VBCC July 2013

JUly 2013 VOL 4 NO 6

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

Nearly 1 in 5 Patients with Cancer Reports Financial Distress

Cancer Rehabilitation: The Next Frontier in the Care Continuum

By Caroline Helwick

But most don’t discuss cost with their oncologist

By Audrey Andrews Chicago, IL—Financial distress is prevalent among insured patients with cancer, and although most patients state a desire to talk to their physicians about costs, this discussion rarely occurs, according to a study conducted at Duke University Medical Center, Durham, NC. Of the 300 insured patients with cancer included in this study, 17%

reported “high” or “overwhelming” financial distress, and only 25% of this group discussed costs with their physicians.

“Financial distress increases the burden of living with cancer. Even insured patients may experience considerable financial distress, but little has been known about whether patients want Continued on page 6

How Employers Are Adapting to the New Landscape in Healthcare Hollywood, FL—Cancer rehabilitation is “the next frontier” in survivorship care, according to Julie K. Silver, MD, Assistant Professor of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA. Dr Silver is the author of numerous books, including After Cancer Treatment: Heal Faster, Better, Stronger, & What Helped Get Me Through: Continued on page 12

Personalized Medicine

Two Genetic Tests Can Prevent Overtreatment of Early Prostate Cancer

By Phoebe Starr

©2013 Engage Healthcare Communications, LLC

Peter Hayes

By Caroline Helwick Hollywood, FL—With the new landscape of healthcare delivery yet to come into sharp focus, employers are living in “the land of confusion,” wondering how they will conform to new requirements, meet the expectations of

their employees, and remain profitable, said Peter Hayes, Principal, Healthcare Solutions, Duluth, GA, at the Third Annual Conference of the Association for Value-Based Cancer Care.

Continued on page 11

inside

Oncotype DX prostate cancer and Prolaris will compete for market share Chicago, IL—The management of patients with prostate cancer will be advanced by 2 new genetic tests— Oncotype DX prostate cancer test and Prolaris. Both tests generate a score that can be used to analyze biopsy specimens of men with low-risk prostate cancer (ie, Gleason score ≤6) to

The “value disconnect” in the current employerbased insurance benefits

determine if they are truly “low risk” and appropriate for watchful waiting, or if they harbor higher-risk genes and need immediate treatment.

These tests, although expensive, have the potential to prevent overtreatment and the associated costs,

Continued on page 35

VALUE PROPOSITIONS . . . . . . . . 4 Quality measures tied to reimbursement

HEALTH POLICY . . . . . . . . . . . . . . 34 Supreme Court ruling on gene patents

5

PROSTATE CANCER . . . . . . . . . . . 36 Strong testosterone suppression during ADT prolongs survival Prostatic inflammation protects against prostate cancer

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

Consolidation in cancer care delivery system

ECONOMICS OF CANCER CARE . . . . 6 Off-label oncology drug use accounts for 18% of spending Can we afford to make progress in cancer care?

CONFERENCE . . . . . . . . . . . 11 CVS Caremark value proposition Healthcare reform and end-of-life care

DRUG SHORTAGES . . . . . . . . . . . . . 38 The leucovorin shortage: similar isomers, huge cost differences DRUG UPDATE . . . . . . . . . . . . . . . 40 Xofigo approved for CRPC with symptomatic bone metastases

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In This Issue 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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VALUE PROPOSITIONS

FDA UPDATE

Value of genetic research for drug development More….

Gilotrif approved for metastatic lung cancer More….

FROM THE EDITOR

PATIENT NAVIGATION

Consolidation in cancer care delivery system: the impact on quality and cost

Patient navigators improve colonoscopy rates, save money

ECONOMICS OF CANCER CARE

HEALTH POLICY

Nearly 1 in 5 patients with cancer reports financial distress Off-label drug use in oncology accounts for 18% of spending Can we afford to make progress in oncology?

More….

Supreme Court ruling on patenting genes: implications for oncology

3RD CONFERENCE Cancer rehabilitation: the next frontier in the care continuum CVS Caremark value proposition for oncology pharmacy Healthcare reform and end-of-life care More….

PERSONALIZED MEDICINE Two genetic tests can prevent overtreatment of early prostate cancer More….

DRUG SHORTAGES PERSPECTIVE The leucovorin shortage conundrum

DRUG UPDATE Xofigo approved for castration-resistant prostate cancer with symptomatic bone metastases

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 Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, New York, NY

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

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

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.

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VALUE PROPOSITIONS Value of Genetic Research for Drug Development: 2 Genes Identify Who Will Benefit from Breast Cancer Prophylaxis

A new study supported by the National Institutes of Health Pharmacogenomics Research Network represents a step forward toward personalized medicine in breast cancer prevention among women who are at high risk for the disease.

“Our study reveals the first known genetic factors that can help predict which high-risk women should be offered breast cancer prevention treatment and which women should be spared any unnecessary expense and risk from taking these medications,” said lead researcher James N. Ingle, MD, Professor of Oncology, Mayo Clinic, Rochester, MN. “We also discovered new information about how the drugs tamoxifen and raloxifene work to prevent breast cancer.”

Dr Ingle and colleagues analyzed genomic data from previous trials that included more than 33,000 women at high risk for breast cancer, investigating the more than 500,000 single nucleotide polymorphism (SNP) genetic markers. Of these SNPs, 2 genes were identified—ZNF423 and CTSO—which occurred more frequently in women who developed breast cancer during the trial than in the women who did not develop breast cancer.

This is the first time that the involvement of the ZNF423 and CTSO genes has been demonstrated in breast cancer. Women with either of these 2 genes were 5.7 times less likely to develop breast cancer while receiving preventive therapy with tamoxifen or raloxifene than women who did not have these genes.

“The results of our collaborative research bring us a major step toward the goal of truly individualized prevention of breast cancer,” Dr Ingle said.

“Our findings also underscore the value of studying the influence of gene variations on drug responses.” National Institutes of Health; June 13, 2013

Quality Measures Are Increasingly Tied to Physician Reimbursement

Quality measures and patient satisfaction are increasingly being tied to a proportion of physicians’ reimbursement, according to a new report from the Medical Group Management Association-American College of Medical Practice Executives (MGMA-ACMPE), “Physician Compensation and Production Survey: 2013 Report Based on 2012 Data.”

Although the percentages are still small, this trend will likely increase with time. “Quality and patient satisfaction metrics are not yet dominant components of physician compensation plans right now; however, as reimbursement models continue to shift, the small changes we’ve observed recently will gain momentum,” said Susan L. Turney, MD, MS, FACMPE, FACP, MGMA-ACMPE President and CEO. “It’s encouraging to see physician practices invested in patient-centered care and continuing to seek ways to better incorporate quality and experience into compensation methodologies.”

According to the survey, 3% of the total compensation of primary care physicians was based on quality measures compared with 2% for specialists, including oncologists. This is the first time that quality metrics are being captured by a large national survey such as the MGMA-ACMPE survey. Patient satisfaction also played a small role in physicians’ reimbursement, representing the increasing role of patient-centered care.

The median compensation for physicians clearly fluctuates by specialty.

The median compensation for primary care physicians was $216,462 compared with a median of $388,199 for specialists. MGMA-ACMPE; June 12, 2013

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Senate Bill Designates $251.9 Million for Electronic Health Records for the VA System

The new US Senate bill for the Veterans Affairs (VA) system provides $3.7 billion for the VA System information technology, which includes $251.9 million for an integrated electronic health record system and $119.4 million for the Veterans Benefits Management System claims systems.

In addition, the bill appropriates $7.6 billion for long-term care for veterans. The funding covers both home-based long-term care and institutional care programs. The bill also provides an additional $85 million for grants for the construction of state extended-care facilities for veterans. US Senate Committee on Appropriations; June 18, 2013

The Promise of Immunotherapy in the Race to Cure Cancer

Many presentations at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) focused on new research involving immunotherapy, including drugs for melanoma and lung cancer that have shown great success in prolonging life in patients with advanced disease. The number of immunotherapy drugs in development is growing, using different antibody mechanisms to identify and destroy cancer cells.

In an interview with Bloomberg News before the ASCO meeting, several oncologists and drug manufacturers expressed their excitement about these new developments. If the new generation of drugs using the body’s immune system to identify cancer cells lives up to its promise, “this is going to be a paradigm shift for treating cancer,” said D. Gary Gilliland, MD, PhD, Senior Vice President at Merck. “We are pretty good at shrinking tumors, but not good at getting rid of them. Immune therapy is a way to begin to approach that.”

Jedd D. Wolchok, MD, PhD, Director of Immunotherapy at the Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, said, “A couple of years ago, the big story was that immunotherapy can work.

Now immunotherapy has entered the mainstream.”

Oncologists “are accustomed to moving from one therapy to another as tumors rapidly develop resistance,” said Michael S. Gordon, MD, President and CEO of Pinnacle Oncology Hematology, Scottsdale, AZ. “It is generating tremendous excitement to have a drug class that might well be able to provide long-term control of metastatic cancer.” Bloomberg News; May 13, 2013

Researchers Discover a Set of Proteins that Cause Many Cancer-Related Mutations

A new study led by researchers at the National Institutes of Health shows that a set of proteins in the body produces a large number of mutations in human DNA, indicating that these naturally produced mutations are just as powerful as cancer-causing agents in producing tumors. The proteins are part of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) cytidine deaminases. The APOBEC mutations can outnumber all other mutations in some cancers. “The presence of APOBEC clusters in the genome of tumor cells indicates that APOBEC enzymes could also have caused many mutations across the genome,” said Dmitry Gordenin, PhD, Associate Scientist at the National Institute of Environmental Health. It remains to be seen how this new discovery will be translated into drug development. National Institutes of Health; July 14, 2013

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From The Editor

Consolidation in Cancer Care Delivery System: The Impact on Quality and Cost

By Craig Deligdish, MD

Chief Medical Officer, Oncology Resource Networks, and Editor-in-Chief, Value-Based Cancer Care

T

he past several years have seen significant consolidation in the healthcare industry. The cost of healthcare in the United States is currently estimated to be 18% of the gross domestic product (GDP), and the costs are projected to increase disproportionately to the GDP during the next decade.1 Healthcare reform has accelerated consolidation and will likely continue to drive consolidation in many markets across the country.

Although some believe that the key to improving quality and reducing costs is an integrated healthcare system that can drive efficiency, there are many examples that have not borne this out. Consolidation in healthcare has a tremendous potential to improve patient care, but studies have demonstrated that it can also significantly increase the cost of care in concentrated markets.2 In many markets across the country, hospitals have been buying physician practices to create such integrated systems, which has resulted in nearly 60% of US physicians being employed by hospitals in 2013.3 These systems frequently allow better sharing of information, with the hope that there can be better coordination of care.

The risk of consolidation, however, is that hospitals can now charge higher prices for the same services that were provided in the community. More important, some monopolies in very concentrated markets have resulted in dramatic price increases in such markets, as has been reported by large insurance companies.4 In the past 5 years, the US Department of Justice and the Federal Trade Commission have challenged and sought enforcement actions in communities where healthcare monopolies have either engaged in anticompetitive conduct or where proposed mergers were thought to be anticompetitive and could have negatively impacted consumers and competitors.

Nearly 10 years ago, Gaynor and Town published their assessment of the impact of consolidation in highly concentrated hospital markets, which they have recently updated.2 They concluded that hospital consolidation in highly concentrated markets generally results in higher prices, but not always in higher quality and innovation. In addition, they showed that physician–hospital consolidation

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In many markets across the country, hospitals have been buying physician practices to create such integrated systems, which has resulted in nearly 60% of US physicians being employed by hospitals in 2013.

has not led to improved quality or reduced costs. Their review of several studies showed that when consolidation was for the purpose of enhanced bargaining power with payers and did not lead to integration, overall performance did not improve.2 It is clear that the primary driver of costs in healthcare is price rather than utilization. Despite the growing concern and focus on utilization of healthcare at the end of life, especially in patients with cancer, it is the overall unit cost of care that results in the high overall costs of healthcare that are seen in this country and has had a significantly greater impact on the overall cost of healthcare rather than on utilization.

During the past several years, the United States has also experienced consolidation in the community cancer care delivery system. Although the reasons for this consolidation are in some cases similar to those seen in the general physician practices, several unique factors have driven oncologists to consolidate into larger groups or to join hospitals. These factors include reduced reimbursement for chemotherapy and supportive care agents in the community setting and

an increase in practice-related costs.

Hospital systems can at times provide enhanced revenue from 340B pricing on chemotherapy drugs and can participate in additional revenue streams, such as radiation therapy and other ancillary services. Greater bargaining power, increased compensation, the ability to participate in clinical research, and the potential for enhanced stability in uncertain times can offset the independence and autonomy of the traditional practice setting.

A recently updated report from the Community Oncology Alliance shows that in the past 15 months, there was a 20% increase in oncology clinics that had closed compared with their previous study and a 20% increase in practices that made an agreement with a hospital to be purchased.5 In addition, 288 clinic sites had closed, 407 practices were struggling financially, and 469 practices had entered into contractual relationships or had been acquired by a hospital during the past 6 years.5 The Community Oncology Alliance in collaboration with the US Oncology Network and ION Solutions commissioned a study by the Moran Company confirming the shift in the site of service from the physician office setting to the hospital setting.6

Private and public payers, including state and federal entities, need to continue to explore payment approaches that reward quality and value, while more effectively supporting and rewarding community practice models that provide costeffective care.

This analysis showed that the share of fee-for-service (FFS) chemotherapy administration procedures increased from 13.5% in 2005 to 33% to 2011.

However, Medicare FFS payments in the hospital outpatient department for chemotherapy administration tripled during the same period.6 Previous studies by Milliman and Avalere have shown increased costs in commercial populations when chemotherapy is

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administered in the hospital outpatient department compared with a physician office setting.7,8 These findings are of concern, given that they suggest a trend of increasing cost and that quality and innovation will be reduced as cancer care moves back into the hospital. Despite discussions about reforming the payment system for medical oncology, hospitals in very concentrated markets are under little pressure to explore innovative approaches to payment methods. Payers who negotiate with large hospital systems often do not focus on the cost of cancer treatment, because of its limited contribution to the overall cost of hospital care in communities where a hospital has a dominant market position.

The payer community will be increasingly challenged to address these issues as a growing component of cancer care is being delivered in the hospital setting. Private and public payers, including state and federal entities, need to continue to explore payment approaches that reward quality and value, while more effectively supporting and rewarding community practice models that provide cost-effective care. n References

1. Congress of the United States Congressional Budget Office. The 2012 Long-Term Budget Outlook. www.cbo.gov/sites/default/files/cbofiles/attachments/06-05-Long-Term_Budget_ Outlook.pdf. Accessed July 10, 2013.

2. Gaynor M, Town R. The impact of hospital consolidation—update. June 2012. www.rwjf.org/ content/dam/farm/reports/issue_briefs/2012/ rwjf73261. Accessed July 10, 2013.

3. Accenture. Clinical transformation: new business models for a new era in healthcare. Physician alignment survey. 2012. www.accenture.com/ SiteCollectionDocuments/PDF/AccentureClinical-Transformation-New-Business-Modelsfor-a-New-Era-in-Healthcare.pdf#zoom=50.

Accessed July 9, 2012.

4. Hyman DA, Kovacic WE. Monopoly, monopsony, and market definition: an antitrust perspective on market concentration among health insurers.

Health Aff (Millwood). 2004;23:25-28.

5. Community Oncology Alliance. Community Oncology Practice Impact Report: the Changing Landscape of Cancer Care. June 25, 2013. http:// glacialblog.com/userfiles/76/Community_ Oncology_Practice_Impact_Report_6-25-13F(1). pdf. Accessed July 10, 2013.

6. The Moran Company. Results of analyses for chemotherapy administration utili­zation and chemotherapy drug utilization, 2005-2011 for Medicare fee-for-service beneficiaries. May 29, 2013. https:// media.gractions.com/E5820F8C11F80915AE699A 1BD4FA0948B6285786/01655fe9-7f3d-4d9a-80d0d2f9581673a1.pdf. Accessed July 10, 2013.

7. Milliman. Site of service cost differences for Medicare patients receiving chemotherapy.

October 19, 2011. http://publications.milliman. com/publications/health-published/pdfs/ site-of-service-cost-differences.pdf. Accessed July 10, 2013.

8. Avalere Health. Total cost of cancer care by site of service: physician office vs outpatient hospital.

March 2012. www.avalerehealth.net/news/201204-03_COA/Cost_of_Care.pdf. Accessed July 10, 2013.

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Economics of Cancer Care

ASCO President Highlights Bridges to Conquer Cancer

By Wayne Kuznar

Disparity in Access to Care Gaps in connecting proven treatments and preventive measures with underserved populations are linked to increased mortality from cancer and more suffering as a result of later disease stages at initial presentation.

These gaps occur in various parts of the United States, and not just in lowand middle-income countries, said Dr Swain. The 48 million uninsured Americans—and those joining the Medicaid rolls—are all part of this picture. One area of concern is the wide variability in Medicaid programs.

“On the plus side, a recent study showed that in states where Medicaid

programs have been expanded to cover more individuals, there has been a reduction in overall mortality,” she said. “While this is an encouraging sign for the general population,

Photo by © ASCO/Silas Crews 2013

Chicago, IL—“Building Bridges to Conquer Cancer” was the theme of the 2013 American Society of Clinical Oncology (ASCO) annual meeting, as well as of the address of ASCO’s outgoing President Sandra M. Swain, MD. Dr Swain’s address focused on 3 pillars of the theme: (1) ensuring global health equity, (2) the need to strengthen future generations of leaders and providers, and (3) the vision for a rapid learning system in oncology.

These 3 issues “belong squarely on our personal and professional radar screens,” she said.

“Not only did the program help patients avoid the pain and suffering associated with aggressive treatment of late-stage illness, it saved millions of dollars in treatment costs.”

—Sandra M. Swain, MD

cancer-specific outcomes for patients covered by Medicaid have been associated with no better outcomes than for those who are uninsured.”

A key predictor of whether an adult will survive cancer is income. This out-

come gap is largely a result of differences in access to care. One innovative effort to bridge equity gaps is a screening program for colon cancer that is available to every citizen in Delaware.

The program’s success is exemplified by screening rates in blacks, which rose from 48% to 74%. The number of blacks presenting with regional and distant colorectal cancer was reduced by 39%. The decline in mortality rates for blacks was 42%, bringing it closer to that of whites.

“Not only did the program help patients avoid the pain and suffering associated with aggressive treatment of latestage illness, it saved millions of dollars in treatment costs,” said Dr Swain.

Although advances in vaccines and screening large populations for breast cancer and cervical cancer have been made, many of these methods are not available globally. And even if the cancer is diagnosed, there are wide gaps in the availability of affordable treatments.

In response to the global cancer crisis, ASCO has started a program called ASCO International, which aims to increase support for existing programs and to invest in new programs aimed at global cancer control. One important strategy will be to use digital resources

(ie, virtual meetings and mentoring) “to knit the world closer together.”

Supporting the Next Generation of Leaders and Providers Supporting the next generation of clinical cancer researchers is a priority, said Dr Swain. Although 98% of past winners of ASCO’s Young Investigator Award and Career Development Award programs are still involved in cancer research, donations to support the program are declining, an unwelcome occurrence at a time when federal research dollars are dwindling.

ASCO is continuing its successful and popular Leadership Development Program in an effort to develop the next generation of leaders, but potential shortfalls in practicing oncologists are a concern. “Will we be able to meet the projected increase in cancer cases? To better understand and monitor these trends, ASCO has established a workforce information system,” she said.

The number of oncologists aged ≥64 years is growing rapidly, and outnumbers those aged <40 years. Furthermore, only 3% of oncology fellows are black and 8% are Hispanic. To address disparities in which populations receive access to cancer care, a diverse professional workforce is necessary. n

Nearly 1 in 5 Patients with Cancer Reports Financial... to include cost discussions in treatment decision-making,” said S. Yousuf Zafar, MD, MHS, Assistant Professor, Division of Medical Oncology, De­ partment of Internal Medicine, Duke University Medical Center, who presented the study results at the 2013 American Society of Clinical Oncology annual meeting.

Nearly 50% of patients with cancer dip into their savings to pay for cancer treatment, according to other research

by Dr Zafar and colleagues (Oncologist.

2013;18:381-390). Other researchers have shown that patients with a cancer diagnosis are 2.6 times more likely to file for bankruptcy than patients without cancer (Ramsey S, et al. Health Aff [Millwood]. 2013;32:1143-1152).

The researchers conducted a crosssectional study of 300 insured adults who were treated for at least 1 month for solid tumors. Participants were surveyed in person and were asked about financial distress (via a validated 10-point scale), out-of-pocket costs, discussions about costs with their doctor, and about decision-making.

6

“We wanted to answer 3 questions,” Dr Zafar said. “Do patients want to discuss costs? Do they want cost to be included in treatment decision-making? And, if these discussions occur, do they result in decreased costs?”

The patients’ mean age was 60 years; 53% were male, 72% had at least a high school education, and 66% were married. The median household income was $60,000. Of the patients, 55% had private insurance and 36% had Medicare.

Colorectal cancer was the most common diagnosis, followed by breast, lung, and pancreaticobiliary cancers; 78% of patients had advanced disease.

A Lot of Stress, Little Conversation High or overwhelming financial distress was reported by 17% of patients.

Approximately 50% of all respondents expressed a desire to talk about cost with their oncologist, but only 19% actually engaged in a cost discussion. Of the 17% of patients with the highest financial distress, only 25% had these discussions. “We found a ‘disconnect’ between a desire to talk

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about cost and actual­ ly having this discussion,” Dr Zafar observed.

“We found a ‘disconnect’ between a desire to talk about cost and actual­ly having this discussion.”

—S. Yousuf Zafar, MD, MHS

Barriers to Cost Discussions The investigators explored the barriers to discussions about cost, and found that 50% of patients did not talk about cost because they had “no difficulties” with cost, approximately 35% hesitated because they wanted “the best care,” and 20% said that cost was “not my doctor’s job,” or “my doctor can’t help.” Overall, 10% of patients reported that they had talked to someone other than their physician about cost, and 10% said they were

Continued from cover

“embarrassed” to bring up the topic.

“The fact that many patients said they wanted the best care, regardless of cost, carries the implication that patients link cost to quality, and if they broach the topic of cost, they may receive lesser quality care,” Dr Zafar suggested.

The cohort was evenly split regarding their desire to include cost in decision-making; 21% wanted to “always take cost into account.” Of the 19% of patients who reported having cost discussions with their oncologist, 57% said these discussions resulted in decreased expenses for them.

In an exploratory analysis of the study, white race and a high level of distress were significantly associated with the likelihood of discussing costs.

The majority of patients who actually have cost discussions find them helpful, which indicates that there are “false barriers” to these discussions, Dr Zafar said. “We need to at least identify patients at greatest risk for financial distress. We may not have all the answers, but broaching the topic can go a long way.” n

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

Connecting your patients who are prescribed Jakafi® (ruxolitinib), and who are eligible for the program, to ongoing support and resources during their treatment ACCESS AND REIMBURSEMENT SERVICES

•Benefit verification •Prior authorization •Appeal support •Co-pay assistance

• Free medication program • 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 • 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. Jakafi is a registered trademark of Incyte Corporation. © 2013, Incyte Corporation. All rights reserved. RUX-1227d 05/13

Economics of Cancer Care

Off-Label Drug Use in Oncology Accounts for 18% of Spending Mean number of claims for unapproved indications averages 11 per patient

By Caroline Helwick Chicago, IL—An examination of the Surveillance, Epidemiology and End Results (SEER)-Medicare database from 1998 to 2008 revealed that a significant number of patients with cancer receive drugs that are neither indicated by the US Food and Drug Administration (FDA) for the specific condition nor endorsed by the National Comprehensive Cancer Network (NCCN) compendia—and 18% of the spending on cancer drugs is for off-label drug use.

“We found a lot of off-label use,” said Dawn L. Hershman, MD, MS, Associate Professor of Medicine and Epidemiology, Division of He­ ma­ tology/Oncology, Columbia Uni­ versity Medical Center, New York, who presented these findings at the 2013 annual meeting of the American Society of Clinical Oncology.

The extent of off-label use is a policy concern, because the clinical benefits of such use for patients may not outweigh the costs or the adverse health outcomes, Dr Hershman said.

The study identified 42,634 patients with multiple myeloma or with metastatic breast, ovarian, lung, colon, or prostate cancer during that period in the SEER database. FDA drug approvals and their dates were identified; if the claim was within 1 year before the FDA approval date, it was categorized as NCCN compendia–supported. If the claim was made after the FDA approval date, it was categorized as FDA-approved. The researchers also determined which of the drugs were ever approved.

The Medicare reimbursement rate was calculated for the most common regimen and dosing, and was not adjusted for inflation.

The following numbers of unapproved anticancer agents used in the 7 common tumor types were: 20 in breast cancer, 8 in colon cancer, 8 in lung cancer, 18 in multiple myeloma, 28 in ovarian cancer, 33 in prostate cancer, and 13 in uterine cancer.

Overall, 55% of patients received an on-label drug only, meaning that 45% of patients received a drug that was neither FDA-indicated nor compendia-supported. A strong variability was evident by tumor type: patients with multiple myeloma were most likely (80%) to receive an offlabel drug and patients with colon cancer were least likely (10%). This

8

Table Cancer Drug Use and Associated Costs for 42,634 Patients, 1998-2008 Drug use status

Cost, $ (%)

FDA-indicated drug for the actual use

531.8 million (64)

Off-label use

149.5 million (18)

Compendia-supported drug

144.7 million (18)

FDA indicates US Food and Drug Administration. pattern was consistent across the 10year period.

Of the drugs with no FDA indication for the specific tumor type, 70% were endorsed by compendia and 30% were not. The mean number of claims for drugs with no FDA indication or compendia support averaged 11 per patient overall.

“The bulk of unapproved drugs are, however, compendia approved, and this is reassuring, because we think the compendia are appropriate,” Dr Hershman noted. Approximately 50% of the compendia-supported drugs were eventually approved by the FDA for that indication, but those that were not FDA-approved were not deleted from the compendia, she added.

“We found a lot of off-label use….We didn’t think we would find any unapproved use of drugs. We thought regulations were in place to stop that.”

—Dawn L. Hershman, MD, MS

Cost of Off-Label Use: $150 Million in This Cohort A breakdown of the cost according to appropriate use revealed nearly $150 million in reimbursement for drugs that were neither FDAindicated nor compendia-supported (Table). Most of the cost for off-label use was for the treatment of multiple myeloma and prostate cancer.

“So, of $850 million spent on drugs in this cohort, $150 million was for drugs only supported by compendia, and $150 [million] was for unapproved indications,” Dr Hershman concluded, adding that the cost of

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drugs has increased substantially in the past 5 years, and thus the actual costs would be much greater.

She cited data from another recent study (Conti RM, et al. J Clin Oncol.

2013;31:1134-1139) that detailed which patent-protected chemotherapy agents were the most likely to be used inappropriately. Conti and colleagues showed that off-label use (neither FDA-indicated nor NCCN compendia–endorsed) was greatest for rituximab (Rituxan) and gemcitabine (Gemzar; approximately 40%), and for bevacizumab (Avastin; approximately 25%). The least inappropriate use was for trastuzumab (Herceptin), for which essentially no inappropriate use was documented, and for pemetrexed (Alimta; <10%).

The estimated national spending on these common, patent-protected drugs was $12 billion, of which $2.5 billion was for off-label use and NCCN compendia–unsupported use, according to the study by Conti and colleagues.

While acknowledging limitations to the study that pertain to the use of billing codes, estimates of cost, and other factors, Dr Hershman commented, “We didn’t think we would find any unapproved use of drugs. We thought regulations were in place to stop that.”

The Good, the Bad, and the Ugly Monika K. Krzyzanowska, MD, MPH, Director, Quality Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, discussed the study, noting that some off-label use is not completely “inappropriate” but may exist in terms of a different administration schedule, or in a different context for the same disease. In some cases, of course, the drug is used for a disease in which it has not been well studied.

Bevacizumab is a good example of

this, Dr Krzyzanowska said.

She noted that “this matters,” because there can be “bad” consequences, such as a negative impact on trial accrual and undue financial costs, or “ugly” consequences, such as harm to the patient. Of course, some consequences are “good,” such as drug access for patients with rare diseases and the promotion of innovation, Dr Krzyzanowska said.

“Greater scrutiny of off-label use is needed, especially for diseases or drugs with a high prevalence of this, for expensive drugs, and for situations where the benefit is likely small and the risk of toxicity substantial.”

—Monika K. Krzyzanowska, MD, MPH

She said that Dr Hershman’s study confirms previous research showing that off-label prescribing is common in oncology and varies by disease, although a substantial proportion of off-label use is supported by the NCCN compendia.

Several questions remain to be answered, including: • Is compendium-compliant use of drugs appropriate?

• What is the impact of off-label prescribing on patients (ie, benefit and toxicity)?

• What is the motivation for off-label prescribing?

• How can the cost of off-label therapy best be estimated?

• What is the incidence of off-label use in oral chemotherapy?

• How would molecular profiling impact off-label prescribing?

Clearly, Dr Krzyzanowska suggested, oncologists are not “choosing wisely” in all circumstances.

“Greater scrutiny of off-label use is needed,” she pointed out, “especially for diseases or drugs with a high prevalence of this, for expensive drugs, and for situations where the benefit is likely small and the risk of toxicity substantial.” n

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Economics of Cancer Care

Can We Afford to Make Progress in Cancer Care?

The Economics of Drug Development

By Caroline Helwick

Chicago, IL—The rapid advances in cancer treatment, especially in personalized medicine, are occurring at an enormous financial cost to the healthcare system. “If we really want to make progress in an economically viable way, we must spend as much time on the economics of drug development as on the basic science,” said Kevin A. Schulman, MD, MBA, Director, Center for Clinical and Genetic Economics, and Director, Health Sector Management Program of the Fuqua School of Business, Duke University, Durham, NC, who spoke about the cost of oncology drugs at an educational session at the 2013 American Society of Clinical Oncology annual meeting.

“There is no quick fix. We must rethink the entire pharmaceutical development process,” said Dr Schulman.

Growth in healthcare spending has slowed; for the first time ever, the spending on pharmaceuticals has declined. But money spent on drugs is shifting from blockbuster products to targeted biologics; within the specialty pharmacy category, spending on drugs actually increased by 18% in 2012, he reported.

The current business model for drug development is unsustainable. The traditional business model is based on manufacturers producing a few high-profit blockbuster drugs that are marketed broadly, but this does not translate to the era of personalized medicine, which requires novel drugs targeted to a vastly smaller population of patients with specific molecular profiles. Spread across a much smaller market, the cost per patient is enormous.

“Of $250 billion spent on prescrip-

tion drugs, $100 billion is spent on biologics,” Dr Schulman said. “The idea that one such pharmaceutical product will cost $100,000 per patient is bad enough, but many patients receive a whole inventory of novel agents in multiple combinations. How many dollars’ worth of expensive therapies does 1 colorectal patient, for example, use in just 1 course of treatment? And look at chronic myelogenous leukemia, where there are different products for different genetic mutations and resistance patterns.”

This raises the question, Dr Schulman asked, “How will we bring multiple new products forward for smaller and smaller cohorts? What we are seeing are products with tremendously high prices, available to a restricted number of patients.”

Economic Reforms to Lower Drug Costs Society cannot label new oncology drugs as too expensive without first understanding why the costs are so high, Dr Schulman suggested.

Out-of-pocket costs to the manufacturer can be hundreds of millions of dollars, with no guarantee that a new compound will prove effective.

Approximately 80% of molecules fail to make it to market—and the figure is closer to 90% in oncology. The probability of market entry for a cancer drug, in fact, has been calculated at 7.2%.

“The cost of these failures is borne by the rest of the molecules that do make it to market. If a compound fails early, the cost is fairly modest. But if a biologic fails on a 1000-person phase 3 trial, it’s incredibly expensive,” he

said, noting that an experimental cholesterol-lowering drug that failed to win approval after phase 3 testing cost Pfizer $800 million.

Financial returns are critical to pharmaceutical companies, which promise a cash flow to Wall Street and a return to their shareholders. The more difficult it is to bring a new compound to

“If we really want to make progress in an economically viable way, we must spend as much time on the economics of drug development as on the basic science….There is no quick fix. We must rethink the entire pharmaceutical development process.”

—Kevin A. Schulman, MD, MBA

market, the higher the price required to meet the needs of investors will be. Increasing the size of a company’s portfolio would allow manufacturers to spread revenue over multiple products and reduce the pressure on individual products to bear the entirety of the company’s returns, Dr Schulman maintained.

“We should think of a way for manufacturers to get access to capital but restrict the returns to innovators— [that is,] firms that use this capital as a way of lowering cost of drugs that get to market,” he suggested. “By reducing the cost of drug development,

we would reduce the barrier to entry for new and competitive firms. This could ignite price competition, and that would help us out.”

Transforming Clinical Research in Drug Development Transformation of the clinical development enterprise can begin by “reimagining” the roles and the responsibilities of patients and clinicians in the realm of clinical research, as well as the roles of institutions and principal investigators, Dr Schulman further suggested.

Data collection in clinical trials must become more compatible with the way that technology is being used in medicine. “We have gone from paper-based systems to electronic medical records to smartphones and tablets. Why are we not using this to change how we conduct research?” he asked. Optimal application of technology could certainly shorten the decades-long clinical trial process, Dr Schulman suggested.

Patients should also become empowered to better navigate the clinical trials system themselves, to share in decision-making, and to reduce the clinical burden of collecting the information needed for enrollment.

Finally, it would help to better understand the demand for new drugs by patients, that is, (the “behavioral economics”), Dr Schulman said. “Why do patients believe that 1 week of life is worth extraordinary amounts of money? It is critical to understand the disconnect between the public anger over high prices for products with modest benefits and the demand that our patients have for hope.” n

Assessing the Value of New, Costly Radiation Therapies in Older Patients with Breast Cancer Financial incentives lead to non–evidence-based use at for-profit hospitals Chicago, IL—For-profit hospitals are more likely than their nonprofit counterparts to treat elderly patients with breast cancer with an expensive form of radiotherapy—despite lacking evidence of its benefit, researchers from the Yale Cancer Outcomes, Public Policy and Effectiveness Research Center reported at the 2013 American Society of

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Clinical Oncology annual meeting.

“We wanted to evaluate how hospital ownership affects the adoption of technology,” said Sounok Sen, BSE, MD, Yale School of Medicine, New Haven, CT. “We found that Medicare beneficiaries receiving breast-conserving surgery at for-profit hospitals disproportionately received brachyther-

apy….While brachytherapy has been rapidly adopted, it costs twice as much as external beam radiotherapy and is reimbursed more substantially,” Dr Sen pointed out.

“While the long-term risks and benefits of brachytherapy are still being defined,” he added, “payers may want to reconsider the wisdom of

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reimbursement policies that promote the rapid adoption of newer and unproven cancer therapies without incorporating rigorous assessments.”

Although for-profit and nonprofit hospitals may have financial incentives, “for-profit providers may have additional incentives to fulfill their Continued on page 10

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Economics of Cancer Care

Assessing the Value of New, Costly Radiation... fiduciary responsibilities and their mission to shareholders,” Dr Sen suggested. “This may affect the pattern of care as it relates to the adoption of new or higher-margin technology.”

“The literature has suggested that financial gain exerts a powerful influence on the individual and the institution,” he added.

Radiotherapy a “Salient Example” Dr Sen and colleagues evaluated the use of brachytherapy, a new radiotherapy modality in breast cancer, against recent evidence indicating that radiotherapy of any form is not always necessary in some patient subsets.

Specifically, the Cancer and Leu­ kemia Group B (CALGB) 9343 trial showed that in women aged ≥70 years with low-risk breast cancer, external beam radiotherapy did not improve overall survival or disease-free survival at 10 years, although it did reduce local or regional recurrences.

The guidelines now therefore state that radiotherapy can safely be eliminated in this population.

New radiotherapy modalities—specifically brachytherapy—have some

Table Brachytherapy Use, by Patient Age and Hospital Type Age of patients with breast cancer All ages

For-profit hospitals, %

Nonprofit hospitals, %

15.6

12.0

66-79 yrs

≥80 yrs (P <.05)

14.8 12.4

advantages over older approaches, including shorter length of treatment and reduced toxicity. Brachytherapy’s efficacy in breast cancer, however, has not been well established, and some studies suggest that the risks are increased with this therapy compared with conventional radiotherapy.

The researchers used the Medicare database of women aged 66 years to 94 years who underwent breast-conserving surgery in 2008 and 2009, and determined hospital ownership status by the Medicare Hospital General Information data set.

A total of 35,118 women were included (mean age, 74 years; 27% aged ≥80 years) who were treated at 2255 nonprofit hospitals and 420 for-profit hospitals. Adjuvant radiotherapy was administered to 72% of the patients,

10.9 8.0

including brachytherapy in 15.7%.

Radiotherapy of any type was more common at for-profit hospitals

“Payers may want to reconsider the wisdom of reimbursement policies that promote the rapid adoption of newer and unproven cancer therapies.”

—Sounok Sen, BSE, MD

among women aged ≥80 years. This 22% relative increase in radiotherapy was largely driven by brachythera-

Continued from page 9

py. Brachytherapy was most common in all women who were treated at for-profit hospitals compared with nonprofit hospitals (20.2% vs 15.2%, respectively; P <.001), with the greatest difference observed among the elderly (Table).

Financial Incentives Influence Use Treatment at a for-profit hospital was associated with an odds ratio of 1.29 for receiving brachytherapy in women aged 66 years to 79 years (P = .04) and of 1.66 in women aged ≥80 years (P = .003).

“Women whose surgery was performed at for-profit hospitals were significantly more likely to receive any radiation, driven by the differential use of newer, less proven brachytherapy,” Dr Sen said.

He suggested that for-profit hospitals may have had “financial incentives and fiduciary responsibilities, or a desire to be at the vanguard of care or build market share,…but it is also possible that brachytherapy was chosen to enhance convenience and tolerability for the patient. It’s challenging to delineate the incentives.”—CH n

Colorectal Cancer

Adenoma Detection Rates in Colonoscopy: The Higher the Better

By Caroline Helwick

Orlando, FL—In screening colonoscopies, high adenoma detection rates (ADRs) by physicians are associated with fewer missed cancers and with better survival from colorectal cancer (CRC), according to 2 studies presented at Digestive Disease Week 2013.

It is assumed that the higher the ADR, the more complete the colonoscopy examination. Although low ADRs have been linked to the occurrence of missed or “interval” cancers—those occurring within 3 years of a negative colonoscopy—this association needed further exploration, according to Douglas A. Corley, MD, PhD, MPH, a researcher at Kaiser Permanente in Oakland, CA, who presented one of the studies.

ADR an Important Quality Indicator An ADR was defined as the percentage of colonoscopy screenings in which at least 1 adenoma or cancer was detected. Current guidelines recommend ADRs of 15% for females and 25% for

10

males, but no data have provided a threshold ADR that should be targeted for intervention, Dr Corley said.

“We found a 3% increase in interval CRC risk and 4% increase in risk of CRC death for every 1% difference in ADR,” he reported.

—Philip S. Schoenfeld, MD

higher ADRs,” Dr Corley noted.

A total of 314,872 colonoscopies were performed by 136 experienced endoscopists, and 712 postcolonoscopy cancers were diagnosed within the next 10 years. The quartile of ADR, from a low of <19% to a high of 33%, was linked to these cancers as an independent predictor after a negative colonoscopy. Patients with the fewest adenomas had more than a 2.6-fold increased risk of dying within 10 years.

“Our findings support the validity of ADR as a quality metric for colonoscopy, and they support the evaluation of interventions to determine if improving ADR will improve outcomes,” Dr Corley concluded.

“Patients whose colonoscopies were performed by endoscopists who had lower ADRs were more likely to be diagnosed with subsequent CRC than patients whose endoscopists achieved

Characteristics of Missed CRCs Investigators from the Huntsman Cancer Institute at the University of Utah, Salt Lake City, also examined the rate and the predictors of missed or interval CRCs in a population-based study of 126,936 adults

“The data from these papers could influence the ADR that we specify in the updated position statement.”

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aged ≥50 years. Of the 2659 patients who developed CRCs, 159 were diagnosed within 6 months to 5 years of the negative colonoscopy, and 91 were diagnosed within 6 months to 3 years. This yielded a missed or interval CRC rate of 6% for the 5-year window and 3.5% for the 3-year window, said N. Jewel Samadder, MD, MSc, Assistant Professor of Medicine at the University of Utah School of Medicine.

Philip S. Schoenfeld, MD, Associate Professor of Medicine at the University of Michigan, Ann Arbor, who is coauthoring a position paper on quality indicators in colonoscopy, commented that these findings suggest that current recommended ADRs may be too low.

“We have not upped the thresholds for recommending ADRs of 25% in men and 15% in women at screening colonoscopy, though I think the data from these papers could influence the ADR that we specify in the updated position statement,” Dr Schoenfeld pointed out. n

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3rd Conference

How Employers Are Adapting to the New...

The “Value Disconnect”

Healthcare Resources Are Finite

“Obamacare is going to fundamentally change how we pay for healthcare, who pays for healthcare, and who will be making the decisions around the healthcare we deliver,” Mr Hayes said. “Employers are faced with deciding whether to continue to offer health benefits or not, and we have been underestimating what that is going to mean.”

Employers will face increasingly burdensome cost pressures, because the average premium is expected to increase by 30%. Employees, by contrast, are underestimating their health insurance benefits: although employers spend an average of $20,000 on an employee’s premium, the employee perceives that it is only half this amount, hence the “value disconnect” between employers and their employees in their approach to health benefits.

Employers are recognizing that conventional health benefit strategies are not working, and they are increasingly deferring the decision-making process to consultants, attorneys, and others, and are “rethinking what they are doing.” Employers are also recognizing that healthcare resources are finite, that there are wide variations in cost and quality, and that they should help address this problem.

Employers are concerned about the uncertainty of the regulatory environment and the economy, which contributes to the need to “rethink” their strategies. In response, some will move from having full-time employees with

benefits to part-time employees without benefits, according to Mr Hayes, who called these “the significant issues shaping the marketplace.”

The Future of Health Insurance Employers choose to adapt in various ways to the changes in the healthcare landscape, to some extent depending on their size and position.

Anticipated changes in healthcare in the next 5 years will likely result in major changes in employer-based

Table The US Healthcare Landscape in 5 Years Likely issues in US healthcare by 2018 include: ➢ The majority of Americans will not have employer-based health coverage ➢ Most Americans will be covered by state exchanges, Medicare, or Medicaid ➢ There will be dramatically different reimbursement models (little fee for service) ➢ Providers and patients will have much greater accountability ➢ Smart devices and/or social media will be the primary communication tools linking patients and physicians ➢ It will be more of a “shared decision-making model” ➢ Therapies will be personalized ➢ Runaway cost spirals will drive the “rationing” discussion of finite healthcare resources front and center, especially for cancer care

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to provide benefits, other retailers will do likewise,” Mr Hayes suggested.

This issue will trigger workforce issues, because many individuals may be shifted to part-time status, he added.

In Search of the Right Care at the Right Place

From an employer’s perspective, “value” can be summed up as highquality, safe, cost-effective care de­ livered at the right place and at the right price, Mr Hayes said.

The problem is that this is rarely realized in actual practice. The “right care” is limited to only approximately 50% of encounters. The “right place” is also not ensured, as evidenced by the fact that only a small percentage of hospitals have received the rating of “clinical excellence.”

“If Medicare patients got their care at those hospitals, 164,000 lives would be saved, and that’s 34% lower mortality. Where you get care makes a difference,” he pointed out.

The “right price” is an interesting concept, Mr Hayes continued.

Employers in focus groups are hard to engage around “price,” but they will have conversations around “quality and outcomes,” he said. And those are often not encouraging.

Continued from cover

“Obamacare is going to fundamentally change how we pay for healthcare, who pays for healthcare, and who will be making the decisions around the healthcare we deliver. Employers are faced with deciding whether to continue to offer health benefits or not, and we have been underestimating what that is going to mean.”

—Peter Hayes health insurance, including many employers not offering insurance (Table).

“There’s a saying that if you’ve talked to one employer, you’ve talked to one employer. There will be big differ­ ences in reactions and strategies between small employers, mid-sized employers, and large employers,” Mr Hayes predicted.

Some specialists estimate that most of the small- or mid-sized employers will discontinue healthcare benefits and will refer their employees elsewhere, such as to the health exchanges. The fact that 70% of Americans are employed by small or mid-sized companies makes this a problem.

Employers’ insurance strategies will also depend on the region of the country and the type of industry. For example, the energy sector is interested in retaining key personnel, and cost is less important to them than to the retail sector, in which margins are small and the cost of premiums is important.

Industry leaders will largely determine this trend. “If Walmart continues

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Hot Trends in Healthcare Employers will also be expected to keep up with “hot trends” in healthcare, such as incentivized wellness, aggressive steerage to providers of excellence, consumer-driven health plans, the use of health advocates, retail and on-site clinics, telemedicine, and smart device apps.

“We are seeing that employers have become interested in sending their employees to the top quartile of providers, who are offering high-quality, cost-effective care, and creating the right incentives to move volume,” Mr Hayes said.

“And the phenomenon of retail clinics is amazing. One of every 4 Americans went to a retail clinic last year for healthcare. The Walgreens and Walmarts are thinking about creating total integrated health delivery systems. The world is really changing,” he added.

Payment reform is of great interest to employers, who are considering outsourcing the decision-making about benefits to private exchanges. Employers are demanding more quality and more price transparency.

“Employers are going to stop paying for every widget of service. It’s no longer going to be a complete pass through,” he predicted.

They will be steering patients to Centers of Excellence and demanding second opinions. They will expect that clinical outcomes relate to the cost of treatment (which is occurring in Europe), and they will be exploring global and episode-based pricing.

The “global marketplace” could become a key player in large plans, Mr Hayes said, and he gave an example from his own experience. “We were paying up to $100,000 for hip replacements. We looked outside the United States and found we could partner with Singapore for a $10,000 hip replacement. The global marketplace will become applicable to cancer care too.” n

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3rd Conference

Cancer Rehabilitation: The Next Frontier...

Cancer Survivors Share Wisdom and Hope.

The main reasons for distress among cancer survivors pertain to physical disabilities and the inability to return to an expected functional level, studies show, said Dr Silver at the Third Annual Conference of the Association for Value-Based Cancer Care. An evidence-based cancer rehabilitation program led by board-certified rehabilitation health professionals can improve most common complaints, including fatigue, mild cognitive impairment, and chemotherapy-induced peripheral neuropathy, according to Dr Silver.

“Even when you can’t change the impairment—for instance, the nerve injury—you can often dramatically change the disability,” Dr Silver said.

She described the role of cancer rehabilitation, and how survivorship care is beginning to incorporate cancer rehabilitation and prehabilitation.

Diagnosed with cancer herself at age 38, Dr Silver felt strong going into treatment, but progressively became weaker as a result of it. “When I was sicker than I had ever imagined, out of work, couldn’t take care of my kids, when I couldn’t function, my oncologist said, ‘You’re done. Go home. Try to accept a new normal. Try to figure out how to heal. Go back to work if you’re able to,’” Dr Silver said.

“I’m a rehab doctor. I’m a physiatrist. I’ve been at Harvard Medical School my whole career. I can tell you I’ve never given anybody that advice,” she said. “I actually think that it’s not okay to tell someone to accept pain and fatigue and disability.

I do not tell patients to accept a new normal.”

Thus began her crusade to develop and promote cancer rehabilitation medical services, to make evidence-based, impairment-driven cancer rehabilitation the standard of care to be offered to all cancer survivors who need it.

Rehabilitation Myths Although there is a near-universal agreement that these medical services are needed, there are still many myths to be debunked:

“Cancer rehabilitation equals medical treatment. It’s critical, but it is not often offered. When it is offered in an evidence-based, best practices manner, it will be reimbursed, and it will improve outcomes.”

—Julie K. Silver, MD • Myth: Cancer rehabilitation is “new” and is not supported by research Fact: Cancer rehabilitation research is outpacing all other fields of rehabilitation research • Myth: Offering cancer rehabilitation medical services is optional Fact: Influential forces are insisting that cancer rehabilitation care be provided to survivors. The Commission on Cancer mandates that every accredited oncology facility have a cancer committee and

Figure Reimbursable Rehabilitation Interventions Focused on Improving Physical Health and Decreasing Disability General exercise for strength and cardiovascular conditioning

Diagnostic imaging for neurologic and musculoskeletal problems Electrodiagnostic studies for nerve and/or muscle problems Oral and/or topical prescription medications

Driving evaluation Work evaluation Home evaluation

Injectable medications

Assistive devices

Manipulation and/or soft-tissue mobilization

Prosthetics Orthotics Modalities

12

that one of its members must be a “rehabilitation representative” • Myth: Health insurers do not cover cancer rehabilitation Fact: Cancer rehabilitation is readily covered by health insurers, including Medicare, when patients have documented impairments and the treatment is delivered by healthcare professionals who are licensed or board certified in rehabilitation medicine. Medicare pays $1880 annually for physical therapy and for speech therapy, and $1880 for occupational therapy, which increases

Swallowing evaluation and Speech treatment evaluation and treatment

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Therapeutic exercise

to $3700 for each when medical necessity can be documented • Myth: Only a small percentage of cancer survivors need cancer rehabilitation Fact: Between 63% and 90% of patients need cancer rehabilitation medical care, and they have many unmet needs • Myth: Cancer survivors are too tired to attend more appointments Fact: Research and clinical experience demonstrate that cancer survivors want this care and attend their appointments • Myth: Emotional recovery is independent of physical recovery Fact: New research has shown that distress is strongly correlated with survivors’ ability to function • Myth: It is acceptable to tell patients that they need to “accept a new normal” Fact: There may be serious repercussions to telling patients that they have reached a medical end point if they are not offered evidence-based cancer rehabilitation covered by their insurance.

Identify, Then Treat Patients with Impairments The great majority of patients with cancer who need rehabilitation services do not receive them. One study of 163 patients with metastatic breast cancer showed that 92% of patients had at least 1 physical impairment, but only 30% received the care they need-

Continued from cover

ed; 88% of patients required physical or occupational therapy, but only 21% received this (Cheville AL, et al. J Clin Oncol. 2008;26:2621-2629).

“For patients with injuries, we don’t say that we are not going to bother recognizing them. We’re not going to figure out if they are treatable, or if insurance pays for them.

We don’t do that in medicine,” Dr Silver emphasized.

The early identification of patients who need cancer rehabilitation is critical, not only for the good of the patient but also to avoid unnecessary workups for metastatic disease when musculoskeletal pain arises as a result of untreated impairment. “We have to screen every patient for physical impairments that are treatable,” she pointed out.

Dr Silver emphasized that exercise programs and lymphedema programs are not substitutes for cancer rehabilitation. The American College of Sports Medicine and the American Cancer Society have produced a Cancer Ex­ ercise Trainer program, but this is a fitness, not a cancer rehabilitation, model. Although exercise programs may be helpful at some point, they do not constitute rehabilitation for most patients with cancer, who have a variety of needs.

Cancer Rehab = Medical Treatment Dr Silver emphasized that a new standard of care within survivorship is an impairment-driven cancer rehabilitation program involving professionals delivering evidence-based services that are reimbursed by health plans (Figure).

“We need to identify impairments all along the continuum and refer those patients to licensed and board-certified rehabilitation healthcare professionals,” Dr Silver said. “The bottom line is that cancer rehabilitation equals medical treatment. It’s critical, but it is not often offered. When it is offered in an evidence-based, best practices manner, it will be reimbursed, and it will improve outcomes.”

“Prehabilitation” an Emerging Concept Research suggests that physical and emotional health outcomes of patients with cancer can be improved with interventions that occur in the time interval between the cancer diagnosis and treatment onset. Cancer “prehabilitation” programs maximize that window of time to prepare patients for cancer treatment physically and emotionally. n

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CVS Caremark Value Proposition for Oncology Pharmacy Adapting to new challenges in cancer drug management

By Caroline Helwick Hollywood, FL—In response to mandates for more efficient and lower-cost cancer drug utilization, CVS Caremark is developing innovative strategies, said Kirby J. Eng, RPh, Director of On­co­logy Medical Pharmacy Manage­ ment, CVS Caremark, at the Third Annual Conference of the Association for Value-Based Cancer Care.

“While society, business, and government try to determine how to address the unsustainable costs in cancer care, we in the pharmacy care management business are going to be fixated on drug therapy, aiming to be good stewards so that the right drugs are used for the right reason at the right cost,” he said.

This will become more challenging, considering that 25 new oncology drugs have been approved in just the past 2 years, and that more than 300 oncology compounds are in development, Mr Eng said.

Most of the cancer drug costs can be attributed to a handful of the 200-plus cancer compounds that are now on the market. Approximately 30% of these drugs are used off label (Conti RM, et al. J Clin Oncol. 2013;31:1134-1139), although not necessarily inappropriately, according to the compendia, society guidelines, and Centers for Medicare & Medicaid Services–recognized peerreviewed journals.

“Look at the complexity of trying to manage cancer drug spending. We have more than 100 diseases included within cancer. We have over 200 drugs.” With this broad reference base, “it obviously becomes very challenging and daunting for employers, as well as health plans, to manage cancer drug spending,” Mr Eng observed.

Managing Cancer Drug Spending Although specialty pharmacy and

pharmacy benefit managers (PBMs) primarily focus on drugs that are covered under the pharmacy benefit, 75% of drug spending still falls under the medical benefit.

“We’ve created a fully dedicated business unit just to focus on drugs that are covered under the medical benefit. Oncology is about 50% of that drug spending. Our value proposition to our clients includes the ability not only to manage drugs under the pharmacy benefit, but to migrate and integrate drugs into the medical benefit.”

—Kirby J. Eng, RPh

“This is where we run into some challenges,” he noted. “To meet that challenge, we’ve created a fully dedicated business unit just to focus on drugs that are covered under the medical benefit. Oncology is about 50% of that drug spending. Our value proposition to our clients includes the ability not only to manage drugs under the pharmacy benefit, but to migrate and integrate drugs into the medical benefit.”

Several research groups have identified key trends in oncology drug management (Table). The trend toward more rigorous approval criteria goes beyond assuring the appropriateness of drug use in general to the appropriate line of therapy, Mr Eng elaborated.

Another trend is to require physicians to submit claims for drugs administered in the office and billed under the

Table Key Oncology Drug Management Trends • Rigorous approval criteria - Line of therapy and clinical pathways

• Management of office-administered agents - National Drug Code–based claims submission - Integration of medical and pharmacy benefit management • Site-of-care management

• Oncologist engagement - Alignment of economic incentives

• Use of lower-cost agents - Formulary and incenting use of generics

Sources: AJMC Health Strategies Group; 2012 Genentech Oncology Trend Report.

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medical benefit with a corresponding National Drug Code. The trend toward the integration of the medical and the pharmacy benefits refers to (1) the clinical criteria that are universally

applied to drug therapy, regardless of benefit design, and (2) the systems that help to support this.

Among the various approaches within the specialty pharmacy and PBM business, the ultimate winners will probably be the approaches that can integrate technology into a health plan’s existing infrastructure and approaches that can allow for “visibility” of drugs “before they’re actually used, either being filled at a pharmacy or being administered in the office. We’re clearly making a concerted effort in that area,” he said.

This pertains to site-of-care management. CVS Caremark would like to provide its clients with utilization management regardless of where the drug is administered, Mr Eng noted.

Integration of Oncology Pharmacy Care Management The integration of pharmacy care management is a key focus for CVS Caremark, Mr Eng said. “We are thinking about the different ways we can engage with patients, beginning with our retail pharmacy, then PBM, our specialty pharmacy (our mail order model), and our retail clinics,” he noted. “There will be a high degree of focus on ‘high-touch’ patient engagement.”

Taking telephonic clinical pharmacy support further, CVS Caremark is designing face-to-face interventions at retail pharmacies and home visits from pharmacists where necessary. Pilot

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at a glance ➤ Managing the cost of cancer drugs is challenging: 25 new cancer drugs have been approved in the past 2 years, and >300 oncology compounds are in development ➤ Specialty pharmacy and PBMs focus on drugs covered under the pharmacy benefit, but 75% of drug spending still falls under the medical benefit, presenting a challenge to payers ➤ Most of the cancer drug costs can be attributed to a few of the 200-plus cancer compounds currently available, and approximately 30% of these are used off label ➤ Approximately 50% of drug spending is on oncology; CVS Caremark is focused on migrating and integrating an increasing number of drugs into the medical benefit

programs are showing improvements in drug adherence and reductions in healthcare costs.

“We were so pleased with the results that we are introducing 5 more chronic care management initiatives, one of which is for breast cancer,” he pointed out.

More convenient drug fills also fall under the “patient engagement” umbrella. “We want to give patients the ability to receive their drugs in whatever form is most convenient for them,” Mr Eng emphasized.

For example, patients can receive their drugs in retail pharmacies at the same rates as if they were mailed. He expects this to be expanded into the oncology area. “Cancer drugs are high on the radar in terms of allowing member or patient flexibility,” Mr Eng said.

CVS Caremark is also considering formulary management strategies for several tumor types (at the request of many of its clients); is involved in clinical pathway programs; and is enhancing collaboration between oncologists and clinical pharmacists.

“We are clearly committed to managing trends across benefit design, regardless of the side of service,” Mr Eng concluded. n

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3rd Conference

Payers Must Step Up Their Utilization Management Programs

By Caroline Helwick

Hollywood, FL—With the Affordable Care Act about to be fully enacted, and growing concerns about managing oncology costs, health plans will put simple processes in place ahead of new drug approvals to more actively manage these medications, said James T. Kenney, Jr, RPh, MBA, Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA, at the Third Annual Conference of the Association for Value-Based Cancer Care.

“This is not something that we’ve seen in the past,” Mr Kenney noted.

“It’s going to be an interesting road for all of us as we determine how to effectively manage the medical drug side,

tracts, and all drugs are tracked by national drug codes. Drugs can be managed down to their individual unit, strength, dosage, and package size.

Data management and reporting can be easily handled.

“Also, if we want to cover a drug that’s oral, but not cover a nasal route, then we can do that. That’s not a luxury we have on the medical side with the current systems,” he said.

Drug Management Strategies There will be growing emphasis on coordinated drug management, which includes the site of care, the utilization management component,

“The degree to which utilization management is applied can have a significant impact on physician practices.

From a plan perspective, ideally, what we want is not to disrupt the practice... but to put reasonable controls in place to manage utilization.”

—James T. Kenney, Jr, RPh, MBA

but not disrupt the practice and the patients in the process.”

Mr Kenney described the resources that payers apply to manage drugs, including cancer drugs, on the medical and on the pharmacy sides. For payers, utilization management is much simpler on the pharmacy benefits side than on the medical side, he said.

Medical benefits include products that are covered and provided commensurate to some type of physician or practitioner service. This can create confusion in tracking and monitoring.

“We may have, actually, 2 products that share a J code,” Mr Kenney noted.

“When that happens, there’s not an easy way for the plan to figure out what was actually provided. When you add to this mix the different strengths and dosage units of a product, it creates a bit of a challenge to manage drugs on the medical side. Historically, there has not been a lot of management on the medical side.”

The pharmacy side is easier. Phar­ macy benefit managers (PBMs) can capably handle tracking and monitoring in real time. All claims from pharmacy channels run through the PBM con-

14

and reimbursement. Some health plans will start shifting their strategies from the physician buy-and-bill model to “white bagging” (ie, the pharmacy ships the drug directly to the practice and the patient receives the drug at the office), as well as shifting from office to home infusion, which is cost-saving for the plan.

Shifts in sites of care are being done selectively at this point by different plans, Mr Kenney pointed out.

Utilization management allows the payer to limit coverage for a particular drug for its US Food and Drug Administration (FDA)-approved indication only, and to use dose management strategies to ensure proper prescribing practices. For example, if the drug’s label indicates a maximum dose of 10 mg/kg, then the payer may cap the reimbursement for that drug at that dose. “This is difficult to do using the medical claim system, and a lot easier to do on the pharmacy side,” Mr Kenney pointed out.

Reimbursement management occurs at the claims level and involves things such as adjusting fee schedules as they relate to specific products.

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Meet the Experts

Brown Bagging versus White Bagging At the Third Annual Conference of the Association for Value-Based Cancer Care, several Meet the Experts roundtable discussions addressed the hottest topics in oncology. James T. Kenney, Jr, RPh, MBA, Pharmacy Operations Manager at Harvard Pilgrim, and Douglas S. Burgoyne, PharmD, President and Managing Partner, VRx Pharmacy Services, discussed the topic of brown and white bagging at one of these sessions.

“Brown bagging” is when a patient acquires specialty medication from a pharmacy and takes it to the physician’s office for administration. “White bagging” is when a physician receives a specialty medication from the pharmacy (on demand) and the patient visits the physician’s office for administration.

Brown and white bagging offers alternatives to the traditional buy-and-bill strategy and is designed to manage expensive specialty drugs.

In oncology, white bagging is the more common strategy: it allows physicians to take more responsibility for the medications, which is important for drugs with specific handling or refrigeration requirements.

With white bagging, providers need to stock and store the medication for each patient, keeping it separate from hospital and office stocks, which can be logistically challenging.

Oncology offices that continue to buy and bill often do so only for generic chemotherapy agents and not high-priced branded agents with low utilization and whose reimbursement status can be tenuous.

Oncology practices could reduce billing and administrative staff if more bagging were done (vs buy and bill).

Medication delivery logistics are handled by pharmacy benefit managers (PBMs) and specialty pharmacies, including those that are focused on oncology.

Data collection (eg, drug utilization, patient compliance) and patient services are often enhanced in these settings, relative to the traditional approach.

Key Challenges • The key challenges with bagging are the risk for waste, and the need for return on investment; patients with cancer may not qualify for the expensive treatment, they may have medication side effects, or their disease may have progressed, so that they cannot use the specific drug, which then must be sent back to the PBM or the specialty pharmacy, and that cost is not reimbursed • Patients often have laboratory testing the day before their treatment at the office to ensure that they qualify for the drug, and they return to the oncologist’s office for treatment; this can be logistically challenging • Communication between oncologists’ offices and PBMs or specialty pharmacies is often poor; some oncology offices are left with a drug stock or leftover drugs, which they often hold and do not get reimbursed for, and some of these drugs are administered to indigent patients, all at a loss for the provider • There are concerns about claims handling for drugs dispensed through the specialty pharmacy that are not obtained secondary to a physician office visit; normally, the chemotherapy agent would be handled under Medicare Part B, but the drug is then covered under Medicare Part D, because it was dispensed by a pharmacy.

Specialty Drugs Contracting Each health plan with which PBMs contract has its own approach to the inclusion of expensive oral agents, including oral oncolytics, depending on its Pharmacy & Therapeutics committee and the tier management preferences of that plan.

Dual coverage (ie, the pharmacy and the medical benefit) is an option; all oral chemotherapies, regardless of price, are covered under the pharmacy benefit, and some are managed by a specialty pharmacy, usually based on the cost of the agent.

For members in risk-sharing contracts, these medical costs are reallocated back to the pharmacy benefit at the end of the month to ensure appropriate cost accounting.

Utilization Management Options Much of utilization management involves benefit design, which encompasses: • Drug formularies (open or closed)

• High-cost specialty tiers for expensive specialty drugs • Coinsurance and deductibles • Retrospective drug utilization review

Continued on page 24

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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.

NOW APPROVED Introducing an oral medication for patients with refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib

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

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial.

Consider prophylactic measures after assessing an individual patient’s underlying risk factors

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

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

To find out more information about POMALYST, go to www.pomalyst.com or use your smartphone to scan this code.

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 02/13 US-POM120044a

FDA Update Gilotrif Approved for Metastatic Lung Cancer with EGFR Mutations, Concurrent with a Companion Diagnostic Test

The US Food and Drug Admini­ stration (FDA) approved the tyrosine kinase inhibitor afatinib (Gilotrif; Boehringer Ingelheim Pharmaceuti­ cals) for the treatment of patients with

metastatic non–small-cell lung cancer (NSCLC) who have the epidermal growth factor receptor (EGFR) gene mutations exon 19 deletions or exon 21 L858R substitution. The FDA approved afatinib under its priority review program, which offers an expedited review for drugs that provide safe and effective therapy when no good alternatives exist or for drugs

that provide significant therapeutic improvement over available agents.

Afatinib was approved concurrently with a companion diagnostic, the thera­­ screen EGFR RGQ PCR Kit (manufactured by QIAGEN, Manchester, United Kingdom), that identifies patients with the EGFR mutations. These types of mutations occur in approximately 10% of NSCLC tumors, and the majority

of these mutations are either exon 19 deletions or exon 21 L858R substitution.

“Today’s approvals further illustrate how a greater understanding of the underlying molecular pathways of a disease can lead to the development of targeted treatments,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug

T:7”

This brief summary does not include all the information needed to use POMALYST® safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.

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

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

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

1 INDICATIONS AND USAGE 1.1 Multiple Myeloma: POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Neutropenia • ANC* < 500 per mcL or Febrile neutropenia (fever more than or equal to 38.5°C and ANC < 1,000 per mcL)

Interrupt POMALYST treatment, follow CBC weekly.

• ANC return to more than or equal to Resume POMALYST at 3 mg daily.

500 per mcL • For each subsequent drop < 500 per Interrupt POMALYST treatment mcL • Return to more than or equal to 500 Resume POMALYST at 1 mg less per mcL than the previous dose Thrombocytopenia • Platelets < 25,000 per mcL

Interrupt POMALYST treatment, follow CBC weekly

• Platelets return to > 50,000 per mcL Resume POMALYST treatment at 3 mg daily • For each subsequent drop < 25,000 Interrupt POMALYST treatment per mcL • Return to more than or equal to 50,000 per mcL

Resume POMALYST at 1 mg less than previous 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

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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.

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

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

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.

FDA Update Evaluation and Research. “Gilotrif is the second drug approved this year for patients with untreated metastatic NSCLC whose tumors have the EGFR exon 19 deletions or exon 21 L858R substitution mutations.” The first agent, erlotinib (Tarceva), was approved in May for the first-line treatment of patients with NSCLC and was also concurrently approved with

a companion diagnostic (the cobas EGFR Mutation Test).

Afatinib’s safety and efficacy were established in a clinical study of 345 patients with metastatic NSCLC plus EGFR mutations. Patients were randomized to afatinib or to chemotherapy with pemetrexed and cisplatin.

Progression-free survival was 4.2 months longer in the group that re-

ceived afatinib than in the chemotherapy group. No significant difference in overall survival was seen between the 2 treatment arms.

The common side effects reported with afatinib include diarrhea, skin breakouts that resemble acne, dry skin, pruritus, inflammation of the mouth, paronychia, decreased appetite and weight, cystitis, nose bleed,

runny nose, fever, eye inflammation, and hypokalemia. Serious side effects include diarrhea that can result in kidney failure and severe dehydration, severe rash, lung inflammation, and liver toxicity.

The FDA’s approval of the thera­ screen EGFR RGQ PCR Kit was based on data from the safety and efficacy Continued on page 20

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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)] • 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.

Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm Trial 1 POMALYSTa

System Organ Class/Preferred Term Number(%) of Patients With at Least One Treatment Emergent Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

107 (100)

112 (100)

59 (55)

70 (63)

Pyrexia

20 (19)

34 (30)

Edema peripheral

25 (23)

18 (16)

Chills

10 (9)

12 (11)

Pain

6 (6)

5 (5)

Blood and lymphatic system disorders Neutropenia

56 (52)

53 (47)

Anemia

41 (38)

44 (39)

Thrombocytopenia

27 (25)

26 (23)

Leukopenia

12 (11)

20 (18)

4 (4)

17 (15)

38 (36)

39 (35)

Gastrointestinal disorders Constipation Diarrhea

36 (34)

37 (33)

Nausea

38 (36)

25 (22)

Vomiting

15 (14)

15 (13)

Infections and infestations Pneumonia

25 (23)

32 (29)

Upper respiratory tract infection

34 (32)

28 (25)

8 (8)

18 (16)

Urinary tract infection

(continued)

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(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

Back pain

34 (32)

34 (30)

Musculoskeletal chest pain

23 (22)

22 (20)

Muscle spasms

20 (19)

21 (19)

System Organ Class/Preferred Term Musculoskeletal and connective tissue disorders

Arthralgia

17 (16)

17 (15)

Musculoskeletal pain

12 (11)

17 (15)

Pain in extremity

5 (5)

16 (14)

Muscular weakness

13 (12)

13 (12)

Bone pain

13 (12)

5 (5)

Dyspnea

36 (34)

50 (45)

Cough

15 (14)

23 (21)

Epistaxis

16 (15)

12 (11)

Respiratory, thoracic and mediastinal disorders

Metabolism and nutritional disorders Decreased appetite

23 (22)

20 ( 18)

Hyperglycemia

13 ( 12)

17 ( 15)

Hyponatremia

11 ( 10)

14 ( 13)

Hypercalcemia

22 ( 21)

13 (12)

Hypocalcemia

6 (6)

13 ( 12)

Hypokalemia

11 ( 10)

12 ( 11)

6 ( 6)

18 ( 16)

23 ( 22)

18 ( 16)

Skin and subcutaneous tissue disorders Hyperhidrosis

Fatigue and asthenia

Lymphopenia

Trial 1 POMALYSTa

Rash Night sweats

5 ( 5)

14 ( 13)

Dry skin

10 ( 9)

12 ( 11)

Pruritus

16 ( 15)

12 ( 11)

Dizziness

21 ( 20)

19 ( 17)

Tremor

10 ( 9)

14 ( 13)

Headache

14 ( 13)

9 ( 8)

Neuropathy peripheral

11 ( 10)

8 ( 7)

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General disorders and administration site conditions

Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm

Nervous system disorders

Investigations Blood creatinine increased

16 ( 15)

12 ( 11)

Weight increased

1 ( 1)

12 ( 11)

Weight decreased

15 ( 14)

9 ( 8)

Psychiatric disorders Insomnia

7 ( 7)

16 ( 14)

Confusional state

11 ( 10)

15 ( 13)

Anxiety

12 ( 11)

8 ( 7)

16 ( 15)

11 ( 10)

Renal and urinary disorders Renal failure aPOMALYST

alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period

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FDA Update Gilotrif Approved for Metastatic Lung Cancer...

Continued from page 19

clinical study that was used for the approval of afatinib. Tumor samples from patients with NSCLC plus mutations helped to validate the test’s benefit in detecting EGFR mutations in this patient population. (July 12, 2013)

New Drug Application for Ibrutinib Submitted to FDA for B-Cell Malignancies

A New Drug Application for the oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (Janssen Biotech/ Pharmacyclics) was submitted to the US Food and Drug Administration (FDA) for the treatment of patients with B-cell malignancies, specifically

for previously treated patients with chronic lymphocytic leukemia (CLL) or with small lymphocytic lymphoma (SLL), and for previously treated patients with mantle-cell lymphoma (MCL).

The New Drug Application from the manufacturer is based on data from 2 pivotal, phase 2 clinical trials, one in patients with relapsed and/ T:7”

Table 3: Grade 3/4 Adverse Reactions Reported in ≥5% of Patients in Any Treatment Arm

or refractory CLL/SLL (PCYC-1102), and the other in patients with relapsed and/or refractory MCL (PCYC-1104).

If approved, ibrutinib would be the first agent in the class of oral BTK inhibitors. In addition, ibrutinib is one of the first drugs to be submitted for FDA approval via the new Breakthrough Therapy Designation pathway. (July 10, 2013) n

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1

Trial 1 POMALYSTa

System Organ Class/Preferred Term [a] Number(%) of Patients With at Least One Treatment Emergent NCI CTC Grade 3 or 4 Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

96 ( 90)

99 ( 88)

Neutropenia

50 ( 47)

43 ( 38)

Anemia

24 ( 22)

23 ( 21)

Thrombocytopenia

24 ( 22)

21 ( 19)

Leukopenia

6 ( 6)

11 ( 10)

Lymphopenia

2 ( 2)

8 ( 7)

Infections and infestations 26 (23)

2 ( 2)

9 ( 8)

Sepsis

6 ( 6)

3 ( 3)

10 ( 9)

1 ( 1)

12 ( 11)

14 ( 13)

6 ( 6)

3 ( 3)

7 ( 7)

14 ( 13)

13 ( 12)

10 ( 9)

6 ( 6)

4 ( 4)

10 ( 9)

7 ( 6)

Metabolism and nutritional disorders General disorders and administration site conditions Fatigue and asthenia Investigations Blood creatinine increased Respiratory, thoracic and mediastinal disorders Dyspnea Musculoskeletal and connective tissue disorders Back pain Muscular weakness Renal and urinary disorders Renal failure a

POMALYST alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period.

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1 POMALYSTa (N = 107)

POMALYST + Low dose Dex (N=112)

System Organ Class/Preferred Term

n (%)

n (%)

Number(%) of Patients With at Least One Treatment Emergent Serious Adverse Reaction

72 ( 67)

69 ( 62)

Pneumonia

15 (14)

21 (19)

Urinary tract infection

0 ( 0)

6 ( 5)

Sepsis

6 ( 6)

3 ( 3)

5 (5)

7 (6)

Pyrexia

3 (3)

5 (5)

General physical health deterioration

0 (0)

2 (2)

Atrial fibrillation

2 (2)

3 (3)

Cardiac failure congestive

0 (0)

3 (3)

Infections and infestations

Respiratory, Thoracic and mediastinal disorders Dyspnea General disorders and administration site conditions

Cardiac Disorders

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n (%)

n (%)

9 (8)

7 (6)

1 (1)

3 (3)

5 (5)

1 (1)

Dehydration

5 (5)

3 (3)

Hypercalcemia

5 (5)

2 (2)

4 (4)

2 (2)

System Organ Class/Preferred Term Renal and urinary disorders Renal failure Gastrointestinal disorders Blood and Lymphatic system disorders Febrile neutropenia Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders Back pain

[a] POMALYST 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 Cosmos Communications K

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Urinary tract infection

Hypercalcemia

POMALYST + Low dose Dex (N=112)

constipation

Blood and lymphatic system disorders

Pneumonia

POMALYSTa (N = 107)

In the Literature Neoadjuvant Lapatinib and Trastuzumab with Hormonal Therapy for HER2 Breast Cancer

A new phase 2 clinical trial is one of the first to investigate the use of hormonal therapy without chemotherapy as a neoadjuvant strategy for patients with HER2-positive breast cancer (Rimawi MF, et al. J Clin

Oncol. 2013;31:1726-1731). Of patients with overexpressed HER2, 50% are also estrogen receptor (ER)-positive.

The HER2 receptor is an ideal target for monoclonal antibody therapy.

Trastuzumab is an effective inhibitor of HER2 but is a weak inhibitor of HER2 heterodimers with HER1 and HER3, which lead to the downstream inhibition of the PI3K/PTEN pathway.

Lapatinib is a dual kinase inhibitor of HER1 and HER2 and therefore inhibits the HER receptors more completely than trastuzumab alone.

This study included 66 patients with stage II or III HER2-positive breast cancer who were stratified by ER status. All patients received oral lapatinib 1000 mg daily and trastuzumab in a 4-mg/kg loading dose,

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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.

Combination Therapy with Nivolumab and Ipilimumab Superior to Monotherapy in Advanced Melanoma

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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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. 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,

followed by 2 mg/kg weekly for 12 weeks. In addition, all ER-positive patients received oral letrozole 2.5 mg daily (with a luteinizing hormone– releasing hormone antagonist for premenopausal status).

The overall pathologic response rate was 49%, with 54% in the ER-positive group and 40% in the ER-negative group. The overall complete pathologic response rate was 22%. Overall, 89% of the patients proceeded to surgery. The treatment was generally well tolerated, with only 6% of patients discontinuing therapy. The most common adverse effects were diarrhea, rash, fatigue, nausea, and elevated liver function tests.

These results show that a nonchemotherapy neoadjuvant targeted hormonal therapy can produce complete remission in a relatively high number of patients with large primary breast cancer tumors. The study shows a high pathologic response to targeted hormonal therapy without systemic chemotherapy, indicating that some patients may be spared the cost and the toxicity of chemotherapy.

Immune blockade has been shown to induce tumor regression in various types of cancer. Ipilimumab is a fully human, immunoglobulin (Ig) G1 monoclonal antibody that blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4); nivolumab is a fully human IgG4 antibody that blocks the programmed death-1 (PD-1) receptor.

A new study investigated whether combined immune blockade with ipilimumab and nivolumab would increase survival in patients with advanced melanoma (Wolchok JD, et al.

N Engl J Med. 2013;369:122-133).

Ipilimumab has demonstrated improved overall survival in patients with advanced melanoma. Nivolumab has produced objective responses in patients with melanoma, as well as other types of cancer.

The combination of CTLA-4 plus PD-1 blockade was shown to be complementary in regulating immune activity, and was hypothesized to increase antitumor activity in patients with advanced melanoma compared with blockade with either pathway alone.

In this phase 1 clinical trial, 53 patients received concurrent therapy with intravenous doses of nivolumab and ipilimumab every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses; this was Continued on page 23

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Coming soon

Another option in short-acting G-CSF therapy

Âť FDA and EMA approved Brought to you by Tevaâ&#x20AC;&#x201D;a global leader experienced in developing and manufacturing biologics. Teva has a substantial portfolio of more than 50 oncology products in the US.

Learn more at tbofilgrastim.com Indication Tbo-filgrastim is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue tbo-filgrastim and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving tbo-filgrastim.

Acute respiratory distress syndrome (ARDS) can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving tbo-filgrastim for ARDS. Discontinue tbo-filgrastim in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue tbo-filgrastim in patients with serious allergic reactions. Do not administer tbo-filgrastim to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of tbo-filgrastim in patients with sickle cell disease. Discontinue tbo-filgrastim in patients undergoing a sickle cell crisis.

The granulocyte colony-stimulating factor (G-CSF) receptor, through which tbo-filgrastim acts, has been found on tumor cell lines. The possibility that tbo-filgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which tbo-filgrastim is not approved, cannot be excluded.

The most common treatment-emergent adverse reaction that occurred in patients treated with tbo-filgrastim at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Prescribing Information on adjacent page.

Š2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. FIL-40083 June 2013. Printed in USA.

In the Literature Combination Therapy with...

Continued from page 21

subsequently followed by therapy every 12 weeks for up to 8 doses. In the sequenced therapy arm, 33 patients who were previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.

The objective response rate in the concurrent regimen arm was 40%, and

clinical activity was seen in 65% of the patients. At the maximum allowed dose, 53% of patients showed objective response compared with only 20% of patients in the sequenced therapy group. Patients in the combined regimen had tumor reductions of ≥80%.

Grade 3 or 4 adverse events were reported in 53% of the patients in the concurrent regimen group, but

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

4 CONTRAINDICATIONS None.

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

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving tbo-filgrastim, for ARDS. Discontinue tbo-filgrastim in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue tbo-filgrastim in patients with serious allergic reactions. Do not administer tbo-filgrastim to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors.

Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease.

Discontinue tbo-filgrastim in patients undergoing a sickle cell crisis.

5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which tbo-filgrastim acts has been found on tumor cell lines. The possibility that tbo-filgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which tbo-filgrastim is not approved, cannot be excluded.

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

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

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

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with tbo-filgrastim at the recommended dose and was numerically two times more frequent

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these were similar to events seen with monotherapy and were reversible overall; the rate was 18% in the sequenced therapy group.

Concurrent treatment with nivolu­ mab and ipilimumab was associated with objective response rates that exceeded the previously reported results with either agent alone. Rapid and durable responses were seen in

than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% tbo-filgrastim, 1.4% placebo, 7.5% non-USapproved filgrastim product).

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

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity.

The incidence of antibody development in patients receiving tbo-filgrastim has not been adequately determined.

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

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

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

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

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

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

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

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

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

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

10 OVERDOSAGE No case of overdose has been reported.

Manufactured by: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA North Wales, PA 19454 Product of Israel FIL-40085

August 2012

This brief summary is based on the tbo-filgrastim full Prescribing Information.

july 2013

I

a substantial proportion of patients in the concurrent regimen group. Of particular significance was the finding that 31% of the patients who had a response in the concurrent regimen group had tumor regression of ≥80% by week 12.

These results suggest that the combined use of nivolumab and ipilimu­ mab in patients with advanced mela­ noma results in rapid and deeper clinical tumor responses than responses observed with either agent alone.

These responses were durable, but longer follow-up is needed to confirm these results.

Crizotinib Superior to Standard Chemotherapy in Patients with ALK-Positive Lung Cancer

Crizotinib, an inhibitor of the anaplastic lymphoma kinase (ALK) gene, has shown significant response rates in patients with advanced non–smallcell lung cancer (NSCLC) and the ALK rearrangement. A new study compared the response rates of standard chemotherapy with crizotinib in patients with ALK-positive advanced NSCLC (Shaw AT, et al. N Engl J Med. 2013;368:2385-2394).

This phase 3, open-label clinical trial included 374 patients with locally advanced or metastatic ALK-positive NSCLC who had previously received 1 platinum-based regimen. The patients were randomized in a 1:1 ratio to oral crizotinib 250 mg twice daily or to intravenous chemotherapy with pemetrexed 500 mg/m2 of body surface area or with docetaxel 75 mg/m2 every 3 weeks. Patients receiving chemotherapy whose disease progressed were allowed to cross over to receive crizotinib as a separate study. The study primary end point was progression-free survival (PFS).

The median PFS was 7.7 months with crizotinib versus 3.0 months with chemotherapy, resulting in a 0.49 hazard ratio for progression or death with crizotinib (95% confidence interval [CI], 0.37-0.64; P <.001). The response rates were 65% (95% CI, 58-72) with crizotinib versus 20% (95% CI, 14-26) with chemotherapy (P <.001).

At the time of the data cutoff, the median follow-up for overall survival was similar between the 2 groups: 12.2 months in the crizotinib group and 12.1 months in the chemotherapy group. Also at that time, 85 (49%) patients in the crizotinib group and 28 (16%) patients in the chemotherapy group were still receiving therapy.

Overall, 58 patients receiving crizotinib continued therapy beyond the predefined period of progression Continued on page 42

www.ValueBasedCancerCare.com

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3rd Conference

Payers Must Step Up Their Utilization Management... (ie, evaluating the historical claims activity) • Dose optimization (eg, providing a week’s supply only of an oral oncolytic drug, shipped from a specialty pharmacy) • Diagnostic tests that match the drug to the suitable patient’s adherence to FDA approval

• Mandatory substitution and interchange of drugs (which will be increasingly important once biosimilars arrive on the market).

Additional utilization management options include step-edits, quantity limits, use of preferred products, use of tiered formularies, cycle management, oncology first-fill programs,

Table Specific Prior Authorization Criteria, by Total Lives Covered PA criteria

Total lives covered, %

FDA indication

100

Compendia listing

85

Previous therapy failure

78

Dose to weight in therapeutic range for indication

61

Treatment cycle/interval tracking

55

Appropriate concomitant medications

50

FDA indicates US Food and Drug Administration; PA, prior authorization.

Source: ICORE Healthcare. Medical injectables & oncology trend report.

2011. www.icorehealthcare.com/media/422047/trend_report_2011.pdf.

buy-and-bill management, and prior authorization.

“The degree to which utilization management is applied can have a significant impact on physician practices,” Mr Kenney noted. “From a plan perspective, ideally, what we want is not to disrupt the practice, not to disrupt the patient flow, but to put reasonable controls in place to manage utiliza­ tion. We monitor these constantly and make changes.”

Many criteria can be applied to prior authorizations. A 2011 trend survey from ICORE Healthcare described the respondents’ prior authorization criteria for injectables (Table).

It is probably easiest for plans to simply state that no prior authorization will be required when drugs are used according to the FDA indication, Mr Kenney suggested.

When practices show good compliance with the appropriate use of a drug, and few requests are made outside of guidance, prior authorizations can be lifted. Prior authorizations should be

Continued from page 14

periodically reevaluated, largely because new drugs become available, Mr Kenney added.

Quality standards and quality measures are also incorporated into practices, along with performance incentives that can be built into contracts.

The Medical Benefit Is Expanding It is likely that much of the resources and tools that have historically been applied to the pharmacy benefit will increasingly be moved to the medical side, Mr Kenney predicted, especially with the increase in oral therapies and new modes of administration, including self-administration of injectables.

“The medical benefit, which no one has paid much attention to, is expanding, thanks to new drugs, infusible products, and so forth,” he said.

Although many of the new oncology drugs will be orals, there will remain a significant amount of drug utilization on the medical side, requiring some level of control and management. n

A PBM Perspective on Biosimilars

By Caroline Helwick

Hollywood, FL—Pharmacy benefit managers (PBMs) will soon have the new challenge of dealing with the confusion of biosimilars, according to Douglas S. Burgoyne, PharmD, President and Managing Partner, VRx Pharmacy Services, Salt Lake City, UT, a full-service PBM company that provides medication therapy management, case management, and other clinical services to employer group waiver plans and commercial payers.

Dr Burgoyne is immediate Past President of the Academy of Managed Care Pharmacy (AMCP), and he described the AMCP’s position on biosimilars at the Third Annual Con­ ference of the Association for ValueBased Cancer Care.

Biologics include a wide range of products that are generally made from human and/or animal materials. They are usually larger than and have a more complex structure than smallmolecule prescription drugs. They may be manufactured through biotechnology, derived from natural sources, or produced synthetically.

“Biologics and specialty drugs, as defined by payers, generally mean the same thing—an injectable, usually—

24

but we’ve also added a definition around cost, and that is that if the product costs more than $600 per

Biosimilars (or follow-on biologics) are biologic products that are very similar to US-licensed reference bio-

“Biologics and specialty drugs, as defined by payers, generally mean the same thing—an injectable, usually—but we’ve also added a definition around cost, and that is that if the product costs more than $600 per month, then we can categorize it as a specialty product.”

—Douglas S. Burgoyne, PharmD

month, then we can categorize it as a specialty product,” Dr Burgoyne said.

“More and more products are going into this specialty bucket. That affects contracting downstream. It also affects member copayment, and how much the member contributes to the cost of the drug.”

Value-Based Cancer Care

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logic products, notwithstanding minor differences in clinically inactive components. There are no clinically meaningful differences between the biologic product and the reference product in terms of the safety, purity, and potency of the product.

The US Food and Drug Admini­ s­

tration (FDA) has been working on a biosimilar pathway for biologic drugs for some time now, but challenges remain and no biosimilar products have yet been approved by the FDA. The AMCP Position on Biosimilars The AMCP supports an abbreviated licensure pathway for the FDA approval of biosimilar biologic drug therapies. In addition, the AMCP believes that an expedited approval process provides a needed incentive for the development of important new therapies. Finally, the expectation is that these drugs will cost less than the originator, or reference, product.

“With biosimilars, we’re looking at an opportunity, basically, to save money, but also to create a pathway for a follow-on biologic that is safe and effective,” Dr Burgoyne said.

The issue of whether to require additional clinical trials for biosimilars remains unresolved, but the AMCP believes that the FDA should consider this on a case-by-case basis. The AMCP proposes a 2-step process: the first step is to determine the actual biosimilarity of an applicant product, and the second Continued on page 29

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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

A PBM Perspective on Biosimilars... step is the interchangeability of the biosimilar with the reference product.

“If it’s interchangeable, that helps us. That helps pharmacies as well,” he noted. “The biosimilar would be dispensed by the pharmacist without having to go back to the physician.”

The AMCP would also prefer that the biosimilar receives the same indication profile as the reference product.

“We’re looking for an opportunity to reduce costs, have effective products that are safe, and leave regulation to the FDA,” Dr Burgoyne said. He pointed out that the PBM’s perspective can be summarized in the following: 1. Interchangeability of the biosimilar agent and the brand-name drug should be “AB” rated, meaning that the biosimilar can be substituted for the brand product as simply and as quickly as possible 2. Biosimilars will be cost-saving 3. Each state will have its own restrictions about its use of biosimilars 4. There will be reliance on specialty pharmacies to navigate the state regulations and to focus on distribution and case management.

Advantages and Disadvantages of Biosimilars Biosimilars are expected to be cost-saving—although perhaps only by 10% to 15% over the originator products, at least for the first generation. Biosimilars should, however, create opportunities to negotiate additional discounts and rebates with manufacturers of biosimilars and branded products, Dr Burgoyne predicted.

But there is expected to be considerable confusion at the patient level and at the provider level in terms of recognizing which products should be dispensed, by whom, and by which strategy.

States Taking Preemptive Action Against Biosimilars The emergence of biosimilars is not met without resistance. More than 17 states have already proposed bills that would restrict the use of biosimilars—even in the absence of available biosimilar products. The presumption, without direct evidence, is that bills have been written and

Continued from page 24

at a glance ➤ Biosimilars are similar to their US-licensed reference biologics but have minor differences in clinically inactive components ➤ Biosimilars are expected to cost less than their reference products ➤ The AMCP suggests 2 steps for clinical trials with biosimilars: determine the product’s actual biosimilarity and assess inter­ changeability with its reference product

assisted by the brand manufacturers in an effort to reduce the in­ter­ changeability of biosimilars, Dr Burgoyne suggested.

The AMCP considers this premature, because the FDA has yet to finalize its guidelines regarding these drugs. Until those guidelines are finalized, there is no way to know if additional steps are warranted before sub-

➤ There are no clinically significant safety, purity, and potency differ­ ences between biosimilars and their reference, brand-name products ➤ The FDA is still working on a biosimilar pathway for biologics ➤ Confusion regarding biosimilars is expected at the patient and provider levels in terms of recognizing which products should be dispensed, by whom, and by which strategy

stituting an interchangeable product, he said.

“We’re saying to states, ‘Wait until there is a biosimilar. Wait until the FDA has determined a pathway. Wait until we know what the interchangeability status is, and then create leg­ islation that will protect members within your states,’” Dr Burgoyne pointed out. n

Meet the Experts

340B Program At the Third Annual Conference of the Association for Value-Based Cancer Care, several Meet the Experts roundtable discussions addressed the hottest topics in oncology. Tony Zappa, PharmD, MBA, Vice President, Contract Pharmacy Services Operations, Wellpartner, moderated this discussion.

The 340B Drug Pricing Program provides access to drugs at a reduced cost to certain institutions; the program limits the cost of outpatient drugs for hospitals that provide care to a high proportion of indigent patients, or to patients who live in rural or remote areas. Hospitals qualified for the program include: • Disproportionate-share hospitals (ie, those treating indigent patients) • Children’s hospitals • Cancer hospitals exempt from Medicare’s prospective payment system • Critical access hospitals • Rural clinics • Sole community hospitals.

Before the implementation of the Affordable Care Act (ACA), 1200 hospitals qualified for the 340B program. Currently, that number is 2200, and all critical care hospitals automatically qualify.

To date, many hospitals have not established mechanisms to effectively track 340B costs, despite being required to do so. Although the Office of Pharmacy Affairs conducts between 200 and 300 audits annually, no penalties or sanctions are used for noncompliance. Drug manufacturers may request audits for hospitals that are using their products. The implementation of the International Classification of Diseases, Tenth Revision coding will add an additional layer of complexity to tracking these costs.

Participation in the Program One of the most important factors influencing participation in the 340B pro-

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gram is the expected cost-savings. Participating rural hospitals are larger and are more likely to administer high-cost drugs than hospitals not participating in the program.

Hospitals participating in the program are free to allocate the cost-savings realized from participating in the program in any way they like.

There have been suggestions that hospitals are taking advantage of lax oversight in the program, with unintended consequences. Some contend that Congress should require that hospitals fully disclose how they use their 340B pharmacy profits.

Furthermore, some specialty pharmacies would like to get involved in the 340B program, but it may not be worth it for big specialty pharmacies, because 340B drugs are a fairly small percentage of the overall US drug spending.

Unintended Consequences According to one provision in the ACA, orphan drugs are excluded from new hospitals that are qualified for the 340B program. This provision has the unintended consequence of disproportionately affecting children’s hospitals, which tend to prescribe more orphan drugs than other hospitals.

The expansion of the Medicaid program may add 300 new hospitals that are qualifying for the 340B program.

Hospitals can change their business structure to become eligible for the 340B program. For example, it can be argued that some hospital systems are buying rural clinics and other facilities so that the entire hospital system qualifies for 340B pricing. Under the proximity clause, however, a provider-owned clinic must be within 30 miles of the parent hospital to qualify for the program. In the case of integrated health systems, not all hospitals will necessarily apply for the program, even if they are owned by the same health system.

There are no statutes limiting hospitals from buying satellite locations or transferring ownership to draw in more provider-owned clinics.

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3rd Conference

Healthcare Reform and End-of-Life Care Myths versus Reality We could do better at meeting patients’ needs, reducing waste

By Caroline Helwick Hollywood, FL—End-of-life issues have advanced in a positive direction since the so-called death panel controversy of 2009, but health plans still need to promote these discussions, said J. Russell Hoverman, MD, PhD, Vice President, Quality Programs, Texas Oncology, at the Third Annual Conference of the Association for Value-Based Cancer Care.

“Death panel” is a term famously popularized by Sara Palin in 2009 after Rep John Boehner suggested that the provision for end-of-life counseling in the Affordable Care Act (ACA) could “start us toward government-encouraged euthanasia.” The statement won the PolitiFact “Lie of the Year” award.

The amendment involving end-oflife care was stricken from the final ACA, but the coverage of end-of-life discussions has been written into the regulations pertaining to the law starting on January 1, 2011. The death panel debate had a serious effect on the American public: • 35% of older Americans said that the ACA would allow a government panel to make decisions about endof-life care for people in Medicare (Kaiser Family Foundation. http:// kff.org/health-reform/poll-finding/ march-2013-tracking-poll/) • 47% of Republicans thought that death panels existed (Pew Research Center. www.people-press.org/2009/ 08/20/health-care-reform-closelyfollowed-much-discussed/) • 59% of Republicans either thought that death panels were part of the ACA or were unsure (Regence Foun­ dation. www.nationaljournal.com/ healthcare/no-death-panels-pleasebut-poll-shows-americans-canhandle-end-of-life-chat-20110308).

The Regence Foundation survey also showed that 78% of the public still believes that palliative care and endof-life issues should be in the public discourse; 93% say that advance care planning and end-of-life decisions should be a top priority for the US healthcare system; 70% agree that “it is more important to enhance the quality of life for seriously ill patients, even if it means a shorter life”; and only 33% of Americans expressed trust in elected officials for delivering accurate information.

With such a gap between myth and reality, and when the political system “is not to be trusted,” the US healthcare system has a responsibility to be a

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“The take-home message is that honoring people’s choices with informed decision-making leads to better, less aggressive end-oflife care. The challenge is to build that into a healthcare system so this is the thing that every patient receives.”

—J. Russell Hoverman, MD, PhD

source for accurate information, Dr Hoverman emphasized.

Rationing in Healthcare The concept of death panels does have some historical basis. In the mid1960s, hemodialysis was apportioned to individuals deemed by a committee to be most worthy. Today, society is being called on to determine how to manage expensive treatments. Arizona has responded, for example, by cutting Medicaid coverage for previously covered organ transplants, creating a subclass of people without access to critical medical treatment.

“To the extent that death panels, of a sort, do exist, they are composed of state officials who must decide whether each state’s version of Medicaid will cover certain expensive, potentially life-saving treatments,” Dr Hoverman said. It is possible that this could extend beyond transplants to pharmaceuticals.

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Meeting Patients’ Needs at the End of Life It does not take a death panel to decipher and provide what patients want at the end of life, especially for patients with cancer; this includes not receiving nonbeneficial treatments, not suffering, and avoiding “financial waste,” as well as receiving “honest information and truthful prognostic disclosure, which does not destroy hope,” Dr Hoverman said.

Studies show that 86% of patients would prefer to spend their last days at home, 87% would not be put on a ventilator to gain 1 week of life, and 77% would not want a ventilator to gain 1 month of life. Seriously ill patients do want freedom from pain, peace with God, presence of family, and mental awareness. They want to have their treatment choices followed and their finances in order. They want to feel that life was meaningful. They want to resolve conflicts and die at home. “The list does not include more chemotherapy,” Dr Hoverman emphasized.

Advance Care Planning Improves End-of-Life Care, Reduces Waste End-of-life conversations result in increased use of hospice services and in less pain. Patients with cancer who have advance care planning are: • 3 times less likely to enter the intensive care unit (ICU) • 7 times less likely to have mechanical ventilation • 8 times less likely to undergo cardiopulmonary resuscitation (CPR), with no difference in mortality rate.

When nursing home patients engage in advance care planning, hospitalization rates are reduced and the global cost of care is reduced by 33%, with the mortality rate again unchanged. Good pain control is far more likely to occur when patients die in hospice care than in the hospital.

Patients who have advance care planning are more likely to die amid family, and their family members report significantly less stress, anxiety, and depression, as well as higher satisfaction with care. By contrast, in the absence of advance care planning, families demand more futile treatments and more CPR and ICU services, and undergo more stress overall.

Suboptimal end-of-life care is very expensive. The United States spends $142 billion on medical care in the last year of life, and $71 billion in the last 2 months, Dr Hoverman noted.

at a glance ➤ A recent survey shows that 78% of Americans feel that palliative care and end-of-life issues should be a top priority for the US healthcare system ➤ End-of-life conversations result in increased use of hospice services and less pain for patients ➤ Advance care planning lowers hospitalization rates and the overall cost of care; it can also generate conversations that lead to better, less aggressive end-of-life care Facilitating the Patient–Provider Discussion “Multiple studies show that patients receive better care after advance care planning. The question is, how do we begin these conversations? How can we make it easier for physicians?” Dr Hoverman asked.

A simple intervention has helped Texas Oncology’s physicians in the Innovent Oncology program. The program involves a 10-item quiz aimed at determining a patient’s wishes for end-of-life care. The list contains such statements as, “It is important for me to be told by my physician when I am dying,” he noted.

“These simple questions serve as a bridge to having these conversations,” Dr Hoverman stated. “The take-home message is that honoring people’s choices with informed decision-making leads to better, less aggressive end-of-life care. The challenge is to build that into a healthcare system so this is the thing that every patient receives.” n

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Fourth Annual Navigation and Survivorship Conference Memphis, Tennessee â&#x20AC;˘ The Peabody Memphis

NOVEMBER 15-17, 2013 CONFERENCE CO-CHAIRS Lillie D. Shockney, RN, BS, MAS AONN Program Director University Distinguished Service Associate Professor of Breast Cancer Departments of Surgery and Oncology Administrative Director, Johns Hopkins Clinical Breast Programs Administrative Director, Johns Hopkins Cancer Survivorship Programs Department of Surgery and Oncology Associate Professor, JHU School of Medicine Departments of Surgery, Oncology, and Gynecology Associate Professor, JHU School of Nursing Johns Hopkins Avon Foundation Breast Center Baltimore, MD

Sharon Gentry, RN, MSN, AOCN, CBCN Breast Health Navigator Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

REGISTER TODAY

www.AONNonline.org AONNKsize31413

Patient Navigation

Patient Navigators Enhance Colonoscopy Screening Rates and Save Money in the Long Run An emerging, cost-effective service, but reimbursement is lagging

By Caroline Helwick Orlando, FL—The use of patient navigators can reduce racial disparities in colorectal cancer (CRC) screening and can potentially reduce the mortality rates—and do both cost-effectively, according to studies presented at Digestive Disease Week 2013.

Through a 1-to-1 relationship, patient navigators bridge disparities by assisting with scheduling appointments; educating patients about bowel preparation; and by addressing cultural, linguistic, and financial obstacles.

The value of patient navigators was documented in a study by Delia Calo, MD, Memorial Sloan-Kettering Cancer Center, New York.

To improve adherence to colonoscopy screening, in 2003 the New York City Department of Health and Mental Hygiene implemented the Colon­ os­ copy Patient Navigator Program at 22 sites. Dr Calo reported on a total of 37,077 scheduled screening colonoscopies and 2198 surveillance colonoscopies (ie, follow-up after a positive finding). With the assistance of patient navigators, 31,215 individuals had screening colonoscopy, for an adherence rate of 84.2%, and 2062 had surveillance colonoscopy, for an adherence rate of 93.8%. No racial dis­crep­ancies were documented, Dr Calo said.

Patient Navigation Is Cost-Effective Patient navigation not only enhances colonoscopy rates, but it is also cost-effective, according to a modeling study that evaluated navigation over a long-term horizon.

“We found that patient navigation for one-time screening colonoscopy appears to increase life expectancy while saving costs,” reported Uri Ladabaum, MD, MS, Interim Chief, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, CA. “This reflects a favorable balance between the increase in screening uptake achieved by navigation, and the costs of providing navigation,” he said.

The investigators examined onetime colonoscopy in a cohort reflecting a population at a major New York City hospital. The study compared the costs for patient navigation versus no navigation and no screening, with a time horizon through age 100 years or death. Outputs were mean discounted quality-adjusted life-years (QALYs) and costs per person. The base-case

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Table Benefits and Costs of Patient Navigation for Screening Colonoscopy Age-group screeneda

Mean QALY per person (discounted), N

Mean costs per person (discounted), $

Navigation

Navigation vs no navigation

17.509

+0.015

2389

Navigation

13.754

2495

9.768

2402

50-59 yrs

60-69 yrs

Navigation vs no navigation

+0.014

70-79 yrs

Navigation

Navigation vs no navigation

+0.008

–91

–198

–195

All races, ethnicities.

QALY indicates quality-adjusted life-year. a

inputs were based on navigation studies and 2012 Medicare payments.

The costs of patient navigation were added to the costs of screening. Basecase inputs assumed screening uptake rates of 40% without navigation and of 65% with navigation. The cost of a diagnostic colonoscopy was $661, and a colonoscopy with intervention was $939. Navigation costs were figured at $29 per colonoscopy completer, $21 per noncompleter, and $3 per incomplete navigation.

“We found that patient navigation for one-time screening colonoscopy appears to increase life expectancy while saving costs….In emerging healthcare models that reward outcomes, payers should strongly consider covering the costs of patient navigation for colorectal cancer screening.”

—Uri Ladabaum, MD, MS The model determined that CRC would be diagnosed in 551 per 10,000 persons without screening, 453 who had colonoscopy without navigation,

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and 392 for colonoscopy with navi­ gation. CRC deaths per 10,000 persons would number 216, 174, and 148, respectively.

“We found that navigation improved life expectancy and was cost-saving,” Dr Ladabaum reported.

“With navigation, for all ages and ethnicities, patients could anticipate a life expectancy of 15.458 QALYs, and without navigation, a lower number, 15.444 QALYs, so there were better clinical outcomes with navigation. The cost per person was $2422 with navigation and $2558 without, so navigation was more effective and less costly, making it the dominant strategy.”

Navigation improved life expectancy and decreased costs for all subgroups (Table), he said.

The clinical and economic benefits were greatest for patients aged 50 to 69 years. Gains in life expectancy were highest in whites, then blacks, and third Hispanics; however, cost-savings were greatest in blacks.

“These results reflect the interplay between subgroup-specific colorectal cancer incidence and age-specific allcause mortality,” Dr Ladabaum noted.

In the sensitivity analysis, navigation became cost neutral when the navigation cost per colonoscopy completer rose to $199, and it cost $25,000 per QALY gained when the navigation cost per colonoscopy completer was as high as $622. With base-case navigation costs, navigation became cost neutral at a modest increase in uptake of

only 3% with navigation, and it cost $25,000 per QALY gained at an increase in uptake of 1% with navigation, he added.

“In emerging healthcare models that reward outcomes, payers should strongly consider covering the costs of patient navigation for colorectal cancer screening,” Dr Ladabaum concluded.

Should You Hire a Patient Navigator?

Based on these results, David Lieberman, MD, Chief, Division of Gastroenterology, Oregon Health and Science University School of Medi­ cine, Portland, asked, “So, if I’m the CEO of a coordinated care organization, I should rush out to hire patient navigators?”

“We are getting more patients in for colonoscopies, our bowel preps are better, and our completion rates are higher. That’s how the hospital makes money: more colonoscopies, higher quality.”

—Steven H. Itzkowitz, MD Dr Ladabaum responded, “Assum­ ing you believe the findings, I think the answer is yes.”

Steven H. Itzkowitz, MD, Associate Director, the Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mt Sinai, New York, said that his patient navigation program “turns a profit for the institution, mainly by increasing the volume of colonoscopies. We are getting more patients in for colonoscopies, our bowel preps are better, and our completion rates are higher. That’s how the hospital makes money: more colonoscopies, higher quality.”

Dr Itzkowitz noted that the navigation of 1000 patients costs 0.43 fulltime equivalent health educators at a salary of approximately $40,000 annually. “So, for $20,000 a year you can navigate 1000 patients,” he suggested.

“If you really want to be cost-effective, you can train volunteers from the community. This is almost a no-brainer at this point.” n

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Health Policy

Implications for Oncology after Supreme Court Ruling that Genes Cannot Be Patented Decision opens new doors in cancer diagnostics, research

By Rosemary Frei, MSc

T

he US Supreme Court’s ruling on June 13 in the case of the Association for Molecular Pathology v Myriad Genetics will have significant implications for the future of cancer testing, molecular diagnostics, and treatment.

The 9 members of the Supreme Court had been asked to answer the question, “Are human genes patentable?”

Their ruling was 2-fold: they ruled that Myriad’s patent claims on the BRCA1 and BRCA2 DNA sequences are invalid, but that sequences known as complementary deoxyribonucleic acids (cDNAs) are patentable by any company or individual. (Myriad tests women’s DNA for the presence of mutations in BRCA1 and BRCA2, which significantly increase the risk for breast and/or ovarian cancer. cDNA is created in the laboratory by annealing DNA base pairs to single-stranded messenger RNA.) In their near-unanimous decision, the judges determined that “a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patent eligible because it is not naturally occurring….It is undisputed that Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes,” they noted. “Nor did Myriad

at a glance ➤ Although the Court ruled that BRCA1 and BRCA2 DNA sequencing cannot be patented, they also ruled that sequencing of complementary deoxyribonucleic acid (cDNA) is patentable ➤ cDNA was deemed patent eligible because it is artificially created in a laboratory and doesn’t correspond to anything in the body ➤ Consequently, companies are still able to patent DNA that has been artificially manipulated for cancer diagnosis ➤ The Court’s decision has left open the ability to claim recombinant constructs or host cells that are transformed with recombinant constructs

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create or alter the genetic structure of DNA….To be sure, it found an impor­ tant and useful gene, but separating that gene from its surrounding genetic material is not an act of invention.”

The judges explained that the US Patent Act states that natural phenomena are not patentable, and that “without this exception, there would be considerable danger that the grant of patents would ‘tie up’ the use of such tools” and slow down or stop innovation.

“This is a sensible decision that tracks closely to the US government’s position and the Bryson dissent.

It will shrink the shadow of infringement liability from first-generation gene patents that hangs over genomic diagnostics, while preserving strong patent rights for valuable protein therapeutics.”

—Robert Cook-Deegan, MD

The History of the Decision This decision was foreshadowed in the oral arguments presented before the Supreme Court on April 15, 2013, as well as in the single dissenting opinion by Circuit Judge William C. Bryson in the July 2011 decision by a 3-judge panel of the US Court of Appeals for the Federal Circuit. Although 2 of the 3 judges on that panel held that Myriad’s BRCA1 and BRCA2 DNA patents are valid (and was the decision the panel issued, which became the basis for the Association for Molecular Pathology’s appeal to the Supreme Court), Judge Bryson said that their claims were too all-inclusive.

“Extracting a gene is akin to snapping a leaf from a tree,” Judge Bryson wrote. “Like a gene, a leaf has a natural starting and stopping point. It buds during the spring from the same place it breaks and falls during autumn. Yet prematurely plucking the leaf would not turn it into a human-­ made invention.”

In his appearance before the Su­

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preme Court in April, representing the federal government, Solicitor General Donald B. Verrilli, Jr, noted, “Our position…is that cDNA is patent eligible because we think, unlike the isolated DNA which is just taken from your body, cDNA is an artificial creation in the laboratory that doesn’t correspond to anything in your body.”

Implications for Cancer Diagnosis and Beyond Value-Based Cancer Care asked Robert Cook-Deegan, MD, Director of Genome Ethics, Law and Policy at Duke University, Durham, NC, for a comment. “This is a sensible decision that tracks closely to the US government’s position and the Bryson dissent. It will shrink the shadow of infringement liability from first-generation gene patents that hangs over genomic diagnostics, while preserving strong patent rights for valuable protein therapeutics,” Dr Cook-Deegan said.

Michael J. Shuster, PhD, a partner at Fenwick & West’s Intellectual Property Practice, San Francisco, CA, was also asked by Value-Based Cancer Care to comment on the decision. Fenwick & West filed an amicus brief in support of Myriad on behalf of the National Venture Capital Association.

Dr Shuster said that the Supreme Court’s ruling leaves room for companies to patent DNA that has been manipulated for the purpose of diagnosing cancer, but that Myriad’s patents on its methods of using DNA to test for cancer susceptibility could be challenged in the future.

“All someone has to do is claim the DNA is labelled for doing hybridization-based assays for diagnostic purposes, and that will be within the parameters of what the Court ruled is patent eligible. And the Court also left open the ability to claim recombinant constructs or host cells that are transformed with recombinant constructs,” said Dr Shuster.

In addition to allowing patients to be tested by new venues for the BRCA mutations, the Court’s decision will affect cancer research and diagnosis in ways that may not yet be fully understood. Many cancer diagnostics today involve a panel of genes rather than a single gene, and treatment decisions are increasingly dependent on combination therapies and multiple gene mutations. n

Oncology/Hematology Meetings 2013 September 7-9 Breast Cancer Symposium 2013 San Francisco, CA Contact: 888-788-1522 or bcsregistration@jspargo.com September 20-21 NCCN 8th Annual Congress New York, NY Contact: 215-690-0300 or www.nccn.org/professionals/ meetings/hematological/ default.asp September 22-25 ASTRO’s 55th Annual Meeting Atlanta, GA Contact: 800-962-7876 or education@astro.org September 27-October 1 17th ECCO-38th ESMO-32nd ESTRO European Cancer Congress Amsterdam, the Netherlands Contact: 32 (0) 2 775 02 01 or ecc2013@ecco-org.eu October 2-5 ACCC 30th National Oncology Conference Boston, MA Contact: 301-984-9496 or ksmith@accc-cancer.org October 4-5 Symposia on Cancer Research 2013-Genomic Medicine M.D. Anderson Cancer Center Houston, TX Contact: 866-849-5866 or register@mdanderson.org October 24-25 Cancer Center Business Summit Chicago, IL Contact: 262-770-9627 or jbrunner@meetings-incentives.com November 1-2 ASCO’s 2013 Quality Care Symposium San Diego, CA Contact: 888-788-1522 or qualityregistration@jspargo.com December 7-10 2013 ASH Annual Meeting New Orleans, LA Contact: 888-273-5704 or ashregistration@jspargo.com December 10-14 2013 CTRC-AACR San Antonio Breast Cancer Symposium San Antonio, TX Contact: 210-450-1550 or sabcs@uthscsa.edu

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Personalized Medicine

Two Genetic Tests Can Prevent Overtreatment... and to improve decision-making and risk assessment.

Studies presented at the 2013 Ameri­ can Society of Clinical Oncology meeting focused on the 2 tests, which experts believe will compete with each other for market share.

Oncotype DX for Prostate Cancer Expecting FDA Approval Launched by Genomic Health on May 18, 2013, the Oncotype DX prostate cancer test is similar to the Oncotype DX breast cancer and colon cancer tests widely used in the United States.

The Oncotype DX prostate cancer test measures the expression of 17 genes in a prostate tissue specimen that can predict the aggressive level of prostate cancer by generating a genomic prostate score ranging from 0 to 100.

H. Jeffrey Lawrence, MD, Senior Director of Medical Affairs, Genomic Health, Redwood City, CA, presented data showing that the expression patterns that predict prostate cancer aggressiveness are similar in tumor tissue and in normal prostate tissue.

The genomic prostate score derived from tumor-based gene-expression

patterns in the tumor was also associated with clinical recurrence when assessed in adjacent normal prostate tissue, but the strength of the association was less robust than in the tumor.

The genes associated with the strong­ est predictive value of the genomic

These genetic tests, although expensive, have the potential to prevent overtreatment of prostate cancer and reduce the associated costs, and may also help to improve decision-making and risk assessment of patients with prostate cancer.

prostate score in normal tissue were those representing stromal response and androgen signaling.

A validation study of the Oncotype DX prostate cancer test was presented at the 2013 meeting of the American Urological Association by Peter

Carroll, MD, Professor and Chair, Department of Urology, University of California, San Francisco.

The test significantly predicted disease aggressiveness (P = .002) beyond clinical factors that included prostate-specific antigen level and Gleason score.

The test is estimated to cost approximately $3800. Genomic Health is in the process of building a dossier of evidence for insurers. Based on Genomic Health’s strong track record with the breast and colon cancer Oncotype DX assays, the company expects the US Food and Drug Administration (FDA) to grant approval to the prostate test.

Prolaris Approved by FDA Prolaris, manufactured by Myriad Genetics, is approved by the FDA for use in low-risk men with a Gleason score of 6, and for patients postprostatectomy who are at high risk for prostate cancer recurrence. Prolaris, which has been available for several months, costs approximately $3400.

The assay generates a cell cycle progression (CCP) score based on the average RNA expression of 31 CCP genes that are normalized by the average expression of 15 housekeeping

Continued from cover

genes as quantitated by reverse transcriptase polymerase chain reaction.

Jack M. Cuzick, PhD, Director, Wolfson Institute of Preventive Medicine, University of London, United Kingdom, presented a retrospective review of 5 studies of the Prolaris test showing that the test-generated CCP score was able to predict prostate cancer outcomes in multiple patient cohorts and in diverse clinical settings.

In a statement issued before the meeting, Dr Cuzick said, “Clinical data show that PROLARIS predicts prostate cancer outcome in multiple patient cohorts and in diverse clinical settings. PROLARIS provides independent information beyond clinicopathologic variables and accurately differentiates aggressive prostate cancer from indolent cancer based on real oncologic outcomes.”

A similar distribution of CCP scores was found in all 5 studies, showing its utility in different settings. The CCP score was a significant predictor of disease outcome.

However, the 5 studies were not randomized; therefore the results should be interpreted with caution, Dr Cuzick said. n

Genomic Sequencing Uncovers the Genetic Landscape of Primary CNS Lymphoma Will likely lead to new targeted therapies for an incurable malignancy

By Dalia Buffery Lugano, Switzerland—The genomic basis of primary central nervous system lymphoma (PCNSL), a very aggressive and incurable type of lymphoma, has not been understood until now. At the 2013 International Con­ ference on Malignant Lymphoma, a team of researchers from the Mayo Clinic and from the University of Virginia presented its recent findings at a poster session involving the most comprehensive study to date of the genomic landscape of PCNSL. Esteban Braggio, PhD, of the Mayo Clinic in Scottsdale, AZ, and colleagues used a variety of tools, in­ cluding array-based comprehensive genomic hybridization (aCGH), whole-exome sequencing, mate pair whole-genome sequencing, and targeted sequencing, to determine whether PCNSL and systemic diffuse large B-cell lymphoma (DLBCL) are different in their molecular makeup and

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pathogenesis, and whether there is a CNS-specific genetic signature in PCNSL. The team identified a total of 35 genes with aCGH in the 51 cases of PCNSL that were investigated, and additional molecular sequencing screenings were selected for targeted sequencing in other patients with PCNSL. The large majority of cases— 89% of the patients—had abnormalities of the CDKN2A gene, which can be seen as a unifying characteristic of this disease. In addition, MYD88 mutations were present in 79% of cases, a high prevalence rate.

Other genes that were previously identified in DLBCL included inactivated mutations of TNFAIP3 (16%), PRDM1 (16%), GNA13, TMEM30A, B2M, and CD58 (11% each); activated mutations of CD79B (28%) and CARD11 (19%); and translocations of BCL6 (22%) in patients with PCNSL.

The genetic signature of PCNSL is associated with post–germinal center DLBCL and is involved in a subset of disease-specific abnormalities. It further shows a large number of genes that are involved in the immune response, lymphocyte differentiation, disease proliferation, and in apoptosis.

By contrast, the following mutations identified in this study (that had not been seen in DLBCL) indicate their unique involvement in PCNSL: 11% of

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PCNSL cases show biallelic inactivation of TOX and PRKCD and 17% of cases show monoallelic inactivation in these 2 genes. The investigators therefore suggest that TOX, a T-cell development regulator, has a key role in the pathogenesis of PCNSL, based on its high prevalence in abnormalities related to this gene.

This study confirms that the genetic signature of PCNSL is associated with post–germinal center DLBCL and is involved in a subset of disease-specific abnormalities. It further shows a large number of genes that are involved in the immune response, lymphocyte differentiation, disease proliferation, and in apoptosis.

Furthermore, this new understanding of the genetic makeup of the disease opens the door to the development of new targeted therapies for this type of cancer and potentially improved outcomes. n

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Prostate Cancer

Comparing the Impact of ADT Agents on Cardiovascular Events and Death in Men with Prostate Cancer

By Rosemary Frei, MSc

Niagara Falls, Ontario—Among men with prostate cancer and preexisting cardiovascular (CV) disease, the risk of CV events or CV-related death is cut in half when they receive androgen-deprivation therapy (ADT) with degarelix (Firmagon) instead of the luetinizing hormone–releasing hormone (LHRH) agonists goserelin (Zoladex) or leuprolide (Lupron), according to results of a new analysis presented at the 2013 Canadian Urological Association annual meeting.

An examination of pooled data from 6 prospective, randomized trials showed that the probability of CV events or death is reduced by 51.2% with degarelix versus one of the 2 LHRH agonists.

Lead investigator Laurence Klotz, MD, Chief, Division of Urology,

“Degarelix is not just a way to lower testosterone, but it has some real advantage over LHRH agonists besides reducing flares.”

—Laurence Klotz, MD Sunnybrook Health Sciences Centre, Toronto, Ontario, said that the results triumphed over his initial skepticism that simply having a different mode of action (degarelix is a gonadotropinreleasing hormone antagonist) would alter the chance of CV events.

“Degarelix is not just a way to lower testosterone, but it has some real advantage over LHRH agonists besides re-

ducing flares,” Dr Klotz concluded after presenting the results of the analysis.

His team focused on CV events and death data from three 3-month and three 12-month randomized controlled trials of ADT agents. A total of 1491 patients in the trials received degarelix, 458 received goserelin, and 379 took leuprolide.

The patients receiving degarelix and LHRH agonists had similar baseline characteristics, including average age (71.7 years vs 71.6 years, respectively) and rates of smokers (59% vs 52%, respectively).

Overall, 53 (3.6%) of the patients who received degarelix and 48 (5.7%) of those who received an LHRH agonist had a CV event or died from any cause during the trials. This translated into a significantly reduced risk of a

CV event or death over 1 year of treatment with degarelix.

Men with a history of CV disease who received degarelix had a significant reduction in events or death versus those who received LHRH agonists, whereas those without a history of CV disease did not experience this reduction. Men receiving degarelix, with or without a history of CV disease, also had a significantly increased probability of overall survival.

A multivariable analysis revealed an estimated hazard ratio of 0.488 for CV events or death in men with a history of CV disease who received degarelix versus men who received an LHRH agonist. Alcohol consumption and having a low serum testosterone level were also protective against having a CV event and against death. n

Strongly Suppressing Testosterone during AndrogenDeprivation Therapy Prolongs Survival Niagara Falls, Ontario—A secondary analysis of a large study on intermittent versus continuous androgen-deprivation therapy (ADT) has confirmed the importance of aiming for very low testosterone levels in men

after they are diagnosed with prostate cancer, according to new data presented at the 2013 Canadian Urological Association annual meeting.

Laurence Klotz, MD, Chief, Division of Urology, Sunnybrook Health

Prostatic Inflammation Protects Against Prostate Cancer Niagara Falls, Ontario—New data presented at the 2013 Canadian Urological Association annual meeting suggest that prostatic inflammation can reduce the risk for developing prostate cancer.

J. Curtis Nickel, MD, Professor, Department of Urology, Queen's University, Kingston, Ontario, and colleagues retrospectively analyzed data from 6269 men who were included in a randomized controlled trial of dutasteride (Avodart) and who had a negative baseline prostate cancer biopsy. Men who had acute inflammation in the baseline biopsy had a 25% lower risk for developing prostate cancer within 2 years, and those with chronic inflammation at baseline biopsy had a 35% reduction in risk.

The data came from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study.

Men who had acute inflammation in the baseline biopsy were significantly

36

younger, had lower PSA levels, and had smaller prostates than men without baseline acute inflammation. Men with chronic inflammation at baseline were older and had larger prostate volumes than those who did not have baseline chronic inflammation.

The univariable analysis indicated that acute inflammation and chronic inflammation independently reduced the risk for a cancer-positive diagnosis based on a repeated biopsy. The multivariable analysis showed that there was a 25% reduction in cancer risk in men with acute inflammation at baseline and a 35% lower risk in men with baseline chronic inflammation.

Dr Nickel noted that he and his colleagues did not have access to previous biopsies for the study participants, and, therefore, it is impossible to tell whether earlier inflammation had an influence on having a cancer-positive biopsy at baseline. —RF n

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Cancer Centre, Toronto, Ontario, was the primary investigator for the PR-7 companion trial, as well as for this new analysis. Dr Klotz and his colleagues determined that maintaining very low testosterone levels nearly halves men’s risk of developing hormone-resistant disease and significantly prolongs their survival time. He commented on these results, “This is one of the most important studies I’ve ever done.”

“If you have failure of testosterone suppression, you should consider changing the drug, perhaps adding an antiandrogen.”

—Laurence Klotz, MD The PR-7 trial involved 1386 patients with a prostate-specific antigen (PSA) level of >3 ng/mL that persisted for more than 1 year after primary or salvage radiotherapy for localized prostate cancer (Crook JM, et al. N Engl J Med. 2012;367:895-903). Intermittent and continuous ADT were associated with similar rates of survival and with 7-year cumulative rates for prostate cancer mortality.

Two previous small, retrospective studies had suggested that testoster-

one levels <0.7 ng/mL are associated with prolonged time to prostate cancer progression. But Dr Klotz expressed significant skepticism about the sturdiness of these studies. To de­fin­itively examine the issue, he and his colleagues analyzed data from the first year of the PR-7 trial of 626 men receiving continuous ADT. They found that having a median testosterone level of ≥1.7 ng/mL was associated with a 1.9-fold increased risk of developing hormone-resistant prostate cancer compared with a testosterone level of <0.7 ng/mL. Furthermore, the hazard ratio (HR) was 2.8 for time to development of hormonal resistance in the lowest testosterone level group compared with the highest testosterone level group.

Similarly, the patients who had the lowest testosterone levels had an HR of 2.8 for time between castration resistance and death compared with the highest testosterone level group.

However, no significant decrease was seen in prostate cancer–related mortality, “probably because of a lack of events,” noted Dr Klotz.

“If you have failure of testosterone suppression, you should consider changing the drug, perhaps adding an antiandrogen,” he concluded.

“Testosterone, as well as PSA, should be monitored on a regular basis in these patients.”—RF n

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Drug Shortages Perspective

The Leucovorin Shortage: A Tangled Web of Similar Isomers and Huge Cost Differences

By William Shimp, MD; Laura R. Bobolts, PharmD, BCOP; Valerie Fishman, RN; Marc Fishman, MD; Jurgen Kogler, MD; Dinah Huff, MD; William Hrushesky, MD

Dr Shimp is Associate Medical Director, Dr Bobolts is Director, Oncology Pharmaceutical Affairs, Ms V. Fishman is Chief Oncology Nurse, Dr M. Fishman is Chief Executive Officer and Chief Medical Officer, Dr Kogler is Associate Medical Director, Dr Huff is Research Program Manager, and Dr Hrushesky is Senior Executive Medical Director and Chief Scientific Officer, Oncology Analytics, Inc, Plantation, FL

A

fter being in short supply since 2008, leucovorin, an analog of folic acid, is now more readily available, and the economics of US cancer care are about to have a bit of a reprieve. Leucovorin is used in part to increase the efficacy of chemotherapy with 5-fluorouracil (FU) for the treatment of colorectal cancer (CRC). While the supply dwindled, the demand rose as chemotherapy regimens containing leucovorin gained popularity. For reasons that are unclear, the 2 main manufacturers of leucovorin (Teva Pharma­ ceuticals and Bedford Laboratories) were unable to keep up with the demand.

Drug shortages are not new in oncology. Almost all chemotherapy drugs in short supply have been generic, because of their lower price and lower profits. With little incentive for manufacturers to invest in low-margin drugs, and with more incentive to produce lucrative patent-protected agents, it is no surprise that shortages develop. Although “production problems” resulting from contamination, regulatory issues, and shortages of raw materials are often cited as causes, it is estimated that these account for only 10% of drug shortage sources; nearly 90% of the issues are economic.1 Amid this evolving chaos, in March 2008, the US Food and Drug Admin­ istration (FDA) approved levoleuco­ vorin (Fusilev; Spectrum Pharmaceu­ ticals), a different version of leucovorin.

These drugs are 2 isomers—namely, 2 chemicals with the same chemical for-

mula, but with different molecular configurations. Racemic leucovorin is a 1:1 mix of d-(dextro) and l-(levo) isomers, which are molecular mirror images of each other. The l-isomer is the active ingredient, whereas the d-isomer lacks biologic activity. Levoleuco­ vorin is a pure form of the l-isomer, a purification of leucovorin that yields only the active ingredient. Spectrum Pharmaceuticals announced that it had developed a product free of “contamination” by the harmless d-isomer.

“It’s not clear to me why somebody decided to make levoleucovorin, but they did.”

—Leonard Saltz, MD It is more costly to manufacture the pure form of levoleucovorin, which allows the use of a dose of only half that of generic leucovorin. However, this purified form exhibits similar efficacy and tolerability (Table) to racemic leucovorin,2 and clinical trials data indicated no true need for such purification.3-6 In the testing leading to the 2011 FDA approval of levoleucovorin for CRC, levoleucovorin proved to be “noninferior” to generic leucovorin. In a March 7, 2008, press release, Richard A. Bender, MD, FACP, Spectrum Pharmaceutical’s former Chief Medical Officer, said, “With this drug, patients

Table Adverse Events Reported with Levoleucovorin versus Racemic Leucovorin

Adverse event

Stomatitis Diarrhea

Nausea and vomiting

Levoleucovorin + 5-FU, (N = 318), N (%)

Grades 1-4

Grades 3-4

222 (70)

61 (19)

229 (72) 197 (62)

37 (12) 25 (8)

Racemic leucovorin + 5-FU, (N = 307), N (%) Grades 1-4

Grades 3-4

201 (65)

51 (17)

221 (72) 186 (61)

44 (14) 26 (8)

Abdominal pain

45 (14)

10 (3)

57 (19)

10 (3)

Dermatitis

91 (29)

3 (1)

86 (28)

4 (1)

Anorexia/decreased appetite Alopecia

76 (24)

83 (26)

13 (4)

1 (0.3)

77 (25)

87 (28)

5 (2)

3 (1)

FU indicates fluorouracil.

Adapted from Chuang VT, et al. Ann Pharmacother. 2012;46:1349-1357.

38

Value-Based Cancer Care

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undergoing cytotoxic chemotherapy are spared the administration of the pharmacologically inactive dextro-isomer.”7 The Medicare allowable monthly price of a standard treatment of levoleucovorin is $2475 compared with the cost of $139 for generic leucovorin.8 The value of being spared the administration of a harmless inactive isomer is regarded by many clinicians and pharmacists as nonexistent.

Many in the oncology community were dumbfounded at the price of levoleucovorin. Leonard Saltz, MD, Chief of the Gastrointestinal Oncology Service at Memorial Sloan-Kettering, noted, “It’s not clear to me why somebody decided to make levoleucovorin, but they did, and they experimented to see if it was any better, and goshgolly-gee-wiz, it’s not.”9 Faced with a shortage of leucovorin, oncologists using 5-FU–based therapy had difficult choices: to not use leucovorin and to increase the planned 5-FU dose by 10%, to purchase leucovorin from “gray market” scalpers at inflated prices, to self-ration leucovorin by administering lower-than-standard doses, to substitute an expensive oral variant of 5-FU (capecitabine), or to use levoleucovorin.

Many thought the choice of substituting levoleucovorin interfered the least with patient care. Insurers had no choice but to provide coverage for the drug, which was heavily marketed.

However, UnitedHealthcare Group’s Senior Vice President, Lee N. New­ comer, MD, MHA, issued a warning.

“What we won’t do is cover levo[leucovorin] as a long-term substitute,” he said. “As soon as this shortage is over, this drug is going to lose coverage, because there is no reason for it.”9 Over the past few years, many oncology practices have become accustomed to using levoleucovorin, and, for them, the economics have been very favorable. In situations where Medicare allows a 6% markup in the sale of chemotherapy drugs in the oncology office, it makes more economic sense to earn $148.50 monthly on levoleucovorin than $8.34 on leucovorin.

What constitutes a financial advantage to some can often be in conflict with the larger societal economics involving third-party payers, Medicare, and all who ultimately pay for the

costs of care. In the example of levoleucovorin, some oncologists continue to insist on using the more expensive drug instead of returning to the less expensive leucovorin. Often the argument is made that patients are doing well on levoleucovorin and there should be no requirement to change drugs mid-treatment. Based on our discussions with providers and payers, some oncologists persist in asserting that generic leucovorin cannot be obtained, and others say they want to avoid confusion in the chemotherapy room where dosages are different from one drug to the other. At times, patients are put in the middle, being told to petition their payers for coverage of a drug essential to their care.

To date, no patients are known to have been harmed by levoleucovorin, which had the advantage of becoming available when a reasonably priced generic agent was in short supply. An expensive alternative is better than no drug. However, with the current steady supply of generic leucovorin, clinicians and payers should consider returning to a cost-effective standard of care. The challenge is to strike a balance that respects the economics of free market innovations and ensures the free flow of important medications for patients with cancer. n References

1. Gatesman ML, Smith TJ. The shortage of essential chemotherapy drugs in the United States. N Engl J Med. 2011;365:1653-1655.

2. Kovoor PA, Karim SM, Marshall JL. Is levoleuco­ vorin an alternative to racemic leucovorin? A literature review. Clin Colorectal Cancer. 2009;8:200-206.

3. Goldberg RM, Hatfield AK, Kahn M, et al. Pros­ pectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol. 1997;15:33203329.

4. Scheithauer W, Kornek G, Marczell A, et al. Fluoro­ uracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study. J Clin Oncol. 1997;15:908-914.

5. Meropol NJ, Petrelli NJ, Rustum YM, et al. A phase II pharmacokinetic study of 6S-leucovorin plus 5-fluorouracil in patients with colorectal carcinoma. Invest New Drugs. 1995;13:149-155.

6. Zittoun J, Tonelli AP, Marquet J, et al. Pharmacokinetic comparison of leucovorin and levoleucovorin. Eur J Clin Pharmacol. 1993;44:569-573.

7. Spectrum Pharmaceuticals. FDA approves new drug application for levoleucovorin, Spectrum’s first proprietary oncology drug. Press release; March 7, 2008. www.drugs.com/newdrugs/fda-approves-new-appli cation-levoleucovorin-spectrum-s-first-proprietary-on cology-888.html. Accessed June 5, 2013.

8. Centers for Medicare & Medicaid Services. April 2013 ASP Pricing File. www.cms.gov/apps/ama/license. asp?file=/McrPartBDrugAvgSalesPrice/downloads/ Apr-13-ASP-Pricing-file.zip. Accessed May 20, 2013.

9. Goldberg P. Drug shortage a boon for levoleuco­ vorin; price is 60 times higher than leucovorin. Cancer Letter. 2009;35:1-2.

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4th AnnuAl ConferenCe

MAy 7-9, 2014

loews hollywood hotel los Angeles, CA www.AvbCConline.org

Drug Update

Xofigo (Radium Ra 223 Dichloride): The First Alpha Particle–Emitting Radioactive Agent for the Treatment of Castration-Resistant Prostate Cancer with Symptomatic Bone Metastases

By Lisa A. Raedler, PhD, RPh

P

rostate cancer is the second leading cause of cancer-related death in the United States among men and the most frequently diagnosed cancer in American males. Among patients with metastatic prostate cancer, up to approximately 90% have bone metastases.1 The median survival after the diagnosis of bone metastasis associated with prostate cancer is approximately 3 years.2 Bone metastases have serious and debilitating clinical consequences, including pain that requires opioids and/or radiotherapy, hypercalcemia, pathologic fracture, spinal cord compression, and nerve root compression.3 Prostate cancer places a significant burden on the US healthcare system.

Using Surveillance, Epidemiology and End Results (SEER) data, Stokes and colleagues estimated the survival of men aged ≥65 years who were diagnosed with prostate cancer between the calendar years of 1991 and 2002.4 The medical cost data were obtained from the SEER-Medicare database and were estimated during specific phases of cancer care. These cost estimates were then combined with survival data to determine the total lifetime costs and the prostate cancer–related lifetime costs. The model estimated total lifetime medical costs of approximately $110,500 per patient (in 2004 US dollars).4 The prostate cancer–related costs made up approximately 31% of the total costs, or more than $34,000 per patient.4 Patients with prostate cancer and bone metastases utilize an inordinate amount of healthcare resources. A retrospective, observational study using health insurance claims data for episodes of care from September 2002 to June 2011 demonstrated that, among patients with prostate cancer, the cost of a skeletal-related event ranged from approximately $11,700 for an outpatient episode to more than $54,000 for an inpatient episode.5 Unmet Need in Patients with Prostate Cancer and Bone Metastases According to the National Cancer Institute, in 2013, more than 238,500 men will be diagnosed with prostate cancer and more than 29,700 will die from the disease. More than 2.5 million American men are currently living with prostate cancer.6

40

Currently, 4 bone-targeted therapies are available for men with prostate cancer, including zoledronic acid (Zometa), denosumab (Prolia), samarium-153 ethylene diamine tetramethylene phosphonate (EDTMP; Quadramet), and strontium-89 (Metastron). None of these 4 agents has been proved to prolong overall survival (OS) in large phase 3 randomized trials.

The 2 radiopharmaceuticals, strontium-89 and samarium-153 EDTMP, are beta-particle emitters. Both were approved by the US Food and Drug Administration (FDA) on the basis of randomized phase 3 clinical trials that demonstrated an improvement in pain in patients with metastatic prostate cancer.7,8 By contrast, sipuleucel-T (Provenge), abiraterone (Zytiga), and enzalutamide (Xtandi) have demonstrated advantages in OS in patients with metastatic prostate cancer, but these agents do not target disease that has spread to bone and are not indicated specifically for patients with prostate cancer plus bone metastases.9-11 FDA Approves Xofigo for Metastatic CRPC with Bone Metastasis In May 2013, the FDA approved radium Ra 223 dichloride (Xofigo Injection [formerly known as Alpharadin]; Bayer HealthCare Pharmaceuticals) for the treatment of patients with castration-resistant prostate cancer (CRPC) plus symptomatic bone metastases and no known visceral metastatic disease.12 In a prespecified interim analysis, radium Ra 223 dichloride (radium-223) combined with best standard of care demonstrated a significant 3.2-month (hazard ratio, 0.70; 95% confidence interval, 0.55-0.88; P = .00185) improvement in median OS compared with placebo plus best standard of care.13 The improvement in OS was supported by a delay in time to the first symptomatic skeletal-related event favoring the radium-223 arm.13 In an interview regarding this new radiopharmaceutical, Daniel P. Petrylak, MD, Director of the Genitourinary Oncology Program at the Yale Cancer Center, New Haven, CT, noted that radium-223 “is the first isotope to show a survival benefit [in advanced prostate cancer]….Now we need to do the studies to know how to best sequence these drugs.”14

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The availability of radium-223 offers a novel therapeutic alternative for patients with CRPC and bone metastasis, particularly for those who wish to avoid the side effects of chemotherapy. According to Nicholas J. Vogel­ zang, MD, a genitourinary oncologist at Comprehensive Cancer Centers of Nevada, Las Vegas, “In general, about half of [patients with advanced prostate cancer] say they will not take chemotherapy. For them, [radium-223] is a wonderful option because it suppresses the cancer, controls the pain, and extends their life.”15 According to the drug manufacturer, 6 cycles of treatment with radium223 cost $69,000.16 Mechanism of Action and Pharmacodynamics The active component in Xofigo is the alpha particle–emitting isotope radium-223, which mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The high energy transfer of alpha emitters increases the breaking frequency of double-strand DNA in adjacent cells, leading to an antitumor effect on bone metastases. The alpha particle range from radium-223 dichloride localizes the impact of the drug and limits damage to the surrounding normal tissue.17 In a phase 2 randomized trial that compared radium-223 and placebo, a significant difference was seen in favor of radium-223 in all 5 biomarkers for bone turnover.17 Dosing and Administration The recommended dose and schedule for radium-223 is 50 kBq/kg body weight, which is administered by slow intravenous injection over 1 minute every 4 weeks for a total of 6 injections.

The safety and efficacy of radium-223 beyond 6 injections have not been studied.17 No dosage adjustment is necessary in elderly patients. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment because of a lack of clinical data.

No dose adjustment can be recommended for patients with severe renal impairment (creatinine clearance <30 mL/min) because of the limited available data.17

ALYMPCA: A Pivotal Phase 3 Clinical Trial Radium-223 was approved by the FDA based on the results of a single, phase 3 clinical trial—the Alpharadin in Patients with Symptomatic Hormone Refractory Prostate Cancer with Skeletal Metastases (ALSYMPCA) trial—a randomized, multicenter, double-blind study of more than 800 patients with CRPC and symptomatic bone metastases. Patients were stratified by baseline alkaline phosphatase, bisphosphonate use, and previous docetaxel exposure.17 Trial Design In the ALSYMPCA trial, patients were randomly assigned in a 2:1 ratio to receive radium-223 50 kBq/kg intravenously every 4 weeks for 6 cycles plus best standard of care (N = 541) or to matching placebo plus best standard of care (N = 268). Best standard of care included local external beam radiation therapy [EBRT], corticosteroids, antiandrogens, estrogens, estramustine, or ketoconazole.17 Therapy was continued until unacceptable toxicity or until initiation of cytotoxic chemotherapy, other systemic radioisotope, hemibody EBRT, or other investigational drugs.

The primary efficacy end point was OS. A key secondary efficacy end point was time to first symptomatic skeletal event, which was defined as EBRT to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention. There were no scheduled radiographic assessments performed during the study. All patients were to continue androgen-deprivation therapy.17 Patient Population Patient demographics and baseline disease characteristics were balanced between the 2 arms. The patients’ median age was 71 years (range, 44-94 years), with a racial distribution of 94% white, 4% Asian, 2% black, and <1% other. The Eastern Cooperative Oncology Group performance status was 0 to 1 in 86% of patients.17 Overall, 85% of the patients had ≥6 bone scan lesions; of those, 40% had >20 lesions or a superscan. For cancer-related pain, 54% of the patients received opiate pain medications, 44%

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Drug Update received nonopiate pain medications, and 2% received no pain medication.

Overall, bisphosphonates were used by 41% of patients. More than half (58%) of the patients had previously received docetaxel.17 During the study period, 83% of the patients in the radium-223 arm and 82% of the patients in the placebo arm were also using gonadotropin-releasing hormone agonists; 21% and 34% of patients, respectively, were using concomitant antiandrogens. The use of systemic corticosteroids (41%) and bisphosphonates (40%) was equal between the 2 arms.17 Efficacy The prespecified interim analysis of ALSYMPCA revealed a significant improvement in OS in patients receiving radium-223 plus best standard of care compared with patients receiving placebo plus best standard of care (Figure), with a median OS of 14.0 months with radium-223 versus 11.2 months with placebo, for a difference of 3.2 months (Table 1).13,17 The median duration of treatment was 20 weeks (6 cycles) with radium-223 and 18 weeks (5 cycles) with placebo.17 An updated OS analysis performed before the patient crossover with an additional 214 events yielded findings that confirmed the OS advantage of radium-223 versus placebo, resulting in a median OS of 14.9 months with radium-223 versus 11.3 months with placebo, for a 3.6-month difference (Table 1).17 The survival results were supported by a delay in the time to first symptomatic skeletal event favoring the radium-223 arm. The majority of events

consisted of treatment with EBRT to bone metastases.17 Safety Profile The most common (≥10%) adverse reactions in patients receiving radium-223 were nausea, diarrhea, vomiting, and peripheral edema (Table 2).18 Grade 3 or 4 adverse events were reported in 57% of patients receiving radium-223 and in 63% of patients receiving placebo.17 The most common (≥10%) hematologic laboratory abnormalities in patients receiving radium-223 were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia.

Grade 3 or 4 lymphocytopenia was reported in 20% of patients receiving radium-223 and in 7% of patients receiving placebo (Table 3).17 Dehydration occurred in 3% of patients receiving radium-223 and in 1% of patients receiving placebo.

Treatment discontinuations resulting from adverse events occurred in 17% of patients who received radium-223 and in 21% of patients who received placebo.17 Warnings and Precautions Fluid status. Radium-223 can result in adverse reactions such as diarrhea, nausea, and vomiting, which may result in dehydration. Patients’ oral intake and fluid status should be care­ fully monitored, and patients who display signs or symptoms of dehydration or hypovolemia should be promptly treated.17 Secondary malignant neoplasms.

Radium-223 contributes to a patient’s overall long-term cumulative radiation exposure, which may be associat-

ed with increased risk of cancer and hereditary defects. Because of its mechanism of action and neoplastic changes, including osteosarcomas in rats after receiving radium-223, radium-223 may increase the risk of osteosarcoma or other secondary malignant neoplasms.

However, the overall incidence of new malignancies in the randomized

Table 1

ALSYMPCA trial was lower in the radium-223 arm compared with in the placebo arm (<1% vs 2%, respectively).

The expected latency period for the development of secondary malignancies exceeds the duration of follow-up for patients in the trial.17 Subsequent treatment with cytotox­ ic chemotherapy. In the ALSYMPCA trial, 16% of patients included in the

Overall Survival of Radium-223 versus Placebo: Interim and Updated Analyses from the Phase 3 Trial

Interim analysis Randomized patients, N Deaths, N (%) Censored, N (%) Median survival, moa (95% CI)

Radium-223 plus best standard of care

Placebo plus best standard of care

541

268

191 (35.3)

123 (45.9)

350 (64.7)

145 (54.1)

14.0

11.2

(12.1-15.8)

P valueb Hazard ratio (95% CI)c

.00185 0.695 (0.552-0.875)

Updated analysis Randomized patients, N Deaths, N (%) Censored, N (%) Median survival, moa (95% CI)

614

(9.0-13.2)

307

333 (54.2)

195 (63.5)

14.9

11.3

281 (45.8)

112 (36.5)

(13.9-16.1)

0.695 (0.581-0.832)

c

Hazard ratio (95% CI)

(10.4-12.8)

Survival time is calculated as months from date of randomization to date of death from any cause. Patients who are not deceased at time of analysis are censored on the last date a patient was known to be alive or was lost to follow-up. b P value is stratified by total alkaline phosphatase, current use of bisphosphonates, and previous use of docetaxel. c Hazard ratio adjusted for total alkaline phosphatase, current use of bisphosphonates, and previous use of docetaxel; hazard ratio <1 favors radium-223 dichloride.

CI indicates confidence interval.

Source: Xofigo (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals, Inc; May 2013. a

Figure Kaplan-Meier Overall Survival Curves from the Phase 3 Clinical Trial of Radium-223 Table 2 Adverse Reactions ≥2% Higher with Xofigo than with Placebo in the Phase 3 Trial

1.0 0.9

Xofigo Placebo

Probability of survival

0.8 0.7

0.5 0.4

Placebo (N = 301)

Grades 1-4, %

Grades 3-4, %

Grades 1-4, %

Grades 3-4, %

Pancytopenia

2

1

0

0

Nausea

36

2

35

2

25

2

15

2

Vomiting

19

2

14

2

Peripheral edema

13

2

10

1

Renal failure and impairment

3

1

1

1

Blood and lymphatic system disorders

0.6

Gastrointestinal disorders

0.3 0.2

Diarrhea

0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39

Number of patients at risk

Time, months

Xofigo 614 578 504 369 277 178 105 80 41 18 7 1 0 0 Placebo 307 288 228 157 104 67 39 24 14 7 4 2 1 0

Source: Xofigo (radium Ra 223 dichloride) injection [prescribing information].

Wayne, NJ: Bayer HealthCare Pharmaceuticals, Inc; May 2013.

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Xofigo (N = 600)

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General disorders and administration site conditions Renal and urinary disorders

Source: Xofigo (radium Ra 223 dichloride) injection [prescribing information].

Wayne, NJ: Bayer HealthCare Pharmaceuticals, Inc; May 2013.

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Drug Update

Xofigo (Radium Ra 223 Dichloride)... Continued from page 41 radium-223 cohort and 18% of patients in the placebo cohort received cytotoxic chemotherapy after completion of the study treatments. Adequate safety monitoring and laboratory testing were not performed to assess how patients who were treated with radium-223 will tolerate subsequent cytotoxic chemotherapy.17 Contraception. Because of the potential effects on spermatogenesis that is associated with radiation treatment, men who are sexually active and their female partners of reproductive potential should be advised to use highly effective contraceptives during and for 6 months after completing treatment with radium-223.17 This new therapy is not to be used in women.

Bone marrow failure. In the ALSYMPCA trial, 2% of patients in the radium-223 arm had bone marrow failure or ongoing pancytopenia compared with none of the patients receiving placebo. In addition, 2 deaths resulted from bone marrow failure. For 7 of the 13 patients who were treated with radium-223, bone marrow failure was ongoing at the time of death.

Among the 13 patients who had bone marrow failure, 54% required blood transfusions. In that study, 4% of patients in the radium-223 arm and 2% of patients in the placebo arm discontinued ther­apy as a result of bone marrow suppression.17 Myelosuppression. Deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of patients receiving radium-223 compared with in 0.3% of patients receiving placebo. The incidence (2%) of infection-related deaths, serious infections (10%), and febrile neutropenia (<1%) was similar for patients receiving radium-223 and for patients receiving placebo.17 Myelosuppression (ie, thrombocytopenia, neutropenia, pancytopenia, and leukopenia) has been reported in patients treated with radium-223.

Complete blood counts were obtained

References

ematologic Reactions ≥10% Higher with Xofigo than with Placebo Table 3 H in the Phase 3 Trial Hematologic laboratory abnormalities

Anemia

Lymphocytopenia Leukopenia

Thrombocytopenia Neutropenia

Xofigo (N = 600)

Placebo (N = 301)

Grades 1-4, %

Grades 3-4, %

Grades 1-4, %

Grades 3-4, %

93

6

88

6

72

20

53

7

35

3

10

<1

31

3

22

<1

18

2

5

<1

Source: Xofigo (radium Ra 223 dichloride) injection [prescribing information].

Wayne, NJ: Bayer HealthCare Pharmaceuticals, Inc; May 2013. every 4 weeks before each dose. Nadir complete blood counts and bone marrow recovery times were not well characterized in ALSYMPCA.17 In a single-dose phase 1 study of radium-223, neutrophil and platelet count nadirs occurred 2 to 3 weeks after the administration of radium-223 at doses of 1 to 5 times that of the recommended dose. Most patients recovered 6 to 8 weeks after administration.17 Monitoring. Hematologic evaluation of patients must be performed at baseline and before every dose of radium-223. Absolute neutrophil counts, platelet counts, and hemoglobin levels must meet minimum requirements as specified in the product’s labeling information. If these values do not recover within 6 to 8 weeks after the last administration of radium-223, despite supportive care, treatment should be discontinued.17 Patients with evidence of compromised bone marrow reserve should be monitored closely and should be provided with supportive-care measures when clinically indicated. Radium-223 should be discontinued in patients who experience life-threatening complications despite supportive care for bone marrow failure.17 The safety and efficacy of concomi-

tant chemotherapy with radium-223 have not been established. Outside of a clinical trial, the concomitant use of radium-223 with chemotherapy is not recommended because of the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, radium-223 should be discontinued.17 Conclusion For patients with advanced prostate cancer and bone metastasis, single-­ agent radium-223 offers clinically and statistically significant efficacy benefits, with a favorable tolerability profile and a convenient dosing schedule.

Experts suggest that this bone-targeting radiopharmaceutical is a viable treatment option for men with CRPC who have received, or who are ineligible for, or who prefer to delay or to avoid cytotoxic chemotherapy.

Combination studies with radium-223 and hormonal agents, immunomodulatory agents, and doce­taxel are pending or are under way to further elucidate the role of radium-223 as a part of the armamentarium for patients with prostate cancer.18 n

1. Scher HI, Morris MJ, Kelly WK, et al. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232.

2. Coleman RE. Skeletal complications of malignancy.

Cancer. 1997;80(8 suppl):1558-1594.

3. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12(20 pt 2):6243S-6249S. 4. Stokes ME, Ishak J, Proskorovsky I, et al. Lifetime economic burden of prostate cancer. BMC Health Serv Res. 2011;11:349.

5. Hagiwara M, Delea TE, Saville MW, Chung K. Healthcare utilization and costs associated with skeletal-related events in prostate cancer patients with bone metastases. Prostate Cancer Prostatic Dis. 2013;16:23-27.

6. National Cancer Institute. Prostate Cancer. www. cancer.gov/cancertopics/types/prostate. Accessed June 13, 2013.

7. Porter AT, McEwan AJ. Strontium-89 as an adjuvant to external beam radiation improves pain relief and delays disease progression in advanced prostate cancer: results of a randomized controlled trial. Semin Oncol. 1993;20(3 suppl 2):38-43.

8. Medical Services Advisory Committee. Samarium153-lexidronam for bone pain due to skeletal metastases.

Final assessment report. MSAC application 1016. August 1999. www.msac.gov.au/internet/msac/publishing.nsf/ Content/FA4579BED311BC15CA2575AD0082F D8A/$File/1016%20-%20Samarium153lexidronam%20 for%20bone%20pain%20due%20to%20skeletal%20 metastases%20Report.pdf. Accessed June 13, 2013.

9. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

10. de Bono JS, Oudard S, Ozguroglu M, et al; for the TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-1154.

11. Xtandi (enzalutamide) capsules [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012.

12. US Food and Drug Administration. Radium Ra 223 dichloride. Updated May 15, 2013. www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm352393. htm?source=govdelivery. Accessed June 13, 2013.

13. Parker C, Heinrich D, O’Sullivan JM, et al. Overall survival benefit of radium-223 chloride (Alpharadin) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer (CRPC): a phase 3 randomized trial (ALSYMPCA).

Eur J Cancer. 2011;47(suppl 2):3.

14. OncLive TV. Dr Petrylak discusses the isotope radium-223. YouTube. February 28, 2012. www.youtube. com/watch?feature=player_detailpage&v=A-jLlybtyeQ. Accessed June 13, 2013.

15. Targeted Communications. Dr Vogelzang reviews radium-223 in metastatic prostate cancer. YouTube. April 22, 2013. www.youtube.com/watch?feature=player_detail page&v=1KLLrQuJk_g. Accessed June 13, 2013.

16. Dooren JC. Bayer gets FDA approval for advanced prostate cancer drug. Wall Street J. May 15, 2013. http://online.wsj.com/article/SB100014241278873247 67004578485552000140508.html. Accessed June 13, 2013.

17. Xofigo (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals, Inc; May 2013.

18. Sartor O. Radium-223 (Alpharadin): a novel targeted alpha-emitter for bone-metastatic castrate-resistant prostate cancer. PCRI Insights. May 2012:9-14.

In the Literature Crizotinib Superior to...

Continued from page 23

compared with 17 of the patients receiving chemotherapy, and the therapy duration was also longer with crizotinib than with chemotherapy—a

42

median of 15.9 weeks versus a median of 6.9 weeks, respectively.

The common adverse events reported with crizotinib included visual disorders, gastrointestinal events, and elevated aminotransferase levels. In

Value-Based Cancer Care

I

JUly 2013

addition, 23 patients (13%) receiving crizotinib had grade 3 or 4 neutropenia compared with 33 patients (19%) receiving chemotherapy. Febrile neutropenia occurred in 1 patient receiving crizotinib and in 16 patients receiving

chemotherapy. In general, patients reported greater reductions in symptoms of lung cancer, including chest pain, cough, and fatigue, and greater improvement in global quality of life with crizotinib than with chemotherapy. n

Vol. 4

I

No. 6

AN 8-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

â&#x201E;˘

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

Â&#x2122;

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

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