Medicare claims were created. The 2 cohorts were exclusive to patients treated only in hospital outpatient settings or only in physician office settings (4.2% of patients received treatment in both settings in 2009-2011).

Because this study is based on an essentially noncontrolled, retrospective review, the investigators are quick to point out that the reasons posited for the different treatment practices observed are merely speculative, and the analysis does not account for patient characteristics or practice styles in a

OCTOber 2013

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given beneficiary cohort or treatment setting.

That said, sampling assumptions of a relative uniformity of practices and patients, especially in consideration of such a large data set—more than 1.5 million Medicare beneficiaries—seem entirely reasonable.

Table 1 lists some of the differences in drug costs when used in the hospital setting versus the community setting.

To further illustrate the cost differences, as well as the waste, under the current pricing policies, the investigators “repriced” certain services and overall costs by calculating the costs related to the volume of services rendered only in the physician office setting by using the OPPS (ie, hospital) rates. Table 2 shows a sampling of procedures and their overall differences.

Overall, repricing office cases to the scale of OPPS payments creates a volume-weighted payment differential of 19% to 38%—an ongoing economic trend that is unsustainable. The full report is available at https://media.gractions.com/E582 0F8C11F80915AE699A1BD4FA0948 B6285786/adebd67d-dcb6-46e0-afc37f410de24657.pdf. n

www.ValueBasedCancerCare.com

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POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

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

100%

Patients, %

80%

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

60% 40% 20% 0%

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

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

ORR 29.2% (n=33)

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

POMALYST + low-dose dex (N=113)

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

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

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

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

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

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

VENOUS THROMBOEMBOLISM • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST

CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

POMALYST is only available under a restricted distribution program, POMALYST REMS™.

Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™.

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity • Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious

adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported

Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia.

Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction.

• In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established.

Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

POMALYST® is a registered trademark of Celgene Corporation.

POMALYST REMS™ is a trademark of Celgene Corporation. © 2013 Celgene Corporation 04/13 US-POM120033a

In the Literature Large-Scale Oncology Pathways Program...

Continued from page 13

oncology clinical pathway program can be implemented on a broad, multistate scale, and can lead to considerable overall cost-savings in drug and hospitalizations at the very least.

blocks the programmed death 1 (PD-1) receptor and reactivates an immune response to the cancer cells. The PD-1 receptor limits the body’s immune response against cancer. Researchers have set out to investigate the safety and antitumor activity of 3 dosing regimens of lambrolizumab in a co-

PD-1 Inhibitor Lambrolizumab Is Safe, Shows Durable Responses in Patients with Advanced Melanoma

Lambrolizumab (previously known as MK-3475) is a humanized monoclonal immunoglobulin G4 antibody that

hort of patients with advanced melanoma (Hamid O, et al. N Engl J Med. 2013;369:134-144).

This multi-institutional, international, phase 1 expansion study included 135 patients with advanced melanoma. Patients who had or had not received treatment with the checkpoint

S:7”

This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy.

POMALYST is a thalidomide analogue.

Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.

• Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)].

POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)].

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)].

Toxicity

Dose Modification

Neutropenia • ANC* < 500 per mcL Interrupt POMALYST or Febrile neutropenia treatment, follow CBC (fever more than or weekly. equal to 38.5°C and ANC < 1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Resume POMALYST at 3 mg daily.

• For each subsequent drop < 500 per mcL

Interrupt POMALYST treatment

• Return to more than or equal to 500 per mcL

Resume POMALYST at 1 mg less than the previous dose

Dose Modification

Thrombocytopenia • Platelets < 25,000 per Interrupt POMALYST mcL treatment, follow CBC weekly • Platelets return to > 50,000 per mcL

Resume POMALYST treatment at 3 mg daily

• For each subsequent drop < 25,000 per mcL

Interrupt POMALYST treatment

• Return to more than Resume POMALYST at or equal to 50,000 per 1 mg less than previous mcL dose. *Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant.

Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].Males Pomalidomide is present in the semen of patients receiving the drug.

Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions

(5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements.

• Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)].

• Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements.

Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors.

5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia.

Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia.

Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)].

5.5 Hypersensitivity Reactions. Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

5.6 Dizziness and Confusional State. In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state.

Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy.

There were no cases of grade 3 or higher neuropathy adverse reactions reported.

5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)]

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1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

2.2 Dose Adjustments for Toxicity Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities

Toxicity

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In the Literature inhibitor ipilimumab were administered the intravenous PD-1 inhibitor lambrolizumab at 10 mg/kg every 2 or 3 weeks or 2 mg/kg every 3 weeks.

Tumor responses were assessed every 12 weeks.

The most common adverse events reported with lambrolizumab in this

study were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. Drug-related adverse events of any grade were reported by 79% of the patients, with grade 3 or 4 adverse events reported by 13%. The highest incidence of overall treatment-related adverse events

was seen among patients receiving the lambrolizumab dose of 10 mg/kg every 2 weeks compared with patients receiving the 10-mg/kg dose every 3 weeks and those receiving 2 mg/kg every 3 weeks (23% vs 4% and 9%, respectively).

The confirmed response rate across

the 3 dose cohorts was 38% (95% confidence interval [CI], 25-44), with the highest confirmed response rate observed in the patients receiving the 10mg/kg dose of lambrolizumab every 2 weeks (52%; 95% CI, 38-66). Previous therapy with ipilimumab did not afContinued on page 22

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(6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%).

Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low dose Dex (69/112).

Serious Adverse Reactions in 2 or more patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, Thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac Disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: constipation (1%, 3%); Blood and Lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period.

Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp).

7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided.

7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided.

Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction.

Patients should be advised that smoking may reduce the efficacy of pomalidomide.

Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects.

Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels.

There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day.

Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption.

8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established.

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• Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions.

The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease.

In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Lowdose Dex (n=112), all patients had at least one treatment-emergent adverse reaction.

Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%).

Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low dose Dex (99/112).

Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia

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In the Literature PD-1 Inhibitor Lambrolizumab Is Safe...

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fect the response to lambrolizumab.

The response rate among patients who were previously treated with ipilimumab was 38% (95% CI, 23-55) compared with 37% (95% CI, 26-49)

among those who had not received treatment previously. Response rates were durable in the majority of patients who had experienced response at a median follow-up of 11 months; 81% of patients with a response were still continuing treatment as of March 2013. The overall median progres-

sion-free survival among the 135 patients was longer than 7 months.

For patients with advanced or progressing melanoma, these findings suggest that treatment with lambrolizu­ mab can result in a high rate of tumor regression, and only limited toxic effects of mainly grade 1 or grade 2.

Molecular Test Identifies Patients at Risk for Early and Late Breast Cancer Recurrence

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13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day.

In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females.

17 PATIENT COUNSELING INFORMATION See FDA- approved Patient labeling (Medication Guide).

Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindicatons (4)]. POMALYST is a thalidomide analog and may cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

• Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy.

• Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test.

• Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during POMALYST therapy, during therapy interruption and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap.

• Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.

• Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

• Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy.

• Advise male patients taking POMALYST that they must not donate sperm [see Warnings and

Precautions (5.1) and Use in Specific Populations (8.6)].

• All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program call POMALYST REMS [see Warnings and Precautions (5.2)].

• Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)].

• POMALYST is available only from pharmacies that are certified in POMALYST REMS program. Provide patients with the telephone number and website for information on how to obtain the product.

Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia and anemia and the need to report signs and symptoms associated with these events to their health care provider for further evaluation.

Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID®. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusion with the drug and to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy Inform patients of the risk of neuropathy and report the signs and symptoms associated with these events to their health care provider for further evaluation. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown.

Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

• The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water.

• Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed.

Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)].

Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation.

POMALYST REMS™ is a trademark of Celgene Corporation.

U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved.

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8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy.

Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm.

8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies.

Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

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VBCC Perspective

Cancer Prehabilitation May Reduce Healthcare Costs... other therapies. There is no doubt that the time between a cancer diagnosis and the start of treatment may offer a unique opportunity to assist newly diagnosed patients to become more physically and emotionally ready for whatever comes next.

What Is Cancer Prehabilitation?

In a recent article on cancer rehabilitation, my colleagues and I defined prehabilitation as “a process on the cancer continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment and includes physical and psychological assessments that establish a baseline functional level, identify impairments, and provide interventions that promote physical and psychological health to reduce the incidence and/or severity of future impairments.”1 Although prehabilitation has been around for more than half a century, cancer prehabilitation is in its infancy.

I recently wrote with my colleague Jennifer Baima, MD, the first ever review on this topic, titled “Cancer Prehabilitation: An Opportunity to Decrease Treatment-Related Morbid­ ity, Increase Cancer Treatment Op­ tions, and Improve Physical and Psychological Health Outcomes.”2 We included a list of the many articles we identified in PubMed related to this topic. This list shows that prehabilitation interventions are not always identified as such in the scientific literature.

A sampling of the terms we found includes “cancer prehab” (2 articles), “preoperative cancer exercise” (257 articles), “preoperative cancer rehabilitation” (570 articles), and “preoperative rehabilitation” (4502 articles).

Cancer Prehabilitation The scientific literature regarding prehabilitation interventions can be confusing. Understanding this concept in clinical practice is equally challenging. I work with hospitals throughout the United States and have come to realize that some form of prehabilitation is offered at many, probably most, institutions that deliver oncology services. Practices include preoperative or other pretreatment assessments and interventions that may not necessarily be well coordinated or involve a scientific approach to improving outcomes.

For example, one nurse told me that at her hospital, the nurses teach patients “mind-body strategies” to help them

relax before starting chemotherapy.

When asked if they had any type of protocol, or if the nurses had any special training, she said, “No, we just knew we had to do more to help our patients.”

Another example is prostate cancer.

Numerous studies have shown that teaching men to do pelvic floor exercises before prostate cancer surgery may improve their urinary continence outcomes. It is therefore reasonable to offer preoperative instruction on pelvic floor strengthening exercises to all men who will undergo such surgery.

However, after dozens of conversations with physicians who treat prostate cancer regarding what protocols they are using in newly diagnosed men, I have found that this approach is utilized inconsistently.

As we learn more about cancer prehabilitation, the goal is to shift away from fragmented pretreatment assessments and interventions and toward a more thoughtful and scientifically based approach using coordinated prehabilitation that is designed to improve outcomes.

Is Cancer Prehabilitation Covered Care?

There are many barriers to effective prehabilitation care, including third-party payer coverage. However, some prehabilitation is covered and should be appropriately utilized. The following 3 examples, in which prehabilitation assessments and/or interventions may be covered by health insurers, including Medicare, highlight opportunities to provide reimbursable care.

1. Smoking Cessation

Smoking-cessation counseling is typically a covered service and is often considered an important modifiable lifestyle behavior that can impact many health issues. In the context of a patient with newly diagnosed cancer who undergoes smoking cessation as a part of a prehabilitation protocol, the relatively immediate goal is to reduce potential morbidity related to cancer treatments. The obvious population to target is patients with lung cancer who will be undergoing surgical resection and are active smokers. But based on the evidence, other at-risk populations may also benefit from a prehabilitation protocol that includes smoking cessation. For instance, women who are electing to have breast reconstruction

Dr Silver developed the evidence-based STAR (Survivorship Training and Rehabilitation) Program certification, which has been adopted by >100 hospitals and cancer centers in the United States (for more information about cancer rehabilitation and the STAR Program, see www.OncologyRehabPartners.com).

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tend to have worse cosmetic outcomes if they are current smokers. Not surprising, many plastic surgeons recom-

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mend discontinuing smoking before breast reconstruction, even if the surgery will be performed soon.

Breast Cancer Prehabilitation Example

Mary is a fairly typical 55-year-old woman who was diagnosed with right-sided stage II breast cancer. She underwent a mastectomy with reconstructive implant, chemotherapy, and radiation therapy and is now receiving an aromatase inhibitor. To illustrate the potential cost-savings for prehabilitation and rehabilitation, let’s follow Mary through 2 scenarios.

Scenario 1: Without Prehabilitation

Mary had mild shoulder pain without significant limitations in range of motion before she began acute cancer treatments. Her shoulder pain continued to worsen over time, but she was able to manage it well by not moving her arm very much, especially overhead. By the time she began radiation, she did have limitations in range of motion, but this did not affect the positioning of her arm.

Throughout treatment, Mary had many complaints of side effects, including nausea, fatigue, chest wall pain, shoulder pain, and generalized aching.

Mary struggled to return to work after her radiation therapy, and 6 months later presented to her oncologist with complaints of daytime generalized pain with diffuse arthralgias and difficulty lifting her arm overhead on the affected right side. She also complained of night pain on the affected side that contributed to insomnia and daytime fatigue, and she had high levels of distress. Mary voiced concern about cancer recurrence, and said that she had read online that night pain was often associated with cancer recurrence. Although her oncologist suspected a common “cluster” of symptoms—musculoskeletal pain, insomnia, fatigue, and distress—he wanted to be sure that Mary did not have a recurrence of her breast cancer before treating her other problems. A metastatic workup was negative, and Mary was sent to physical therapy with the diagnosis of right-shoulder adhesive capsulitis, as well as to an oncology social worker to help with her distress.

After physical therapy, she was able to attend a hospital-based exercise class, and she returned to work full time 1 year after finishing radiation therapy.

Scenario 2: With Prehabilitation

Mary was evaluated in a prehabilitation clinic before starting acute cancer treatments and was noted to have a mild right-sided rotator cuff impingement.

She was sent to physical therapy and was treated twice weekly for 3 weeks (ie, 6 visits) before having surgery. Preoperatively, Mary’s rotator cuff impingement resolved, and she was given specific instructions for postoperative shoulder range-of-motion exercises. Mary’s complaints during and after the acute cancer treatments were significantly fewer than in scenario 1. She had some nausea that resolved after chemotherapy, and she was fatigued but slept well; overall, her condition was not as severe as in scenario 1, and her pain complaints were generalized arthralgias that were relatively mild and consistent with the aromatase inhibitor’s side effects, and did not cause her significant distress.

Mary returned to part-time work shortly after finishing radiation therapy and was able to gradually increase to full time 6 months later. She participated in a hospital-based exercise program for breast cancer survivors and was engaged in other survivorship support services that the hospital offered, but she did not need further individualized rehabilitation or mental health interventions. No metastatic workups were necessary after the acute cancer treatment was completed.

Cost Analysisa

Scenario 1b Metastatic workup (imaging shoulder x-rays + whole-body bone scan): $213 + $1249 = $1462 Metastatic workup (radiologists’ fees): $46 + $100 = $146 Metastatic workup (blood tests: alk phos/chem 12/CA 27-29/Ca + phlebotomy fee) = $204 Physical therapy (16 visits to treat adhesive capsulitis): $212/visit × 16 = $3392 Oncology social work (consultation and 3 follow-up visits): $200 + ($150 × 3) = $650 Total cost = $5854.

This is an example, and diagnostic work up, treatment, and the associated costs can vary. These costs are real and were obtained from a STAR Program–certified community hospital and are based on billed charges for the services. Direct costs only were calculated; indirect costs, including lost time from work, were not included. b These costs reflect a relatively streamlined work up; additional costs may include a shoulder magnetic resonance imaging for $2348 (which would bring the total cost to $8202) or other studies and consultations. a

Scenario 2 Physical therapy (6 visits to treat mild rotator cuff impingement): $212 × 6 = $1272 Continued on page 24 OCTOber 2013

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Prostate Cancer

FDG-PET Helps Predict Prostate Cancer Prognosis Increased FDG uptake strongly correlates with poor outcomes

By Rosemary Frei, MSc Niagara Falls, Ontario—Research­ ers have determined that 18F-fluoro­ deoxyglucose (FDG) positron emission tomography (FDG-PET), a widely available and relatively inexpensive imaging modality, could be used to shape treatment plans for patients who have been diagnosed with high Gleason score prostate cancer.

Frédéric Pouliot, MD, PhD, Urologist Oncologist, and Assistant Professor, Department of Surgery, Université Laval, Quebéc, Canada, and his team found that increased FDG uptake by the prostate is strongly correlated with factors that are indicative of a poor prognosis, such as advanced clinical stage, a pathologic Gleason score of ≥8, and percentage of intraprostatic cancer.

In addition, patients without intraprostatic FDG uptake had a high probability of 5-year progression-free survival (PFS), based on the MSKCC

(Memorial Sloan-Kettering Cancer Center)’s pretreatment and the CAPRA-S (University of California, San Francisco Cancer of the Prostate Risk Assessment score) postradical prostatectomy nomograms. Patients with FDG uptake had a significantly lower probability of 5-year PFS, particularly based on the CAPRA-S results.

“These results suggest that with a single imaging modality, you might predict how your patients might do with surgery preoperatively,” said Dr Pouliot in a poster presentation at the 2013 Canadian Urological Association annual meeting.

The team analyzed information from 54 patients who had a Gleason score of ≥8 at transrectal ultrasound biopsy between July 2011 and July 2012 and who underwent an FDGPET bone scan; 41 patients also had radical prostatectomy and extended

pelvic lymph node dissection and the other 13 received androgen-deprivation therapy and/or radiotherapy.

“These results suggest that with a single imaging modality, you might predict how your patients might do with surgery preoperatively.”

—Frédéric Pouliot, MD, PhD

FDG uptake had a 27% sensitivity for detecting lymph node metastases, a 100% specificity, and positive predictive value. It also was significantly

correlated with a range of clinicopathologic factors, including clinical stage and pathologic Gleason score.

In addition, FDG uptake was predictive of prostatectomy-determined Gleason score. Fully 81.8% of the patients with increased FDG uptake had a Gleason score of ≥8. None were downstaged to Gleason 6 or 7 at prostatectomy.

Dr Pouliot’s team also found a 91.5% probability of 5-year PFS when they entered information from patients with FDG uptake into the MSKCC pretreatment nomogram. Patients without increased FDG uptake in the prostate had a 72.0% probability of 5-year PFS. Even more impressive discrimination was shown with the CAPRA-S nomogram—a 70.2% probability of 5-year PFS in patients with no FDG uptake and only a 26.9% probability in patients with increased uptake. n

VBCC Perspective

Cancer Prehabilitation May Reduce Healthcare Costs...

2. Physical/Occupational Therapy

Physical or occupational therapy would typically be covered before upcoming oncology treatments in patients with head and neck cancer who are screened and are found to have limitations and/or pain with cervical range of motion. This population is at risk for further loss of cervical range of motion that results in significant disability, such as an inability to safely see oncoming traffic while driving.

Similarly, physical or occupational therapy would usually be covered for patients with breast cancer who are screened and are found to have preexisting musculoskeletal issues that involve the shoulder, neck, or chest.

These preexisting problems can interfere with the delivery of upcoming cancer treatments and/or be exacerbated by cancer interventions, leading to significant disability. For instance, a shoulder problem, such as rotator cuff impingement syndrome, in a woman newly diagnosed with breast cancer may cause problems during radiation therapy when trying to position her arm. Even if she has no positioning problems initially, a mild rotator cuff impingement syndrome may progress to a more severe and disabling condition, such as adhesive capsulitis

24

(or “frozen shoulder”), if it is not identified and addressed before starting cancer treatments (Box, page 23).

3. Psychosocial Assessment

Psychosocial assessments and/or interventions may be covered. The period between diagnosis and the beginning of cancer treatments is an opportune time to do an initial distress screening and consider whether prehabilitation interventions may improve a patient’s psychological health outcomes. Moreover, because a leading cause of distress in cancer survivors is physical disability, it is ideal to perform dual screening for physical and psychological problems during the prehabilitation period (Figure).

Conclusion Many other examples of prehabilitation assessments and interventions may be covered now or will be in the future. Interest in cancer prehabilitation from clinicians and researchers will undoubtedly drive changes in the delivery of oncology care and reimbursement for the services. Cancer prehabilitation may also have an impact on the market share for various oncology practices. For example, theoretically it makes sense that a newly

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Continued from page 23

Figure Opportunities for Dual Screening at Pivotal Medical Visits New cancer diagnosis Physical and psychosocial screening

Prehabilitation services Acute cancer treatments

No impairments

Physical and psychosocial screening

Impairments

Rehabilitation services

Psychosocial services Physical and psychosocial screening

General exercise/wellness Copyright © Oncology Rehab Partners. All Rights Reserved. Reprinted with permission.

diagnosed patient who is scared and anxious would respond very favorably to a high-quality cancer prehabilitation program designed to prepare him or her for upcoming treatments.

Would this favorable response decrease the likelihood of seeking care elsewhere (eg, decreasing outmigration)? It is too soon to tell, but clearly prehabilitation is something that every

oncologist should be paying close attention to now and in the future. n References

1. Silver JK, Baima J, Mayer RS. Impairment-driven cancer rehabilitation: an essential component of quality care and survivorship. CA Cancer J Clin. 2013;63:295-317.

2. Silver JK, Baima J. Cancer prehabilitation: an opportunity to decrease treatment-related morbidity, increase cancer treatment options, and improve physical and psychological health outcomes. Am J Phys Med Rehabil. 2013;92:715-727.

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SHOULDN’T A PATIENT SUPPORT PROGRAM BE EASY TO NAVIGATE?

• REIMBURSEMENT SERVICES

• EDUCATION AND SUPPORT SERVICES

• BENEFIT VERIFICATIONS

• PATIENT ASSISTANCE

• DELIVERY COORDINATION

• CO-PAY ASSISTANCE

An uncommon condition requires a common solution— IncyteCARES IncyteCARES helps connect your patients with intermediate or high-risk myelofibrosis (MF), who qualify for the program, to ongoing support and resources during their treatment with Jakafi® (ruxolitinib).

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

•Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are

each dose-related effects, with the most frequent being thrombocytopenia and anemia • Monitor CBCs, and in patients with cytopenias, consider dose reductions, temporarily withholding Jakafi, or transfusions, as clinically indicated Please see additional Important Safety Information and the Brief Summary of Full Prescribing Information within this ad.

HELPING PATIENTS RECEIVING JAKAFI ® (ruxolitinib) STAY CONNECTED TO CARE

Patients living with intermediate or high-risk MF face many challenges. IncyteCARES is a program created by Incyte to connect patients who qualify for the program to ongoing support and resources during their treatment with Jakafi.

IncyteCARES HELPS PEOPLE BEING TREATED WITH JAKAFI ACCESS AND REIMBURSEMENT SERVICES

•Benefit verification •Prior authorization •Appeal support • Delivery coordination of Jakafi

•Co-pay assistance •Free medication programs • Referrals and assistance with independent not-for-profit organizations

PATIENT EDUCATION AND SUPPORT

• Access to trained nurses • Educational information to help teach your patients about their condition and Jakafi Patient packet

•

Visit www.IncyteCARES.com or call 1-855-4-JAKAFI (1-855-452-5234), Monday–Friday, 8 AM –8 PM ET, to learn more about how to connect your patients to IncyteCARES.

IncyteCARES: ASSISTING PROVIDERS AND PATIENTS IN OBTAINING ACCESS TO JAKAFI

Enrollment sent to

95% of patients had insurance coverage for

Patients without insurance coverage were screened for patient assistance eligibility

94% of prior authorizations were approved for

86% of commercially insured patients had co-pays of less than $100/month

Information is based upon 1421 patients enrolled in IncyteCARES between April 1, 2012 and April 1, 2013.

91% of patients referred to the IncyteCARES commercial co-pay assistance program were eligible for assistance Important Safety Information (continued)

•Risk of Infection: Assess patients for signs and symptoms of infection and initiate

appropriate treatment promptly. Serious infections should have resolved before starting therapy with Jakafi • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache Please see additional Important Safety Information and the Brief Summary of Full Prescribing Information within this ad.

Jakafi is a registered trademark of Incyte Corporation. © 2013, Incyte Corporation. All rights reserved. RUX-1227e 07/13

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 thrombocythemia myelofibrosis.

Neutropenia 18.7 5.2 1.9 4.0 0.7 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pretreatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur.

Active serious infections should have resolved before starting therapy with Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions].

ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo.

Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discontinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; however, it has not been established whether discontinuation of therapy contributed to the clinical course in these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.

Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi Placebo (N=155) (N=151) Adverse All All Grade 3 Grade 4 Grades Grade 3 Grade 4 Reactions Gradesa (%) (%) (%) (%) (%) (%) Bruisingb 23.2 0.6 0 14.6 0 0 Dizzinessc 18.1 0.6 0 7.3 0 0 Headache 14.8 0 0 5.3 0 0 Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 Weight Gaine 7.1 0.6 0 1.3 0.7 0 Flatulence 5.2 0 0 0.7 0 0 Herpes Zosterf 1.9 0 0 0.7 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain f includes herpes zoster and post-herpetic neuralgia

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

Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Grade 4 (%) 0 3.3 1.3

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

Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.

16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations.

DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent administration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.

Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).

Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information].

Jakafi is a registered trademark of Incyte Corporation. All rights reserved.

U.S. Patent No. 7,598,257 © 2011-2013 Incyte Corporation. All rights reserved.

Issued: June 2013 RUX-1216

3rd Conference

Growing Pressures on Oncolytics to Demonstrate... agents from midsize and large pharmaceutical companies • Prices are not diminishing, but questions are being raised by payers and providers • Payers respond by cost-cutting and requiring companion diagnostics and real-world evidence of benefit.

Specialty medicines in the United States were an $89-billion business in 2012. Oncolytics are the number one category in the specialty class, currently growing by 8% annually. Two cancer drugs—rituximab (Rituxan) and bevacizumab (Avastin)—are among the top 10 specialty drugs, but the growth in cancer drugs is actually slowing down, largely because of multiple agents coming off patent.

Today, many new agents are replacing rather than adding on to regimens, and payers are being more attentive to the “crowded” oncology space, where there are multiple options for the same indications, Mr Long said.

Targeted Therapies Dominate Although global growth in oncology has slowed, there are signs of a rebound as a result of emerging treatments for neglected cancers. Several classes are predicted to demonstrate the most growth by 2016, with specialty drugs far outpacing traditional retail-dominated areas and with oncology by far the biggest piece of this pie.

The dominance of targeted therapies in the marketplace will shape the future, Mr Long predicted. In 2002,

“I think we will see that if a drug doesn’t show value, the price will come down.”

—Doug Long

targeted therapies accounted for just 2% of the market, but this rose to 15% by 2007, and skyrocketed to 33% in 2012. More than 200 targeted agents are in the pipeline just for non–smallcell lung cancer and breast cancer (Figure).

Pricing Cancer Drug Although new cancer drugs are coming at a great expense, “downward pressures” provide counterbalance, Mr Long said.

“On one side of the equation you have price elasticity of demand, physician reimbursement confidence, patient out-of-pocket expense, payer/

employer actions, physician moral outrage (at drug prices), and competitors and substitutes. On the other side, insurance separates the financial responsibility from selection and benefit; you have a rising benefit to patients, increasing duration of therapy, improved ability to identify responders, and recent launches and analogs. It is a balancing act, and we’re seeing these products see-saw in terms of their pricing,” he noted.

There are signs that prices are coming down, with the average monthly cost for oncology/supportive therapies declining from $10,725 to $9304 per patient, according to IMS analyses. The adoption of expensive drugs is slowing, he noted. Prices pushed beyond the $10,000 monthly in 2010, but they have since moderated slightly. However, branded drugs have achieved sustained price increases despite the average sales price “supposed restraints,” he said.

To justify their cost, new agents need to show greater benefit. “The market does not value incremental improvements anymore. A drug has to be much better than what it is replacing….It has to prove value,” he said.

Companion diagnostics will also be playing a greater role in future drug launches to ensure access to and demonstrate value for expensive oncolytics. The benefit of companion diagnostics has been demonstrated in metastatic melanoma, where the companion diagnostic for vemurafenib (Zelboraf) that tests for BRAF mu-

Figure The Late-Stage Pipeline Is Dominated by Targeted Therapies, Mostly in Solid Tumors Global oncology pipeline by mechanism of action

5%

Global oncology pipeline by tumor type

16%

79%

n Chemotherapy n Targeted agents n Hormonals Agents with multiple indications are counted twice.

Source: IMS Knowledge link and R&D focus. September 2012.

Copyright © IMS Health. All Rights Reserved. Used with permission.

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tations may be responsible for this drug’s significantly greater market growth versus ipilimumab (Yervoy), Mr Long suggested.

Need for Real-World Evidence Scrutiny of a drug’s benefit across the life cycle, along with requirements of real-world evidence of benefit, will impact the continued use of a drug. In Germany, drugs receive conditional approval with a conditional price tag, and are reevaluated later to determine whether the outcomes justify the cost.

“I think we will see that if a drug doesn’t show value, the price will come down,” Mr Long predicted.

“The oncology business has to prove value.

Manufacturers have to prove value and practices have to prove value, because healthcare expenditures are rising at an unsustainable pace.”

—Doug Long

The emerging importance of real-­ world evidence for benefit will likely impact new drugs, he said. New agents will receive access at launch, but some reevaluation will occur, including phase 4 clinical trials and other metrics. As was observed with bevacizumab in metastatic breast cancer, drugs may not always live up to their initial promise.

Also on the radar are biosimilar monoclonal antibodies, which could enter the market by the end of the decade. But although welcomed by many, biosimilar monoclonal antibodies may not greatly impact the cost of cancer care, because of their production expense—an investment of $102 million per biosimilar compound versus $1 million to $2 million for a small monoclonal generic. “It’s 100 times more investment, suggesting there’s not going to be a lot of players in the marketplace. Some savings will be there, but it will be more like 25%, not 90%,” Mr Long predicted.

“The oncology business has to prove value,” Mr Long concluded.

“Manufacturers have to prove value and practices have to prove value, because healthcare expenditures are rising at an unsustainable pace.” n

www.ValueBasedCancerCare.com

29

NOW INDICATED

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

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

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

• Note: An albumin form of paclitaxel may

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

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

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

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

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

Median OS

1.0

ABRAXANE + gemcitabine (n=431)

0.9

Proportion of survival

0.8 0.7 0.6

Gemcitabine (n=430)

0.5

8.5

months (95% CI: 7.9-9.5)

6.7

months (95% CI: 6.0-7.2)

0.4 0.3

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

0.2

P<0.0001b

0.1 0.0 0

3

6

9

12

15

18

21

24

27

30

33

36

39

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

1 0

0 0

Time (months)

Patients at risk

A+G: 431 G: 430

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

metastasis (yes vs no).

b

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

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

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

USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

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

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

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

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

ABRAXANE® is a registered trademark of Celgene Corporation. © 2013 Celgene Corporation 09/13 US-ABR130068a

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

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a brief summary for metastatic adenocarcinoma of the pancreas; refer to full prescribing information for complete product information.

WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.3)].

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

2 DOSAGE AND ADMINISTRATION 2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)].

2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1.

Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreaticc Adenocarcinoma Mild < 10 x ULN AND > ULN to ≤ 1.25 x ULN 125 mg/m2 Moderate < 10 x ULN AND 1.26 to 2 x ULN not recommended Severe < 10 x ULN AND 2.01 to 5 x ULN not recommended > 10 x ULN OR > 5 x ULN not recommended a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic cancer 2.5 Dose Reduction/Discontinuation Recommendations Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3.

Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level

ABRAXANE (mg/m2)

Gemcitabine (mg/m2)

Full dose

125

1000

1st dose reduction

100

800

2nd dose reduction

75

600

Discontinue

Discontinue

If additional dose reduction required

Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4.

Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day Day 1 Day 8

ANC Platelet count ABRAXANE / Gemcitabine (cells/mm3) (cells/mm3) < 1500 OR < 100,000 Delay doses until recovery 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5.

Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at next Febrile Neutropenia: Grade 3 or 4 lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at No dose reduction next lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at next Grade 3 mucositis lower dose level or diarrhea

4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.

• Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer.

Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 (for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3.

In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)].

5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions ( 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 for pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)].

5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics.

For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].

5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine.

5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug.

5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote.

No cases of transmission of viral diseases or CJD have ever been identified for albumin.

5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.

There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)].

5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)].

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%).

6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients.

Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm ABRAXANE(125 mg/m2)/Gemcitabined Gemcitabine Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group.

Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group.

Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE (125 mg/m2) and gemcitabine (N=421) System Organ Class General disorders and administration site conditions

Gemcitabine (N=402)

Adverse Reaction

All Grades

Grade 3 or Higher

All Grades

Grade 3 or Higher

Fatigue

248 (59%)

77 (18%)

183 (46%)

37 (9%)

Peripheral edema

194 (46%)

13 (3%)

122 (30%)

12 (3%)

Pyrexia

171 (41%)

12 (3%)

114 (28%)

4 (1%)

Asthenia

79 (19%)

29 (7%)

54 (13%)

17 (4%)

Mucositis

42 (10%)

6 (1%)

16 (4%)

1 (<1%)

Nausea

228 (54%)

27 (6%)

192 (48%)

14 (3%)

Diarrhea

184 (44%)

26 (6%)

95 (24%)

6 (1%)

Vomiting

151 (36%)

25 (6%)

113 (28%)

15 (4%)

Skin and subcutaneous tissue disorders

Alopecia

212 (50%)

6 (1%)

21 (5%)

0

Rash

128 (30%)

8 (2%)

45 (11%)

2 (<1%)

Nervous system disorders

Peripheral neuropathya

227 (54%)

70 (17%)

51 (13%)

3 (1%)

Dysgeusia

68 (16%)

0

33 (8%)

0

Headache

60 (14%)

1 (<1%)

38 (9%)

1 (<1%)

Decreased appetite

152 (36%)

23 (5%)

104 (26%)

8 (2%)

Dehydration

87 (21%)

31 (7%)

45 (11%)

10 (2%) 6 (1%)

Gastrointestinal disorders

Metabolism and nutrition disorders

Hypokalemia

52 (12%)

18 (4%)

28 (7%)

Respiratory, thoracic and mediastinal disorders

Cough

72 (17%)

0

30 (7%)

0

Epistaxis

64 (15%)

1 (<1%)

14 (3%)

1 (<1%)

Infections and infestations

Urinary tract infectionsb

47 (11%)

10 (2%)

20 (5%)

1 (<1%)

Musculoskeletal and connective tissue disorders

Pain in extremity

48 (11%)

3 (1%)

24 (6%)

3 (1%)

Arthralgia

47 (11%)

3 (1%)

13 (3%)

1 (<1%)

Myalgia

44 (10%)

4 (1%)

15 (4%)

0

Depression

51 (12%)

1 (<1%)

24 (6%)

0

Psychiatric disorders a

Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal.

Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema

Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.

Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent.

Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died.

6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

Cardiovascular There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.

Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus.

Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline.

Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.

Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.

Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration.

Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported.

Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia.

Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.

6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness.

7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)].

There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).

8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.

8.5 Geriatric Use Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older.

No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients.

8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal.

8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment.

In the Literature Molecular Test Identifies Patients at Risk...

Continued from page 22

endocrine therapy for late recurrence in patients with estrogen receptor (ER)-positive breast cancer would be a valuable tool for enhancing the treatment decision-making of oncologists.

A new study compared the ability of 3 modalities—the new Breast Cancer Index (BCI) molecular test, the 21-gene recurrence score known as Oncotype DX, and the immunohistochemical (IHC4) prognostic model—to predict B:7.5” early and late disease recurrence in paT:7” tients with ER-positive, node-negative S:6.5”

breast cancer (Sgroi DC, et al. Lancet Oncol. 2013;14:1067-1076).

In this prospective, comparison study, tumor samples from 665 postmenopausal women with ER-positive breast cancer were evaluated; the women were enrolled in the ATAC (Arimidex, Tamoxifen, Alone or

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration.

• Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)].

• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal. [see Warnings and Precautions (5.5)].

• Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.

16.2 Storage Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light.

16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].

• Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)].

• Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)].

Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved.

Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: See www.celgene.com.

ABR_PANC_HCP_BSv006 9_2013

Value-Based Cancer Care

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OCTOber 2013

T:10”

34

B:10.5”

S:9.5”

in Combination) clinical trial. The samples had been previously tested by the 21-gene recurrence score (Oncotype DX) and the IHC4 prognostic model.

The researchers conducted a BCI analysis in matched samples using 2 BCI models—cubic (BCI-C) and linear (BCI-L)—and previously validated cutoffs. The researchers identified the BCI groups with prespecified cutoff points for each model.

The primary end point was the ability of the BCI test to predict distant recurrence over 10 years compared with that of the 21-gene recurrence score or the IHC4 model. The researchers also tested the ability of the 3 assays to predict early (0-5 years) and late (5-10 years) distant recurrence.

The primary analysis showed significant differences in the risk of distant recurrence over 10 years in the BCI-C risk groups (P <.001), with 6.8% (95% confidence interval [CI], 4.4-10.0) of patients in the low-risk group, 17.3% (95% CI, 12.0-24.7) in the intermediate group, and 22.2% (95% CI, 15.3-31.5) in the high-risk group of having distant recurrence.

The secondary analysis showed that BCI-L was a stronger predictor for the overall 10 years of distant recurrence compared with BCI-C (P <.001).

Overall, the 21-gene recurrence score was less able to predict distant recurrence than the BCI test (P = .002) as was the IHC4 model (P <.001). In a multivariable analysis, all 3 assays had significant prognostic ability for early distant recurrence; however, only the BCI-L test showed significant ability to predict late recurrence (P = .048) compared with the 21-gene recurrence score (P = .47) or the IHC4 model (P = .20).

“This information generated by BCI could be extremely valuable and have fundamental relevance to breast cancer oncologists and patients, especially those who are at 5 years postdiagnosis,” said lead investigator of the study, Dennis C. Sgroi, MD, Professor, Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Boston. “This is highly relevant to clinical management, as it has been demonstrated in previous studies that late disease recurrence is a hallmark of ER-positive breast cancer, with more than half of recurrence occurring after 5 years of adjuvant therapy.”

This new study shows that all 3 modalities are able to predict early recurrence of ER-positive breast cancer, but only the BCI molecular test is a significant prognostic test in relation to both early and late distant disease recurrence. n

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3rd Conference

Community Oncology Practices Trying to Keep Afloat

By Caroline Helwick

Hollywood, FL—There are perplexing considerations for community oncology practices under sequestration, but adapting to future practice models poses even bigger questions, according to Leonard H. Natelson, Chief Executive Officer of Hematology/ Oncology Associates of Rockland, NY. Mr Natelson has a good track record of improving the profitability of community oncology practices, and he shared his insights at the 3rd Annual Conference of the Association for Value-Based Cancer Care.

Sequestration has offered some pressing considerations for community oncology practices. Sequestration has cut reimbursement for evaluation and management and reimbursement for drugs, decreased the number of Medicare recipients seen in the practice, decreased the number of patients available for clinical trials, and demanded that practices manage their current patient load with fewer resources and staff.

The 2% slash in income from Medicare has had far-reaching effects, because Medicare beneficiaries account for approximately half the patient population of a typical community oncology practice. With less income to cover the same number of patients in a practice, oncologists have to cut their practice costs somewhere, and the question is, where?

Consider These Approaches Mr Natelson offered some approaches for consideration for com-

at a glance ➤ Sequestration has cut reimbursement for evaluation and management and for drugs ➤ It has decreased the number of Medicare patients seen in the practice and patients who are available for clinical trials ➤ Community oncology practices need alternatives to buy and bill, such as oncology medical homes or renegotiations with non-Medicare payers ➤ Practices must be collaborative and involved in the fight to save community oncology

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munity oncology: • Review the buy-and-bill model and determine if there are other alternatives • Review rules to create an oncology medical home • Reach out to non-Medicare payers to renegotiate current contracts; get paid to provide data • Be collaborative and get involved; the problem extends beyond any one given practice • Get patients involved in the fight to save community oncology.

“I need to keep patients out of the hospital. That’s what payers want me to do, too, but I can’t give away my services for free.”

—Leonard H. Natelson

One of the biggest expenses to the oncology practice is drugs, and it may be worth considering alternatives to buy-and-bill, Mr Natelson said.

“I actually got away from buying and billing based on our contracts and on what I was getting reimbursed,” he said. “I was actually making 5%, not 6%, because you only get that if you do everything perfectly, which no practice does.”

Controlling waste is crucial. Nurses will document what they use, but not what they waste, and this amount cannot be recouped, Mr Natelson pointed out. “I had a nurse who twice gave Aranesp to a patient with a hemoglobin level above 10. Aranesp costs me $8500 each time I give it, so I just lost $1700,” he related.

In thinking of office expenses, oncologists and managers should consider the time it takes to make appeals to payers. Four hours of phone time for a

nurse cost his practice $168 plus taxes and benefits. “You have to consider the indirect costs when determining the expense of making an appeal, and whether it makes sense,” Mr Natelson suggested.

Don’t Give Information and Services Away for Free Mr Natelson advised practice managers and oncologists to initiate conversations with non-Medicare payers.

Commercial payers want and need data, which he offers them, but he also asks them to pay for this information.

He sees this as being collaborative and a means toward a mutual relationship in which payers may be more willing to consider higher reimbursements.

“You can also marry good patient care with your finances if you are thoughtful about what you do.” Mr Natelson suggested oncologists evaluate the services they offer—such as clinical trial enrollment, support groups, nutrition counseling, and so forth—and ask payers to pay for these things. “I need to keep patients out of the hospital. That’s what payers want me to do, too, but I can’t give away my services for free,” he said. “The biggest thing is figuring out how you work with the payers to get them to understand the value that you bring to oncology.”

Mr Natelson cautioned oncology practices to check out their practice on “Physician Compare”—the government’s effort to make practices transparent and informative to Medicare recipients. A pilot study showed, however, that much of the data are erroneous. “I go to Physician Compare, look at what CMS [Centers for Medicare & Medicaid Services] is putting up there, and if it’s wrong, go through the laborious task of getting the information corrected,” he said.

Mr Natelson predicted future challenges as a result of the Independent Payment Advisory Board—the 15-­ member appointed panel who will decide what treatments can and cannot be given—and the expansion of the Medicaid population through the healthcare exchanges. “Our doctors will want to see everybody and treat everybody, whereas I will want to keep my doors open,” he said.

Community- versus Hospital-Based Oncology Models Increasingly, community practice

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oncologists are questioning whether to maintain their status, join a larger organization, or affiliate with a 340B-eligible hospital.

Mr Natelson sees hospital employment as a loss of physician autonomy, and an expensive one at that. He has told his physicians, “It will cost at least $1 million to put back your infrastructure, and you will go at least 6 months without money from CMS, which is a 55% payer to the practice…unless you have $1.5 million at least, it’s difficult,” he said.

“The biggest thing is figuring out how you work with the payers to get them to understand the value that you bring to oncology.”

—Leonard H. Natelson

“My physicians make half a million dollars. If my hospital offers them $750,000, a 50% increase in their salary, they are going to say ‘yes.’ The problem is my physicians are 44 to 56 years old, so at the end of a 5-year agreement, when the hospital has obtained all their patients, those physicians are not going to get this kind of money,” Mr Natelson predicted.

A professional service agreement is another emerging option, under which the practice remains an entity but has arrangements with the local hospital for something the hospital wants—for instance, drug infusions—which is a money maker for the hospital.

“I think professional service agreements are going to be a little bit more flexible than hospital employment. I think that’s the right way to go. It keeps your practice together, and gives you the ability to get extra money from the hospitals, since the hospitals have 340B pricing,” Mr Natelson said.

“I think there will be some push back out to community oncology in the next 3 to 5 years, once CMS realizes how expensive it is to have practices move into the hospital. And when that pushback occurs and CMS restricts this 340B program, you will be there, so you don’t have to recreate the wheel,” he said. n

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3rd Conference

Seeking Value in Oncology Care

By Caroline Helwick

Hollywood, FL—“How do different stakeholders define value in oncology? This is a complex question, and definitely a mainstream, though at times controversial, issue,” according to Pamela Morris, Director, Syndicated Research, Zitter Health Insights. Ms Morris discussed the search for value in oncology care, informed by results from the Zitter Group’s research, at the 3rd Annual Conference of the Association for Value-Based Cancer Care.

“Everyone views value differently,” Ms Morris said. Patients are faced with the economic impact of their treatment. Employers must cover these costs and oversee the well-being and productivity of their employees.

Payers seek to balance the cost with appropriate clinical care across a wide population for which all healthcare costs are rising, she said.

“This conversation isn’t just about cost, and it’s not limited to a specific stakeholder. It’s becoming a mainstream conversation. Payers are saying they’re fed up, oncologists are saying they’re fed up, and patients are saying they’re fed up, too,” Ms Morris commented.

Value from the Payer’s Perspective When Zitter Health Insights asked 100 payers to name their top management priority, the “unequivocal” response was “cancer care.” In the same survey of 100 employers, cancer care was the second highest priority.

But a gnawing concern is cost relative to outcomes, and payers see plen-

ty of waste in cancer treatment. When asked to estimate how much excess cost could be eliminated from cancer treatment without negatively impacting health outcomes, 44% of payers said 11% to 20%, and another 21% estimated 21% to 30%. “That’s quite a bit of cancer care,” Ms Morris noted.

A survey of 100 oncologists found

“We asked payers, ‘If Medicare were to cut reimbursement from ASP + 6% to ASP + 4%, would you follow suit for your commercial population?’

Nearly half said they would likely negotiate for a decrease at their next contract discussion with physicians or would likely institute a decrease.”

—Pamela Morris less agreement, with 73% estimating that only 1% to 10% of excess cost could be eliminated without compromising outcomes. Altogether, though, “payers and oncologists agree there is room to eliminate costs from the system,” especially in end-of-life care and unnecessary diagnostic testing.

Payers’ Efforts to Manage Cost How are payers managing these costs? Yearly surveys indicate that payers are starting to succumb to employer pressures and are reevaluating

Figure 1 Prior Authorizations Are Ubiquitous Which of the following utilization management tools have been applied to manage cancer therapies? Please select all that apply.

85%

Prior authorization Quantity limits

52% 66%

47%

Tying drug approval to diagnostic tests/ biomarkers

73% 65% 59% 59%

44%

27% 26%

44%

Preferred products Clinical treatment pathways

92% 97%

67%

39%

Specific laboratory or diagnostic values

Step edits

36%

61%

70% Payers (N = 103)

56% 54%

Oncologists (N = 103) Practice managers

(N = 101) No significant changes from winter 2012 report.

Copyright © 2013 Zitter Health Insights. All Rights Reserved. Used with permission.

36

their oncology management policies.

This is resulting in some changes in employee cost-sharing, utilization management policies (such as prior authorization and step edits), therapy coverage decisions, and physician reimbursement.

“When payers are getting squeezed more by employers, patients ultimate-

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ly get squeezed as well,” Ms Morris suggested.

Prior authorization may be the most common cost-management tool, used by virtually all payers. Zitter analyzed the content of prior authorization policies of more than 200 health plans and found that the percentage of plans not requiring prior authorizations is dwindling (Figure 1). In breast cancer, for example, 1 year ago 37% of plans surveyed had few or no prior authorization requirements, but this figure dropped dramatically to 10% in 2013.

Prior authorizations encompass quantity limits, diagnostic testing, and to a lesser degree step edits, preferred products, and clinical treatment pathways. Payers, oncologists, and practice managers apply these tools differently.

Another approach to value, not only by payers but increasingly also by oncologists, is to shun the most expensive agents when less expensive, and essentially comparable, agents are available. One recent example was the decision by Memorial Sloan-Kettering Cancer Center’s oncologists not to offer ziv-aflibercept (Zaltrap) for colo­ rectal cancer treatment, because of cost concerns relative to the drug’s efficacy and the availability of comparable alternatives.

Payers and oncologists agree on which of the “wonder drugs” are clinically desirable, despite cost. In a Zitter survey, both groups listed imatinib (Gleevec), trastuzumab (Herceptin), rituximab (Rituxan), and bevacizumab (Avastin). Among their list of overly

expensive or overhyped drugs were bevacizumab, sipuleucel-T (Provenge), and ziv-aflibercept; the oncologists added nab-paclitaxel (Abraxane), and the payers added ipilimumab (Yervoy) and cetuximab (Erbitux).

Oncologists’ View of Value Although half of oncologists report a decline in revenue (10%-20%) as a direct result of average sales price (ASP) reimbursement contracts, payers believe that “they can squeeze more out of” the ASP, Ms Morris said.

“We asked payers, ‘If Medicare were to cut reimbursement from ASP + 6% to ASP + 4%, would you follow suit for your commercial population?’ Nearly half said they would likely negotiate for a decrease at their next contract discussion with physicians or would likely institute a decrease, because their reimbursement rates are linked to the Medicare rate,” Ms Morris reported.

The adoption of clinical pathways as an avenue toward value receives mixed reviews from oncologists, she continued. Only 42% of oncologists surveyed believe that the adoption of pathways has improved patient outcomes, whereas 50% said that pathways had not changed patient outcomes, or they were unsure about their value.

The Value of ACOs in Oncology Accountable care organizations (ACOs) are intended to provide value for the entity that is bearing the risk and provide value to the patient. At a Zittersponsored ACO leadership summit, 14 leaders in the ACO movement predicted that within the next 3 to 4 years, more than 50% of all care in the United States will be delivered through an integrated delivery system and financial risk-bearing model, such as ACOs. They also said that they are facing challenges in terms of physician alignment, but they do see more and more oncologists starting to practice within an ACO type of contract (Figure 2).

The Power of Copay With the average American family earning in the $50,000 range annually, a $200 monthly copay can affect adherence to treatment recommendations. In a recent Zitter survey, 50% of patients indicated that they would stop taking the prescribed drug if the benefits from a copay-offset program were discontinued; only 24% said they would remain using the treatment as planned.

In making these decisions, patients Continued on page 38

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Now enrolling

Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial.

Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

NCT#01889186 Reference: ClinicalTrials.gov.

@ 2013 Genentech USA, Inc. All rights reserved. BIO0001961500 Printed in USA.

To learn more about this study, please visit www.ClinicalTrials.gov.

3rd Conference

Contracting in the Current Oncology Landscape

By Caroline Helwick

Hollywood, FL—Contracting in oncology has become a more complicated process, now that it involves many entities beyond physicians and payers. Dawn G. Holcombe, MBA, Vice President, Strategic Relationships, Florida Cancer Specialists, Sarasota, FL, described the scenario at the 3rd Annual Conference of the Association for Value-Based Cancer Care.

Different Perspectives Make for Complications The different perspectives from payers and providers make contracting difficult. Payers want to reduce variation and cost, and they expect providers to be good business partners. Providers want to give patients with cancer help and hope, and although they believe in evidence-based medicine, they also have to stay in business. Finding the common ground can be a challenge.

The result is “dissonant messaging,” Ms Holcombe said (Table). At the end of the day, “it is about the management of costs and care for efficiency and effectiveness—seen from each perspective.”

Contracting in oncology used to be between payer and provider, but it is more complex now, because it also involves hospital systems, pharmacy benefit managers, specialty pharmacy, retail infusion clinics, and others. Layered upon this are navigators, disease management companies, oncology management companies, and the like.

Table Dissonant Messaging • I need to be paid more for…

• I need to be incentivized • I need to be rewarded for…

• I am special because…

• I provide quality care • I treat on evidence • I am at least concordant with NCCN Guidelines • Trust my judgment

NCCN indicates National Comprehensive Cancer Network.

“Build relationships and future projects after you establish trust and communication….

Collaboration is the fastest route to success.”

—Dawn G. Holcombe, MBA

“With some of the arrangements we are seeing now, you may not be at the table with the same people you are used to,” Ms Holcombe noted.

Among the issues that influence contracting are the role of care navigators and case managers; various channels for treatment approval; data and their sources; quality and how to define, measure, and fund it; and pay for performance and how to determine it.

“We used to just talk fee schedule,

rates, drug fees. Now we have a laundry list of things to deal with, and it’s not just you driving the choices in medical decision-making. Shifting sites of care also affect the physician’s direct involvement in negotiations.

And with less money available, retooling is critical,” Ms Holcombe said.

Dealing with Total Cancer Spending Issues surrounding cost are not just about drugs anymore but the total cancer spending, which includes physician services and drugs, diagnostics, drugs prescribed outside of the physician office, hospital care, end-of-life care, and other services. The continuum of care should be evidenceand treatment-focused, moving away from a single cost focus (eg, prior authorizations, step edits, preferred formularies, fee schedules).

Going forward, payers have a long list of drug management expectations for physicians or specialty pharmacy.

This list includes clinical assessment,

Seeking Value in Oncology Care...

Figure 2 Payers Believe ACOs and PCMHs are on the Horizon for Oncologists Within the given time frame, approximately what percentage of oncologists within your commercial network practice will practice within the given practice structures?

Currently 4% 6%

Payers (N = 103) 4% 3% 5%

78%

12 months from now 5%

n

n n

n n

n

• There is no more money • There are even less data • Full costs of care —Allows “cost shift” for reason —Many issues do not affect MDs, may affect hospital centers • Medical oncologists just one piece of cancer care • Payers and providers hold the data, but not together

Primary care–centered Medicare ACO Primary care PCMH Oncology-centered Medicare ACO Oncology PCMH Non-ACO/non-PCMH community practices Other

Continued from page 36

take into account their income level, disease stage, current health status, impact of the treatment on the family, and whether the treatment provides true clinical or only supportive-care

12% 8% 9% 8%

58%a

“We know that the availability of copay programs does matter, and it changes patients’ value equation.”

—Pamela Morris

Percentage of payers

Percentage of payers

Significant decrease anticipated.

ACO indicates accountable care organization; PCMH, patient-centered medical home.

Copyright © 2013 Zitter Health Insights. All Rights Reserved. Used with permission.

a

38

Value-Based Cancer Care

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counseling, education, outreach, monitoring, and reporting—with proper documentation. Providers will need to carve out policies pertaining to all these areas.

“Keep it simple,” Ms Holcombe concluded. “Build relationships and future projects after you establish trust and communication.”

Address pressure points—the common practices and services that can be cataloged, measured, valued, and marketed, such as emergency room and hospital visits avoided, conversations about end-of-life care conducted, and disease and symptom management steps documented.

Reform in oncology will require a change in perspective, away from drug costs to total spend. Collaboration will be increasingly required, because data will be “in different pots,” Ms Holcombe pointed out. “No one of us can develop a solution in and of ourselves….Collaboration is the fastest route to success, but trust is needed.” n

benefits. “We know that the availability of copay programs does matter, and it changes patients’ value equation,”

Ms Morris suggested.

Copay programs alter the value equation not only for patients but also for oncologists and ultimately for payers as well. Most oncologists (80%) surveyed indicated to Zitter that copay programs influence their decision to prescribe a newly approved oncology drug; 47% said they had prescribed a cancer drug solely because of its relationship to a copay benefit program.

Although payers are typically critical of copay programs, they will cooperate with them, given the need and the right situation, Ms Morris pointed out.

“Some payers do see value in copay programs when there’s an appropriate unmet need from the patients,” such as for orphan diseases and in expensive specialty categories, Ms Morris concluded. n

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3rd Conference

Addressing Medication Nonadherence: A Patient– Provider Perspective Tips for successful interventions that can improve patient outcomes

By Caroline Helwick Hollywood, FL—Adherence to medications is critical for effective cancer treatment. Oncologists must understand the reasons for nonadherence and help patients to keep taking their medications, said Lillie D. Shockney, RN, BS, MAS, Associate Professor, Johns Hopkins University School of Medicine and School of Nursing, Baltimore, at the 3rd Annual Conference of the Association for Value-Based Cancer Care.

“As medical providers, we need to ensure that the correct drug is given at the right dosage, at the proper time, on a specific schedule, under the appropriate conditions, and following the right precautions,” Ms Shockney said, but this “can be very overwhelming for patients.”

For patients with cancer, nonadherence can seriously affect outcomes, shortening the time to relapse, reducing survival time, and increasing physician visits and hospitalizations.

A 21-year breast cancer survivor herself, and currently a caregiver of a parent with metastatic cancer, Ms Shockney focused on the patient– provider perspective.

When the Patient Is in the Driver’s Seat The increasing use of oral oncolytics would appear to make treatment easier and less burdensome for patients; however, “the catch” is that patients are more apt to take oral drugs incorrectly, and these drugs are less frequently monitored by providers, unlike conventional intravenous chemotherapy, where the provider controls the process, Ms Shockney noted.

When the patient is told, “I’m not

Table Reasons and Types of Nonadherence • Failure to get the first prescription filled • Failure to refill a prescription • Skipping or omitting doses • Choosing to take a “drug holiday” based on personal choice • Overuse: increasing dosage or taking too often • Discontinuing the drug before scheduled to stop, often because of side effects • Taking the medication with contraindicated compounds (eg, foods, other medications, herbal supplements)

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going to see you for 6 months,” this is often interpreted as, “I don’t need to see you for 6 months,” regardless of any problems with the drug, she said.

Rather, oncology staff should stay in touch with the patient, to ensure that the patient has filled the prescription and the side effects are manageable.

“We need to emphasize the purpose of the drug, and why it may be, in some cases, the most important treatment that the patient is going to be receiving.”

—Lillie D. Shockney, RN, BS, MAS

It is crucial to explain to patients and their families why taking the drug properly is so important. “We need to emphasize the purpose of the drug, and why it may be, in some cases, the most important treatment that the patient is going to be receiving,” she said. “Without this knowledge, we are risking nonadherence.”

Patients need to be given explicit instructions about when to take the medicine, and the potential for specific interactions with other drugs or compounds (Table).

Types of Nonadherence and Common Excuses There are many reasons for and types of nonadherence, including the complexity of treatment instructions, unbearable side effects, lack of understanding the drug’s purpose, treatment fatigue, cost (ie, high copayments), and simple forgetfulness. Nonadherence can happen right away—failing to fill the prescription from the start—or over time, as patients adjust to their illness or tire of the side effects (Table).

“When patients are diagnosed with cancer, initially they are so petrified that they’ll do anything that we tell them to do,” Ms Shockney said. “If I said, ‘You’re going to need a mastectomy,’ a patient might answer, ‘You can take my arm off, too. It’s okay.’

They are frightened they’re going to die. They’ve got that foxhole religion.”

“When the acute treatment is done and we move into chronic care, that foxhole religion has worn off a bit.

Over time, it will wear off even more, and patients will start questioning, ‘Do I really need to take these medicines? I don’t think this cancer’s going to come back,’” and they may discontinue the regimen too soon, she said.

Personal Health Beliefs Drive Behavior Each patient has personal health beliefs, based on various sources. Some patients develop their own theories that may negatively affect adherence, such as a fear of becoming dependent on or addicted to medication. Others may take pride in not taking any medication at all. The occasional patient may even share medication with others, believing that “if it helped me, it will also, in some way, be good for my spouse,” Ms Shockney said.

Cultural and ethnic reasons can underlie the failure to follow through with medication, as can psychological characteristics and personal values and goals.

One of the most common, and understandable, reasons for nonadherence is related to the toxicity of treatment. Referring to some 200 e-mails she receives daily through the Johns Hopkins Breast Center website, Ms Shockney said that patients first write to ask her which of several chemotherapy options will offer the best chance of survival, but later in the treatment journey, patients ask instead which regimens are associated with the least side effects.

“We need to help patients focus on why are they taking this drug, as well as provide them some solutions to the side effects,” Ms Shockney said.

Nonadherence Disguised as “Treatment Failure” “Treatment failure” is often not because of efficacy of a given drug but because the patient is simply not taking the drug. Clinicians often fail to

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at a glance ➤ Medication nonadherence is a common problem even in oncology, and is often misinterpreted as a “treatment failure” rather than the patient is simply not taking the drug ➤ Oral oncolytics are not necessarily easier to handle for patients; providers must ensure the patient has filled the prescription and the side effects are manageable ➤ When test results suggest a drug is not working, providers fail to consider nonadherence and prescribe a new drug ➤ Ask your patients openly about barriers to taking their medications ➤ Make sure your patients understand the importance of adherence; also ask about cost issues consider this possibility, she said.

“When test results suggest a drug is not working, we will assume this drug has failed, and the patient needs a prescription for a different drug. But it may not have anything to do with how well the drug works; rather, it may have to do with whether the patient is taking the medication as prescribed,” Ms Shockney said.

Through a “thoughtful and nonthreatening” conversation with the patient whose disease is progressing, the clinician may uncover nonadherence.

“It was not the drug that failed the patient, but it’s that we failed to help the patient find solutions for dealing with side effects or financial issues.”

Successful Interventions Ms Shockney advised providers to make sure that patients are taking their medications as prescribed, using the following interventions: 1. “Give your patient permission to describe the barriers that prevent him or her from taking the medication as prescribed.” This should occur as part of a “partnership” and not a dictatorial relationship on the part of the provider; “maintaining their medication schedule as prescribed should be a shared goal, Continued on page 40

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3rd Conference

Patient Assistance Programs The ACA will not reduce the demand

By Caroline Helwick Hollywood, FL—“Patient assistance is not an option but a very important part of the fabric of our healthcare system,” said Patrick McKercher, RPh, PhD, President of the Patient Access Network Foundation, at the 3rd Annual Conference of the Association for Value-Based Cancer Care. “While some predict that when the donut hole squeezes shut there will be no need for patient assistance programs, this could not be further from the truth.”

Patient assistance takes a variety of forms, mostly (1) “the free goods” provided by pharmaceutical manufacturers, (2) coupons and vouchers, which provide approximately $6 billion worth of aid, and (3) manufacturer’s copay cards.

The 5 major charitable foundations that provide most of the assistance include the Patient Access Network, the Chronic Disease Fund, HealthWell Foundation, Patient Services, and the Patient Advocate Foundation. The estimated total aid provided through these 5 entities alone is $600 million. Another half dozen or so 501c3 organizations also provide funds, bringing the total patient assistance budget to about $1 billion, Dr McKercher estimated.

The need for patient assistance can also be appreciated by visualizing a typical workday at the Patient Access Network, he said. “We will handle 1000 phone calls in a given day. When people call us, they’re calling for a single purpose: they are looking for help.”

“We’ll pay the cost share on about 1000 claims each business day. We’ll approve about 500 patient grants, worth about $1 million in expenditures,” he said. “And we are relatively small….To indicate how the need is growing, consider that 4 years ago our

patient load was about 13,000. We finished 2012 with 59,000 patients on our books, and we’ll end 2013 with over 100,000 patients.”

“This is a rapidly growing, demanding business,” he noted. “The magnitude of what we do, and the number of patients that we touch, is probably quite a bit more significant than what the average person thinks.”

“Patient assistance is not an option but a very important part of the fabric of our healthcare system….4 years ago our patient load was about 13,000. We finished 2012 with 59,000 patients on our books, and we’ll end 2013 with over 100,000 patients.”

—Patrick McKercher, RPh, PhD Will the ACA Lower the Demand on Patient Assistance Programs?

Patient assistance programs exist for the estimated 50 million Americans who are uninsured or otherwise outside the “entitlement safety net. Many have been paying insurance premiums their whole lives but are underinsured when cancer strikes.” Altogether, many Americans are essentially “above the indigent and below the affordability thresholds,” Dr McKercher said.

Figure

Healthcare Reform Creates New Needs for the Underinsured: >30 Million New Insured to Enter the Market by 2016

■ Exchanges

■ Employer-sponsored

2016 with reform

40

Value-Based Cancer Care

keeping with treatment; for example, a man whose wife is experiencing low libido, vaginal dryness, night sweats, and hot flashes may suggest she stop the cancer-related hormonal therapy, because “he wants their life back on track….That partner should be present for that consultation when you are handing the prescription over. You tell them that they are going to be taking this medicine together, and you talk about some of the solutions for the side effects that can be predicted”

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21

2016 without reform 15

2010 14

■ Medicaid

159

55

162

55

150

44

■ Uninsured 52

35

40

22

52

50

Source: Congressional Budget Office. Cost estimate for the combined effect of H.R. 4872, the Reconciliation Act of 2010 and H.R. 3690, the Patient Protection and Affordable Care Act, March 20, 2010.

The Affordable Care Act (ACA) is not expected to reduce these numbers or lessen the demand for patient assistance, according to Dr McKercher.

“I'm expecting 2 things,” he said.

“While there may be a smaller obligation or smaller liability on the part of the patients, because there are patient premium supports and some subsidies built into the system, there will be a much larger patient population exposed to probably larger copay obligations” (Figure).

He noted that several “preexisting accelerators” will ensure that the need for patient assistance remains unabated, such as the shift to more expensive oral cancer medications, the expanded market in specialty pharmacy, with high out-of-pocket costs; the impact of the new insurance exchange market; and challenges and regulations that will slow the implementation of government out-of-pocket subsidies.

Moving into the era of the ACA, charitable foundations will feel some restrictions, Dr McKercher predicted.

For example, foundations cannot give preferential treatment to any single treatment, healthcare system, or provider and cannot disclose the source of

Addressing Medication Nonadherence... and patients should understand its importance” 2. Providers, perhaps nurses, should work with the patient to develop a reliable method of remembering to take their medications; nurses or navigators may be the staff most able to invest the time and “due diligence” one-on-one with the patient and family 3. Caregivers, including family members, should be included in these conversations to ensure that they also understand the importance of

■ Medicare

funding to the provider or the patient.

He hopes that a positive change, because of increasing need, will be the establishment of standards for patient assistance programs. Duration of aid would be a good place to start, he said.

“It’s cruel to give somebody assistance for 6 months, but have it be exhausted halfway through the patient’s therapy,” Dr McKercher said. His own program seeks to provide aid for the entire treatment duration (or for 12 months), and preferentially uses its funds for treatment renewals. “The only thing that holds us back from guaranteeing renewals is whether or not the funding is going to be there,” he added.

With the persistence of economic barriers, Dr McKercher predicted that a significant population of Americans could, at least theoretically, get “boxed out” of access to progressive therapies.

Numerous studies have documented that about 25% of lower income Medicare beneficiaries abandon therapy because of costs. Under the ACA, the need for cost-sharing will only become greater, as will the continued need for patient assistance programs, Dr McKercher emphasized. n

Continued from page 39

4. Pill organizers can assist patients with adherence, as can smartphone apps that can provide reminders 5. Patient assistance programs can help find solutions to financial issues 6. Problems related to the cost of care need to be brought to light at the start of treatment to avoid treatment gaps because of inability to pay.

Quality of Life and Adherence Oncologists must appreciate the impact of cancer treatment on the patient’s quality of life. “I personally did

my own 5-year tour of duty to prevent my cancer from recurring, and I found it hard, even though I clearly understood why it was important,” Ms Shockney said.

If the quality-of-life issue relates to sexuality and intimacy, patients will seldom broach this topic with their providers. “It behooves you to have someone available who is comfortable discussing this with these patients.

I’ve had discussions I never thought I would have. Patients and spouses value it.” n

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4TH ANNUAL CONFERENCE

MAY 6-9, 2014 LOEWS HOLLYWOOD HOTEL â&#x20AC;˘ LOS ANGELES, CA Government and Employers Co-Chairs Jayson Slotnik, JD, MPH

F. Randy Vogenberg, PhD, RPh

Partner Health Policy Strategies, LLC

Principal Institute for Integrated Healthcare

Personalized Medicine and Payers Co-Chairs Michael Kolodziej, MD

National Medical Director, Oncology Solutions Aetna

Grant Lawless, RPh, MD, FACP Program Director Associate Professor University of Southern California

Oncology Practice Management, Navigation, and Advocacy Co-Chairs Linda Bosserman, MD, FACP

President Wilshire Oncology Medical Group

Vicki Kennedy, LCSW

Vice President, Program Development and Delivery Cancer Support Community

AVBCC Leadership Burt Zweigenhaft, BS President and CEO OncoMed

Gary M. Owens, MD

President Gary Owens Associates

Craig K. Deligdish, MD Hematologist/ Oncologist Oncology Resource Networks

www.AVBCConline.org AVBCC2014chairs Ksize_91313

NEW FOR 2014! Principles in Value and Market Access Educational Session for Product Managers, Reimbursement Specialists, Account Managers, and Marketers focusing on access, reimbursement, proving product value, and international markets.

Personalized Medicine

Genomics of Acute Myeloid Leukemia Explored

By Phoebe Starr

New York, NY—To paraphrase Winston Churchill, “we are at the end of the beginning” of the era of clinical genomics in acute myeloid leukemia (AML), said Richard M. Stone, MD, Clinical Director, Adult Leukemia Program, Dana-Farber Cancer Insti­ tute, Boston, at the 2013 National Comprehensive Cancer Network congress on hematologic malignancies.

Faced with the wealth of information from the recently published genome atlas for AML (Cancer Genome Atlas Research Network. N Engl J Med. 2013;368:2059-2074), oncologists must choose wisely what studies to order for the risk assessment of AML. Dr Stone said that 2 studies should definitely be ordered—FLT3-ITD and CEBP alpha.

It is still not clear whether to assess for the KIT mutation, he noted.

“The publication of the genome atlas for AML is very exciting and an important milestone. We understand the molecular biology to a certain degree. AML has fewer mutations than some other cancers,” Dr Stone said.

A total of 23 mutated genes that fall into 9 categories have been identified in AML. Founder mutations could provide the best target for treatment, because they are present through-

out the disease. Mutations that confer an unfavorable prognosis include the FLT3-ITD and KIT mutations; the NPM1 and CEBP alpha mutations confer a favorable prognosis.

“Right now, I would not recommend deep genomic sequencing for every patient, but the list will change, and then knowing mutations might influence protocols and trial eligibility for patients.”

—Richard M. Stone, MD

“Right now, I would not recommend deep genomic sequencing for every patient, but the list will change, and then knowing mutations might influence protocols and trial eligibility for patients,” Dr Stone said.

Prognostic factors for AML include patient age, cytogenetics, type of AML, tumor burden at diagnosis, and other molecular markers. Adverse molecular markers include FLT3-ITD, and good prognosis markers include CEPB alpha.

Key assessments in the workup include bone marrow aspiration; complete blood count with differential; cytogenetics; and mutational analysis for FLT3-ITD, NPM1, CEBP alpha, and c-KIT (but KIT only because it is cheaper to include it in the mutational analysis), Dr Stone said.

Relapse-free survival depends on 2 genes—combined NPM1 and FLT3ITD. Patients with NPM1-positive and FLT3-ITD–negative have the best prognosis. NPM1-positive patients with FLT3-ITD mutations have worse outcomes.

Older patients with AML have worse outcomes, and it is important to be able to distinguish between those with a bad and a very bad prognosis, Dr Stone said. Perhaps older patients with AML have an intrinsically more difficult biological disease, he suggested.

There are not many options for patients aged <60 years. In younger

patients, those treated with 90-mg daunorubicin (Cerubidine) do better than those who receive the 45-mg dose, if they have non-FLT3 mutations and have lower white blood cell counts at presentation. Younger patients who are chemosensitive can probably benefit from intensified therapy, Dr Stone noted.

The role of allogeneic stem-cell transplant is evolving. It appears to be as good as chemotherapy alone in patients in first remission (CR1).

There is no benefit for allogeneic stem-cell transplant in patients with mutated NPM1 and FLT3-ITD wild type, but in all other cases, allogeneic stem-cell transplant may be superior to high-dose chemotherapy.

Chromosomal findings and genetic findings in AML can be integrated.

AML can be separated into 8 subgroups based on clinical genomics: the favorable group does not need stemcell transplant in CR1.

“Genetic analysis is important at diagnosis for de novo AML—at least for prognosis and choice of post-CR therapy. Mutations may point toward certain clinical trials, and the landscape of important mutations is likely to change with more data,” Dr Stone said. n

Panitumumab-FOLFOX4 Therapy Extends Survival in Patients with CRC without RAS Mutations BRAF mutations are a negative prognostic factor

By Eileen Koutnik-Fotopoulos

T

esting for KRAS mutations is recommended to guide treatment decisions in patients with metastatic colorectal cancer (CRC) by pointing to the patients who would most likely benefit from anti–epidermal growth factor receptor (EGFR) therapies. The KRAS mutation is a predictive biomarker of resistance to anti-EGFR therapy in this patient population. Specifically, patients with KRAS mutations in exon 2 do not benefit from this therapy and may have poor outcomes if an antiEGFR is combined with an oxaliplatin (Eloxatin)-containing chemotherapy regimen. Other activating RAS mutations (KRAS or NRAS) may also be negative predictive biomarkers for anti-EGFR therapy. A team of researchers investigated whether the presence of activating mutations in the KRAS or NRAS genes may further identify

42

patients who would not respond to anti-EGFR therapies (Douillard JY, et al. N Engl J Med. 2013;369:1023-1034).

They conducted a biomarker analysis of the treatment effect of the full spectrum of the currently characterized RAS (ie, KRAS and NRAS) and BRAF mutations, using data from the randomized, phase 3 Panitumumab Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME). In this secondary, exploratory, prospective-retrospective analysis, the safety and efficacy of panitumumab (Vectibix) plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) were compared with FOLFOX4 alone in the first-line treatment of patients with metastatic CRC, according to KRAS exon 2 status.

The primary end point was progression-free survival (PFS). Secondary

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end points included overall survival (OS) and safety.

The study included 1060 patients in whom RAS status could be ascertained—512 patients had tumors with

Panitumumab plus oxaliplatin–containing regimens have no value in patients with RAS mutations. nonmutated RAS, and 548 had tumors with RAS mutations in exons 2, 3, or 4. Among the subgroup of patients without RAS mutations, panitumumab-FOLFOX4 therapy was associated with a significant improvement in PFS compared with FOLFOX4 alone—10.1 months versus 7.9 months, respectively

(P = .004), and the OS was also significantly improved by 5.8 months with the panitumumab-FOLFOX4 regimen compared with FOLFOX4 alone—26.6 months versus 20.2 months, respectively (P = .04).

Shorter Survival in the Absence of Mutation A total of 108 patients (17%) without KRAS mutations in exon 2 had mutations in other RAS exons. In this subgroup of patients, outcomes in the primary analysis and in the exploratory updated analysis of OS showed that PFS and OS were shorter in the group receiving panitumumabFOLFOX4 than in the group receiving FOLFOX4 alone, but the difference was not significant. These findings were consistent with those observed in the subgroup of patients with KRAS mutations in exon 2. In this subgroup,

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Personalized Medicine

Redesigning Clinical Trials Necessary to Enhance Discovery of Effective Targeted Drugs in the Genomic Era

By Wayne Kuznar

Boston, MA—Defining optimal therapeutic efficacy in the genomic era will require that clinical trial design in oncology move from a drug-centric approach to a patient-centric one.

Retrofitting current knowledge into old paradigms will slow the progress in discovering effective targeted agents, said Razelle Kurzrock, MD, Director, Center for Personalized Therapy and Clinical Trials, Moores Cancer Center, University of California, San Diego, at the Global Biomarkers Consortium Second Annual Conference.

Common cancers are comprised of multiple subgroups in which different pathways may be activated. Patients with cancer may have hundreds of different genetic mutations, especially in the metastatic setting. “The individual landscape of a patient is unique,” said Dr Kurzrock.

The uniqueness of each patient with cancer means that each patient requires a specially tailored treatment regimen. In a randomized trial of unselected patients, however, a drug that hits the more common pathway will be declared the superior drug to one that hits a less common pathway. This unselected approach runs the risk of abandoning an effective therapy that works on the less common pathway, Dr Kurzrock said.

Tailored treatment regimens may include drug combinations to hit the multiple targets involved in a patient’s cancer. Conducting clinical trials the traditional way would take a millennium to decipher the optimal drug combination for a cancer, because the

number of 2-drug combinations would approach 45,000, assuming 300 effective oncology drugs, and would exceed 4 million 3-drug combinations.

“We can’t be simplistic enough to just say there’s a mutation in a gene.

We have to know precisely where that mutation occurs.

It may make a big difference in how the disease behaves, and what therapies it will respond to.”

—Razelle Kurzrock, MD

Genomic Profiling: Impact on Outcomes Enriching clinical trial populations for molecular targets is more efficient at finding successful treatments.

Genomic profiling has resulted in superior response rates compared with the traditional clinical trial paradigm in unselected patients.

Before the genomic era, complete response rates obtained with therapies approved for solid tumors based on clinical trial results in unselected patients were typically near 0%, and the

Panitumumab-FOLFOX4 Therapy...

Continued from page 42

PFS in the primary analysis was considerably shorter (7.3 months) in the panitumumab-FOLFOX4 group versus the FOLFOX4-alone group (8.8 months; P = .02).

The incidence rates, types, and severity of adverse events associated with panitumumab-FOLFOX4 in the nonmutated RAS and mutated RAS subgroups were similar to the previously reported safety findings in the PRIME study.

In addition, in the subgroup of patients without RAS and BRAF mutations, a 7.4-month increase in OS was

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seen in the combined regimen of panitumumab plus FOLFOX4. However, as was seen in other trials, BRAF mutations overall were associated with a negative prognosis in these patients, regardless of the treatment regimen.

The study investigators concluded, “Pani­tumumab plus oxaliplatin-containing regimens have no value in patients with metastatic colorectal cancer and mutated RAS,” noting that the benefitrisk profile of the panitumumabFOLFOX4 regimen was improved by excluding patients with CRC associated with RAS mutations. n

survival gains were in the range of 1 to 3 months. In contrast, when phase 2 clinical trials of single agents in the treatment of lung cancer were enriched for patients with putative molecular drug targets, the median response rate improved to 49% versus 9.7% in clinical trials of unselected patients, and overall survival reached 11.3 months versus 7.5 months in trials of unselected patients.

The P13K/AKT/mTOR pathway is activated in a subset of a large number of cancers. In some patients, other pathways, such as the MAP kinase, may also be activated at the same time and may form a resistance pathway.

Many drugs target the P13K/AKT/ mTOR pathway, and others target the resistance pathway. “There are trials in which both pathways are targeted simultaneously by 2 drugs that are matched to target part of each pathway,” said Dr Kurzrock. “Pathways are a different way of looking at cancer rather than organ of origin. We are looking at it by the molecular driver.”

A PIK3CA mutation is evident in 10% of advanced cancers originating in various organs. Approximately 30% of heavily pretreated patients with PIK3CA-mutant gynecologic and breast metastatic malignancies exhibit a partial response when treated with inhibitors of P13K/AKT/mTOR. Patients with the PIK3CA H1047R mutation are more amenable to treatment than patients with other mutations, with a 38% response rate. “We can’t be simplistic enough to just say there’s a mutation in a gene,” Dr Kurzrock said.

“We have to know precisely where that mutation occurs. It may make a big difference in how the disease behaves, and what therapies it will respond to.”

Mutations in PTEN can also activate the PIK3CA pathway. Patients having either of these mutations are much more likely to have the resistance pathway (ie, KRAS, BRAF) also activated, adding another layer of complexity to treatment. “If we target the PIK3CA pathway,…we have to look for mutations in the resistance pathways and give combination therapy to those patients,” Dr Kurzrock said.

The complexity of cancer means that clinical trials of new targeted agents will also have to be smaller to improve the chance of finding effective agents in patients with particular subsets of cancer. Phase 1 cancer trials should be redesigned to include patients with the

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relevant mutations or genetic defects, believes Dr Kurzrock.

Example in Colorectal Cancer FOCUS4 is an integrated clinical trial program of parallel, molecularly stratified randomized comparisons for patients with advanced or metastatic colorectal cancer who are fit for firstline chemotherapy. The trial design exploits a “window of opportunity” to test the clinical efficacy of targeted agents after first-line chemotherapy but before resistance to standard agents oc-

“We want to evaluate multiple treatments and biomarkers in the same protocol. We don’t want to have to write a new protocol every time there’s a new drug or biomarker, because of the delays that brings in.”

—Rob Coleman, MBBS, MD

curs in prespecified biomarker-defined subgroups, explained Rob Coleman, MBBS, MD, Director, Sheffield Cancer Research Centre, United Kingdom.

The program is designed to be “adaptable to new biomarker and clinical data as they proceed,” Dr Coleman said. “We want to evaluate multiple treatments and biomarkers in the same protocol. We don’t want to have to write a new protocol every time there’s a new drug or biomarker, because of the delays that brings in.” Each biomarker and treatment has its own control group.

The goal is to look for early signals of efficacy and also early stopping rules for lack of efficacy. “We’re not looking for small differences with targeted therapy…we’re looking for hazard ratio of 0.4 to 0.6,” said Dr Coleman.

The adaptive design allows for interim analyses to test new hypotheses, biomarker cohorts, and agents after patients are randomized. Select arms of the study can be closed when a conclusion is reached. n

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Drug Update

Revlimid Receives a New Indication for the Treatment of Patients with Relapsed or Progressing Mantle-Cell Lymphoma

By Lisa A. Raedler, PhD, RPh

M

antle-cell lymphoma (MCL), which accounts for approximately 6% of new non– Hodgkin lymphoma diagnoses, is a rare and often aggressive cancer.1,2 MCL is most often diagnosed in older white adults (typically patients are in their mid-60s) and is usually in advanced stages.1,2 Splenomegaly and lymph node enlargement are typically present, in addition to bone marrow, liver, and gastrointestinal tract involvement.2 Although genetic abnormalities (ie, translocations of chromosomes 11 and 14) and the overexpression of cyclin D1 are characteristic of MCL, their

clinical and prognostic implications remain unclear.1,3 A recent analysis of 62 cases of MCL demonstrated that other disease features, particularly blastoid (vs classical) morphology and the presence of TP53 gene mutations, are significantly correlated with poor clinical outcomes.3 MCL is an uncommon diagnosis in the United States. A study using Surveillance, Epidemiology and End Results (SEER) registry data collected between 1992 and 2001 documented an incidence rate of 0.51 per 100,000 person-years.4 In this analysis, patients diagnosed with MCL were more likely to be white and male.4 An

Phase 2 Study Efficacy Results: Lenalidomide in Patients with Table 1

Relapsed/Refractory or Progressing MCL Independent central Investigator assessed Efficacy end point review (N = 134) (N = 134) Overall response rate, % Complete response, % Median duration of response, mo Median time to response, mo

28 7.5 16.6 (95% CI, 7.7-26.7)

32 16 18.5 (95% CI, 12.8-26.7)

2.2

2.0

Median progression-free survival, mo Median overall survival, mo

4 (95% CI, 3.6-5.6)

3.8 (95% CI, 3.5-6.8)

19.0 (95% CI, 12.5-23.9)

19 (95% CI, 12.5-23.9)

CI indicates confidence interval; MCL, mantle-cell lymphoma.

Source: Revlimid (lenalidomide) capsules [prescribing information]; June 2013.

Table 2

Lenalidomide Dose Adjustments for Hematologic Toxicities during Treatment of MCL Lenalidomide dose Toxicity recommendation

Thrombocytopenia When platelets fall to <50,000/mcL

Interrupt lenalidomide treatment and perform CBC tests weekly

When platelets return to ≥50,000/mcL

Neutropenia

Resume lenalidomide at 5 mg less than the previous dose Lenalidomide should not be dosed below 5 mg daily

When neutrophils fall to: Interrupt lenalidomide <1000/mcL for at least 7 days treatment and perform CBC or to <1000/mcL with tests weekly an associated temperature ≥38.5°C or to <500/mcL When neutrophils return to ≥1000/mcL

Resume lenalidomide at 5 mg less than the previous dose Lenalidomide should not be dosed below 5 mg daily

Other grade 3 or 4 Treatment should be held for other grade 3 or 4 toxicities that toxicities are judged to be related to lenalidomide When toxicity has resolved to grade 2 or lower, lenalidomide can be restarted at next lower dose level, at the physician’s discretion CBC indicates complete blood count; MCL, mantle-cell lymphoma.

Source: Revlimid (lenalidomide) capsules [prescribing information]; June 2013.

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8% annual increase in the incidence of MCL was noted during the 10-year time frame over which data were collected, but researchers hypothesized that changes in diagnostic practices explained this trend.4 The clinical course of MCL can be indolent or moderately aggressive at diagnosis. Over time, however, the disease invariably becomes clinically aggressive and refractory to cytotoxic chemotherapy.5 Data reported in 1995 suggest that patients with MCL have the worst long-term survival among patients with all B-cell lymphoma subtypes, with a median survival of approximately 3 years.6 In a more recent series of patients with MCL, this estimate has increased to approximately 5 years, possibly as a result of the use of anthracycline-containing treatment regimens, stem-cell transplantation, advances in supportive care, and the general improvement of life span.7 Although assessments of the cost burden associated with MCL are few, the results of a recent cost-effectiveness analysis that was conducted using US payer data showed that total per-patient costs for patients with MCL exceeded $100,000.8 This study, which compared the combination of bendamustine and rituximab (BR) with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in treatment-naïve patients with MCL, calculated average per-patient costs of $115,191 and $100,261 for BR and R-CHOP, respectively.8 Until recently, bortezomib (Velcade) was the only drug approved by the US Food and Drug Administration (FDA) for the treatment of patients with MCL, specifically those who have received at least 1 previous therapy.9 In clinical practice, combinations of chemotherapy with anti-CD20 monoclonal antibody therapy, high-dose chemotherapy followed by stem-cell transplant, and radioimmunotherapy are viable options for the treatment of patients with MCL.5 Novel options that are being investigated in MCL clinical trials include cytotoxic agents (bendamustine, cladribine); monoclonal antibodies (rituxumab); mTOR inhibitors (temsir­ olimus, which is approved in Europe for MCL); cyclin-dependent kinase inhibitors (flavopiridol); histone deacetylase inhibitors; B-cell leukemia/lymphoma-2 inhibitors; Bruton’s tyrosine kinase inhibitors; and immunotoxins.10

Revlimid a New Treatment Option for Patients with MCL In June 2013, the FDA approved the immunomodulatory agent lenalidomide (Revlimid, Celgene Corporation) for the treatment of patients with MCL whose disease has relapsed or progressed after 2 previous therapies, one of which included bortezomib.11 The approval of lenalidomide for MCL was based on the demonstration of efficacy (overall response rate [ORR] and duration of response) in a phase 2 multicenter clinical trial of 134 heavily pretreated patients with MCL.11 Data from this trial, known as the MCL-001 EMERGE study, were presented at the annual meeting of the American Society of Hematology in December 2012 and were published in September 2013.12,13 In a recent interview regarding his experience in this phase 2 trial of lenalidomide in patients with MCL, Andre Goy, MD, MS, Chairman and Director, and Chief of Lymphoma, John Theurer Cancer Center, Hackensack, NJ, stated, “What was very important was the duration of response….Here, the median duration of response was more than 16 months…regardless of the number of prior therapies; bulky, high tumor load; [and] prior high-dose chemotherapy refractory to the last therapy or refractory to bortezomib.”14 Lenalidomide is also approved for use in combination with dexamethasone in patients with multiple myeloma (MM) who have received at least 1 previous therapy, and in patients with transfusion-dependent anemia resulting from low- or intermediate-1–risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.15 Mechanism of Action As an analog of thalidomide, lenalidomide has immunomodulatory, antiangiogenic, and antineoplastic properties. In vitro, the drug inhibits cell proliferation and induces programmed cell death of specific hematopoietic tumor cells, including MM, MCL, and MDS associated with a deletion 5q abnormality. Lenalidomide also has immunomodulatory properties: it activates T-cells and natural killer cells, increases the number of natural killer T-cells, and inhibits proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, by monocytes.15

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Drug Update

Phase 2 Clinical Trial: MCL-001 EMERGE In the phase 2 multicenter MCL-001 EMERGE trial, Goy and colleagues enrolled 134 patients with MCL who had been treated with multiple therapies, including rituximab, cyclophosphamide, and anthracycline.13 All patients had MCL that had relapsed or had progressed within 12 months of therapy with bortezomib or whose disease was refractory to bortezomib.

Lenalidomide was given as a single agent at a dose of 25 mg daily administered on days 1 to 21 of a 28-day cycle until disease progression, unacceptable toxicity, or voluntary withdrawal.13 The lenalidomide dose was 10 mg once daily for 21 days every 28 days for patients with a creatinine clearance between 30 mL/min and 59 mL/min.15 The primary end points of the MCL-001 EMERGE study were ORR and duration of response.13 Duration of response was defined as the time from initial response to documented disease progression.15 Secondary end points included complete response (CR), progression-free survival, time to progression, overall survival, and safety.13 The efficacy parameters were assessed by investigators, as well as by an independent central review committee.13

Patient Population

The median age of patients enrolled in the phase 2 study of lenalidomide was 67 years.13 The majority of patients in this trial were male (81%) and white (96%), with advanced (stage III/ IV) MCL (93%).13,15 Of these patients, 78% had received 3 or more previous treatments (median, 4; range, 2-10).13

Efficacy

The phase 2 study demonstrated that lenalidomide monotherapy is active and safe in patients with MCL whose disease has relapsed or progressed after bortezomib therapy or whose disease was refractory to bortezomib. According to independent central review, the ORR was 28% (7.5% CR) and the median duration of response was 16.6 months. According to investigators, the ORR was 32% (16% CR) and the median duration of response was 18.5 months. Table 1 includes these data, as well as secondary end point data, from the phase 2 study of lenalidomide.13

Adverse Events

More than half of the patients (58%)

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received 3 or more cycles of lenalidomide in this trial.13 The median duration of therapy was 95 days (range, 1-1002 days) and the average dose of lenalidomide was 20 mg daily.13 Of the patients with MCL, 38% required a dose reduction of lenalidomide.13 The most common grade 3 or 4 adverse events reported in the study were neutropenia (43%), thrombocytopenia (27%), anemia (11%), pneumonia (8%), and fatigue (7%).13 Other adverse events of any grade included tumor flare reaction (10%), deep-vein thrombosis (4%), pulmonary embolism (2%), and invasive second primary malignancies (2%).13,15 A total of 19% of the patients in this study discontinued lenalidomide therapy because of adverse events.13 Dosing and Administration For patients with MCL whose disease relapsed or progressed after bortezomib therapy or was refractory to bortezomib, the recommended dose and schedule for lenalidomide is 25 mg orally once daily on days

“What was very important was the duration of response….Here, the median duration of response was more than 16 months… regardless of the number of prior therapies.”

—Andre Goy, MD, MS

1 to 21 of repeated 28-day cycles.15 Lenalidomide should be taken at approximately the same time each day, either with or without food.15 The FDA approval of lenalidomide for the treatment of patients with MCL also included an approval of a new 20-mg capsule strength of this agent.15 Table 2 summarizes lenalidomide dose modification guidelines for patients with grade 3 or 4 neutropenia or thrombocytopenia, or with other grade 3 or 4 toxicities that are believed to be drug-related.15 Because lenalidomide is primarily excreted unchanged by the kidneys, patients with moderate or severe renal impairment, including patients on dialysis, should receive lower initial starting doses.15 Specific dose recommendations for lenalidomide in pa-

Table 3 Starting Dose Adjustments for Patients with MCL and Renal Impairment Renal impairment level

Creatinine clearance (Cockcroft-Gault)

Lenalidomide adjusted dose

Moderate impairment

30-60 mL/min

10 mg every 24 hrs

Severe impairment

<30 mL/min not requiring dialysis

15 mg every 48 hrs

End-stage renal disease

<30 mL/min requiring dialysis

5 mg once daily On dialysis days, lenalidomide should be administered after dialysis

MCL indicates mantle-cell lymphoma.

Source: Revlimid (lenalidomide) capsules [prescribing information]; June 2013. tients with MCL and renal insufficiency are provided in Table 3.15 Warnings and Precautions

Embryo-Fetal Toxicity

Lenalidomide, a thalidomide analog, should not be used during pregnancy. Thalidomide causes human birth defects and embryo-fetal death.

Pregnancy must be excluded before the start of lenalidomide treatment and must be prevented during treatment by the use of 2 reliable contraception methods. Because the blood may be given to a pregnant female patient whose fetus must not be exposed to lenalidomide, patients taking lenalidomide must not donate blood during treatment and for 1 month after discontinuation of the drug.

Given this embryo-fetal risk, access to lenalidomide is restricted under a Risk Evaluation and Mitigation Strategy (REMS) program, known as the Revlimid REMS program.15

Hematologic Toxicity

In the phase 2 trial of lenalidomide in MCL, grade 3 or 4 neutropenia and grade 3 or 4 thrombocytopenia were reported in 43% and 28% of patients, respectively.13 Patients with MCL who take lenalidomide should have their complete blood count (CBC) monitored.15 CBC tests are recommended weekly for the first cycle (28 days), every 2 weeks during cycles 2 to 4, and then monthly while receiving lenalidomide therapy.15

Venous Thromboembolism

Some patients with MCL who received lenalidomide experienced venous thromboembolic events, typically deep venous thrombosis and pulmonary embolism.15 It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with lenalidomide can minimize the risk of venous thromboembolism.15

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Allergic Reactions

Lenalidomide has been associated with angioedema and serious dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Such reactions can be fatal. Physicians should consider interruption or discontinuation of lenalidomide for grade 2 to 3 skin reactions. Lenalidomide must be permanently discontinued if angioedema, grade 4 rash, exfoliative or bullous rash occur, or if Stevens-Johnson syndrome occurs or toxic epidermal necrolysis is suspected. Lenalidomide should not be given to any patient who experienced a grade 4 rash while receiving thalidomide.15

Tumor Lysis Syndrome

Fatalities secondary to tumor lysis syndrome have been documented in patients taking lenalidomide.

Because patients with high tumor burden before treatment are at risk for tumor lysis syndrome, healthcare professionals should monitor these patients closely and take appropriate precautions.15

Tumor Flare Reaction

Patients with MCL taking lenalidomide should be monitored for tumor flare reaction, which is characterized by lymph node swelling, low-grade fever, pain, and rash.15 Of patients in the MCL trial, 10% experienced grade 1 or grade 2 tumor flare reaction in the first cycle of lenalidomide treatment.13 One of these patients developed tumor flare reaction again in cycle 11.13 If grades 1 and 2 tumor flare reaction occur, lenalidomide can be continued without interruption or modification, at the physician’s discretion.15 Corticosteroids, nonsteroidal anti-inflammatory drugs, and/ or narcotic analgesics can be used for symptom management.15 Patients who experience more severe tumor

Continued on page 46

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Emerging Therapies

Idelalisib and Ibrutinib 2 Promising B-Cell Receptor– Signaling Inhibitors for B-Cell Malignancies Both oral therapies currently under review by the FDA

By Phoebe Starr New York, NY—Targeted therapy to the B-cell receptor signaling is paying off in chronic lymphocytic leukemia (CLL) and in other B-cell lymphomas. Two novel oral agents—the PI3K inhibitor idelalisib and the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib—show great promise for these malignancies. These drugs have been studied in phase 3 trials, and current studies are focusing on combination strategies and new schedules to improve outcomes. In addition, both drugs have recently been submitted for review by the US Food and Drug Administration (FDA).

“These drugs are breakthrough drugs” in the treatment of B-cell malignancies, said Jeffrey Jones, MD, MPH, Assistant Professor of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, at the National Comprehensive Cancer Network congress on hematologic malignancies. The FDA has designated each of these drugs as a “breakthrough drug” earlier this year.

The B-cell receptor is present on the surface of normal cells and cancer cells. Abnormal B-cell receptor signaling is implicated in B-cell malignancies, promoting leukemia-cell

survival and proliferation. Therefore, B-cell receptor signaling has become a therapeutic target for new therapies in development.

PI3K Inhibitors The oral PI3K inhibitor idelalisib achieves rapid regression in lymph node volume, accompanied by a concomitant rise in absolute lymphocyte count. Many patients treated with the drug do not achieve complete response, because of the rise in absolute lymphocyte count and lymphocytosis.

The toxicity profile is good, with relatively little grade 3 and 4 toxicity, with the exception of pneumonitis (in approximately 24% of patients) and neutropenia (in approximately 18%) reported in clinical trials. Hematologic toxicity is easily managed.

Combination strategies are being studied to improve response rates in relapsed and/or refractory CLL, relapsed non-Hodgkin lymphoma (NHL), and mantle-cell lymphoma (MCL). Also, idelalisib is currently being studied in combination with rituximab (Rituxan) for the treatment of patients with CLL. On September 11, 2013, Gilead Sciences (the drug manufacturer)

submitted a New Drug Application (NDA) to the FDA for idelalisib for the treatment of patients with indolent NHL based on the results of a phase 2 clinical trial in this setting in patients with indolent NHL that is refractory to alkylating-agent-containing chemotherapy and to rituximab.

A second PI3K inhibitor—IPI-145— is less well studied. The drug has achieved excellent responses in indolent lymphomas and NHL. The major toxicity is risk of pneumocystic pneumonia, suggesting that patients should receive prophylaxis.

Approval of idelalisib is expected shortly, and IPI-145 is about to enter phase 3 testing.

BTK Inhibitors The majority of the clinical data on BTK inhibitors, which also have a role in B-cell receptor signaling, are related to ibrutinib. In CLL, response rates were high—68% in treatment-naïve patients and 71% in highrisk patients with relapsed and/or refractory disease, based on recently published results (Byrd JC, et al. N Engl J Med. 2013;369:32-42).

Ibrutinib achieves excellent responses even in patients with high-risk cy-

togenetics, such as chromosome deletions of 17p/13.1 and deletions of 11q/22.r. Stable remission has been achieved in patients with these genetic abnormalities.

Ibrutinib causes mainly mild adverse events, such as diarrhea, nausea, and fatigue.

In addition, ibrutinib combined with rituximab achieves a marked reduction in lymphocytosis in previously untreated high-risk CLL or small-cell leukemia (SCL). However, longer-term follow-up is needed to determine the value of this strategy.

Higher doses of ibrutinib achieve overall response rates of more than 70% in patients with MCL, and the response continues to improve with longer treatment. Ibrutinib is also being studied in combination with the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen in large-cell lymphoma.

On August 27, 2013, the FDA accepted the NDA submitted by Pharmacyclics (the drug manufacturer) for ibrutinib for 2 indications in B-cell malignancies—CLL and SCL. Studies of the oral BTK inhibitor CC-292 BTK have not been as promising as those of ibrutinib. n

Drug Update

Revlimid Receives a New Indication... flare reaction (grade 3 or 4) should not receive lenalidomide treatment until the TFR resolves to grade 1 or less.15

Second Primary Malignancies

Patients taking lenalidomide should be monitored for the development of second malignancies.15 In the MCL trial, 3 patients (2%) developed invasive second primary malignancies.13 Conclusion Lenalidomide, the first oral drug approved for the treatment of patients with MCL, has demonstrated efficacy with manageable toxicities in heavily pretreated patients whose disease has relapsed or progressed after bortezomib or is refractory to bortezomib. Lenalidomide joins bor-

46

tezomib as the only 2 FDA-approved agents currently available for this rare and often aggressive form of B-cell lymphoma. Because it is not cytotoxic, lenalidomide may offer clinical value when combined with other treatments for MCL. Current clinical trials are evaluating the use of lenalidomide in combination with rituximab, bendamustine, and/or bortezomib in patients with MCL for use as first- or second-line treatment.16 n References

1. Leukemia and Lymphoma Society. Mantle cell lymphoma facts. Revised July 2012. www.lls.org/ content/nationalcontent/resourcecenter/freeeduca tionmaterials/lymphoma/pdf/mantlecelllymphoma. pdf. Accessed July 30, 2013.

2. National Cancer Institute. Mantle cell lymphoma: disease information. 2010 Hematopoietic and Lymphoid Database. Updated February 5, 2013. http://seer.cancer.gov/seertools/hemelymph/

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2010/. Accessed July 30, 2013.

3. Slotta-Huspenina J, Koch I, de Leval L, et al. The impact of cyclin D1 mRNA isoforms, morphology and p53 in mantle cell lymphoma: p53 alterations and blastoid morphology are strong predictors of a high proliferation index. Haematologica. 2012;97:1422-1430.

4. Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006;107:265-276.

5. Ghielmini M, Zucca E. How I treat mantle cell lymphoma. Blood. 2009;114:1469-1476.

6. Zucca E, Roggero E, Pinotti G, et al. Patterns of survival in mantle cell lymphoma. Ann Oncol.

1995;6:257-262.

7. Herrmann A, Hoster E, Zwingers T, et al.

Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27:511-518.

8. Su W, Quon P, Whalen J, et al. Cost-effectiveness analysis of bendamustine plus rituximab versus CHOP-R in treatment-naive patients with mantle cell (MCL) and indolent lymphomas (IL). J Clin Oncol.

2012;30(suppl). Abstract 6553.

9. US Food and Drug Administration. FDA ap­ proves bortezomib (Velcade) for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy. Updated May 21, 2009. www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CDER/ucm09 4929.htm. Accessed September 17, 2013.

10. Goy A, Kahl B. Mantle cell lymphoma: the promise of new treatment options. Crit Rev Oncol Hematol.

2011;80:69-86.

11. US Food and Drug Administration. Drugs: lenalidomide. Updated June 5, 2013. www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm355438. htm. Accessed September 18, 2013.

12. Goy A, Sinha R, Williams ME, et al. Phase II multicenter study of single-agent lenalidomide in subjects with mantle cell lymphoma who relapsed or progressed after or were refractory to bortezomib: the MCL-001 “EMERGE” study. Presented at the American Society of Hematology annual meeting; December 8-11, 2012; Atlanta, GA. 13. Goy A, Sinha R, Williams ME, et al. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study.

J Clin Oncol. 2013 Sep 3. Epub ahead of print.

14. OncLiveTV. Dr. Goy on lenalidomide for mantle cell lymphoma. YouTube. June 10, 2013. www.youtube. com/watch?v=l-oV-Y6OvBE. Accessed July 30, 2013.

15. Revlimid (lenalidomide) capsules [prescribing information]. Summit, NJ: Celgene Corporation; June 2013.

16. ClinicalTrials.gov. Lenalidomide mantle cell lymphoma. Search results. http://clinicaltrials.gov/ ct2/results?term=lenalidomide+mantle+cell+lym phoma&Search=Search. Accessed September 18, 2013.

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