VBCC September 2013

september 2013 VOL 4 NO 7

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

New Collaborative Advance Care Planning Program for Patients with Cancer Enhances Quality while Mitigating Costs

By J. Russell Hoverman, MD, PhD Medical Director, Managed Care, The US Oncology Network; Medical Oncologist and Vice President, Quality Programs, Texas Oncology

Clinical GUideLines

ASCO Adds Aromatase Inhibitor to Breast Cancer Prevention Options in Postmenopausal Women

By Charles Bankhead

A

n aromatase inhibitor has joined tamoxifen (Nolvadex) and the selective estrogen receptor (ER) modulator raloxifene hydrochloride (Evista) as chemoprevention for women who are at an increased

risk for breast cancer, according to the recent update of the American Society of Clinical Oncology (ASCO) practice guideline (Visvanathan K, et al. J Clin Oncol. 2013;31:2942-2962).

Continued on page 4

Defining Value in Cancer Care: AVBCC 2013 Steering Committee Report

T

he cancer care landscape is rapidly evolving, in light of promising new therapies, as well as changing reimbursement strategies in response to the healthcare reform. With the cost of some cancer drugs exceeding $100,000 annually, and with patients living longer, cancer care consumes a large portion of healthcare dollars. Medical expenditures for cancer are projected to reach at least $158 billion in 2020, an increase of 27% Continued on page 6

Economics of Cancer Care

Balancing Cost and Quality in Oncology Challenge for policymakers, payers, and the pharmaceutical industry

By Caroline Helwick Hollywood, FL—The goal of balancing cost and quality leaves no stakeholder without a challenge, said Grant D. Lawless, MD, RPh, Director, Healthcare Decision Analysis Program, and Associate Professor of Clinical Pharmacy, University of Southern California, Los Angeles.

“If one does not know to which port one is sailing, no wind is favorable,” ©2013 Engage Healthcare Communications, LLC

and the United States is still struggling to chart a course for healthcare reform, Dr Lawless said.

He noted that the “A” in the Afford­ able Care Act (ACA) should stand for “accountable” to reflect the need for accountability in healthcare. “That is as important as figuring out how to make it affordable,” Dr Lawless said.

Continued on page 8

T

he AVBCC Annual Meeting experiences exponential growth in attendance and participation as oncologists, payers, employers, managed care executives, patient advocates, and drug manufacturers convened in Hollywood, FL, on May 2-5, 2013, for the Third Annual Conference of the Association for Value-Based Cancer Care (AVBCC).

The AVBCC 2013 Steering Com­ mittee was held on the first day of the conference to define value in cancer care. The committee was divided into

7 groups, each representing a key stakeholder in oncology. The goal of the Steering Committee was to define value from the particular point of view of each of the stakeholder groups and to suggest how that particular perspective can contribute to the value proposition in oncology, by balancing cost, quality, and access to care to improve overall patient outcomes. The following summary highlights the major points addressed by each group.

Continued on page 20

inside FROM THE EDITOR . . . . . . . . . . . 4 How will we pay for cancer care in 2018?

PERSONALIZED MEDICINE . . . . . 43 Olaparib use in ovarian cancer

VALUE PROPOSITIONS . . . . . . . . . 5 NC cuts hospital readmissions by 20%

HEALTH POLICY . . . . . . . . . . . . . . . .

Yet another blow to the Medicaid expansion

ECONOMICS OF CANCER CARE .

Poor adherence to oral therapies Causes for hospital readmissions

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46

CANCER PREVENTION . . . . . . . . . 50 High marks for nutritional supplement

FDA UPDATE . . . . . . . . . . . . . . . . . 24 Abraxane for pancreatic cancer

DRUG UPDATE . . . . . . . . . . . . . . . 51 Tafinlar and Mekinist for melanoma

3RD CONFERENCE . . . 32 Healthcare exchanges and oncology

CONTINUING EDUCATION . . . . . . 56 Advances in hematologic malignancies

For patients prescribed Gilotrif™ (afatinib) tablets

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• Coverage and reimbursement support • Financial support • Distribution options* • GILOTRIF Pledge™†

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Visit us online at www.bisolutionsplus.com Call us at 1-877-814-3915 from 8 AM to 8 PM EST *GILOTRIF is available through our specialty pharmacy partner, Accredo, as well as through select on-site pharmacies. † GILOTRIF Pledge provides patient and payer refund for first month of therapy if eligible patients (commercially insured through participating health plans and serviced through Accredo) discontinue before first refill. ‡ For patients serviced through Accredo. § GILOTRIF Dose Exchange offers replacement drug and eliminates an additional co-pay for the replacement drug. It is offered for up to 2 dose adjustments for patients serviced through Accredo who are exchanging ≥9 pills.

Copyright © 2013. Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (8/13) GF572109PROF-K

In This Issue FROM THE EDITOR Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Vice President/Director of Sales & Marketing Joe Chanley joe@greenhillhc.com Publisher Cristopher Pires cris@engagehc.com Editorial Director Dalia Buffery dalia@engagehc.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Production Manager Melissa Lawlor The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 9 times a year by Engage Healthcare Communica­tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2013 by Engage Healthcare Communications, LLC. All rights reserved.

Value-Based Cancer Care is a registered trademark of Engage Health­care Communi­cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

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

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3RD CONFERENCE

How will we pay for cancer care in 2018?

VALUE PROPOSITIONS

Defining value in cancer care: AVBCC 2013 Steering Committee Report More….

North Carolina cuts readmissions by 20% More….

PERSONALIZED MEDICINE

ECONOMICS OF CANCER CARE

Early ponatinib suppresses new mutations in CML More….

Mammography screening rates boosted by copay elimination Annual costs of hospital readmissions approximately $16 billion More….

Yet another blow to the Medicaid expansion

IN THE LITERATURE

New approaches in double-refractory myeloma More….

Industry-funded studies get more exposure at ASCO meetings Ibrutinib shows durable remissions in relapsed CLL More….

FDA UPDATE Abraxane approved for pancreatic cancer

HEALTH POLICY DRUG THERAPY

CANCER PREVENTION High marks for nutritional supplement

DRUG UPDATE Tafinlar and Mekinist for metastatic melanoma with BRAF mutations More….

VBCC Editorial Board Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL Al B. Benson III, MD, FACP, FASCO Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 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: 732-992-1880 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.

september 2013

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From The Editor

How Will We Pay for Cancer Care in 2018?

By Craig Deligdish, MD

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

J

ust this month, the Institute of Medicine (IOM) published a report titled “Delivering High-Quality Can­ cer Care: Charting a New Course for a System in Crisis.”1 This consensus report convened a committee of experts to examine the quality of cancer care in the United States and formulate recommendations for its improvement. The committee came to a number of conclusions and made 10 recommendations for the purpose of improving what it described as a system in “crisis,” which is associated with rising costs and growing demand.

In addition to reviewing a number of issues that impact the quality of cancer care, the IOM report addressed disparities and access issues for patients undergoing treatment for cancer.1 The report also examined factors that impact the cost of care; the state of outcomes reporting and quality metrics;

and the growing need for survivorship care, palliative care, and family caregiving. The IOM report made several recommendations to improve the affordability of cancer care by reforming the current fee-for-service (FFS) system of payment and recommending that the Centers for Medicare & Medicaid Services (CMS) and others transition from an FFS reimbursement model to new payment models.

The Affordable Care Act (ACA) has provided CMS with a number of tools to encourage healthcare innovation.

Recently, the Center for Medicare and Medicaid Innovation announced round 2 of the Health Care Innovation Awards for the purpose of funding applicants who propose new payment and service delivery models that provide better healthcare and lower costs through improved quality for Medicare, Medicaid, and Children’s Health Insurance Program (CHIP) enrollees.2 Applicants were encouraged to propose new service delivery mod-

els, along with the design of a corresponding new payment model.

The ACA has further authorized the Center for Medicare and Medicaid Innovation to test innovative healthcare payment and service delivery models that have the potential to lower Medicare, Medicaid, and CHIP spending while maintaining or improving the quality of beneficiaries’ care. Thus far, the Innovation Center has worked to support care transformation efforts through similar initiatives that have covered a broad range of payment and service delivery models and has supported the creation and development of accountable care organizations, bundled payment models, and other initiatives that accelerate the development and testing of new payment and service delivery models.2 Round 2 of the Health Care Inno­ vation Awards, which provides for nearly $1 billion in funding, specifically targets high-cost, physician-administered drugs; therapeutic services,

ASCO Adds Aromatase Inhibitor...

Tamoxifen and raloxifene have been recommended for breast cancer risk reduction since the ASCO clinical guideline was introduced in 1999, and remained options in the 2002 and 2009 updates. However, the 2009 update specifically excluded aromatase inhibitors as an option for chemoprevention.

After a systematic review of randomized trials and meta-analyses, the guideline committee, cochaired

by Kala Visvanathan, MD, MHS, Associate Professor of Epidemiology and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, concluded that “exemestane (25 mg per day for 5 years) should also be discussed... for BC [breast cancer] risk reduction.”

The results of a recent randomized, placebo-controlled clinical trial showed that high-risk postmenopausal women who received prophylactic therapy with exemestane (Aromasin) had almost a 70% lower risk for breast cancer compared with highrisk women receiving placebo. The new exemestane recommendation comes with some qualifiers that limit its use to “ER-positive breast cancer, in postmenopausal women age ≥35 years with a 5-year projected breast cancer absolute risk ≥1.66%, according to the NCI [National Cancer Institute] Breast Cancer Risk Assessment Tool

4

Value-Based Cancer Care

Drug

Dose

Recommendations

Not recommended

Tamoxifen

20 mg daily for 5 yrs

Should be discussed as an option to reduce the risk of invasive BC, specifically ER-positive, in any woman aged ≥35 yrs at increased BC risk or with LCIS

Not for women with a history of DVT, pulmonary embolus, stroke, or TIA; during prolonged immobilization; or in women who are or may become pregnant, or are nursing mothers; not for use in combination with hormone therapy

Raloxifene

60 mg daily for 5 yrs

Should be discussed as an option to reduce the risk of invasive BC, specifically ER-positive, in postmenopausal women aged ≥35 yrs at increased BC risk or with LCIS

Not for BC risk reduction in premenopausal women, or for women with a history of DVT, pulmonary embolus, stroke, or TIA, or during prolonged immobilization

Exemestane 25 mg daily for 5 yrs

Discuss as an alternative to tamoxifen or raloxifene to reduce the risk of invasive BC, specifically ER-positive, in postmenopausal women aged ≥35 yrs at increased BC risk or with LCIS or atypical hyperplasia

Not for BC risk reduction in premenopausal women

NOTE: For tamoxifen and raloxifene, the most favorable risk-benefit profile is seen in women who are at the greatest risk of developing breast cancer. Discussions with patients should include the risks and benefits of each agent under consideration.

BC indicates breast cancer; DVT, deep-vein thrombosis; ER, estrogen receptor; LCIS, lobular carcinoma in situ; TIA, transient ischemic attack.

Source: Visvanathan K, et al. J Clin Oncol. 2013;31:2942-2962.

september 2013

Continued on page 5

Continued from cover

Table Key Pharmacologic Interventions for Breast Cancer Risk Reduction

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such as radiation therapy; populations with specialized needs, including patients with cancer; and models that test approaches for oncologists to transform their financial and clinical models.

Public regional and national health plans are focusing great efforts on payment models that move beyond FFS, can be rapidly implemented, are scalable, and are sustainable. As part of this second round, CMS encouraged applicants to propose models that included shared savings for providers, shared risk, tiered value-based payment schedules, hybrid models, new patient models that support innovative care service delivery models, and other approaches that rewarded efficient, high-quality, evidence-based care.2 CMS further encourages proposals that provide for and incentivize shared decision-making and engage patients.

As part of this program, CMS further encourages providers to propose pro-

(or equivalent measures), or with LCIS [lobular carcinoma in situ] or atypical hyperplasia” (Table).

“Exemestane should not be used for breast cancer risk reduction in premenopausal women,” continued the guideline authors. “Discussions with patients and healthcare providers should include both the risks and benefits of each agent under consideration.”

The panel noted that exemestane does not have a US Food and Drug Administration–approved indication for use as a chemopreventive agent.

The drug is currently indicated as adjuvant therapy for early breast cancer and for the treatment of advanced breast cancer. Furthermore, premenopausal women should not use exemestane for breast cancer chemoprevention.

The guideline notes several contraindications for each of the agents (Table). The committee found the data insufficient to make a recommendation about other aromatase inhibitors, including anastrozole (Arimidex). The results of an ongoing randomized, placebo-controlled clinical trial with this drug may help guide the decision-making in the future.

Tamoxifen and raloxifene have the most favorable risk-benefit profile in women at the highest risk for breast cancer, the panel noted. n

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Advance Care Planning

VALUE PROPOSITIONS North Carolina Cuts Hospital Readmissions by 20%

Hospital readmissions for chronic diseases, including cancer, are associated with a significant and often preventable financial burden in the United States. In 2008, North Carolina instituted a statewide transitional care model to prevent repeated hospitalizations in high-risk patients with Medicaid insurance who have multiple chronic conditions. The transitional care model comprises comprehensive medication management, self-management education sessions for patients and families, and outpatient follow-up with a medical home that is informed of the hospitalization. In a study investigating the merits of the model between 2010 and 2011, the rate of repeated hospitalizations was 20% lower for patients receiving transitional care than for patients not receiving such care. The authors suggest that “locally embedded, targeted care coordination interventions can effectively reduce hospitalizations for high-risk populations.” Health Aff (Millwood). 2013;32:1407-1415

First-in-Class Drug, CFI-400945, Funded

by Donor Grants Alone, Inhibits Growth of Several Cancers

A group of scientists led by Tak Mak, MD, Director of the Princess Margaret Cancer Centre, and Dennis Slamon, MD, PhD, Director of Clinical/Translational Research, University of California, Los Angeles, and supported by funding from donor grants only, has filed a New Drug Application with the US Food and Drug Administration (FDA) for a drug developed based on the target enzyme PLK4, which plays a crucial role in cancer-cell division. “Dr Slamon and I are proud to stand shoulder to shoulder with our fellow scientists and the donors who believe in our vision and have generously helped to finance our critical work,” said Dr Mak. “It is extremely rare for an academic group to have discovered and advanced a novel ‘first-in-class’ drug candidate to this level, and it would not have been possible without the fundamental support provided by donors.”

Laboratory studies have shown that CFI-400945 effectively inhibits the growth of breast, ovarian, colorectal, lung, pancreatic, and prostate cancers, as well as glioblastoma and melanoma. The FDA’s initial response was positive. The $40 million of donations for this discovery were mainly from walkers and their donors in the Shoppers Drug Mart Weekend To End Women’s Cancers, the Campbell family, the Canadian Institutes of Health Research, Genome Canada, and the California Institute for Regenerative Medicine.

“I truly believe in this important discovery and its therapeutic potential for cancer patients,” said Dr Slamon, who is best known for discovering Herceptin. The drug will enter clinical trials in the near future. Princess Margaret Cancer Foundation; June 18, 2013

First Phase of ASCO’s Data-Sharing Standards Completed, Connecting Oncologists during Patient Care

The completion of the Breast Cancer Treatment Plan and Summary Standard and Implementation Guide, the first phase in a set of interoperability standards, was announced at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO). The new ASCO electronic data-sharing standards are aimed at facilitating information sharing among oncologists, patients, and researchers to enhance patient care. “This data standard will allow oncologists to share data during care, but also provide a summary for primary care physicians and patients after treatment ends,” said ASCO President Sandra M. Swain, MD, FACP. ASCO press release; June 1, 2013

Senate Approves $5.1 Billion for the National Cancer Institute in 2014

The Senate Appropriations Committee approved a bill for fiscal year 2014 that provides $30.9 billion to the National Institutes of Health, of which one sixth—$5.1 billion—is designated for the National Cancer Institute (NCI).

This bill constitutes an increase of $23 million in money provided to the NCI compared with 2012. However, the bill has yet to be approved by the House, which is more than likely to reduce these amounts, based on its previous actions related to scientific research. ASCO; July 24, 2013

Healthcare Decision Makers’ Perspectives on Improving Care Quality, Controlling Costs

The following quotes were assembled from interviews and news coverage by FierceHealthFinance, revealing healthcare decision makers’ valuebased perspectives on some of the main problems currently facing providers and the US healthcare system: • “You can bankrupt an organization very quickly if you don’t understand your patient population.”—Tina Buop, CIO, La Clínica de la Raza, Oakland, CA • “We are spending gazillions of dollars and we don’t have interoperability.”—Marc Probst, CIO, Intermountain Healthcare • “All of the care coordination in the world does not amount to a hill of beans if patients go home and they don’t take their medications.”—Will Shrank, MD, Harvard Medical School • “The people who really consume those services are the physicians. So you have physicians who, with a stroke of their pen, can make or break a hospital.”—Brent James, Chief Quality Officer and Executive Director, Institute for Health Care Delivery Research, Intermountain Healthcare.

FierceHealthFinance; August 9, 2013

How Will We Pay for Cancer Care... grams that improve care and quality outcomes through the measurement of patient satisfaction; improve adherence to evidence-based practices; and improve clinical quality, patient access, and patient outcomes.

CMS has clearly made a tremendous investment in accomplishing the recommendations made by the IOM. Time will tell whether models will be developed that could be applied to cancer care and achieve the goals defined by the IOM and the Center for Innovation.

Also in September, the US Oncology Network, the Community Oncology Alliance (COA), and ION

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Solutions released a report prepared by the Moran Company showing that Medicare sustained significantly higher costs for patients receiving chemotherapy in hospital outpatient settings compared with the community cancer clinics setting.3 The report reveals that Medicare patients receive more chemotherapy treatments, with more expensive chemotherapy drugs, in hospital outpatient settings compared with the physician-run clinics, resulting in chemotherapy costs that are as much as 47% higher.3 Given the current consolidation in our country’s cancer delivery system,

Continued from page 4

with an increasing number of patients being treated in the hospital outpatient setting, one wonders how cancer care will be delivered in 2018, and whether many of the new programs will be sustainable in the treatment settings where many patients will receive their care.

It also needs to be examined whether programs that reward quality, better measure and reward improved outcomes, and address the cost of care in a meaningful way, will be viable and scalable. Will payers be willing to pay more for the cost of the same treatment when it is administered in one setting versus another? These are

september 2013

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compelling questions that will ultimately need to be answered, if we are to develop a sustainable system that provides high-quality, cost-effective care for all patients with cancer. n References

1. Institute of Medicine. Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. September 10, 2013. www.iom.edu/reports/ 2013/delivering-high-quality-cancer-care-chartinga-new-course-for-a-system-in-crisis.aspx. Accessed September 11, 2013.

2. Center for Medicare & Medicaid Innovation. Health Care Innovation Awards Round Two. May 15, 2013. http://innovation.cms.gov/Files/x/HCIA-TwoFOA.pdf. Accessed September 11, 2013.

3. The Moran Company. Cost Differences in Cancer Care Across Settings. August 2013. http://glacialblog. com/userfiles/76/Moran_Cost_Site_Differences_ Study_P2(1).pdf. Accessed September 11, 2013.

www.ValueBasedCancerCare.com

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Advance Care Planning

New Collaborative Advance Care Planning Program... over 2010, according to the National Cancer Institute.1 There is little debate that these costs are unsustainable, and that cancer care must migrate to a more value-based treatment model.

The US Oncology Network, with the support of McKesson Specialty Health—one of the largest US cancer care networks, representing nearly 1000 physicians—recognizes the need for value-based reform and is at the forefront of developing innovative strategies that optimize value while supporting quality care and improving outcomes.

One area that presents a potential for improved cost control and, more important, for an improved patient and family experience, is end-of-life care. A recent study by the Dartmouth Institute concluded that approximately 25% of all Medicare spending is for patients in their last year of life.2 Providers who treat patients with advanced-stage cancer know that aggressive care at the end of life is often ineffective and costly. High-intensity, last-attempt efforts can have a negative effect on the quality of life of patients, as well as on the lives of caregivers. Patients at this stage need a thorough understanding of the risks and benefits of the treatment that they are requesting or getting.

As providers for terminally ill patients, and as stakeholders in a healthcare field with limited resources, we must ask if there is a better way to manage late-stage disease, so that patients have the opportunity to determine their own care preferences and to better comprehend the pros and cons of various treatment options. Helping patients understand and specify the care they want can minimize unwanted and ineffective treatment, provide a better end-oflife experience, and help reduce the cost burden on our patients and on society.

My Choices, My Wishes Program The US Oncology Network, in collaboration with McKesson Specialty Health, has tackled this problem by developing a patient-centered advance care planning program to mitigate costs, improve quality care, and provide a better patient experience. The program, “My Choices,

My Wishes,” provides an avenue for quality, cost-effective care by helping patients explore, define, and document the care they desire throughout their cancer journey. Providers seek to discover a patient’s values and goals for care across their disease trajectory, including end-of-life care.

Discussions begin early, at a time when medical decision-making can still be thoughtful.

Reduced Utilization at End of Life

J. Russell Hoverman, MD, PhD

Helping patients understand and specify the care they want can minimize unwanted and ineffective treatment, provide a better end-of-life experience, and help reduce the cost burden on our patients and on society.

The program is typically introduced to patients by their physician early on and includes specially trained mid-level providers and social workers, and educational and resource materials. Healthcare information technology is used to identify patients, store treatment progress and preferences, define and document directives, and honor patients’ wishes throughout their care plan.

My Choices, My Wishes uses an ongoing, systematic process that gives patients the opportunity to continually revise their healthcare goals and reevaluate the care and experience they desire during their cancer treatment.

The goal is to simplify a complex

Disclaimer: This article is not medical advice and should not be deemed as such. This article is for informational purposes only, and individuals should assess their unique needs with their respective providers.

6

situation by helping patients understand and continually define what is important to them as disease progression occurs, giving them a voice in advanced-stage treatment decisions and helping them to live well during their illness.

The program is unique in providing benefits to all stakeholders―patients, families, physicians, and payers. It helps patients to achieve the quality of life they desire by explaining their care options and placing these options into their values perspective. Advance care planning empowers patients to make decisions before a medical crisis occurs, while they still have time to carefully think about what gives their life meaning and purpose.

Value-Based Cancer Care

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september 2013

Patients with terminal cancer who participate in similar programs typically stop chemotherapy at a reasonable point and transition to a comfort care plan, allowing them to experience the benefits of palliative and hospice care. Because the patient has clearly documented and made known the treatments he or she wants over time, the program can reduce the patient’s stress level and can also provide a better experience for loved ones, who are relieved of the bur­ den of decision-making in emotional circumstances.

My Choices, My Wishes also delivers significant benefits to cancer practices and can strengthen referring physician relationships. Practices can use the program’s provider documentation tools and outcome metrics to increase appropriate hospice referrals and to help ensure appropriate chemotherapy utilization patterns. In addition, the program provides potential for multiple revenue streams from innovative, value-based savings payment models and increased evaluation and management coding.

Potential for Reduced Costs

Payers can also benefit by participating in the program. By approving evaluation and management charges for mid-level providers and/or social workers to discuss and document healthcare goals with patients, payers can support more cost-effective care.

A recent study in the Journal of Clinical Oncology showed a clear connection between early discussions with patients about end-of-life preferences and savings on unwanted or ineffective care.3 My Choices, My Wishes supports

Continued from cover

at a glance ➤ This collaborative program enhances high-quality care at the end of life and helps to reduce costs ➤ Patients are encouraged to explore, define, and document early in the cancer care process the care that they want throughout the care continuum ➤ Members are empowered to proactively self-determine their quality-of-life issues, with the support of payers ➤ Payers can support more cost-effective care by approving charges for mid-level providers to discuss patient goals and reduce waste at end of life

the documentation of advance directives and do not resuscitate orders, while promoting increased hospice referrals and hospice length of stay— all of which play a vital role in the enhancement of a patient’s quality of life and a reduction of high-intensity treatments and their associated costs.

Payers also have the opportunity to collaborate with providers to review outcomes from the program, including analyzing claims data in ways that assess acute care savings, decreased chemotherapy in the last month of life, and hospice utilization.

The ability to create opportunities to reduce overall healthcare costs while enhancing high-quality care and the patient experience makes the program attractive to payers, and several national insurance companies are collaborating with practices within the US Oncology Network to provide their members access to the program.

My Choices, My Wishes is a promising step toward transforming can­ cer care into a more value-based system, without sacrificing quality and outcomes. n References

1. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010-2020.

J Natl Cancer Inst. 2011;103:117-128.

2. Goodman DC, Esty AR, Fisher ES, Chang CH. Trends and variation in end-of-life care for Medicare beneficiaries with severe chronic illness: a report of the Dartmouth Atlas Project. April 12, 2011. www.dartmouthatlas.org/downloads/reports/EOL_Trend_ Report_0411.pdf. Accessed July 2, 2013.

3. Mack JW, Cronin A, Keating NL, et al. Associations between end-of-life discussion characteristics and care received near death: a prospective cohort study. J Clin Oncol. 2012;30:4387-4395.

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Economics of Cancer Care

Balancing Cost and Quality...

According to Donald M. Berwick, MD, former Administrator of the Centers for Medicare & Medicaid Services, the “triple aim” of the ACA was the coordination of care, population health, and cost control, to which Dr Lawless would add 2 more goals—delivery reform (moving from specialty care to primary care) and reimbursement reform (moving from volume and intensity to quality and cost), 2 changes with far-reaching implications, he said.

Changing Payer Role Within the rapidly changing landscape for payers are many components that could prove cost-saving, but not all will be easily accomplished.

For example, formularies and clinical pathways can help limit choices and the cost of medications, but bundled payments may be a harder sell and could represent “an eternal battle between the provider and the hospital,” Dr Lawless said.

Preventive services and primary care are pivotal areas that have received less attention. Approximately 80% of Medicare enrollees have at least 1 chronic care disease, and 45% have at least 2. Studies have shown that 2 serious medical conditions essentially render patients chronically ill and “complex” in terms of healthcare utilization and costs, such as patients with rheumatoid arthritis or multiple sclerosis. Three overlapping medical conditions put patients on par with a catastrophic illness, such as cancer.

“We are seeing that as more and more patients come through the system with these overlapping chronic problems, they’re consuming healthcare at the rate that we thought was only applicable to very complex medical problems,” Dr Lawless said.

Figure 2 2014 and Beyond: Budget Considerations

Fixed federal budgets

“As more and more patients come through the system with these overlapping chronic problems, they’re consuming healthcare at the rate that we thought was only applicable to very complex medical problems [such as cancer]. We’re wondering where the dollars are going to come from.”

—Grant D. Lawless, MD, RPh “We’re wondering where the dollars are going to come from.”

Impact on the Pharmaceutical Industry The pharmaceutical industry will be affected by many factors, such as the emergence of biosimilars and generics, the increasing costs of research and development, caps by drug class and dollar limits, and the standardization of care, “all interlocking with one another and putting pressure on the system,” Dr Lawless said.

This is occurring at the end of what Dr Lawless calls a 3-generation evolution (Figure 1). The first generation focused on the development of new products and the creation of “ro-

Pharma 2.0 Market model Diversified

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• Trading dollars for quality/outcome while insuring more patients • “New Dollars”—Patient-Centered Outcomes Research Institute, Agency for Healthcare Research and Quality, an interagency shell game Reduced payments to Medicare

Figure 1 The 3-Generation Evolution in the Pharmaceutical Industry:

Changing Opportunity

Pharma 1.0 Blockbuster model Volume • Innovation • Chronic disease • Provider-driven • Strong returns

Continued from cover

• Cost-efficient • Diversified portfolio • Segment expansion • Cost-cutting competition • Generics and biosimilars

Value-Based Cancer Care

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Pharma 3.0 Payer model Value and austerity • Patient-centric primary care • New customer base, payer-driven • Improving health outcomes and health technology assessment • New partnerships and academia • Evolutionary change from 2.0 • Emerging market: imitation to innovation

september 2013

• Setting higher standards for success • Reducing choice • Federal mandates without compensation Shifting financial management to • Risk aversion the states and • Budget control Accountable care • Discounts and exchanges organization rebates Bundled payments Creating new business models: Patient-centered home focus on Health innovation zone primary care Independence at home

bust volume.” The second generation evolved toward “intensity of care,” with diversified portfolios and greater involvement of payers. The third generation, which is occurring today, is focused on outcomes and value, he said.

“The provider-driven model is evaporating into the payer-driven model, and the primary care model is taking over what used to be specialty care. We may see a complete reversal,” Dr Lawless predicted.

“I think the US may muddle along at the current pace, but if there is another significant downturn in our economy, or tremendous pressure on the system by more people entering and using more services, we may see a massive change in coverage. This is what happened in Germany, which was once a liberal payer, within 1 year of the European Union’s financial downturn,” he said.

Implications for Drug Development The need to balance cost and quality will no doubt have an impact on clinical research, Dr Lawless predicted.

The idea of “high throughput,” risky investing in a multitude of compounds to find a few blockbuster drugs, will fade, because there is limited value in that business model. Only approximately 6% of compounds now enter phase 3 clinical trials, and fewer are approved. “Those kinds of numbers don’t work anymore,” he said.

There will be a push toward new kinds of partnerships and licensing agreements, and new standards will be set. There will be greater use of electronic data collection (prelaunch and postlaunch), and an expansion of comparative effectiveness research (CER) into the areas of devices, diagnostics, physical medicine, mental

health, and wellness. CER adds 15% to the cost of clinical trials, and, as yet, there is no clear understanding of how to interpret and apply the data from these comparisons.

Gold standards for determining efficacy will have to change to accommodate new outcomes, value, and the need for personalized medicine.

Sample size for clinical trials will need to increase to facilitate subgroup analyses, which are becoming critical for optimizing a drug’s target population.

International trials will be accompanied by new requirements for a shifting world market and the control of data integrity away from the source; for instance, some countries now mandate that drug manufacturers maintain a presence there if they intend to test or market drugs in that country.

The skyrocketing expenses related to these changes could result in fewer clinical trials initiated. “Everything just rolls in the wrong direction. I think there’s a real challenge out there,” Dr Lawless said.

Shifting Financial Strategies The future healthcare climate will be accompanied by fixed federal budgets, reduced payments to Medicare, the shifting of financial management to the states and exchanges, and new business models with a focus on primary care (Figure 2). If healthcare dollars are spent on primary care and prevention, which is part of the government mandate, will enough money be left for complex care, such as cancer care, and catastrophic care? It is possible, Dr Lawless said, that “our thinking might be turned upside down” when the goal of having the best outcome at a reasonable price shifts toward “a reasonable outcome at the price.” n

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Now enrolling

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

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

Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

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

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

NCT#01889186 Reference: ClinicalTrials.gov.

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

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

Economics of Cancer Care

Quality Measures, Pricing, and Policy Challenges in the Oncology Landscape

By Caroline Helwick

Hollywood, FL—Seismic shifts in the oncology landscape have led to pricing and policy changes that affect the delivery of quality care in oncology, said Michael N. Dubroff, DO, FACOP, Senior Director, Payer Support for Genentech, who lent his perspective at the Third Annual Conference of the Association for Value-Based Cancer Care.

The oncology landscape is affected by the increasing influence of quality measures, the growing importance of clinical pathways (not yet standardized), comparative effectiveness research and real-world experience, emerging partner policy groups, increase in hospital claims from private payers, declining reimbursements, and sequestration.

Other factors include the emergence of biosimilars, shifting of the cost burden to patients (the driver of this change is yet to be determined), and trends in personalized medicine, which is an important but costly step toward quality. Of the $2.1 billion spent on cancer drug development,

at a glance ➤ The shifting oncology landscape has led to price and policy changes that affect delivery of quality care ➤ Declining reimbursements and sequestration are among the main challenges in oncology today ➤ Of the $2.1 billion spent on cancer drug development, approximately $300 million is for personalized medicine ➤ In 2015, providers’ reimbursement will be cut by 1.5% for failure to report on quality, rising to 2% by 2016 ➤ Rising costs in oncology are linked to the shift from community practice to hospital settings, the broad scope of the 340B drugs program, increasing drug and service costs, and growing prevalence of cancer ➤ Changes in the oncology scene are expected to include standardized pathways, fee-forservice, no reference pricing, patients’ active involvement in their treatment, and a small copay increase

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approximately $300 million goes toward personalized medicine.

Measuring and Reporting Quality The measurement of quality has become vital in healthcare. The Institute of Medicine defines quality as the extent to which health services provided to individual patients and to patient populations improve health outcomes.

Care should be based on the strongest clinical evidence and provided in a competent manner with good communication and shared decision-making.

As of 2012, the Centers for Medicare & Medicaid Services (CMS) Physician Quality Reporting System (PQRS) contains 225 quality indicators, 24 of which are applicable to oncology. As mandated in the Affordable Care Act, physicians who successfully report on quality measures are eligible for a 0.5% incentive payment. Currently, it is a volunteer pay-for-reporting system, but a financial disincentive for not participating will soon be added. In 2015, providers’ reimbursement will be docked 1.5% for failure to report on quality, rising to 2% by 2016.

This may be the reason why reporting rates have risen by 50% a year since the program’s inception. PQRS incentive payments grew from $236 million in 2009 to $391 million in 2010.

Has the 340B Program Overreached?

Some of the reasons for the rising costs in oncology are the shift in site of care from community practices to hospitals; the unintentionally broad scope of the 340B drugs program; higher prices for products and services, which is magnified within the hospital setting; and the increasing prevalence of cancer as the population ages.

The number of hospitals taking advantage of the 340B program is increasing, and there are questions as to whether the true purpose of the program is being fulfilled. A disproportionate-share hospital that qualifies for the reduced drug costs under the 340B program must have an 11.75% proportion of inpatient Medicare and Medicaid days. This qualifies the hospital for discounts that are fairly equivalent to Medicaid’s best price in the outpatient setting.

The Threat to Community Practices The sustainability of community

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practices is related to economics and to changes in the oncology landscape. The costs of delivering cancer care are accelerating, remuneration is decreasing, and sequestration and changes in average sales price are having an effect.

“The voluntary contribution [for Medicare Advantage] stays the same, at a $3400 out-of-pocket cost, and this allows benefit managers and plans to be flexible with their benefit as long as they meet Medicare requirements for services.”

—Michael N. Dubroff, DO, FACOP

The Zitter Group examined payer awareness regarding biologics and injectables in fall 2010 and made interesting observations regarding the ability to manage and track costs, cost efficacy, and site-of-care shift. “Most compelling was that 77% of payers perceive that it is not cost-effective to have patients treated in the hospital outpatient setting,” Dr Dubroff said.

In addition, 49% of payers in that survey said that the outpatient department provides the poorest treatment efficacy, and 54% said it has the poorest ability to manage or track cost compared with physicians’ offices or home care.

New aspects of Medicare Advantage plans could be good news for community practices. Each year, CMS establishes mandatory and voluntary maximum out-of-pocket limits for these plans. The voluntary limit is lower than the mandatory, and plans may opt for that in return for greater flexibility in cost-sharing for specific services. For 2014, CMS indicates that the voluntary out-of-pocket limit will

remain unchanged, and the mandatory limit will increase.

“The voluntary contribution stays the same, at a $3400 out-of-pocket cost, and this allows benefit managers and plans to be flexible with their benefit as long as they meet Medicare requirements for services,” Dr Dubroff said.

“The mandatory limit is up to $6700, but it rigidly defines what you can do with patients and services.”

Regarding Medicare Part B costsharing requirements for chemotherapy drugs for 2014, CMS has proposed that it be capped at 20%, or $75. This means that any drug that costs more than $375 would be paid directly to the provider, he added.

“That would be remunerated at the sequestration rate, which is 4%, but people wouldn’t be chasing copays.

Whether that comes to pass remains to be seen, but technically, it is in the law,” Dr Dubroff said.

Future Changes Looking ahead, there will be shifts in structures and decision-making among providers, in the role of government and physician decision incentives within the payer community, and in the economics of cancer care for patients.

Dr Dubroff predicted that treatment guidelines, outcomes, and data will become very important to payers and to providers. Pathways will become narrower, protocols will become more refined, and variance will decrease.

Government will set and enforce tighter treatment guidelines, and private payers will follow.

“Buy-and-bill” will disappear, Dr Dubroff says, and capitated treatment budgets will emerge for many diseases (although not so soon for oncology). Patients will become more involved in their treatment decisions and disease monitoring as copays increase, but their choices will be more limited. Hospitals and payer systems will gain more control. Industry salespeople will lose access to physicians.

Some employers will refer their workers to consumer-directed health plans.

Dr Dubroff anticipated the oncology landscape will be characterized eventually by standardized treatment protocol or pathways for evidence-based decision-making, some type of fee-for-service arrangement, no reference pricing, patients actively involved in treatment selection, and most likely, only a small increase in copays. n

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Economics of Cancer Care

Mammography Screening Rates Enhanced by Copay Elimination

By Wayne Kuznar

Chicago, IL—Removing copays may help boost mammography screening rates for all age-groups above age 40 years. One insurer found a significant increase in screening rates with the removal of a copay, said Jeffrey M. Peppercorn, MD, MPH, Medical Oncologist at Duke Cancer Institute, Durham, NC. A significant number of middleaged women who live in rural locales do not pursue even biennial breast cancer screening, and cost may play a role, according to insurance claims data Dr Peppercorn presented at ASCO 2013.

He and his colleagues evaluated the rates of annual screening mammography utilization and biennial screening mammography utilization in women in rural US regions.

“Despite the benefits of screening, we also know that not all patients are

getting screened,” Dr Peppercorn said.

Lower screening rates are found in places such as rural North Carolina, where a 2004 study showed that only 58% of women had a screening mammography over the past 3 years, and a sizable 24% had never had screening mammography. A 2008 study reported annual mammography screenings for only 57.9% of women from rural Pennsylvania.

For the present study, Dr Peppercorn and his colleagues used claims data for screening mammography between 1999 and 2009 from the National Rural Electric Cooperative Association (NRECA) database, an organization that insures more than 100,000 electrical workers and their families nationwide. The researchers focused on women aged 40 to 64 years who had no history of invasive breast cancer or noninvasive ductal carcinoma in situ.

The study’s overarching goals were to review screening rates and to determine the effect of removing coinsurance for screening mammography on the use of mammography screening for a mostly rural population.

“Despite the benefits of screening, we also know that not all patients are getting screened.”

—Jeffrey M. Peppercorn, MD, MPH

More than 20,000 women had annual insurance through NRECA. There was a rise in annual mammography screening utilization from 38.1% to 49.5% during the study period.

Similarly, biennial mammography screening utilization climbed from 57.2% to 68.1% during the 10-year study period.

Of note, in 2006, NRECA unveiled a well woman examination that eliminated copays, coinsurance, and deductibles for screening mammography for women aged ≥40 years. As a result of the elimination of the copay, screening rates jumped significantly. The percentage of women who at least elected to have biennial screening rose from 60.9% in 2006 to 68.8% in 2007. The absolute difference in screening by age ranged from 5.3% for women aged 40 to 45 years to 10% for women aged 60 to 64 years.

Given the findings to date, the researchers are continuing to review the financial and nonfinancial obstacles to screening, as well as the perceptions of current screening guidance. n

Poor Adherence to Oral Cancer Drugs a Growing Concern Chicago, IL—The number of oral oncolytic drugs has increased dramatically, but despite increased convenience, there is growing concern regarding adherence, said Winson Y. Cheung, MD, MPH, Assistant Professor, University of British Columbia Division of Medical Oncology, Vancouver, at a session on adherence at ASCO 2013.

“Oral drugs shift the onus of treatment adherence from healthcare providers to patients,” Dr Cheung said.

Cancers at more tumor sites are being treated with oral therapy, and the duration of therapy is lengthening.

Adherence is an issue not only with antineoplastic drugs but also with nononcology drugs, he said.

In one study of 169 patients with chronic myelogenous leukemia (CML), only 14% were 100% adherent to a daily regimen of imatinib (Gleevec) over a 3-month period. Although 91% of the prescribed doses were taken, 71% of the patients took less than the dose prescribed, and 15% took more.

Suboptimal responses were more likely in patients with a higher mean percentage of missed doses.

Treatment response is related to adherence, noted Dawn L. Hershman, MD, MS, Associate Professor of Med­ icine and Epidemiology, Columbia University Medical Center, New York.

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In chronic-phase CML, nonadherence to imatinib adversely affected eventfree survival: the 5-year event-free survival rates were 76.7% in adherent patients and 59.8% in nonadherent patients.

“Reducing copayments can potentially improve adherence for large numbers of geographically diverse patients.”

—Winson Y. Cheung, MD, MPH

Predictors of Nonadherence Predictors of treatment discontinuation or nonadherence have been identified. Among women with earlystage breast cancer, those aged <40 years had the highest risk of discontinuation of endocrine therapy. Age ≥65 years and the presence of comorbidities were other factors associated with increased rates of discontinuation. Approximately 33% of women with early-stage breast cancer discontinued aromatase inhibitor therapy within 2 years because of an adverse effect; the rate of discontinuation be-

cause of musculoskeletal symptoms was 24.3%.

Higher prescription copayments also predict nonpersistence with aromatase inhibitor therapy. Focusing on patients at the highest risk of discontinuation is an effective use of resources, Dr Hershman said.

Other factors that predict cancer drug discontinuation are being single, being nonwhite, and therapy not being administered by an oncologist, said Dr Hershman.

Strategies to Improve Adherence Improving adherence requires a multifaceted approach that relies on several strategies: • Patients should be encouraged to call with questions about their regimen • The regimen should be as simple as possible • The consequences of missing doses should be explained to the patient.

Involving family members and significant others can aid adherence.

Simply “asking patients about adherence detects 50% of nonadherence,” she said.

Technology may be a helpful resource for improving adherence.

Phone consultation and daily text messaging reminders increased adherence to imatinib from 79.3% to 98.2% in a

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study of patients with chronic-phase CML. Texting reminders twice a week for 3 years also reduced the rate of discontinuation of anastrozole (Arimidex).

Dedicated nurse managers assigned to patients at high risk for nonadherence, as well as collaborative care models are other potential solutions, said Dr Cheung. Pharmacist-led interventions are also effective, especially in the setting of polypharmacy.

“There is evidence to suggest that the reduction of out-of-pocket expenses improves medication adherence across clinical conditions,” Dr Cheung said. “Compared with other effective interventions that are relatively complex and resource intensive, reducing copayments can potentially improve adherence for large numbers of geographically diverse patients.”

“Overadherence” “Overadherence” is an emerging concern in oncology, because patients sometimes believe that “more is better.” It is often overlooked, because most research has focused on underadherence, but the transition to oral oncolytics requires attention from providers and researchers to this new phenomenon.—WK n

www.ValueBasedCancerCare.com

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Economics of Cancer Care

Causes for Hospital Readmissions of Patients with Cancer Annual cost of rehospitalization is approximately $16 billion

By Wayne Kuznar Chicago, IL—Hospitalizations and readmissions add substantial costs to healthcare. The annual cost of 30-day hospital readmissions in the United States is estimated to be $16 billion.

In addition, bundled payment models may eliminate additional payment for readmissions in a specified period after discharge.

Several poster presentations at ASCO 2013 explored factors associated with readmission or unplanned hospitalizations in patients with cancer.

Risk Factors Cancer site, Medicare severity diagnosis-related group (MS-DRG), admission status, length of stay, and payer status are significantly associated with readmission in patients with gynecologic cancer, found Kristy K. Ward, MD, Gynecologic Oncology Fellow, Department of Reproductive Medicine, University of California, San Diego Moores Cancer Center, La Jolla. Dr Ward and colleagues queried the database of the University HealthSystem Consortium (with 217 academic medical centers) to identify readmissions among patients with gynecologic cancer.

For each risk factor found to be independently associated with readmission, the low-risk group was scored 0 and the high-risk group was scored 1.

A risk of readmission score was created using findings from the multivariate analysis.

The overall readmission rate for patients with gynecologic cancer was 4.5%. Vulvar cancer, medical MS-DRG, urgent or emergent admission, length of stay of >4 days, and coverage by a public payer were each independently associated with readmission. The probability of readmission rose significantly with increasing risk score.

“Just 2 of these risk factors put you at greater risk of readmission than the general population.”

—Kristy K. Ward, MD Patients with a risk of readmission score of 0 or 1 have a readmission rate of 3.9% compared with 10.7% for patients with a risk of readmission score of >1.

“Just 2 of these risk factors put you at greater risk of readmission than the general population,” according to Dr Ward.

“The risk of readmission score may be used to determine which patients you would expect to be readmitted; then you could allocate your resources better toward those patients.”

Unplanned Hospitalization High hospital admission rates among patients with gastrointestinal (GI) cancer are driven by unplanned hospitalization and are potentially preventable,

according to researchers from M.D. Anderson Cancer Center, Houston.

They used Texas Cancer Registry and Medicare claims data for in-hospital admissions from 30,199 patients with GI cancer aged >66 years. The rate of unplanned hospitalization was 58%, and 77% of these hospitalizations occurred within the first year of the cancer diagnosis. The top 5 reasons for unplanned hospitalization were volume depletion, congestive heart failure, pneumonia, urinary tract infection, and septicemia. These are “diagnoses that are considered potentially preventable and should be a focus for intervention,” noted Joanna-Grace M. Manzano, MD, M.D. Anderson Cancer Center, Houston.

On multivariate analysis, unplanned hospitalization was more likely among patients with esophageal cancer (relative risk [RR], 1.16), gastric cancer (RR, 1.07), pancreatic cancer (RR, 1.04), and rectal cancer (RR, 1.03). Patients with regional and distant diseases were at higher risk for unplanned hospitalization (RR, 1.14 and 1.13, respectively).

Having ≥1 unplanned hospitalizations was associated with poorer survival. Of the entire cohort, 14% had ≥3 unplanned hospitalizations, which amounted to 49% of the unplanned hospitalizations.

Academic versus Nonacademic Hospitals Readmission after an index hospital-

ization for cancer surgery is higher in nonteaching hospitals than in teaching hospitals, found Nina A. Bickell, MD, Codirector, Center for Health Equity and Community Engaged Research, Mount Sinai, NY, and colleagues.

As part of the Healthcare Cost and Utilization Project, common cancer hospitalizations in New York State in 2009 were identified and 30-day readmissions were assessed. From 21,945 index admissions for cancer surgery, the overall readmission rate was 9.3%, with 11.2% readmissions in nonteaching hospitals and 8.6% in teaching hospitals (P <.001).

“Our hypothesis is that academic hospitals are more likely to have clinical protocols, and that may reduce readmission rates.”

—Nina A. Bickell, MD Being male, undergoing surgery at a nonteaching hospital, black race, and certain comorbidities increased a patient’s risk of 30-day readmission for a preventable cause.

“Our hypothesis is that academic hospitals are more likely to have clinical protocols, and that may reduce readmission rates,” said Dr Bickell. n

Routine Surveillance CT Costly, Unnecessary in Lymphoma in Remission

By Caroline Helwick

Chicago, IL—Routine surveillance imaging is of little value in patients with diffuse large B-cell lymphoma (DLBCL) or classical Hodgkin lymphoma who are in remission, researchers from 2 institutions reported.

“DLBCL is clinically aggressive but potentially curable, even after relapse,” said Carrie A. Thompson, MD, Hematology Division, Mayo Clinic, Rochester, MN. “However, the optimal follow-up strategy is not clear.”

The National Comprehensive Cancer Network recommends a surveillance computed tomography (CT) scan every 3 months to 6 months for 5 years posttreatment. Dr Thompson’s study enrolled 644 patients with DLBCL; 537 of them entered posttreatment observa-

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tion. Of these, 20% (109) relapsed.

Of the 100 patients who were evaluable, 62 presented earlier than the planned follow-up visit because of symptoms. Overall, 87% of patients had at least 1 feature indicative of relapse.

Of the 38 patients whose relapse was detected at a planned visit, only 12 had the relapse detected solely by a surveillance scan. Only 1.5% of patients had a relapse that would have only been detected by a surveillance CT scan while in remission, Dr Thompson said.

“Routine surveillance scans posttherapy add little to the detection of DLBCL,” Dr Thompson said.

A second study presented at ASCO 2013 included 241 patients with lym-

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phoma: 164 had surveillance CT and 77 had clinical surveillance only.

Patients who relapsed in the clinical surveillance group had an average of 17.6 scans per relapse compared with 123.8 scans in the imaging group, resulting in additional costs of $593,698 per relapse.

At a median follow-up of approximately 4 years, there were 5 (3.8%) deaths in the imaging group and 4 (5.3%) in the clinical surveillance group, yielding a similar overall survival rate.

“We don’t feel that the potential risks and costs, without overall survival benefit or any other clinical benefit, justify the practice” of routine imaging in patients with lymphoma, said Sai Ravi Pingali, MD, of the Medical College of

Wisconsin Affiliated Hospitals, who conducted the study.

Leo I. Gordon, MD, Abby and John Friend Professor of Oncology Research, Northwestern University Feinberg Medical School, Chicago, IL, said that a physical examination can detect most relapses: the cost of an office visit is relatively inexpensive and does not expose patients to radiation, whereas 1 scan costs approximately $5000 and involves radiation exposure.

“We can at least say that no data support the use of routine surveillance CT scans in clinical practice in classical Hodgkin lymphoma and diffuse large B-cell lymphoma in remissions. I think we must reeducate ourselves as clinicians,” Dr Gordon said. n

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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

In the Literature Finasteride Does Not Affect Survival Rates in Prostate Cancer

Widespread adoption of prostatespecific antigen (PSA) screening has been associated with a 44% reduction in prostate cancer mortality. Although early detection of prostate cancer with PSA testing may lead to reduced mortality, it also leads to significant over-

detection of cancer. Another approach that complements early detection is prostate cancer prevention. The use of finasteride, a 5-alpha reductase inhibitor, was evaluated in the Prostate Cancer Prevention Trial (PCPT).

The investigators randomized nearly 19,000 healthy, cancer-free men aged ≥55 years to daily finasteride or to placebo for 7 years. Data published

in 2003 showed that the drug was associated with a 24.8% reduction in the risk for prostate cancer. Participants in the finasteride arm, however, had a 26.9% increased incidence of highgrade prostate cancer. With up to 18 years of follow-up, ending October 31, 2011, a new study analyzed the survival rates among all participants in the PCPT and among those with prostate

cancer (Thompson IM Jr, et al. N Engl J Med. 2013;369:603-610).

PCPT was a randomized, placebocontrolled study that ran from 1993 to 2003 and included 18,880 men. The updated results showed that prostate cancer was diagnosed in 10.5% of men in the finasteride group and in 14.9% of men in the placebo group (relative risk [RR] in the finasteride group, 0.70;

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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.

In the Literature 95% confidence interval [CI], 0.65-0.76; P <.001). The results also showed that the finasteride arm had a 3.5% incidence of high-grade prostate cancer compared with 3.0% in the placebo arm (RR, 1.17%; 95% CI, 1.00-1.37; P = .05). Of the 5034 deaths reported, 2538 were in the finasteride-treated group and 2406 were in the group receiving placebo, for 15-year survival rates of

78.0% and 78.2%, respectively. The unadjusted hazard ratio for death in the finasteride arm was 1.02 (95% CI, 0.971.08; P = .46). When stratified by cancer grade, the 10-year survival rates were 83.0% in the finasteride-treated group and 80.9% in the group receiving placebo for low-grade prostate cancer and 73.0% and 73.6%, respectively, for those with high-grade prostate cancer.

These results show that finasteride reduced the risk of prostate cancer by nearly 33%. Although high-grade prostate cancer was more common in the finasteride group than in the placebo group, 18 years of follow-up showed no significant difference between the 2 groups in overall survival rates or survival after a diagnosis of prostate cancer.

Industry-Funded Studies Receive Greater Prominence at ASCO Meetings

The American Society of Clinical Oncology (ASCO) revised its policy on financial conflicts of interest (FCOIs) in 2005, establishing for the first time certain types of financial relationships for clinical trial principal investigators.

Continued on page 18

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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

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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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In the Literature Industry-Funded Studies Receive Greater Prominence at ASCO Meetings Continued from page 17

ASCO also clarified its requirement for those submitting research presentations at the annual ASCO meeting to disclose potential FCOIs with any entity having a commercial interest in the subject matter.

Despite widespread implementation of conflicts of interest policies in academic centers, federal agencies, and professional medical societies, evidence is limited about the effects and influence of financial support from the pharmaceutical industry on the type of research conduct, the outcomes, and dissemination of the results.

A new study, supported in part

by the National Institutes of Health/ National Cancer Institute and ASCO, examined the prevalence of FCOIs in oncology and the association between pharmaceutical industry funding, based on self-disclosure by authors, and research prominence and peerreview score among abstracts presented at ASCO annual meetings (Moy B, et al. J Clin Oncol. 2013;31:2678-2684).

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

The analysis included 20,718 abstracts that were presented at ASCO annual meetings over a 5-year period (2006 and 2008-2011). The ASCO database for 2007 was incomplete, thus excluding this period from the study. FCOIs were classified as employment stock, consultant, honoraria or research funding, and expert witness. The order of meeting placement

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 prominence was defined in descending order of plenary session, clinical session, oral presentation, poster discussion, general posters, and published only. The peer-review score was determined by 2 individuals who independently assigned a score of 1 to 5 to the abstracts, with the lower value indicating higher merit.

Overall, 36% of the abstracts had at

least 1 author with a financial relationship to the pharmaceutical industry.

The rate increased from 33% in 2006 to 38% in 2011 (P <.001) for the proportion of abstracts with any FCOIs. Of the 12,058 abstracts accepted for presentation, those whose authors disclosed any financial relationship increased from 39% in 2006 to 47% in 2011 (P <.001). Abstracts with FCOIs

were also found to have been given higher meeting prominence compared with general posters. Specifically, odds ratios compared with general posters were 7.3 (95% confidence interval [CI], 2.5-21.4) for plenary sessions, 2.2 (95% CI, 1.8-2.7) for clinical science symposia, 1.9 (95% CI, 1.6-2.1) for oral presentations, and 1.7 (95% CI, 1.5-1.8) for poster discussions (P <.001).

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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.

Ibrutinib Shows Durable Remissions in Patients with Relapsed CLL

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,

Abstracts with FCOIs had significantly better peer-review scores compared with abstracts without such conflicts. For all abstracts, the peer-review score was 2.76 with FCOIs compared with 3.01 without FCOIs. Excluding published-only abstracts, the peerreview score was 2.62 with FCOIs versus 2.73 without FCOIs. The findings show that studies with deemed financial influence from the pharmaceutical industry receive more prominent placement in ASCO meetings and better peer-review scores than studies or abstracts whose authors did not disclose financial relationships. The study also found that financial relationships with commercial interests were reported more frequently over a period of several years, suggesting an increasing influence of the pharmaceutical industry on cancer research, greater disclosure, or both.

This is the first study to use primary evidence provided by authors regarding the prominence of cancer research conducted with self-disclosed financial relationships.

Treatment for chronic lymphocytic leukemia (CLL) has resulted in few cases of durable remissions. Bruton’s tyrosine kinase (BTK), an essential component of B-cell receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. Ibrutinib, an oral covalent inhibitor of BTK designed for the treatment of B-cell cancers, has shown that treatment with this drug inhibits numerous processes. Ibrutinib also does not have toxic effects on normal T-cells. A new study investigated the safety and efficacy of 2 different ibrutinib doses in patients with relapsed or refractory disease (Byrd JC, et al.

N Engl J Med. 2013;369:32-42).

In this phase 1b-2, open-label, multicenter study, 85 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) were randomized to receive 420 mg of ibrutinib (N = 51) or 840 mg of ibrutinib (N = 34). Both doses were administered orally on a continuous schedule until the onset of disease progression or unacceptable toxicity. A majority of these patients had high-risk disease and had received a median of 4 previous therapies. At a median follow-up of 20.9 months, 64% were still receiving treatment and 36% had discontinued treatment.

Long-term therapy with ibrutinib was associated with modest toxicity; most adverse events were grade 1 or 2.

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AVBCC 2013 Steering Committee Co-Chairs Burt Zweigenhaft, BS President and Chief Executive Officer OncoMed Onco360 Great Neck, NY

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

Linda Bosserman, MD, FACP Medical Oncologist and President, Wilshire Oncology Medical Group Rancho Cucamonga, CA

Kevin B. Knopf, MD, MPH Hematologist/Oncologist California Pacific Medical Center, Sutter Health San Francisco, CA

Jennifer Malin, MD, PhD Medical Director of Oncology WellPoint, Inc Los Angeles, CA

atthew C. Palmgren, M PharmD President Int’Ovation Signal Mountain, TN

Douglas S. Burgoyne, PharmD President, VRx Pharmacy Services Salt Lake City, UT

James R. Lang, PharmD, MBA Vice President, Pharmacy Services BlueCross BlueShield of Michigan, Detroit, MI

Thomas A. Marsland, MD President, Integrated Community Oncology Network (ICON) Orange Park, FL

Lillie D. Shockney, RN, BS, MAS Administrative Director John Hopkins Medical Institutions Baltimore, MD

John E. Hennessy, CMPE Vice President of Operations Sarah Cannon Cancer Services, Nashville, TN

Grant D. Lawless, MD, RPh, FACP Program Director Associate Professor, University of Southern California Los Angeles, CA

atrick McKercher, RPh, PhD P President, Patient Access Network Foundation Washington, DC

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

James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care, Wellesley, MA

Douglas M. Long Vice President Industry Relations IMS Health Totowa, NJ

Leonard Natelson Chief Executive Officer Hematology/Oncology Associates of Rockland Rockland, NY

F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare and Bentelligence Greenville, SC

Defining Value in Cancer Care...

Group I: Pathways

Gary M. Owens; Grant D. Lawless; Jennifer Malin: The question of value from the perspective of pathways in oncology is focused on how to decrease care variabil­ ity to improve

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Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE

clinical outcomes at an acceptable and sustainable cost. Using pathways to eliminate care variability and to improve outcomes should ultimately result in cost efficiencies as well.

Pathways must balance (1) population

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needs, which reflects how healthcare payers perceive the issue of pathways; (2) individual needs, which are dependent on the physician–patient relationship; and (3) societal needs, which involve patient outcomes and cost of care. The key value considerations re­lated to oncology pathways involve: • Comparative efficacy, which allows us to compare various products and decide which product delivers the best efficacy • Toxicity, which is directly related to efficacy and is directly related to the value of a product • Cost, which also must be incorporated into the definition of the value of pathways • Finally, pathways cannot be universal but must apply to specific

populations (ie, population needs); pathways need to apply to 80% or 85% of the population, but there will always be the need to deviate from pathways to meet selected individuals’ parameters.

When discussing value, it is also necessary to ask who sets the pathway; is the pathway a national or a local standard? That is, is the pathway being set up by pathways companies that are in the business of promoting pathways and selling a product, or by a public organization? We raised some of the pros and cons related to national versus regional pathways, whether private or public.

Pro: Pathways developed by national organizations can be authoritative. Theoretically, they could be

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3rd Conference un­biased, and they would create uniformity across regions. Variability of care as a problem has already been recognized in the 1970s, and it is still a problem today. National pathways would create uniformity of care, and such a large, authoritative source could drive comparative effectiveness that does not exist now.

Con: National pathways would be slower to implement. Anything done at a national level is going to take more time. It might be hard to get all of the proper stakeholders together on a national level. More important, a national guideline or a national pathways office has a large potential to do harm, because it is conducted on a national basis.

Pro: Regional pathways, similarly, could be unbiased, and a regional group would be easier to structure and put together to get the right stakeholders across the table.

Con: A regional pathway is going to result in variations of care by those regions. Because it will not be at the local level but rather at a regional level, regions may not have the power to drive effective activities that are so essential.

The goal of implementing pathways is to drive better outcomes and more cost-effective care. For that, we need unbiased comparative effectiveness data on cost and outcomes. Pathways also need to be able to create payment models that align financial incentives across all stakeholders, so that they are not inadvertently driving care based on financial drivers. We believe that advocates could provide a supporting role for this by helping to reinforce pathways, because cancer care has evolved to the point where not every treatment choice needs to be available, regardless of cost.

In addition, end-of-life care concepts must be incorporated into pathways.

The resources spent on unnecessary care at the end of life can be carefully monitored; they are often used unnecessarily and can better serve other patients who would benefit more from care. End-of-life care must be part of the pathways to prevent futile and potentially unnecessary care, considering the limited resources.

Finally, pathways probably need to include branches to allow for proven precision (or personalized) medicine decisions. But we must insist on “proven” medicine, because many precision medicine tests are directional, or they do not necessarily create decision points. We need to make sure genetic tests can actually do what they promise to do before they are incorporated into pathways. Once they are established with evidence, they can be incorporated into the pathways.

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Therefore, pathways have to be a “dynamic process” that incorporates new products that come to market with appropriate evidence.

Group II: Reimbursement

Burt Zweigenhaft; Douglas S. Burgoyne; John E. Hennessy: Our dis­­cussion involved current payment methods and what they should be in the future, focusing on 2 key points.

We need to move away from the oldschool fee for services that are inclusive and bundled to new approaches that will incorporate individual value-added services that are not currently covered and recognized, such as advance care directives, care planning, medication treatment management, drug adherence, side-effect management,

and educational services that carry value for patients with cancer. We probably all agree that our current system of payments and reimbursements is not appropriate for the breadth of services that need to be incorporated into appropriate care today, as we need to improve how we pay for services. Recognizing and then scoring or monetizing individual components of care that have clinical utility is the greater part of the value proposition in oncology care tomorrow.

We are beginning to recognize the great value that multidisciplinary care team members and oncologists can provide in terms of clinical management, diagnostics, and treatment, and not just dispensing drug therapy. So it will be important to measure and score clinical value-added activities to receive reimbursement for additional cogitative services. We need to move to unbundling or decoupling bundling from dispensing drugs, and start to demonstrate the value that oncologists and oncology treatments deliver for patients globally, by breaking the costs apart to recognize the value of each service; for example, administrative services improve outcomes in terms of patient compliance with oral therapies, but that service is currently not being reimbursed.

The provider will have to define what is fair market value for the addi-

tional clinical management services delivered. It is always nontransparent and extremely difficult to recognize the value of the entire treatment continuum when we are bundling so many services into the drug-dispensing margins. One novel idea would be paying a premium reimbursement modifier for the first time that an oncologist treats a new patient versus the eighth or tenth round of treatments. How do we assess the value of these differences in the care continuum, and how should the reimbursement reflect that difference?

We did not come up with the solutions to these questions, but these are the types of questions that should be raised in relation to value and quality of care in oncology. We are, however,

in agreement that we must recognize the differences in these services, and it is time to begin to pay for these different services. We need to separate the first encounter with a patient from other components of the treatment, and from reimbursement for drugs.

Group III: Regulatory/ Government

Jayson Slotnik; Douglas M. Long: How does the federal government define value? The short answer is, it does not consider value in its decisions in oncology. So, our discussion quickly evolved into what the role of the federal government is in terms of value in cancer care. However, although we said that the government does not define value, value is directly related to cost, and the government overall defines value as the lowest cost. But the government and everybody need to take a broader perspective of value so that cost is not the only component of value.

In terms of value, we should be looking at patient care as a total engagement of the provider care and the global episode of care. We think that the Association for Value-Based Cancer Care should drive the conversation around value by making sure that the definition incorporates all related costs of cancer care, not only drug costs, as well as outcomes and

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measurements; we also need to provide tools to measure the outcomes in oncology. So, the definition of value from a regulatory perspective should include all of these components—total costs, outcomes, and measurements.

Mr Zweigenhaft: The Centers for Medicare & Medicaid Services (CMS), which is responsible for 45% of the patients with cancer in this country, is really the 800-lb gorilla we often talk about in healthcare. CMS truly influences the market, and your group believes that this regulatory body does not know where it is going, and it is not setting the tone in the industry; does this mean that the tone will be set outside of government services? How do you see this evolving?

Mr Slotnik: CMS is a complicated entity, because of the rules that have been written for it by Congress on how CMS can provide access to care. Medicare coverage policies have evolved over time as a result of what Congress has allowed CMS to do in terms of drug coverage (eg, in the case of fail-first drug coverage in Part B, or by trying to shift drugs over to Medicare Part D or vice versa). CMS is trying to limit what it has to pay for. Nevertheless, over the past 7 or 8 years, we have seen a shift toward paying for value by Medicare, paying for what works, and paying for evidence. This began when the Medicare Modernization Act (MMA) of 2003 was passed. It has taken time to implement the MMA, because regulatory bodies, such as CMS, move slowly as a result of the politics around any change in policy, particularly as it relates to cancer care.

But, over time, we will likely start to see more boundaries to expanded access to care. Certain things will be less accessible over time, and we have already seen this in policies evolving to limit what Medicare is paying for, using the approach of only paying for what works; however, CMS must first figure out what works, which complicates things. Sometimes when we know we pay for something that does not work, if we cannot get it there, we do not go back; we just end up with more questions than answers. This is hard to balance.

Group IV: Advocacy Groups

Lillie D. Shockney; Patrick McKercher; F. Randy Vogenberg: From an advocacy group’s perspective, which represents the patient’s perspective, we determined that value has to be very patient-specific: what each individual thinks is important and has value. One patient sees one thing as important, and yet another patient may see that as not being Continued on page 22

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Defining Value in Cancer Care... important. Certainly both patients should receive patient-centered care, which is easy to say but not always easy to deliver. And that care should be provided at the right time, in the right setting, and obviously with the right treatment, based on evidence-based medicine. There is a need to develop what we call “a new platform” that can guide patients and physicians in addressing a patient’s life goals.

One of the very first things we should do before we touch patients is to talk to them about their goals, their work, their plans, and find out who the patient is. For example, if the patient is planning to start a family next year, you need to consider fertility preservation to help her or him to be able to have a family after the chemotherapy.

Value for the patient includes getting decision-making tools. In the case of patients who may become longterm survivors, we need to empower them to be able to participate in the decision-making about their treatment. We must not have treatment done to the patient, but have treatment done with the patient. The same applies to patients with metastatic disease, in terms of decision tools, to give them the power to participate in, and have their voice heard about, their treatment. More treatment does not make it better treatment, especially in the metastatic setting.

A recent study showed that between 40% and 60% of patients with metastatic cancer believe that the chemotherapy they are getting will cure them, which indicates that there is no discussion with the patient.

We also have to promote survivorship care to begin at the time of diagnosis. We need to be proactive about side effects and try to prevent them, instead of telling patients to expect them. Fatigue is the number one struggle for patients with cancer.

The evidence shows that if a patient with cancer is power walking 3 times weekly for 30 minutes, fatigue will be reduced significantly. So why are we not making sure patients do that?

There is also value in patients having a patient advocate, which in most cases would be an oncology nurse advocator who understands the disease and the treatment and can provide education and support, and identify barriers, including cultural or financial barriers.

It is crucial to change the goals of health insurance coverage. Rather than focusing on covering treatment,

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the value to patients is in coverage for preventive care, which promotes health. There is more value in paying for keeping people healthy than paying for sickness.

“Value for the patient includes getting decisionmaking tools. We must not have treatment done to the patient, but have treatment done with the patient.”

Another big value issue for patients (as well as for providers) is continuity of care. Value-based care must ensure that we are delivering care in an efficient way, that it is effective, that we are not overtreating or undertreating, and that patients have access to care, in terms of geography and time. For example, many patients cannot afford to take time off from work to get a screening test. So that patient will not have the test. Geographic access and extended-hours access to a facility can improve overall care.

Finally, quality of life (QOL) must also be included in the patient’s definition of value. When QOL is poor, survival may not be what the patient perceives as value. Patients without QOL often prefer not to survive. Survival without QOL is not the ultimate value for patients.

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oncologists, and the question is, do we need physicians to run the business and do the negotiations, or do we need them to use their 14 years of training to lead teams that take care of patients, which no one else can do?

We believe that more systems of care are being created because patients want to have integration and focus on their overall health. As we move toward a patient-centered system, we need to remember that patients do not care how their doctor gets paid.

Patients want to get the care they need—the right care, at the right time, in the right setting, for the best price.

Cancer care is no longer about the doctor, it is about the patient. And it is moving from a focus on treatment at any cost to education and discussions with patients and payers about the overall health impact of care.

The physicians are willing to work in systems, and it does not matter if the system is owned by physicians (as in the HealthCare Partners, IPA),

by Kaiser (when the payer owns the system), or by a hospital or hospital system. As systems compete, we are going to have real-world data and outcomes-based care that will allow us to continually refine what is offered to achieve the best value, but the fact is that patients today want to go into a health system. In California, for example, we have 3 systems in the north:

just recently, annual out-of-pocket maximums have been established. One of my patients with stage I breast cancer said, “If I have a recurrence, I don’t want to have copays. I’m switching to Kaiser.” We are seeing people with private PPO insurance, including professors and business professionals, switching to Kaiser for comprehensive, integrated care; these are people who would not have gone with Kaiser before. This is a culture change, and we all have to reengineer our practices to engage the patient, the payer, and our colleagues. To do that, we need to standardize care, we need to have care and payment integration, and we need to have scale.

It is possible that not every small private oncology practice will have to go out of business, but all practices are going to need some networked resources to empower them to have the right pathways and all of the latest information to be able to make decisions at the point of care, to provide patient education and patient resources online and in the community. We are going to have to rethink our systems and put the patient at the center, which is where value is in cancer care.

A physician does not have the expertise in every cancer and every new treatment in rare diseases, nor the administrative expertise and support for the business sophistication

Sutter Health, Catholic Healthcare West, and Kaiser, and some outliers.

San Diego also has 3 big systems.

And although our big region in southern California is fighting and arguing, everyone is going to come together quickly, because Kaiser has taken a 40% market share in California: this is a clear message from consumers that they want integrated and cost-effective care that is focused on their health.

In the Medicare Advantage plans in Kaiser, patients do not have a copayment for chemotherapy or radiation.

Other Medicare Advantage plans with smaller Individual Practice Associations in California can have up to 20% copays;

that we need, which will be based on personalized data. Oncologists are going to need all of the tools to deliver value-based care. We need to know which mutation requires which drug to deliver the most cost-effective, value-based care.

We are going to have to decide what data we need and how to transfer the data into real-world information that is useful. This means that we have to standardize and learn to work in and provide leadership to teams, including nurse practitioners, physician assistants, registered and licensed vocational nurses, medical assistants, navigators,

Group V: Oncology Practices

Linda Bosserman; Thomas A. Marsland; Leonard Natelson: Oncol­ ogy care is provided in academic practices and community practices but 80% of cancer care has been given in community practices. However, many of these practices are being bought up by hospitals that offer the opportunity to reduce fragmented care but will be challenged to maintain the innovation and engagement of entrepreneurial physicians. We believe that we are going to have a culture change in oncology. Until now, practices have been very physician-centric. Most physicians within a private oncology practice have 4 driving principles: (1) they love to practice medicine; (2) they value “cowboy independence” in patient decision-making and in care innovations, which was drilled into all of us in medical school; (3) they have business interests in running the practice; and (4) they are interested in research.

But we now have a shortage of

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Another option in short-acting G-CSF therapy » FDA approved Brought to you by Teva—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 GRANIXhcp.com Indication » GRANIXTM is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease.

Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatmentemergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Prescribing Information on adjacent page.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. FIL-40099 August 2013.

FDA Update Abraxane Receives New Indication for Metastatic Pancreatic Cancer

The US Food and Drug Administra­ tion (FDA) approved a new indication for paclitaxel protein-bound particles for injectable suspension, albumin-bound (Abraxane; Celgene) for the treatment of patients with metastatic pancreatic cancer. Removal of

the pancreas by surgery is the only curative option in pancreatic cancer, but this option is no longer useful by the time this type of cancer is diagnosed, when the cancer has metastasized.

“Patients with pancreatic cancer are often diagnosed after the cancer has advanced and cannot be surgically removed,” said Richard Pazdur, MD, Director of the Office of Hematology

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

4 CONTRAINDICATIONS None.

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

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

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

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

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

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

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92).

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

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the

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and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “In these situations, and in situations when the cancer has progressed following surgery, options like Abraxane can prolong a patient’s life.”

Paclitaxel protein-bound is a chemotherapy agent that has been shown to slow certain types of tumors.

The FDA approval of paclitaxel pro-

recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).

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

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

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

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

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

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

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

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

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

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

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

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

10 OVERDOSAGE No case of overdose has been reported.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Product of Israel FIL-40045 July 2013 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

september 2013

tein-bound for patients with pancreatic cancer was based on a clinical trial with 861 patients who were randomized to paclitaxel protein-bound plus gemcitabine (Gemzar) or to gemcitabine alone. The overall survival in patients receiving the combination therapy was an average of 1.8 months longer than in patients receiving gemcitabine alone. In addition, progression-free survival was also, on average, 1.8 months longer with the addition of paclitaxel protein-bound to gemcitabine than in patients receiving only gemcitabine. The common side effects with paclitaxel protein-bound include neutropenia, thrombocyto­ penia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, fever, vomiting, rash, and dehydration. The most severe effects in this trial were fever, dehydration, pneumonia, and vomiting.

Paclitaxel protein-bound is already approved for the treatment of breast cancer and non–small-cell lung cancer. (September 6, 2013)

Ibrutinib Shows Durable Remissions... Continued from page 19

The most common adverse events included transient diarrhea (47%), upper respiratory tract infection (33%), and fatigue (28%); a majority of adverse events resolved without the need for treatment suspension. The overall response rate was 71% for both treatment arms, and an additional 20% in the 420-mg group and 15% in the 840-mg group experienced a partial response with lymphocytosis.

The response was independent of clinical and genomic risk factors present before treatment. After a follow-up of 26 months, the estimated rate of progression-free survival was 75%, and the rate of overall survival was 83% for all patients, irrespective of the dose.

These results suggest that monotherapy with ibrutinib is associated with an increased frequency of durable disease remission in patients with relapsed and refractory CLL and SLL, including patients with high-risk genetic disease.

It is noteworthy that this study, which was initially designed with 2 arms, was expanded to include a third arm of patients with high-risk disease. Complete or partial responses increased over time and peaked at 18 months of therapy.

The drug was rapidly absorbed and blocked the BTK enzyme almost completely (a reflection of surrogate kinase inhibition). Ibrutinib is still not available commercially, but this study may provide enough data to allow for its approval as an orphan drug. n

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3rd Conference

Defining Value in Cancer Care... social workers, therapists, administrators, and payers to come to terms with new realities in oncology. As a senior oncologist, the exciting reality is that the doctors we have interviewed over the past 3 years are exceptionally well trained and enthusiastic to work in a comprehensive team environment.

Our partners in the pharmaceutical companies know what they currently need from a regulatory perspective to get a drug on the market, and they have been able to use data from clinical trial patients on progression-free survival, disease-free survival, and overall survival, with support for significant toxicities to get those drugs on the market. But they do not know where real-world data come into this picture: which real-world data, from whom, and for which comorbidities have what benefits, with what toxicities and preferences for impact on their overall health, especially in advanced terminal diseases. These are all relevant questions.

We need our drug development partners to pay for all the new and expensive drugs and to figure out the value of those drugs with data that matter to patients. The value perspective means that we know what the cost is in relation to all the relevant outcomes and whose outcome is going to be the most important. How can we begin to get honest data to patients? We have had a lot of data provided to doctors, and we have been incentivized to give drugs to patients, but we have not been incentivized to improve health. We are now moving toward improving health. If patients with lung cancer in the real world live about 1 year, what educational materials should be provided to a patient at various ages, with various comorbidities, to discuss a therapy that may delay death but with significant risks of hospitalizations, suffering from toxicities, and the possibility of dying from the therapy? We have been incentivized and trained to focus on treatment using the few patients who might achieve an unusual longterm benefit while overlooking the many who suffer needlessly during the time they have left to live. As was noted in one example, we can reduce patient fatigue during chemotherapy by instituting power walking, which is treating to improve health—not a major focus of doctors.

Most physicians have not been trained or able to focus their teams on the benefits of nutrition and exercise on long-term health, despite all the data we have. Survivorship is

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just now starting to be addressed by physicians, yet it lowers recurrence risk and improves overall health outcomes. Most women with breast cancer are going to die of heart disease, not cancer. As oncologists, we have been incentivized only to focus on the risk of recurrent breast cancer and not to deal with other health issues, such as lipids, bone density, or cardiac risk that interact with adjuvant therapies to impact long-term health. That’s not treating for health.

“We need a different payment system that will recognize the components of care that patients need in these new systems.”

Personalized medicine will require teamwork. We need to change the physician role. Young physicians are willing to lead and participate in teams, and they want to practice medicine. They are happy to go into systems, but they need a fair compensation to lead an integrated team, regardless of whether it is with a pharmacist, nurse practitioners, physician assistants, or nurses, who are also undervalued in our system. Nurses are experts at compliance, adherence, patient education, and overcoming barriers for our patients, but when the reimbursements for infusion and drugs were removed, that changed the role of nurses, who are now only administering chemotherapy. Nurses need to be better valued in the system for their knowledge and their skills.

We need a different payment system that will recognize the components of care that patients need in these new systems. Our group had many challenges in deciding what the actual outcome end points should be. Until we standardize the data and demand real health outcomes from our care, we will remain challenged in our current delivery models, which are fragmented, with costs that are not sustainable now. As we see systems delivering integrated care with real-world data on health outcomes, we see consumers choosing them.

Mr Zweigenhaft: Do you believe that community oncology will be around in the future, or are we all going to be working in the systems?

Dr Bosserman: I think we will have many different models. Healthcare is still regional, but a community prac-

Continued from page 22

tice cannot do it alone anymore. They have to be a part of some system, which is empowered by an electronic medical record system or a network.

Telemedicine is going to have a bigger role. I think we will have big integrated systems with managed care, but primary care physicians do not want to manage cancer. That remains the role of the oncologists, and that is cost-effective.

Mr Zweigenhaft: Our group agreed that the reimbursement system has to change to recognize the value of nurses to patients. We also need to agree what the diagnostic value is for the patient. Is the first positron emission tomography (PET) scan worth more than the seventy-­fifth scan? At a recent meeting’s survivorship session, a woman who had lost her husband to cancer asked, “How many PET scans do you think he had in his last 2 years of life? He had 75 scans. Was the value of the first scan the same as the value of the seventy fifth scan?” This is a sign of a broken system. We need to move to a system of reimbursement that only pays for value-based care.

Group VI: Hospitals

Kevin B. Knopf; Craig K. Deligdish: The ability of hospitals to deliver value is unclear. Hospitals are not focused on value as cost versus quality of care but on value as volume. In northern California, for example, there are 3 main systems: Kaiser has more than one third of the market share; Sutter Health system has 28 hospitals in various foundations and different maturities; and Catholic Healthcare West is still surviving. There are also several academic centers. Sutter Health is looking for larger contracts and is focused on attracting patients with good insurance or Medicare, but not Medicaid.

We had difficulty defining what a hospital actually is. The model is different with each system. In Kaiser, a hospital is part of a large staff model HMO, with alignment of outpatient and in-­ patient healthcare financially. Catholic Healthcare West has a private practice model with some interplay between the oncologists and the hospital system. By contrast, Sutter Health, as well as Catholic Healthcare West, have a traditional hospital model, in which oncologists are separate from the hospital and so are the ancillary services.

There is a growing movement toward “Foundation acquisition” of oncology practices in the Sutter Health system.

So, overall, hospitals consider value not by traditional economic terms of cost versus quality, but value by mar-

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ket share—how many patients they serve, how many doctors they have, the status of the doctors, the size of the hospital, and the hospital’s appeal to the patient, who is seen as a consumer—the traditional “heads and beds” model. Therefore, buying a proton beam therapy machine, for example, to deliver radiation to patients with prostate cancer makes sense, because it gives the hospital status to have this expensive type of radiation, the healthcare system can charge a $50,000 premium per patient for this advanced technology, and it impresses people within the organization and can serve as a marketing tool. The hospital can advertise that it has this advanced type of radiation, with no regard to whether it has true value to the patient or to the payer. Cost is not seen as part of the value equation.

Whether this will change depends on the payment system and on how hospitals and providers will be paid in the future. At present, hospitals are still looking at the number of beds that are being occupied by patients and the number of patients being treated, and in oncology the number of “chairs per person per day” being used for chemotherapy. They are not looking at the cost-effectiveness of a particular chemotherapy regimen as much as how many patients are being treated daily. Hospitals are not yet in the habit of looking at overhead costs or even at patient outcomes.

A landmark development was when Leapfrog partnered with the CMS and another policy think tank to review hospitals based on their CMS violations and made this information available online to patients. The idea is that patients would be able to choose a hospital based on how many (or few) CMS violations it has and would go to the one with the best compliance.

But, in many cases, patients still select a hospital based on their health plan.

We wonder when hospitals would start to look at value. We believe that hospitals would not look at value until they are forced to by reporting systems from the public about their outcomes. That may take a while until the outcomes from cancer services are reported, and the outcomes are based on what we can measure and what we, as oncologists, think are important things to measure. The value of these outcomes may not be public knowledge and may not be tracked for a while, even though we have increasingly better information systems. Ultimately, we believe that value Continued on page 26

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3rd Conference

Defining Value in Cancer Care... lies in patients’ outcomes based on the treatment received.

The model that hospitals are using to define value remains based on the number of daily computed tomography scans, the number of daily PET scans, and the number of patients in the hospital per bed per day rather than the value of the specific procedure or imaging study.

Hospitals will change the way they define value depending on future changes in healthcare, such as the implementation of accountable care organizations (ACOs) or competition among health systems. If systems begin to compete on costs, hospitals may begin to look at them.

We had different views on whether pay for performance will become the new payment system or whether it is a failed model. Patients today choose a hospital in part based on their perception of quality of care, which may be affected by the marketing efforts of hospitals rather than on meaningful outcomes. Will that change in the future? How does the patient define quality of care?

This takes us to the providers and the way that they practice medicine today, which is changing, even in oncology. Many physicians today prefer to work in a hospital, where they work fewer hours than in private practice and are paid a set salary. They are not willing to take on administrative responsibilities or any risk. But there is a shortage of oncologists today, and we believe that nurse practitioners will play a bigger role in oncology in the future. Their role in patient care may level out with that of oncologists at some point. It is not clear how this will affect oncologists in a hospital system.

Will hospitals start to tease apart the value of the care provided by oncologists? Evidence shows that the newer generation of doctors increase the cost of care, because, rather than thinking about what is possible, they tend to order many tests, which may reduce the value of care, when the testing is not necessary or is not cost-effective; this depends on the individual physician. This leads us to ask, “Will we eventually begin to measure the value of an individual physician or the value of the cost data?” We don’t have information systems ready to measure that at this point.

We do not believe that hospital systems are in a position to manage risk.

In most communities, hospital systems drive the relationship between the health plan and the providers, and if they are unwilling to accept risk in

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the oncology arena, this indicates that they are not ready to assume risk management elsewhere. We are not aware of many situations in which hospitals have created relationships where they have agreed to accept downside risk.

Some hospital systems have created relationships with health plans that are based on a profit-sharing type of arrangement, which is a different type of an ACO. These ACOs are specific to oncology (ie, they have no primary care patients), and they are based on a relationship in which the hospital has agreed to provide some services that potentially could measure quality or outcomes for providers who care for patients with cancer.

“Hospitals will change the way they define value depending on future changes in healthcare. If systems begin to compete on costs, hospitals may begin to look at them.”

Another development in hospitals is that, in the past, an oncologist in a private clinic had access to all hospital systems. But recently, hospitals have been trying to capture physicians and restrict them to the specific hospital, where a provider is limited to one system. This is not fully enforced yet, but it could become an issue. This takes us back to the idea that to continue to be a community practice, the practice has to be large enough to be dominant in that particular community so that the hospital system cannot afford to not have the practice as part of their team.

Group VII: Managed Care Organizations

James R. Lang; James T. Kenney, Jr; Matthew C. Palmgren: We began the discussion by focusing on risk. We are unaware of anyone taking downside risk in oncology. Oncologists are trying to survive, and some programs involve upside risk, especially related to pathways. There is downside risk for those who do not participate in pathways, because the standard fees have not changed over time, and the only increases are the pathways fees. In addition, inflation reduces payments for providers, but there is no true downside risk. Next, we discussed payment for quality, which for us means payment for HEDIS (Healthcare Effectiveness Data and

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Continued from page 25

Information Set) measures, not actual outcomes. Managed care organizations (MCOs) are paying for various markers, which are not the same as true outcomes. MCOs have enough data, or enough collected information, to determine outcomes.

Drug reimbursement is a big issue.

Both CMS managed care health plans have been squeezing reimbursement.

There are many cases where managed care is driving down reimbursement collectively, forcing providers or patients to buy alternate types of drugs based on cost. Can we avoid this? BlueCross BlueShield (BCBS) of Michigan, for example, as well as other plans, increased the payments for generic chemotherapy drugs, so the payment for a small vial of generic 5-fluorouracil, for example, is small, but the overall treatment involves a much bigger reimbursement; that is, many plans are moving away from the “buy-and-bill” model for drugs to the bundling payments model.

Starting January 1, 2014, BCBS of Michigan will begin to reimburse nurses for managing the patient. The patients will be identified by the plan, which will add extra reimbursement to the physician’s practice.

We are also seeing a significant increase in outpatient clinic costs. It is difficult for the health plan to try and manage this process, because the plan often has contracts with the hospital networks. When the plans squeeze the system in one place, it impacts the rest of the contracts. The problem is that it is very difficult to isolate the outpatient hospital reimbursement within the totality of the reimbursement contracts.

In addition, plans would like to incentivize home infusion and ambulatory infusion, but this is often very difficult to do. In addition, there is not much effort today to educate patients about infusion, and there are no benefits designed to help patients transition to home or ambulatory infusions.

With regard to drug innovation and

companion diagnostics, the main issue is the lack of appropriate clinical data for companion diagnostics, especially in oncology. There is a great need for more data and outcomes related to the use of diagnostics tests in association with specific oncolytics. The problem for health plans is that there is not enough evidence to try to understand the outcomes and make coverage decisions regarding what tests and what downstream drugs should be used and when.

A related topic is comparative effectiveness research (CER). Clearly health plans want CER-based evidence, but, to date, the information coming from this research is not comprehensive enough. A study may compare 1 drug versus another type of treatment or 2 drugs, but not the entire scope of therapies available for the same condition. For example, there are at least 7 major therapies for prostate cancer, but the research only compared 2 or 3 treatments. That is not sufficient.

Furthermore, there is not enough money to study all of these companion tests. Doing a government-supported comparative effectiveness study for these tests would require approximately $2 billion annually, and who has this type of money?

Plans would like formularies to be evidence-based, but that is not always the case, because plans do not have all of the necessary evidence to make decisions based on it. Today, with health plans having 80% to 90% generic drug dispensing rates, or even higher in the case of Kaiser, formularies are going to change their approach to benefits from time to time. To address costs, we sometimes offer coupons for areas that include expensive brands.

Currently, formularies have 3 to 5 tiers, and it is difficult to know where formularies will be in 3 years.

The use of prior authorizations is increasing in the medical benefit. Prior authorization is not easy, because plans are not used to dealing with Continued on page 31

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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.

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

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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

Defining Value in Cancer Care... claims data. The data are often not in real time, and therefore may not be accurate, because the claims can come in 3 weeks after the patient received the medication or treatment.

Nevertheless, plans are clearly focusing on prior authorization on the medical benefit side.

Mr Natelson: As a representative of small oncology private practices, we are being squeezed by health plans, and they refuse to negotiate an increase with us. Prior authorization is costing us money, but the payer will not increase our reimbursement, even though we have to hire staff to do the prior authorization. This pushes many oncologists to join a hospital, where they will not have to deal with all this.

But payers will negotiate with the hospital, because hospitals are a lot bigger and have market share, which makes it necessary for payers to deal with them.

But the payer tells the private practice, “if you don’t play by our rules, we are going to not keep you in our network.”

It is surprising that private insurance plans do not see that they should help community oncology stay in business, because they are less expensive and deliver quality care at a lower cost.

A level 3 office visit in community oncology costs 60% of what a level 3 visit would cost in a hospital setting.

It costs the payer more, but the payer is forcing community oncology to sell out to a hospital. The reality is that hospitals can then put pressure on payers to increase their reimbursement, because hospitals have market share; if the payer is not complying, the hospital will find another payer.

So, the dilemma is why payers are squeezing community oncology out of business, while they end up dealing with a hospital system that is bigger than they are and can therefore put pressure on the payer to increase their fees. How do you balance this gap?

Dr Lang: It is fair to ask how we can keep oncologists inside different plans.

One way some plans try to do this is by the use of pathways, as was discussed earlier. Everyone is trying to tie value to pathways, whether it is pay-for-performance pathways, pathways based on the National Comprehensive Cancer Network (NCCN) Guidelines®, or the pathways used by P4Health (by Cardinal Health) in Michigan. What they are all trying to do is bring value by changing the profit margins.

Eliminating the margins altogether on drugs will take 5 or 6 years, because we have to come up with a new payment system. Many plans are using generics to adjust the margins. We are

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adjusting the margins based on the guidelines now, because this helps to use generics in oncology. Our current payer system is broken, and we need to fix it. Most of the reimbursement in oncology today is based on drugs.

The question is how to take advantage of that in the near future while changing the dynamics of the system later, after getting rid of all the margins and paying for value and quality, as every group has been discussing here.

Mr Natelson: We need to use pathways to replace prior authorization.

Payers should tell community oncology that they are not going to increase their overhead and that they are going to work with the community oncology.

Dr Lang: That is where quality of management comes in. Payers are willing to replace prior authorization with pathways, mostly with pathways that follow the NCCN guidelines.

Payers are telling providers that if they follow these pathways they will eliminate the prior authorizations and get rid of some of the administrative overhead that is caused by the payer.

The truth is, we need a tool to ensure that doctors and pharmacists follow the best evidence; not all doctors and pharmacists follow the latest information. That is what prior authorization does and what pathways based on clinical guidelines can do.

You are right that oncology is moving so fast, and the prior authorizations are changing almost every 6 months because of new evidence, new published research, and new evidence-based guidelines. Health plans have no intention of putting oncologists out of practice, but the system is moving too fast and we need time to adapt to new information. Payers have created some of the problems for oncology practices, but that is not their intention. There is a major shift in the dynamics of oncology.

As noted, BCBS of Michigan is rewarding for quality of care in its new program. Providers that are 80% compliant get a 10% increase in payment.

For oncologists, this could be up to 20%, and we are paying the increased margin on 13 generics. As mentioned before, on January 1, 2014, BCBS of Michigan is instituting provider-delivered care management fees, which will also pay for oncology nurses, who are not being paid today for their patient management.

The program started with 50 practices 3 years ago, paying for these fees for primary care physicians. A year ago, it expanded the coverage to 400 practices, and they have 400

Continued from page 26

nurses in the state of Michigan who are employed by these organizations.

The third phase will be launched in January by paying these fees to oncology practices. It involves many changes to the practice, such as making nursing appointments and having space for nurses to see patients. This is not bulletproof, and it has taken much work to get started, but it is working and it is a major shift. The payment is on a patient-by-patient basis, and the plan sends monthly reports that indicate which patients are eligible.

“BCBS of Michigan is instituting provider-delivered care management fees, which will also pay for oncology nurses, who are not being paid today for their patient management.”

Value in Oncology

Dr Owens: Taking this discussion as a whole, 4 words have emerged from every group, identifying 4 major issues that are directly related to the definition of value in cancer care.

The first word is change. Everybody here recognizes that the status quo cannot continue, and change looks very different for the various stakeholders. The next word is data. Each group mentioned data, and not just data, but data that can be turned into information that ultimately could be used to make reasonable clinical, economic, and management decisions.

The third word is outcomes—understanding what outcomes the specific stakeholder is looking for, how they can be measured, and how to provide for them. Finally, the fourth word is cost. Clearly, cost is the elephant in the room. We know that the current cost trends are unsustainable. We know that we need more value out of what we spend. Cost is a concern for every single stakeholder in this room. Other important words that were mentioned today include quality and access, and they are inherently related to the 4 key concepts we have just discussed.

There are many other common important words or concepts that are relevant to the definition of value in oncology, but those 4 were the ones that registered for me across the entire discussion.

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Call to Action

• C linical pathways: Oncology pathways must incorporate the needs of the population, the individual patient, and society at large in determining the best allocation of resources. Pathways must also allow for some degree of variation, and should be informative not only for active treatment but for discontinuing unwarranted treatment.

Pathways must always be a dynamic process to adapt to new evidence and to new clinical guidelines.

• Reimbursement: New models for reimbursement in oncology are needed, moving away from fee for service. These models should consider the value of different services, not only of the oncologist but also services related to patient education and management provided by nurses, as well as cognitive services, administrative duties, and other services that are not traditionally covered by insurance, and these should also seek to eliminate waste.

• Regulatory: The government should define value in oncology in a broad way to incorporate quality of care, access, and other significant measures of value, and not only cost, as is currently the case.

• Patient advocacy: The patient’s unique perception of value should be honored, recognizing that value for patients with cancer is not always to extend survival, but rather to maintain quality of life.

Patients must also become wiser partners in shared decision-making.

• Oncology practice: Community oncology practices continue to be threatened, largely because of payment and reimbursement concerns; they must therefore reengineer their practice models to meet the changing needs and realities in healthcare overall and specifically in oncology.

• Hospitals: Hospitals that provide cancer care must redefine themselves and their approach to the patient. They must become more transparent and be able to deliver value for patients and for society as their core principle. They must also begin to look at cost and waste.

• Managed care organizations: Health plans must work in collaboration with providers and provide more support and better direction to oncologists. To improve outcomes, payers must be willing to partner with providers to meet current and increasing challenges in oncology. n

www.ValueBasedCancerCare.com

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3rd Conference

Implications of the Healthcare Exchanges for Oncology

By Caroline Helwick

Hollywood, FL—The complexity of healthcare exchanges has heads spinning. Attendees at the Third Annual Conference of the Association for Value-Based Cancer Care came away with a better understanding of the exchanges after a presentation by Matthew C. Palmgren, PharmD, Presi­ dent, Int’Ovation, Signal Mountain, TN. Although Dr Palmgren helped craft the Medicare Advantage program— something of a forerunner to the exchanges—much of what he knows stems from his recently becoming a licensed insurance broker himself. “If I could participate in the exchanges, I figured I could really understand them better,” he said.

The individual exchanges for uninsured Americans will be open for enrollment on October 1, 2013, and will “go live” on January 1, 2014.

Approximately 7 million persons are expected to participate. Each state will have its own exchange, or can partner with other states to form a regional exchange (although this seems rare at the moment). Multiple exchanges within a given state are also allowed, but there seems to be little interest in this option as yet, Dr Palmgren said.

Cancer Survivor Pre- and Post- Exchange To personalize his description of the exchanges, Dr Palmgren described the insurance options of a theoretical patient with cancer before and after the establishment of the exchanges.

Mike is a 44-year-old bone cancer survivor who is self-employed and has an annual income of $38,000. In

“You are going to be surprised October 1 to see health plans you’ve probably never seen before, which is what we saw in 2006 with the Part D expansion.

And in 2015, with the small employer-based plans coming on board, you’ll see an explosion.”

—Matthew C. Palmgren, PharmD

the traditional scenario, Mike applies to 9 health plans online and is offered coverage by 5 plans; 4 impose a benefits limit and no coverage for any cancer treatment, because of his preexisting condition, and 1 imposes higher cost-sharing for prescription drugs and doctor visits. All plans include a

• Bronze • Silver • Gold • Platinum

More generous

Figure The Exchange Plans

• All plans must offer at least Silver and Gold • Compete on plan ratings —Quality —Price —Enrollee satisfaction

Exchange minimum benefits: • Ambulatory patient services • Emergency services • Hospitalization • Maternity and newborn care • Mental health and substance abuse disorder services, including behavioral health treatment • Prescription drugs • Rehabilitative and habilitative services and devices • Laboratory services • Preventive, wellness, and chronic disease management services • Pediatric services, including oral and vision care

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premium surcharge, averaging 70% of the base premium, because he is a cancer survivor.

“That’s called underwriting. That’s what companies do in the individual market,” Dr Palmgren said. With the exchanges, some of these restrictions and higher costs should disappear, he predicted, “and Mike will be able to divert some of the risk that he’s experiencing with healthcare costs.”

Under the new law, Mike goes online and enters his age, zip code, and income. He is notified that he is eligible for a small premium tax credit.

There are 15 plans available in his area; these must provide coverage if he applies, and they are forbidden to exclude cancer care. Mike considers the quality and premiums of each, and uses a calculator to establish his future share of the costs, should his cancer return.

Mike enrolls in a plan with a premium of $260, with the tax credit, and his maximum out-of-pocket cost is $3900.

The Exchange Marketplace The exchanges will allow consumers like Mike to compare health plans in terms of eligibility, availability, covered benefits, premium rates, cost-sharing, provider networks, and the plan’s financial information (including medical loss ratio). The plans will offer a calculator for estimating the actual cost of coverage, account premiums, and premium assistance specific to the individual member.

“All this information has to be out there for the member to view in order to understand what’s going on, and it should be in real time,” Dr Palmgren said. The aim is to provide prompt responses and resolution of questions and issues.

There will be 4 types of exchange plans, known as Bronze, Silver, Gold, and Platinum, which differ in terms of coverage, premium rates, out-ofpocket costs, and cost-sharing. They will all offer the required benefits and will compete on the basis of ratings (Figure).

“You are going to be surprised October 1 to see health plans you’ve probably never seen before, which is what we saw in 2006 with the Part D expansion,” Dr Palmgren predicted.

“And in 2015, with the small employer-based plans coming on board, you’ll see an explosion.”

The requirements of the “in-exchange” plans are numerous. Most

important, there is guaranteed issue and renewability of coverage, and a prohibition on excluding persons based on preexisting conditions.

Premiums cannot vary based on health status or gender, and only limited variation is allowed based on age, geography, family size, and tobacco use.

There is a ban on lifetime and annual dollar limits on coverage of essential benefits. Preventive health services are covered without cost-sharing. Plans must also allow their members to participate in clinical trials related to the prevention, detection, or treatment of cancer and must cover the routine costs of trial participation.

“Cancer will probably hit the maximum out-of-pocket for every one of these plans, and enrollees need to prepare for that.”

—Matthew C. Palmgren, PharmD The maximum out-of-pocket cost (not including the premium) will adhere to federal guidelines for health savings accounts: $6000 per individual; and $12,000 per family. The hope is that consumers will invest in health savings accounts and will have this money available, should they need it.

“Cancer will probably hit the maximum out-of-pocket for every one of these plans, and enrollees need to prepare for that,” Dr Palmgren said.

Outside of the exchange there are few requirements. Not all plans need to be qualified, and there are no federal or state premium subsidies. For the time being, “you can still continue to do business. ‘No change in coverage’ is true for now, even though you are not doing things that the in-exchange plans are mandated to do,” but there will be lack of access to state subsidies, Dr Palmgren added.

Exchange Plans Will Be Monitored for Adverse Selection State boards will be monitoring the enrollee makeup of the plans, and will be empowered to decertify plans that demonstrate “adverse selection,” Dr Palmgren said.

“Let’s face it—this is an actuarial Continued on page 34

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When it comes to oncology, reliable supply is critical

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© 2013 Pfizer Inc.

All rights reserved.

July 2013

3rd Conference

NCCN/National Business Group on Health Collaboration Produces Guide for Employers

By Caroline Helwick

Hollywood, FL—A collaboration between the National Comprehensive Cancer Network (NCCN) and the National Business Group on Health can help employers navigate the confusing landscape of employee benefits.

Patricia J. Goldsmith, Executive Vice President and Chief Operating Officer of the NCCN, described the project, and the needs of employers that helped shape the project, at the Third Annual Conference of the Association for Value-Based Cancer Care.

“We heard from many employers that while they have rich and deep benefits, they were not really working together,” Ms Goldsmith said. “We wanted to help employers to get those benefits to work together and to have tools for evaluating the effectiveness of what they were purchasing. We convened a very high-profile group of stakeholders across many disciplines to help advise us on this project.”

The goals of An Employer’s Guide to Cancer Treatment and Prevention are to develop a comprehensive approach to cancer care benefits that is driven by evidence; to provide easy-to-use tools for evaluating and designing benefit plans and for selecting vendors; to promote standardization and integration of cancer-related benefits across vendors, programs, providers, and beneficiaries; and to support quality improvement, tools, and processes to help employers evaluate the effectiveness of these services.

The Figure outlines the approach and plan of the employer’s guide developed by the NCCN and the National Business Group on Health.

Cancer is important to employers not only because of its high cost but also because of the associated loss in productivity, which is estimated to be $19 million annually. Short-term disability claims average almost 90 days and are often exhausted, so that patients with cancer often tap into long-term disability benefits.

Figure Employer’s Guide to Cancer Care • Healthcare benefits plan (2011) —Medical benefit, including behavioral health —Pharmacy benefit —Care management • Health and productivity (2012) —Short-term disability —Family medical leave —Employee assistance program • Health promotion and wellness (2013) —Beneficiary education —Prevention, screening, and surveillance —Survivorship NOTE: All resources developed through this collaboration are available free at www.nccn.org/ network/nbgh/default.asp and www.business grouphealth.org/cancer/resources.cfm.

“This will give the employers additional understanding of what the benefit recommendations may cost them or, hopefully, in some circumstances, what dollars it may actually save them.”

—Patricia J. Goldsmith “We learned from employers that they lacked the knowledge, and sometimes the resources, they need to really understand how to develop a benefit design,” Ms Goldsmith said.

A Clear, Simple Resource for Employers The project was undertaken to provide clear, simple resources for employers, including benefit recommendations, objectives, rationale, and other guidance. Employers will find it easy to compare benefits and simple to assess whether changes in benefits make sense. The guide includes request-for-proposal tools to aid in vendor selection, and provides guidance about vendor accountability and communication with employees.

Interviews with large employers indicated that they most want evidence-driven benefits, evidence-based and personalized care for beneficiaries, integration and coordination across the benefit and cancer continuums, and standardization of benefits across

Implications of the Healthcare Exchanges... game in terms of how many highrisk patients you’re going to get, how many low-risk patients you’re going to get, how many elderly you’re going to get….Adverse selection is something they’re really going to look for, to make sure the bronze plan doesn’t get ‘adverse selected’ against,” he emphasized.

“We call that the death spiral, when it comes to insurance,” Dr Palmgren continued. “You get people into your plan whose premiums aren’t covering them. You can raise the premium 80%, but they are still high utilizers.”

34

The monitoring applies to in-exchange plans, but companies that are in the exchange can have their out-ofexchange practices examined as well for adverse selection. “You might see new companies that only have out-of-exchange plans, but the older companies—the Blue Crosses and the Cignas of the world—are playing in the exchange. If they’re playing in the exchange, they’re going to be monitored outside of the exchange to make sure they’re not pushing adverse patients into the exchange,” he explained.

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A working group consists of staff from the National Comprehensive Cancer Network and the National Business Group on Health, and is supported by an Advisory Committee that approves all deliverables and includes representatives from all stakeholder groups, including: • Cancer centers (physicians) • Employers and benefit managers • Patient advocates • Managed care plans • Pharmacy benefit managers • Pharmaceutical industry • American Cancer Society • Benefit consultants • Disability and employee assistance program vendors

health plans and vendor accountability. The guide has attempted to meet these needs, and its recommendations extend beyond medical, surgical, and pharmaceutical benefits into the areas of prevention screening and hospice survivorship.

An actuarial analysis is being incorporated into the project, which will estimate cost-savings, cost neutrality, or cost increases related to the medical, surgical, and pharmaceutical recommendations provided to the employers.

“We believe that this will give the employers additional understanding of what the benefit recommendations may cost them or, hopefully, in some circumstances, what dollars it may actually save them,” Ms Goldsmith said. n

Continued from page 32

Plan Transparency, Quality, and Cost The exchange plans will be transparent in terms of their benefits, cost-sharing, and business practices.

They must provide full, uniform, and detailed definitions and information relayed in understandable language.

They must provide information about payment policies and the number of claims denied.

With regard to containing premiums, exchange plans will post online their premium increases and justification via actuarial analysis. The ex-

change can exclude plans with unjustified increases.

Exchange plans must report details of their implemented programs to the US Department of Health and Human Services, as a means of improving health outcomes, reducing hospital readmissions, improving patient safety, promoting prevention and wellness, and reducing health disparities. The plans must implement quality measures, which will be publicly disclosed and will form the basis of selecting providers for their networks. n

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No. 7

3rd Conference

Defining the Role of Government in Future Oncology Care

By Caroline Helwick

Hollywood, FL—Regardless of one’s personal opinion of the role of government in healthcare, the Affordable Care Act (ACA) will be implemented, which means government will be playing a more significant role, as 2 speakers pointed out at the Third Annual Conference of the Association for Value-Based Cancer Care.

The Centers for Medicare & Medicaid Services (CMS) has tremendous authority to implement the provisions that Congress has written.

Beyond the ACA, Medicaid expansion, and healthcare exchanges, many other government activities dramatically affect cancer care because of the wheels that have been in motion for years under Medicare Part B and in the payer sector, said Jayson Slotnik, JD, MPH, Partner, Health Policy Strategies, LLC. “What’s going on in the coverage world on a national level is interesting, yet not unpredictable,” Mr Slotnik said. CMS currently has few resources at the national level; it has lost staff that, because of sequestration, cannot be replaced. The agency is overworked and morale is very low, and CMS is “going after the low-hanging fruit,” he said.

“Given the resources, given the political environment, given where the agency is focused,” change within CMS, as it relates to cancer care, may come about slowly, Mr Slotnik predicted. “That having been said, CMS has local contractors that administer the plan, and that is where the action is.”

Denise K. Pierce, President and Chief Executive Officer, DK Pierce and Associates, agreed that there are many stressors at the national level, but “the machine” still runs at the local level.

“It is the local implementation of healthcare that all of us feel, and this differs across the United States. For example, when a new oncology drug comes to market, not every contractor deals with that drug in the same manner,” Ms Pierce pointed out.

Approaches vary regarding how coverage is established and the expectations for claims processing. This all impacts oncology practices.

For example, a change is occurring in the criteria for drug coverage.

“Previously, many of the contractors would have very specific criteria for covering cancer drugs. You knew the particular indications of use and where the drug would be covered. Over time, many contractors have gone to a global coverage and are not being very

36

distinct with the coverage criteria,” she noted.

Although this may indicate that providers are being trusted to utilize drugs appropriately, it could also make providers nervous about the possibility of a claim being rejected.

There has also been a shift to more high-cost claim audits. “You know that if you’re looking at a high-dollar claim audit, notoriously, oncology drugs are ending up under that category,” she said.

Medicaid: Local Concerns The expansion of Medicaid under the ACA will undoubtedly mean that more patients with cancer will be treated under Medicaid. Different Medicaid agencies are taking different actions, “because they are already in dire straits with their budgets,” Ms Pierce said.

“The people who actually pay to provide the care, in my opinion, are better positioned to engage, communicate, educate, and ultimately decide what role the government should have in healthcare.”

—Jayson Slotnik, JD, MPH

“Whereas Medicaid, in the past, had not paid much attention to oncology drugs and never really established coverage criteria, we have now seen Medicaid agencies establishing very distinct clinical criteria and prior authorization approaches.”

—Denise K. Pierce

An extreme example comes from Oregon, where Medicaid has established a marginal benefit for a highcost policy that ties coverage of high-cost drugs to the patient’s life expectancy. A treatment will not be covered if a patient has an expected survival of <6 months; this patient will be referred for palliative or hospice care. For patients with an expected median survival of 6 to 12 months, the treatment must be expected to increase survival by 50%. For those expected to

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live at least 12 months, the treatment must provide a 30% improvement in survival.

“Whereas Medicaid, in the past, had not paid much attention to oncology drugs and never really established coverage criteria, we have now seen Medicaid agencies establishing very distinct clinical criteria and prior authorization approaches. These are going to be evolving over time, not only because of the ACA and the Medicaid expansion, but because the increased cost of care impacts their budgets and they must find ways to manage them,” Ms Pierce said.

Call to Action: Get Involved Mr Slotnik urged stakeholders “who are in the know, who see patients, who make the drugs, who manage the dollars,” to get involved in setting policies regarding what society should pay for healthcare, what guidelines should be set, and what outcomes should be expected. “The people who actually pay to provide the care, in my opinion, are better positioned to engage, communicate, educate, and ultimately decide

what role the government should have in healthcare,” he maintained.

Whereas the United States has shied away from a public discussion focused on substantial change, England did not, and their discussion led to the creation of the National Health Service.

“Perhaps we are going to have that conversation soon,” Mr Slotnik added.

“To me, at the end of the day, it’s up to each individual to voice their opinion…though some opinions will hold more water,” he offered.

Craig K. Deligdish, MD, Hema­ tologist/Oncologist, Oncology Re­ source Networks, Orlando, FL, and Co-Chair of the meeting, asked what will happen if the government avoids this larger discussion, or if novel programs being rolled out do not prove capable of improving quality and reducing cost. The options may be to ration healthcare, as Oregon is essentially doing, or to globally reduce payments for healthcare, Dr Deligdish said.

Ms Pierce pointed out that costs have been growing astronomically for a long time, but what is new is the conversation about cost and its impact.

The conversation now revolves around how to create value propositions for caring for patients, how to use data, and how to identify solutions.

“Now, there are different organizations all working to identify options that can reduce the need for a drastic systemwide change,” she said, adding that the Oregon example, although objectionable on many levels, may trigger more conversation toward rational solutions.

Mr Slotnik predicted that it will be years before big changes are obvious.

What will happen depends on the state of the economy, which party rules Congress, who the president is, and whether there is a major international crisis between now and then.

The potential changes constitute a “laundry list” from interested parties, including price reductions, tax increases, changes in Medicare eligibility, elimination of employer-based insurance, and much more.

“But yes, something is going to happen. The question is, do you want to be under the bus or driving the bus?”

Mr Slotnik asked. n

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No. 7

3rd Conference

Bracing for Change in Healthcare Coverage with Medicaid Expansion: What This Means for Cancer Care Delivery

By Caroline Helwick

Hollywood, FL—As part of the Affordable Care Act (ACA), Medicaid expansion necessitates that states soon come to grips with massive change in healthcare coverage. Matthew E. Brow, Vice President, Public Policy and Reimbursement Strategy, McKesson Specialty Health and the US Oncology Network, updated attendees at the Third Annual Conference of the Association for Value-Based Cancer Care on progress in this area.

“What this provides to oncologists— particularly community oncologists and maybe cost conscious community hospitals—is the opportunity to compete on price in a market where this typically does not happen. If you can drive volume and drive exclusivity, and prove quality and value at the same time—that’s where the real opportunity is in this space.”

—Matthew E. Brow

The ACA was designed against a framework that was principally dominated by large group insurance mostly accessed through employers or unions. This accounted for 50% of the market, whereas government coverage (ie, Medicare, Medicaid) comprised 30%, individual insurance accounted for just 5%, and the 45 million uninsured Americans comprised the remaining 20%.

According to Mr Brow, the ACA mainly attempts to accomplish 2 simple things in a 2-part process—create a new federal regulatory body responsible for everything that occurs in the health insurance space, and obtain the funds to expand coverage to at least 30 million additional Americans.

The first 15 million newly insured persons would be covered under a streamlined Medicaid program open to anyone with income up to 133% of

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the federal poverty level (pending state expansion decisions). The second 15 million persons would be covered

under a reformed commercial market for individuals and small groups. This would include the creation of a new

federal subsidy program for families with up to $120,000 of household in-

Continued on page 38

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3rd Conference

Bracing for Change in Healthcare Coverage... come, supplying money for these individuals to buy private health insurance through state- or federal-based exchanges that will serve as marketplaces for the purchase of insurance.

“In a nutshell, ACA involves a regulatory regime and coverage expansion.

Everything else is kind of extraneous but tangential to the core goals of the ACA,” Mr Brow said.

Medicaid Expansion Medicaid spending is a huge part of the US gross domestic product already, and this will likely increase unless a different approach is adopted.

Currently, “managed Medicaid” is largely how coverage through Medi­ caid is delivered. Nearly 75% of beneficiaries are in managed care plans that are largely served by private insurers.

These insurers receive a premium payment from the government for managing the plan, paying providers, and creating a network.

This trend is expected to grow. Even states that are pushing back on the Medicaid expansion are sometimes agreeing to the expansion if they can move their patients into managed Medicaid plans.

At the same time, states are restricting what they are willing to spend on their Medicaid beneficiaries (Figure 1).

“Every state, except for North Dakota, in the last 2 years, has seen some sort of provider payment cut in Medicaid” to reign in one of their biggest expenses, Mr Brow noted.

However, most states are not restricting eligibility for Medicaid. “They are allowing more people onto the rolls, and then trying to ratchet down how much they spend on these things,” he observed.

States face very difficult long-term choices. Some would have to expand their populations under Medicaid by ≥50% to meet the requirements under the ACA expansion, and each state takes its own approach to eligibility.

Although states are pushing back in a variety of ways, the Obama Administration expects that most states will eventually adopt the Medicaid expansion and pull in the federal money to finance it. The administration will point out, Mr Brow added, that when Medicaid was created along with Medicare in the 1960s as part of the “Great Society,” not all states jumped on board right away, though eventually all did.

Although currently only approximately 50% of the states are participating in or leaning toward participating in Medicaid expansion (Figure 2), the expectation is that over several years, even many recalcitrant states will come on board, Mr Brow said.

Regarding state-run exchanges, Mr Brow indicated that most states have said they will not build their own exchanges but will rely on the federal government exchange. Some states, however, are expressing more resistance and intend to block the government’s exchanges for their citizens.

Continued from page 37 aggregate together and drive changes to their plans. If they are dissatisfied, their option is to choose another plan in the next enrollment period,” Mr Brow said.

Under the exchange model, the incentives for the plan and the individual purchaser are quite different, as is the consumer’s ability to move change in this environment. This offers greater flexibility for payers in determining how to provide the services they have agreed to provide to the patient and to their members. It is acceptable, therefore, for payers to eliminate the highest-cost providers in the marketplace, as long as they can provide value-based care in that same marketplace.

“What this provides to oncologists—particularly community oncologists and maybe cost conscious community hospitals—is the opportunity to compete on price in a market where this typically does not happen,” Mr Brow commented. “If you can drive volume and drive exclusivity, and prove quality and value at the same time—that’s where the real opportunity is in this space.” n

Implications for Oncology Having even a minimum level of coverage will be a positive change for many patients with cancer, Mr Brow emphasized, but the way healthcare is provided will represent a “massive shift” away from the traditional mode of delivery. “Coverage that is subsidized by the government but managed by a private plan will be different,” he predicted.

In employer-based health plans, the goal is for the patients-employees to “feel good about their benefits, and therefore feel more tied to the organization they work for as a result,” Mr Brow said.

The employer and payer aim to keep a large group of employees satisfied, and to do so they continue to spend more dollars on benefits, such as allowing patients to seek care at expensive academic centers. The employers “are paying for stability and are not really trying to lower costs significantly,” he noted.

“What’s significantly different about plans that are composed of people who don’t know each other and select a plan on a website is that they cannot

Figure 2 States Split on Participation in Medicaid Expansion, by January 29, 2013

WA

ME MT

ND

ID

Cuts to provider payments/pay rates

CA

Increased regulation of medication MT administration OR

UT

ID

MN

WI

CO

AZ

OK NH MA NY CT

NM

AK

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PA

IA IL

OH

IN

WV HI

MO

KY

AZ Restrictions to eligibility

NM

OK

VA

SC

AR MS

AL

GA

VT

TX

AK

Analysis: HI

States with cuts

States without cuts

Only North Dakota made no cost-cutting program changes since 2011.

Source: Kaiser Foundation. National Journal.

a

38

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NJ

OH WV KY

RI

NJ DE MD DC

NC

TN

SC

AR

RI

VA

NH MA CT

MS

AL

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DE MD DC

FL

NC

TN

Benefit reductions

TX

IN

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KS

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NE UT

CA

IL

VT

SD

NV

CO

PA

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WY

NY MI

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WI

SD WY

Figure 1 State Cuts to Medicaid Programs in 2011 or 2012a

VT

MN

OR

LA FL

Participating (N = 18) Leaning toward participation (N = 5) Will not participate (N = 10) Leaning toward not participating (N = 5) Undecided/no comment (N = 12)

• The Supreme Court’s ruling on the Affordable Care Act allows states to opt out of the law’s Medicaid expansion, leaving this decision with state governors and leaders.

• Governors of states participating in Medicaid expansion cited support for increased coverage for residents as reason for opting in; governors of nonparticipating states cited high cost of expansion as reason for opting out; governors of undecided states weighing costs of expansion before opting in or out.

Source: The Daily Briefing. Updated January 29, 2013. www.advisory.com/Daily-Briefing/ 2012/11/09/MedicaidMap.

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No. 7

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

The median age of patients in the VISTA† trial was 71 years (range: 48-91).

Indication and Important Safety Information for VELCADE® (bortezomib) INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost IF YOU DEFINE VALUE AS AN OVERALL SURVIVAL ADVANTAGE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage At 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

IF YOU DEFINE VALUE AS DEFINED LENGTH OF THERAPY: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

IF YOU DEFINE VALUE AS MEDICATION COST: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,544 per 3.5-mg vial as of July 2013 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

Please see Brief Summary for VELCADE on the next page of this advertisement.

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial.

J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

Head and Neck Cancer

Lymphedema a Common Problem in Head and Neck Cancer

By Alice Goodman

Berlin, Germany—Although little is known about the prevalence of lymphedema in patients with head and neck cancer, a series of studies showed that

75% of patients with head and neck cancer have problematic lymphedema internally and externally.

B:7” “Lymphedema is a significant prob-

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

42

NEPA3X0007_Payer_Ad_TABLOID_r6.indd Value-Based Cancer3

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Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).

A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%.

Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. V-12-0306 All rights reserved.

Printed in USA

september 2013

08/13

8/9/13 2:28 PM

py can damage lymphatic structures leading to scar tissue and fibrosis.

Lymphedema can be detected noninvasively, and this can inform clinical practice,” stated Sheila H. Ridner, PhD, RN, MSN, Martha Rivers Ingram Professor, Vanderbilt University School of Nursing, Nashville, TN, at the 2013 Multinational Association of Supportive Care in Cancer.

Dr Ridner reviewed a series of studies that measured prevalence, symptoms, measurement techniques, and symptom assessment tools for head and neck cancer.

“Lymphedema is a significant problem affecting a majority of patients with head and neck cancer.”

—Sheila H. Ridner, PhD, RN, MSN

Study 1 included 81 patients who were at least 3 months after treatment. After a median posttreatment interval of 17.7 months, 75.3% of the patients had late-effect lymphedema; of these, 9.8% had external lymphedema exclusively, 39.4% had internal edema exclusively, and 50.8% had both types.

Study 2 included 25 patients with head and neck cancer. Swelling, internal and external, was measured pretreatment and posttreatment at 6 weeks and 12 weeks. Internal swelling was identified at baseline in 10 patients, and only 4 patients had been treated with surgery.

Study 3 included 100 patients and followed the time course and patterns of internal and external swelling over 36 weeks. The preliminary findings regarding external lymphedema, using 3 different tools, show that by 36 weeks posttreatment for head and neck cancer, more than 50% of patients have lymphedema.

Internal lymphedema is present in 10% to 20% of patients before treatment in a few structures. At 36 weeks posttreatment, approximately 30% of patients have internal lymphedema.

Study 4 included 30 patients and showed that 10 major symptoms were reported by more than 50% of them. n B:10”

WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported.

Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%.

These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur.

Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline.

The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

lem affecting a majority of patients with head and neck cancer. Treatments such as surgery, chemotherapy, radiation, and combined modality thera-

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Personalized Medicine

Ponatinib Given Early May Suppress New Mutations in Patients with CML

By Alice Goodman

Chicago, IL—A new analysis of mutations at baseline and at the end of treatment provides information about the response to ponatinib (Iclusig) in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome– positive acute lymphocytic leukemia (ALL) enrolled in the phase 2 PACE study. The results were presented at the 2013 annual meeting of the American Society of Clinical Oncology.

Ponatinib is an oral pan-BCR-ABL1 Bruton’s tyrosine kinase (BTK) inhibitor with potent activity against native and mutated BCR-ABL1 and other kinases. The drug has demonstrated activity against all clinically relevant mutations associated with resistance to tyrosine kinase inhibitor (TKI) therapy in vitro, including the T315I mutation. Ponatinib is the first BTK that has shown activity against the T315I mutation in phase 2 studies.

The PACE study included 203 patients with disease that is resistant to or intolerant of the TKIs dasatinib

(Sprycel) and/or nilotinib (Tasigna) and 64 patients with a confirmed T315I mutation at baseline. All patients were heavily pretreated—93% had previously received ≥2 TKIs and 58% had received ≥3 TKIs. “We observed that the overall rate of mutations increases with [disease] stage, and so does the number of mutations for each individual,” noted lead investigator Michael W. N. Deininger, MD, PhD, Chief, Division of Hematology, Huntsman Cancer Institute, University of Utah, Salt Lake City.

When ponatinib was given at therapeutic doses during this study, no single mutation that confers resistance to ponatinib was found. In previous studies of TKIs used in patients with CML, the T315I mutation has typically been associated with resistance.

Patients with chronic-phase ALL and T315I mutations tend to respond very well to ponatinib, but patients with no single mutation do slightly worse, with only 25% showing major

cytogenetic response in the chronic phase, Dr Deininger noted.

Overall results were reported separately, according to disease stage. In

“The overall rate of mutations increases with [disease] stage, and so does the number of mutations. If we introduce ponatinib early in the course of therapy, this drug may be able to suppress the emergence of single BCRABL1 mutations, and…of compound mutations.”

—Michael W. N. Deininger, MD, PhD

chronic-phase CML, few patients who discontinued treatment with ponatinib gained single mutations at the end of

treatment, and many of the patients who did gain mutations had been receiving low-dose ponatinib. A few of these patients developed compound mutations, and there was no change in mutation status for the majority of the patients at the end of treatment.

Of patients with accelerated-phase CML, approximately 80% had no change in mutation status at the end of treatment.

The situation in patients with blastcrisis CML was different. Slightly more than 50% of patients who discontinued treatment with ponatinib developed multiple or compound mutations, but others did not.

“These findings suggest that mechanisms other than compound mutations are responsible for resistance to ponatinib in patients in blast crisis,” Dr Deininger said.

“If we introduce ponatinib early in the course of therapy, this drug may be able to suppress the emergence of single BCR-ABL1 mutations, and as a result, the development of compound mutations,” he stated. n

BRCA Mutation a Robust Biomarker for Olaparib Benefit in Patients with Ovarian Cancer Olaparib maintenance slows disease progression, especially in mutated tumors Chicago, IL—Olaparib maintenance therapy prolonged progression-free survival (PFS) and the time to disease progression after a second subsequent therapy in patients with platinum-sensitive relapsed serous ovarian cancer.

This effect was particularly robust in patients with a BRCA mutation, based on an updated analysis of Study 19.

“Olaparib maintenance therapy led to the greatest clinical benefit compared with placebo in patients with a BRCA mutation. As a result of these compelling data, phase 3 confirmatory trials will begin this year in patients with serous ovarian cancer and a BRCA mutation, said Jonathan A. Ledermann, BSc, MD, Professor of Medical On­ cology, University College London Cancer Institute, United Kingdom.

Dr Ledermann presented these findings at the 2013 annual meeting of the American Society of Clinical Oncology.

Study 19 randomized 265 patients with platinum-sensitive serous ovarian cancer to olaparib 400 mg twice daily or to placebo, until disease progression.

The primary results showed that

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olaparib maintenance therapy significantly extended PFS in patients with serous ovarian cancer compared with placebo (P <.001). Overall survival (OS) was not prolonged with olaparib, however (Ledermann J, et al. N Engl J Med. 2012;366:1382-1392).

“Olaparib maintenance therapy led to the greatest clinical benefit compared with placebo in patients with a BRCA mutation.”

—Jonathan A. Ledermann, BSc, MD

Updated Analysis of Patients with BRCA Mutations A prespecified subgroup analysis of Study 19 showed that patients with a known BRCA mutation had improved survival with olaparib maintenance compared with placebo.

This led to a retrospective analysis to

analyze the effect of olaparib maintenance in patients with BRCA mutations.

Using 2 different assays, 136 patients were identified with a germline BRCA mutation or a somatic BRCA mutation, and 118 had the wild-type BRCA. In the 136 patients with BRCA mutations, a significant 82% reduction in risk of progression was observed for olaparib maintenance therapy (P <.005). Median progression after a second subsequent therapy was 11.2 months with olaparib versus 4.3 months with placebo. A significant but less robust advantage was also observed for olaparib in patients with wild-type BRCA (P = .007).

No OS difference was seen with olaparib versus placebo, but a trend toward improved OS was found with olaparib in patients with a BRCA mutation. Dr Ledermann said that longer-term follow-up may show a difference in favor of olaparib.

Median progression after a second subsequent therapy significantly favored olaparib maintenance therapy in patients with a BRCA muta-

september 2013

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tion—23.8 months with olaparib versus 15.3 months with placebo.

Quality of life in patients with BRCA mutations was similar with olaparib and placebo. Tolerability was similar in patients with mutations and those with wild-type disease; low-grade nausea and fatigue were the most frequently reported adverse events.

Paul Sabbatini, MD, Deputy Phy­ sician-in-Chief for Clinical Research, Memorial Sloan-Kettering Cancer Center, New York, pointed out that it is difficult to show a survival advantage for maintenance olaparib in patients who received several subsequent lines of treatment. Evidence is accruing to suggest that maintenance therapy is most effective in ovarian cancer when initiated later in the course of disease, and this question is being addressed in clinical trials, he noted.

The take-home point from this study, Dr Sabbatini stated, is that the BRCA mutation is a robust biomarker for the benefit of olaparib and will be included in phase 3 studies going forward.—AG n

www.ValueBasedCancerCare.com

43

Prostate Cancer

New Technologies Bring No Upward Shift in Treatment of Local Prostate Cancer

See also page 46

By Wayne Kuznar

Chicago, IL—The rate of therapy for localized prostate cancer does not increase in markets with higher penetration of robotic surgical technology and intensity-modulated radiation therapy (IMRT), according to an examination of trends using the Surveillance, Epidemiology and End Results (SEER)-Medicare–linked data­ base, according to a poster presentation at the 2013 American

at a glance ➤ The use of robotic surgical technology or intensitymodulated radiation therapy for localized prostate cancer does not increase the rate of patients receiving treatment ➤ A rise in treatment would also mean increased costs and treatment-related morbidity ➤ The use of these technologies does, however, affect the type of treatments patients receive

Society of Clinical Oncology meeting by lead investigator Florian Rudolf Schroeck, MD, MS, Clinical Lecturer, Urology, University of Michigan, Ann Arbor.

“The major concern with diffusion of technology is that people might shift their treatment recommendations, either consciously or subconsciously, toward treating more people than they did before they had the new technology,” said Dr Schroeck.

An expansion of the population treated would increase costs and the number of men exposed to treatment-related morbidity.

“But we found that new technology does not spur additional therapy of prostate cancer,” he said.

Dr Schroeck’s group categorized markets as having low, medium, or high technological capacity based on the number of physicians who provided robotic prostatectomy and IMRT. Technology penetration was characterized separately for each hospital referral region and year. Using the SEER-Medicare–linked database, the investigators identified 59,043

“The major concern with diffusion of technology is that people might shift their treatment recommendations, either consciously or subconsciously, toward treating more people than they did before they had the new technology.”

—Florian Rudolf Schroeck, MD, MS

patients with locoregional prostate cancer who were treated or managed expectantly from 2003 to 2007. The use of radiotherapy, radical prostatectomy, or observation was obtained from Medicare claims.

Multinomial logistic regression was used to examine the association of technology penetration with receipt of prostatectomy, radiotherapy, or no local therapy.

Technological capacity increased

over time. “There was no shift in the overall number of men who got treated, but what we do see is a shift in what kind of treatment they get,” said Dr Schroeck.

With more robotic technology, patients received more prostatectomy at the expense of radiotherapy. Among all age-groups, the adjusted number of men receiving treatment per 1000 men diagnosed was not significantly different in the low- and high-technology markets. Markets with high robotic prostatectomy penetration compared with low penetration had higher use of prostatectomy (175 vs 141 per 1000, respectively; P = .004), but a lower use of radiotherapy (584 vs 613 per 1000, respectively; P = .046).

“It seems like patients are moved, to some extent, from the radiotherapy group to prostatectomy, but we are not expanding the pool of patients that get treated,” he said. “It makes a lot of sense too, because the urologists are the ones seeing the prostate cancer patients first and they’re the ones who have access to the robot.” n

MR-Guided Laser Ablation of Prostate Cancer Producing Promising Results

By Rosemary Frei, MSc

Niagara Falls, Ontario—Magnetic resonance (MR) imaging or MR-guided laser focal therapy for ablating lowto intermediate-risk prostate tumors is showing promise in the hands of a Toronto team, despite a relatively high failure rate.

In a series of 40 patients, 37 of whom were biopsied 4 months after MR-guided laser focal therapy ablation, 21 (48%) of the men had completely negative biopsies; 8 had negative biopsies in the ablated area but positive in a different area of the prostate, including 5 in a contralateral lobe. The remaining 11 patients were positive in the ablated area.

Uri Lindner, MD, a Urologic Oncol­ ogy Fellow, Department of Surgical Oncology, University Health Network, Toronto, Canada, presented the results at the 2013 Canadian Urological Association annual meeting.

“This will change the way we treat prostate cancer in a parallel way to how colonoscopy changed the treat-

44

ment of colorectal cancer: with colonoscopy, if you see a polyp, you just snare and remove it, and if you don’t get it all, so what? You have the patient come back in 4 months and do it again,” said Dr Lindner.

“This will change the way we treat prostate cancer in a parallel way to how colonoscopy changed the treatment of colorectal cancer.”

—Uri Lindner, MD

The 40 patients underwent 42 procedures (all as outpatients) and were followed for an average of 710 days. The men’s mean baseline prostate-specific antigen level was 5.3 ng/

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mL. The average tumor volume was 1.0 g and the average volume of ablated tissue was 8.8 g.

No intraprocedure complications were seen and 3 postprocedure urinary infections resolved within 1 week. One man with an apical tumor had stress incontinence for 6 weeks postprocedure, which resolved without intervention.

Of the 11 men who failed treatment, 5 received a radical prostatectomy or radiotherapy, and the other 6 remain on active surveillance.

This procedure has a 100% cancer-specific survival and overall survival rate, said Dr Lindner.

Overall, 31 of the 33 patients with mild or no erectile dysfunction (ED) before the procedure were still potent after the procedure, without using ED medication. Two men who had mild ED before the procedure needed lowdose phosphodiesterase type 5 inhibitors to maintain erections sufficient for intercourse.

Dr Lindner stated that the team members are continuing to improve their success rate, but the approach is technically challenging. “The MR is not able to delineate all the tumor, so if you ablate only the MR target, you’re still going to get a positive biopsy on the rim of the ablation [zone]....And it’s not very easy in the MR environment to place the needle exactly where you want,” he said. But ablating the rim beyond the targeted area should be able to get all or most of the tumor.

Dr Lindner defended this approach by saying that in approximately 94% of patients who had an MR-visualized tumor and underwent prostatectomy, the index lesion was the one that was detected by the MR. “And you might find minute cancers somewhere else, but... by ablating the [index] area, you’re probably preventing extracapsular extension and perhaps metastatic disease,” he told the audience. n

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Health Policy

Yet Another Blow to the Medicaid Expansion

By Ross D. Margulies, JD, MPH, and Igor Gorlach, JD, MPH Mr Margulies and Mr Gorlach are Associates at Foley Hoag, LLP

Ross D. Margulies

T

Igor Gorlach

he Affordable Care Act extends and simplifies Medicaid eligi­ bility beginning January 1, 2014, by replacing Medicaid’s previous multiple categorical groupings and limitations with one simplified overarching rule: all individuals aged <65 years with incomes less than 138% of the federal poverty level ($15,415 for an individual or $26,344 for a family of 3 in 2012) who meet citizenship/lawful US status and state residency requirements are entitled to Medicaid benefits.

The expansion, however, has suffered several setbacks to date, including a Supreme Court ruling that states that do not wish to participate in the expansion cannot be penalized for not participating. The latest—and less expected—setback was a decision by the Centers for Medicare & Medicaid Services (CMS) to only provide limited drug coverage for Medicaid bene-

ficiaries in the expansion population.

In the final rule on essential health benefits (EHBs), published July 5, 2013, CMS noted that requiring alternative benefit plans (ie, the plans that are offered to the Medicaid expansion population) to offer the same drug coverage as what is offered under existing Medicaid would be “overinclusive,” because it would conflict with the states’ flexibility in defining the amount, duration, and scope of the benefit for covered outpatient drugs for the alternative benefit plans.

Individuals who are enrolled in “traditional” Medicaid have access to all drugs that are manufactured by companies that participate in the Medicaid drug rebate program (meaning that Medicaid beneficiaries have access to most medications on the market).

The decision by CMS departs from the proposed rule, in which CMS proposed to require the same Medicaid coverage for alternative benefit plans as is required for the existing Medicaid program. Instead, individuals in the Medicaid expansion are entitled to a set of basic services (also known as EHBs), which include coverage of prescription drugs, along with inpatient and outpatient services, physicians’ services, laboratory services, mental health services, well-child care services, preventive

services, and vision and hearing services. The prescription drug coverage available to individuals in the expansion population will be the greater of one drug per class of drugs or the same number of drugs as contained in each class of drugs included in the state Medicaid benchmark plan that is selected by the state. In many cases, the prescription drug benefits that are

In many cases, the prescription drug benefits available to individuals in the expansion population will be less robust than the coverage available to those in traditional Medicaid. available to individuals in the expansion population will be less robust than the coverage that is available to those in traditional Medicaid.

The overall effect on patients with cancer remains to be seen. The shift of discretion from federal standards to the states could result in a patchwork of coverage models for the Medicaid expansion population among the states (because each state’s benchmark coverage will be

different). The originally proposed federal standards would have constituted minimum requirements for the states as a component of EHBs. Thus, the change in policy allows alternative benefit plans to reduce the coverage of prescription drugs for the Medicaid expansion population (alternative benefit plans are always free to cover additional drugs).

For the oncology provider, CMS’s final rule means that a patient with Medicaid is no longer just a patient with Medicaid. Rather, whether an individual is enrolled in traditional Medicaid or in an alternative benefit plan (as part of the expansion population) will determine the covered drugs that are available to them, and will therefore affect the physician’s prescribing behavior. The news is not all bad—most benchmark plans will offer robust prescription drug coverage and, in some cases, may prove less cumbersome than some of traditional Medicaid’s existing requirements (including fewer “fail-first” and “step-therapy” requirements).

As the expansion rolls out in 2014, we will keep an eye on coverage trends, and we plan to update you midyear with a status report. n Reprinted with permission from American Health & Drug Benefits. 2013;6(7):418.

Prostate Cancer

Number of Metabolic Syndrome Risk Factors Influences Risk for Prostate Cancer

See also page 44

By Rosemary Frei, MSc

Niagara Falls, Ontario—Previous studies have shown an association between metabolic syndrome and prostate cancer. A study presented at the 2013 Canadian Urological Association annual meeting during a poster presentation investigated the level of prostate cancer risk in relation to the number of risk factors of metabolic syndrome and prostate cancer grade.

The results suggest that the risk for prostate cancer increases in stepwise fashion with each additional metabolic syndrome risk factor. A stepwise increase in the risk of clinically significant prostate cancer or high-grade

46

The risk for prostate cancer increases in stepwise fashion with each additional metabolic syndrome risk factor. prostate cancer was associated with 1, 2, and then ≥3 risk factors. Only ≥3 risk factors reached statistical significance, however.

Lead investigator Neil E. Fleshner, MD, MPH, Head, Division of Urology, University Health Network, Toronto, Canada, and colleagues, focused on

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men whose biopsy samples are included in the Genito-Urinary BioBank at the Princess Margaret Hospital in Toronto.

The researchers did not include men on active surveillance. A total of 2144 patients were included in the analysis, and 1301 (60.7%) of them were diagnosed at biopsy with prostate cancer.

Among the men with prostate cancer, 593 had a Gleason score of ≥7.

The odds ratio for developing clinically significant or high-grade prostate cancer was calculated for 5 components of metabolic syndrome—elevated fasting glucose concentration or diabetes, obesity, elevated levels of

triglycerides, low concentration of high-density lipoprotein cholesterol, and hypertension. None of the odds ratios were statistically significant.

The risk for developing prostate cancer was 38% higher with ≥3 risk factors for metabolic syndrome than with none; the risk was 52% higher for clinically significant prostate cancer, and 43% higher for high-grade prostate cancer. Furthermore, there was a stepwise, but not significant, increase in prostate cancer risk between having no metabolic syndrome risk factors and 1 risk factor, and between zero or 1 risk factor and 2 risk factors. n

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SECOND

ANNUAL CONFERENCE

GLOBAL BIOMARKERS Clinical Approaches CONSORTIUM to Targeted Technologies â&#x201E;˘

October 4-6, 2013 â&#x20AC;˘ Seaport Boston Hotel â&#x20AC;˘ Boston, Massachusetts CONFERENCE CO-CHAIRS Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom

AGENDA* FRIDAY, OCTOBER 4 3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

SATURDAY, OCTOBER 5 7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 8:30 am

Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ&#x20AC;&#x201D;Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP

8:15 am - 11:45 am

General Session I â&#x20AC;˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â&#x20AC;˘ Taking Stock of Molecular Oncology Biomarkers â&#x20AC;˘ Genomics â&#x20AC;˘ Bioinformatics â&#x20AC;˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â&#x20AC;˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â&#x20AC;˘ The Challenges of Biomarker-Based Clinical Trials â&#x20AC;˘ Keynote Lecture: Understanding Cancer at the Molecular Level

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

General Session II â&#x20AC;˘ Introduction to Case Studies - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part I â&#x20AC;˘ Lung Cancer â&#x20AC;˘ Breast Cancer â&#x20AC;˘ Multiple Myeloma â&#x20AC;˘ Prostate Cancer â&#x20AC;˘ Leukemia â&#x20AC;˘ Lymphoma â&#x20AC;˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â&#x20AC;˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

COMMERCIAL SUPPORT ACKNOWLEDGMENT

SUNDAY, OCTOBER 6

Jorge E. Cortes, MD Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

CONFERENCE OVERVIEW

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

TARGET AUDIENCE

This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

LEARNING OBJECTIVES

Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â&#x20AC;˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â&#x20AC;˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

DESIGNATION OF CREDIT STATEMENTS SPONSORS

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

PHYSICIAN CREDIT DESIGNATION

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 11:45 am

General Session III â&#x20AC;˘ Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Today - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part II â&#x20AC;˘ Melanoma â&#x20AC;˘ Colorectal Cancer and Other GI Malignancies â&#x20AC;˘ MDS â&#x20AC;˘ Myeloproliferative Neoplasms â&#x20AC;˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

General Session IV â&#x20AC;˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â&#x20AC;˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â&#x20AC;˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â&#x20AC;˘ Regulatory Perspectives on PMO â&#x20AC;˘ PMO: The Payerâ&#x20AC;&#x2122;s Perspective â&#x20AC;˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â&#x20AC;˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management The official publication of â&#x20AC;˘ Reimbursement Challenges

â&#x20AC;˘ Closing Remarks

3:00 pm

Departures

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

REGISTERED NURSE DESIGNATION

Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.5 contact hours.

REGISTERED PHARMACY DESIGNATION

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit.

The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION

EARLY BIRD REGISTRATION NOW OPEN! $175.00 until June 30, 2013

www.globalbiomarkersconsortium.com

In partnership with *Agenda is subject to change.

GBCKsize20813

PMPMERSONALIZED EDICINE IN ONCOLOGY O

Implementing the Promise of Prognostic Precision into Personalized Cancer Care TM

TM

Drug Therapy

Chemotherapy-Induced Neuropathy Can Persist a Decade after Stopping Treatment for Colorectal Cancer

By Wayne Kuznar

S

ymptoms of neuropathy may be evident a decade or more after completion of chemotherapy regimens that had been for the treatment of patients with colorectal cancer (CRC), reported researchers from Tilburg University in the Netherlands.

Their recent study (Mols F, et al. J Clin Oncol. 2013;31:2699-2707) was supported by the Netherlands Organization for Scientific Research and the Dutch Cancer Society.

Oxaliplatin (Eloxatin), a component of the standard FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) regimen for CRC, was associated with more lower-extremity sensory symptoms than regimens without oxaliplatin.

The researchers propose screening for and alleviating neuropathy symptoms in patients with CRC who are receving chemotherapy.

A total of 1643 patients were included in this study; they were diagnosed with CRC between 2000 and 2009 and completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 to assess health-related quality of life (HRQOL), and the EORTC QLQ Chemotherapy-Induced Peripheral Neuropathy 20, which has 3 subscales that assess sensory, motor, and autonomic symptoms.

The neuropathy symptoms that were most bothersome included: • Erectile difficulty, 42% • Trouble hearing, 11% • Trouble opening a jar or bottle, 11% • Tingling in toes or feet, 10% • Trouble walking stairs or standing up because of weakness in the legs, 9%.

Among patients who were diagnosed since 2007, when oxaliplatin was introduced into the standard treatment regimen in Europe, patients who received oxaliplatin reported tingling, numbness, and aching or burning pain in the toes and feet more often than patients who did not receive chemotherapy, and reported tingling in the toes or feet more often than patients who received chemotherapy without oxaliplatin.

As can be expected, patients reporting many neuropathy symptoms had worse scores on the EORTC HRQOL scale than patients who reported few or no neuropathy symptoms.

Although transient neuropathy is nearly a universal side effect with the use of oxaliplatin, chronic oxali­ platin-induced neuropathy is a result of dose-dependent accumulation of platinum compounds in the dorsal root ganglia. The worst of the neuropathy symptoms tend to occur 3 to 4 months after the last dose of oxali­ platin, said Leonard Saltz, MD, Chief

of Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York. “If we wait until patients have substantial neuropathy, we’ve waited too long,” Dr Saltz said.

“I like to pull back on the drug before it gets problematic.” He makes it a point to interview patients about any numb-

“If we wait until patients have substantial neuropathy, we’ve waited too long….It’s important for oncologists and patients to understand that the neuropathies from chemotherapy don’t always get better.”

—Leonard Saltz, MD ness, tingling, or problems with fine motor coordination on the scheduled day of oxaliplatin treatment, which is typically dosed every 2 weeks.

“It’s important for oncologists and patients to understand that the neuropathies from chemotherapy don’t always get better, and we need to think about that, especially when using them in patients being treated for cure,” Dr

Saltz told Value-Based Cancer Care. “We have to be very careful about giving them a permanent toxicity along the way.”

Effective treatments for chemotherapy-induced neuropathy are lacking, said Dr Saltz. High-dose calcium and magnesium infusions were once considered prophylactic therapy for oxaliplatin-induced neuropathy, but a definitive study presented at the 2013 annual meeting of the American Society of Clinical Oncology (Loprinzi CL, et al. J Clin Oncol. 2013;31[suppl].

Abstract 3501) showed no benefit to this approach.

Eliminating oxaliplatin from the FOLFOX regimen after 3 months (6 cycles) was shown to be as effective as continuing oxaliplatin, but with less toxicity, in a study known as OPTIMOX (Tournigand C, et al. J Clin Oncol. 2006;24:394-400). “Since oxali­ platin is a pricey drug, the value of the care was dramatically better,” he said.

Drugs used for painful diabetic neuropathy, such as duloxetine (Cym­ balta) and other antidepressants, would not be expected to be effective for treating the overwhelming majority of chemotherapy-induced neuropathies, given that pain fibers are different from paresthesia and numbness, Dr Saltz added. n

Emerging Therapies and New Approaches in the “DoubleRefractory” Setting in Myeloma Chicago, IL—Advances in the understanding of the biology of multiple myeloma and the identification of new drugs have resulted in improved management of myeloma, including for disease refractory to the recent proteasome inhibitors and immunomodulatory agents that have been added to the treatment of patients with myeloma.

New therapeutic strategies are needed in this challenging population, said Robert Z. Orlowski, PhD, MD, Professor, Department of Lymphoma/Myeloma, M.D. Anderson Cancer Center, Houston, TX, at the 2013 American Society of Clinical Oncology annual meeting.

Double-Refractory Setting Carfilzomib (Kyprolis) and pomalidomide (Pomalyst) have demonstrated benefit in the double-refractory setting, resulting in their recent

48

approval by the US Food and Drug Administration (FDA) for patients with myeloma. In patients with relapsed and/or refractory myeloma, carfilzomib was associated with a 15.4% overall response rate (ORR) and a median response duration of 7.8 months. The median overall survival (OS) was 15.6 months in the overall population and 11.9 months in the double-refractory subgroup.

Pomalidomide has been shown to be active against double-refractory mye­ loma in phase 2 and 3 trials. The ORR was 31%, progression-free survival (PFS) was 3.8 months, and OS was 13.8 months in patients with relapsed and/ or refractory myeloma who received pomalidomide and weekly dexamethasone (Decadron).

In one phase 3 clinical trial, patients were randomized to pomalidomide

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and low-dose dexamethasone or to single-agent high-dose dexamethasone. In patients with double-refractory disease, the median PFS was 3.2 months in the pomalidomide arm versus 1.7 months in the high-dose dexamethasone arm (P <.001); median OS was not reached in the pomalidomide arm versus 7.4 months in the high-dose dexamethasone arm (P <.001), said Dr Orlowski.

KSP Inhibitor A novel treatment strategy targets kinesin spindle protein (KSP) in patients with myeloma, said Dr Orlowski.

ARRY-520 is a potent, highly selective KSP inhibitor that was studied in a phase 2 trial as a single agent (cohort 1) and in combination with low-dose dexamethasone (cohort 2). After a median treatment time of 3.9 months, the ORR was 22% and the median

response duration was 5.4 months. In cohort 1, 53% of patients had disease refractory to bortezomib and 75% had disease refractory to lenalidomide. Of the 32 patients in cohort 1 with assessable response, ORR was 16%; of these, 16% had partial responses.

Daratumumab Daratumumab is an investigational human monoclonal antibody that has received “breakthrough therapy” designation from the FDA for the treatment of patients with myeloma who have received at least 3 previous lines of therapy or patients with myeloma that is “double refractory” to a proteasome inhibitor and an immunomodulatory agent. A phase 1/2 dose-escalation study of 32 patients with relapsed myeloma showed at least a minimal response in 8 of the 12 patients who received ≥4 mg/kg of daratumumab, with no major safety issues.—WK n

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No. 7

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

TO VIEW THE SERIES ONLINE PLEASE LOG ON TO:

www.valuebasedcancer.com/myeloma AVBCC100Ksize21213

Cancer Prevention

High Marks for Nutritional Supplement in Patients with Localized Prostate Cancer

By Alice Goodman

Berlin, Germany—A food supplement containing pomegranate seeds, green tea, broccoli, and turmeric— called Pomi-T (natureMedical)— taken twice daily significantly lowered prostate-specific antigen (PSA) levels versus placebo in men with localized prostate cancer, according to the results of a double-blind, placebo-controlled clinical trial. Use of the supplement allowed more men to remain on observation alone, according to results of a new study presented at the 2013 meeting of the Multinational Association of Supportive Care in Cancer.

Phase 2 clinical studies have demonstrated that polyphenol-rich foods, such as those found in Pomi-T, have anticancer effects. This new, independent study (ie, not funded by the manufacturers of Pomi-T) is the first adequately powered, randomized, placebo-controlled phase 3 clinical trial of Pomi-T in men with localized prostate cancer.

The investigators enrolled 203 men (average age, 74 years) whose PSA levels were rising after radiotherapy or surgery for localized prostate can-

group, a significant 63.8% difference.

PSA levels were stable or lower than baseline in 46% of men using the supplement versus 14% of men taking

“These results are awesome. We didn’t expect such a big response. This can change practice, because men and their doctors look at their PSA as a deciding factor in whether to continue on active management.”

—Robert J. Thomas, MD, Mb, Chb

cer. They were managed with active surveillance (59%) or watchful waiting (41%) and were randomized to 2 capsules of Pomi-T daily or to placebo for 6 months.

At 6 months, the median rise in PSA levels was 14.7% in the Pomi-T group compared with 78.5% in the placebo

placebo, a significant (P = .001) 32% difference.

At follow-up, 7.4% of the men taking Pomi-T required treatment with radiation, surgery, or androgen-deprivation therapy compared with 26% of the men in the placebo group (P = .01).

No differences were found between

the 2 groups in laboratory measurements of cholesterol, blood pressure, serum glucose, C-reactive protein, or adverse events.

Taking the supplement allowed the majority (92%) of the men to remain on active surveillance compared with 74% of those receiving placebo.

“These results are awesome. We didn’t expect such a big response. This can change practice, because men and their doctors look at their PSA as a deciding factor in whether to continue on active management,” stated lead investigator Robert J. Thomas, MD, Mb, Chb, Consultant Oncologist, Bedford Hospital National Health Service Trust, Cambridge, United Kingdom.

Of note, this supplement is well tolerated and may improve digestion and urinary symptoms, Dr Thomas said.

Men are more amenable to taking a nutritional supplement than to receiving active drugs, especially hormone therapy. This agent does not appear to act on hormones. n

Survivorship

Including Caregivers in the Care of Patients with Cancer Improves Quality of Life Washington, DC—Real-life experience translated into a research interest for Fedricker D. Barber, RN, MSN, of the M.D. Anderson Cancer Center, Houston, TX. At the 38th Annual Congress of the Oncology Nursing Society, Ms Barber presented a poster about the relationships between adult cancer survivors’ and caregivers’ social support, self-efficacy for physical activity, and quality-of-life (QOL) issues.

The sample included 101 cancer survivors and caregivers with a median age of 62 years. Physical QOL was significantly higher for caregivers than for cancer survivors at baseline, but after 1 month of caregivers exercising with their patients, no differences were seen in this parameter between the 2 groups. Social support from caregivers or friends in performing physical activity improved participation in physical activity.

“We found that cancer survivors and their caregivers rely on social

50

support to encourage and motivate them to participate in physical activity. These findings suggest that priority should be given to strategies that encourage physical activity for both cancer survivors and their caregivers,” she said.

Approximately 10 years ago, her husband was diagnosed with prostate cancer and had received 6 months of antiandrogen hormone therapy.

During that relatively short course of treatment, he gained a lot of weight and was very tired. Ms Barber was concerned, because her husband was a young man in his late 40s, and she knew that lack of exercise and weight gain were associated with the risk of developing heart disease, diabetes, a second primary cancer, and cancer recurrence. So she sprang into action, so to speak.

“When I saw what was happening to my husband, I decided to become part of the solution. I helped him by buying exercise videos and doing

Value-Based Cancer Care

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september 2013

the exercises with him,” Ms Barber explained. “I emphasized to him that exercise would improve his immune

“Cancer survivors and their caregivers rely on social support to encourage and motivate them to participate in physical activity.”

—Fedricker D. Barber, RN, MSN

system, reduce his fatigue, and prevent muscle wasting.”

She found that her participation encouraged him to exercise, and soon he was losing weight and gaining energy.

This experience led to the incorporation of caregivers and spouses of patients with cancer into an exercise plan in her practice. “I give all patients an education sheet on physical activity, even if they are advanced cancer patients. Exercise helps fatigue, mood, function, and sleep. Some patients think that if they have fatigue, they should stay in bed, but the opposite is true. If you exercise, the fatigue is reduced,” Ms Barber said.

Exercise has been found to prevent the recurrence of cancers of the gastrointestinal tract, ovaries, esophagus, and breast. It also helps reduce some of the late effects of cancer treatment, such as poor wound healing, bowel urgency, and outlet obstruction, and it helps build up immune function, she said.—AG n

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No. 7

Drug Update

Tafinlar and Mekinist: Two Oral Targeted Kinase Inhibitors for the Treatment of Patients with Metastatic Melanoma and BRAF Mutations

By Lisa A. Raedler, PhD, RPh

C

utaneous melanoma, although not the most common skin cancer, is the most deadly.1 Based on data collected between 2003 and 2009, the 5-year survival rate for Americans with metastatic melanoma remains very low—only 16%— for all disease stages and for both sexes.2 The National Cancer Institute has estimated that approximately 1 in 49 people will be diagnosed with melanoma in the United States, and more than 9450 people will die of this disease in 2013.2 The incidence of melanoma is increasing in the United States, particularly among children and adolescents.2 An analysis of first-time melanoma diagnosis in patients aged 18 to 39 years that occurred between 1970 and 2009 showed that the incidence of melanoma increased 8-fold among young women and 4-fold among young men.3 A study using data from 1973 to 2009 documented an average 2% annual increase in melanoma for children under age 19 years, particularly for girls and adolescents between 15 and 19 years.4 These trends in melanoma diagnosis rates are concerning because of the severity of the disease and the potential impact on healthcare resource utilization. An analysis of Medicare claims data from 1991 to 2005 demonstrated that patients with melanoma, particularly those with metastatic disease, utilize substantial healthcare resources.5 In this study, patients with metastatic melanoma had a monthly average of more than $11,000 in total healthcare costs, the majority of which was related to inpatient hospital services.5 Of note, this cost analysis was conducted before the availability of novel therapies recently approved for metastatic melanoma, including ipilimumab (Yervoy) and vemurafenib (Zelboraf).

FDA Approves 2 New Options for Melanoma In May 2013, the US Food and Drug Administration (FDA) approved 2 BRAF-mutation targeted agents— da­brafenib (Tafinlar; GlaxoSmithKline), a BRAF mutation inhibitor, and trametinib (Mekinist; GlaxoSmithKline), a MEK inhibitor—for the treatment of patients with metastatic melanoma.6,7 Dabrafenib is indicated for the treatment of patients with unresectable or metastatic melanoma and the BRAF V600E mutation as detected by a test

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that was approved by the FDA together with this agent. Dabrafenib is not indicated for the treatment of patients with the wild-type BRAF melanoma because of the potential risk of tumor promotion in those patients.8 Dabraf­ enib’s approval was based on a progression-free survival (PFS) benefit, as demonstrated in a multicenter, international, open-label, randomized, active-controlled trial.8 Trametinib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or BRAF V600K mutation as detected by the FDA-approved test.

Trametinib is not indicated for the treatment of patients who have received previous therapy with a BRAF inhibitor.9 The approval of trametinib was based on the demonstration of improved PFS in a multicenter, international, open-label, randomized, active-controlled trial.9 Approximately 50% of patients with cutaneous melanoma have a BRAF gene mutation.10,11 Concurrent with the approvals of dabrafenib and trametinib, the FDA approved the THxID BRAF assay (bioMérieux, Inc; Hazlewood, MO) for the detection of BRAF V600E and BRAF V600K mutations.6,7 In an interview regarding the recent advances in treatments for patients with metastatic melanoma, Lynn M. Schuchter, MD, Chief of Hematology/ Oncology at the University of Pennsyl­ vania, stated, “Now we have this wealth of options to consider.…It is amazing that, in 2013, chemotherapy is not the first or second choice for patients with melanoma. It is now targeted therapies, if appropriate, or immunotherapy.”12 Dosing and Administration The recommended dabrafenib dose is 150 mg taken orally twice daily, approximately 12 hours apart, until disease progression or until unacceptable toxicity occurs.8 Patients should take dabrafenib at least 1 hour before a meal or at least 2 hours after a meal. A missed dose of dabrafenib can be taken up to 6 hours before the next dose.

Dabrafenib capsules should not be opened, crushed, or broken.8 No dose adjustment is recommended for patients with new primary cutaneous malignancies.8 The recommended trametinib dose is 2 mg taken orally once daily until

Table 1 Dabrafenib versus Dacarbazine: Progression-Free Survival and Confirmed Objective Response Results in the Pivotal Phase 3 Trial Dabrafenib Dacarbazine Results (N = 187) (N = 63) Progression-free survival 41 (65) 78 (42) Events, N (%) 41 (65) 76 (41) Progressive disease 0 2 (1) Death 2.7 (95% CI, 1.5-3.2) 5.1 (95% CI, 4.9-6.9) Median, mo

Hazard ratioa P valueb

0.33 (95% CI, 0.20-0.54) <.001

Confirmed tumor responses Objective response rate Complete response, N (%) Partial response, N (%)

52% (95% CI, 44-59) 6 (3) 91 (48)

17% (95% CI, 9-29) 0 11 (17)

Median duration of response, mo

5.6 (95% CI, 5.4-NR)

NR (95% CI, 5.0-NR)

Pike estimator, stratified by disease state.

Stratified log-rank test.

CI indicates confidence interval; NR, not reached.

Source: Tafinlar (dabrafenib) capsules prescribing information. May 2013. a

b

disease progression or until unacceptable toxicity.9 Patients should take trametinib at least 1 hour before a meal or 2 hours after a meal. A missed trametinib dose should not be taken within 12 hours of the next dose.9 Mechanism of Action In cancer cells, mutated BRAF genes lead to overactive BRAF signaling and uncontrolled downstream signaling via the MEK/ERK pathway. Ulti­ mately, overactive BRAF signaling results in cell proliferation and resistance to programmed cell death or apoptosis.13,14 Both dabrafenib and trametinib inhibit kinases that are involved with these signaling pathways to arrest cancer-cell growth.8,9 Specifically, da­ brafenib inhibits some mutations of BRAF kinases,8 and trametinib reversibly inhibits MEK1 and MEK2 activation and MEK1 and MEK2 kinase activity.9 Phase 3 Clinical Trial: Dabrafenib In a pivotal phase 3 clinical trial of dabrafenib, 250 patients with unresectable stage III or stage IV melanoma and a documented BRAF V600E mutation were randomly assigned to oral da­brafenib twice daily (N = 187) or to intravenous dacarbazine 1000 mg/m2 every 3 weeks (N = 63), respectively, in a 3:1 ratio.8,15 Patients who had received previous treatment with a BRAF inhibitor or a MEK inhibitor were excluded.15 Randomi­ zation was stratified by disease stage at baseline.15 The primary end point of this study

september 2013

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was PFS, as determined by investigators.8,15 An independent radiology review committee assessed the additional efficacy outcome measures of PFS, confirmed objective response rate (ORR), and duration of response in prespecified supportive analyses.8,15 The patients in the study were allowed to cross over to the alternative treatment when their disease progressed.

The median age of the patients was 52 years. Most patients were male (60%), white (99%), with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (67%), and had M1c disease (66%) and normal lactate dehydrogenase (62%). All patients had BRAF V600E mutations as determined by a clinical trial assay at a centralized testing site.8,15 Efficacy In this study, the median PFS was significantly greater with dabrafenib compared with dacarbazine—5.1 months versus 2.7 months, respectively (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.20-0.54).8 The median PFS findings were similar in an independent review (6.7 months vs 2.9 months, respectively; HR, 0.35; 95% CI, 0.20-0.61).16 Table 1 summarizes the PFS, the confirmed ORR, and the duration of response in the phase 3 study of da­ brafenib in patients with BRAF mutation–positive advanced melanoma.8 Updated overall survival (OS) data from the phase 3 study of dabrafenib versus dacarbazine were presented during the June 2013 American Continued on page 52

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Drug Update

Tafinlar and Mekinist: Two Oral Targeted Kinase Inhibitors... Continued from page 51 Society of Clinical Oncology annual meeting.17 With median follow-up times of 15 months and 13 months for the dabrafenib and dacarbazine cohorts, respectively, OS was 18.2 months in patients who received dabrafenib compared with 15.6 months for those receiving dacarbazine (HR, 0.76; 95% CI, 0.48-1.21), but this difference was not statistically significant.17 Because 57% of the patients who had originally received dacarbazine crossed over to dabrafenib, the OS benefit from the initial dabrafenib therapy was likely obscured.17 Safety In the phase 3 trial, 53% of patients

who received dabrafenib and 44% of patients who received dacarbazine had treatment-related adverse events (grade ≥2).15 The most common adverse events with dabrafenib were skin-related effects, fever, fatigue, arthralgia, and headache.15 Table 2 summarizes the adverse reactions that occurred in ≥10% (all grades) or in ≥2% (grade 3 or 4) of patients who received dabrafenib.8 Grade 3 or 4 adverse events were uncommon in both groups.15 The incidence of adverse events resulting in the permanent discontinuation of the study medication in this trial was 3% with dabrafenib and with dacarbazine.8,15

Table 2 S elected Common Adverse Reactions in ≥10% (All Grades) or in ≥2% (Grade 3 or 4) of Patients Receiving Dabrafenib Dabrafenib (N = 187) Dacarbazine (N = 59) b System organ class/ All grades, Grade 3 or 4, All grades, Grade 3 or 4, adverse reactionsa % % % % Skin and subcutaneous tissue disorders Hyperkeratosis

37

1

0

0

Alopecia

22

NA

2

NA

Palmar-plantar erythrodysesthesia syndrome

20

2

2

0

Rash

17

0

0

0

32

0

8

0

10

0

Nervous system disorder Headache

General disorder/administration site condition Pyrexia

28

3

Musculoskeletal and connective tissue disorders Arthralgia

27

1

2

0

Back pain

12

3

7

0

Myalgia

11

0

0

0

Benign, malignant, and unspecified neoplasms Papillomac

27

0

2

0

Cutaneous squamous-cell carcinomas and keratoacanthomasd

7

4

0

0

11

2

14

Table 3 Recommended Dose Modifications for Dabrafenib Adverse reactiona

Discontinue permanently or withhold dabrafenib until reaction resolves; resume dabrafenib at a reduced dose level according to the drug labeling

0

Withhold dabrafenib until reaction resolves to grade ≤1; resume dabrafenib at a reduced dose level according to the drug labeling

12

0

5

0

Intolerable grade 2 adverse reactions or any grade 3 adverse reactions

10

0

3

0

First occurrence of any grade 4 adverse reaction

Discontinue permanently or withhold dabrafenib until adverse reaction resolves to grade ≤1; resume dabrafenib at a reduced dose level according to the drug labeling

Recurrent grade 4 adverse reaction, intolerable grade 2 or any grade 3 or 4 adverse reaction with dabrafenib 50 mg twice daily

Discontinue dabrafenib permanently

Adverse drug reactions reported using MedDRA and graded using CTCAE version 4.0 for assessment of toxicity. b Grade 4 adverse reactions limited to hyperkeratosis (N = 1) and constipation (N = 1). c Includes skin papilloma and papilloma. d Cases of cutaneous squamous-cell carcinoma were required to be reported as grade 3 per protocol.

CTCAE indicates Common Terminology Criteria for Adverse Events; MedDRA, Medical Dictionary for Regulatory Activities; NA, not applicable.

Source: Tafinlar (dabrafenib) capsules prescribing information. May 2013. a

52

Dose modification

Fever >104°F or fever complicated by rigors, hypotension, dehydration, or renal failure

Infections/infestation Nasopharyngitis

Phase 3 Clinical Trial: Trametinib The FDA approval of trametinib was based on the demonstration of improved PFS in a phase 3, international, open-label, randomized, active-­ controlled trial that enrolled 322 patients with histologically confirmed stage IIIc or stage IV melanoma.9,18 Patients were determined to be BRAF V600E or V600K mutation–­positive based on centralized testing.9 No more than 1 previous chemotherapy regimen was permitted, and patients with previous exposure to BRAF inhibitors or to MEK inhibitors were ineligible for the trial.9,18 Patients with abnormal left-ventricular ejection fraction (LVEF), a history of acute coronary syndrome within the past 6 months, or with current evi-

Withhold dabrafenib until fever resolves; resume dabrafenib at same dose or at a reduced dose level according to product labeling

Respiratory/thoracic/mediastinal disorder Cough

Serious Febrile Drug Reactions In the phase 3 study, 3.7% (7:187) of patients receiving dabrafenib and none of the patients treated with dacarbazine had serious febrile drug reactions (ie, serious fever or fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure in the absence of another identifiable cause such as infection).8,15 Fever (serious and nonserious) occurred in 28% of patients who received dabrafenib and in 10% of patients receiving dacarbazine.8,15

Other Adverse Events, Precautions Dabrafenib has also been associated with hyperglycemia, uveitis and iritis, and glucose-6-phosphate dehydrogenase deficiency.8 Patients receiving dabrafenib should be routinely monitored for visual symptoms, as well as for hemolytic anemia.8 Serum glucose levels should be monitored in patients who have preexisting diabetes or hyperglycemia.8 Because dabrafenib can cause fetal harm, women of reproductive potential should be warned of the potential risk to a fetus. Dabrafenib may also render hormonal contraceptives less effective, such that an alternative method of contraception should be used.8 Table 3 summarizes the recommended dose modifications related to adverse reactions potentially associated with dabrafenib.

Fever of 101.3ºF-104°F

Gastrointestinal disorder Constipation

Warnings and Precautions New Cutaneous Malignancies Dabrafenib is associated with an increased incidence of cutaneous squamous-cell carcinoma, keratoacanthoma, and melanoma.8 In the phase 3 clinical trial, cutaneous squamous-cell carcinomas (cuSCC) and keratoacanthomas occurred in 7% (14:187) of patients who received dabrafenib and in none of the patients receiving dacarbazine.8,15 The incidence of cuSCC was 11% across the clinical trials of dabraf­ enib that included 586 patients, with a median time to first cuSCC of 9 weeks (range, 1-53 weeks).8 Of the patients receiving dabrafenib, 3 (2%) developed new primary malignant melanomas. None of the patients receiving dacarbazine were diagnosed with new primary malignant melanoma in the phase 3 trial.8,15 Dermatologic evaluations are recommended before the initiation of dabraf­ enib, every 2 months while receiving dabrafenib, and for up to 6 months after the discontinuation of dabrafenib.8

Value-Based Cancer Care

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Common Terminology Criteria for Adverse Events version 4.0.

Source: Tafinlar (dabrafenib) capsules prescribing information. May 2013.

a

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Drug Update dence of New York Heart Association Class II or greater congestive heart failure were excluded from the trial.9 The patients in the trial were randomized to oral trametinib once daily or to intravenous chemotherapy with either dacarbazine or paclitaxel every 3 weeks.9 On disease progression, patients who were randomized to chemotherapy were allowed to cross over to trametinib.9,18 The patients’ median age was 54 years, and they were mostly male (54%) and white (99%).9 All patients had a baseline ECOG performance status of 0 or 1. Most patients (94%) had metastatic disease, had stage M1c (64%), had no history of brain metastasis (97%), and had not previously received chemo­therapy for advanced or metastatic disease (66%).9 BRAF V600 mutations included BRAF V600E (87%), BRAF V600K (12%), or both (<1%).9 Almost half (47%) of the patients crossed over to the trametinib arm at the time of disease progression with chemotherapy.9,18 Efficacy PFS, the study’s primary end point, and OS, a secondary end point, were significantly improved with trametinib. The investigators reported a statistically significant increase in PFS in the patients who were treated with trametinib compared with the patients who received chemotherapy (HR, 0.45; 95% CI, 0.33-0.63; P <.001).9,18 The median PFS was 4.8 months for patients taking trametinib (95% CI, 4.34.9) compared with 1.5 months for patients receiving chemotherapy (95% CI, 1.4-2.7).9,18 The significant improvement in PFS was observed in all patient subgroups, with the exception of the subgroups with the V600K mutation and in patients aged ≥65 years.18 The 6-month OS rate was 81% in the trametinib group compared with 67% in the chemotherapy group, a significant difference despite crossover (HR, 0.54; 95% CI, 0.32-0.92; P = .01).18 Table 4 summarizes the PFS, confirmed ORR, and the duration of response findings in the phase 3 study of trametinib in patients with BRAF mutation–positive advanced melanoma.9 Safety Rash, diarrhea, and peripheral edema were the most common adverse effects in patients who received trametinib in the phase 3 clinical trial.18 No secondary skin neoplasms were observed.18 Of patients receiving trametinib, 9% had adverse reactions that resulted in permanent drug discontinuation, in-

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cluding decreased LVEF, pneumonitis, renal failure, diarrhea, and rash.9 Table 5 summarizes the adverse reactions that occurred in ≥10% of patients who were treated with trametinib and at a higher incidence than in the control arm.9 Warnings and Precautions Several serious adverse events have been seen with trametinib in clinical trials. Serious events include cardiomyopathy, skin toxicity, and retinal pigment epithelial detachment (RPED).

Cardiomyopathy In the phase 3 trial, cardiomyopathy (including cardiac failure, left-ventricular dysfunction, or decreased LVEF) occurred in 7% (14:211) of patients who received trametinib and in none of those receiving chemotherapy.9,17 Cardiomyopathy resolved in 10 of these 14 patients.9 Trametinib therapy should be discontinued if the absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal.9 If symptomatic cardiomyopathy or persistent, asymptomatic LVEF dysfunction does not resolve within 4 weeks, trametinib should be permanently discontinued.9 Skin Toxicity The overall incidence of skin toxicity—including rash, dermatitis, acneiform rash, palmar-plantar erythrodys­ esthesia syndrome, erythema—was 87% in patients who received trametinib compared with 13% in chemotherapy-receiving patients in the phase 3 study.9 Severe skin toxicity occurred in 12% of the patients in the trametinib arm.9 Overall, 6% of patients who received trametinib were hospitalized, most often for secondary skin infections requiring intravenous antibiotics or severe skin adverse events without secondary infection.9 Patients receiving trametinib should be carefully monitored for skin-related adverse events and for secondary infections.9 Retinal Detachment Ophthalmologic examinations, including retinal evaluations, were performed before treatment and at regular intervals during the phase 3 study. One patient receiving trametinib developed RPED, and no cases of RPED were identified in patients receiving chemotherapy.9 The reduction in visual acuity secondary to RPED resolved after a median of 11.5 days (range, 3-71 days) after interruption of trametinib dosing.9 Ophthalmologic evaluations should be performed any time a patient reports visual disturbances while using trametinib. If available, these results should

be compared with baseline.9 Withhold trametinib therapy for up to 3 weeks if RPED is diagnosed.9 Additional Adverse Events Trametinib has also been associated with retinal vein occlusion, interstitial

lung disease, and embryofetal toxicity.9 Patients diagnosed with treatment-related retinal vein occlusion, interstitial lung disease, or pneumonitis should discontinue trametinib therapy permanently.9 Female patients of reproductive potential should use

Table 4 Trametinib versus Chemotherapy: Progression-Free Survival and Confirmed Objective Response Results in a Phase 3 Trial Trametinib Chemotherapy Results (N = 214) (N = 108) Progression-free survival 77 (71) 117 (55) Events, N (%) 70 (65) 107 (50) Progressive disease 7 (6) 10 (5) Death 1.5 (95% CI, 1.4-2.7) 4.8 (95% CI, 4.3-4.9) Median, mo Hazard ratioa P value (log-rank test)

0.47 (95% CI, 0.34-0.65) <.001

Confirmed tumor responses Objective response rate, % Complete response, N (%) Partial response, N (%) Median duration of response, mo

22 (95% CI, 17-28) 4 (2) 43 (20)

8 (95% CI, 4-15) 0 9 (8)

5.5 (95% CI, 4.1-5.9)

NR (95% CI, 3.5-NR)

Pike estimator, stratified by disease state.

CI indicates confidence interval; NR, not reached.

Source: Mekinist (trametinib) tablets prescribing information. May 2013.

a

Receiving Trametinib and Table 5 Selected Adverse Reactions in ≥10% of Patients at a Higher Incidence than in the Control Arma Trametinib Chemotherapy (N = 211) (N = 99) b c All grades, Grade 3 or 4, All grades,b Grade 3 or 4,c Adverse reactions % % % % Skin and subcutaneous tissue disorders Rash

57

8

10

0

Dermatitis acneiform

19

<1

1

0

Dry skin

11

0

0

0

Pruritus

10

2

1

0

Paronychia

10

0

1

0

Diarrhea

43

0

16

2

Stomatitisd

15

2

2

0

Abdominal paine

13

1

5

1

Lymphedemaf

32

1

4

0

Hypertension

15

12

7

3

Hemorrhageg

13

<1

0

0

Gastrointestinal disorders

Vascular disorders

Events included are higher in the trametinib arm compared with in the chemotherapy arm by ≥5% in overall incidence or by ≥2% grade 3 or 4 adverse reactions higher in the trametinib arm compared with the chemotherapy arm. b National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. c Grade 4 adverse reactions were limited to rash (N = 1) in the trametinib arm and diarrhea (N = 1) in the chemotherapy arm. d Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation. e Includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. f Includes lymphedema, edema, and peripheral edema. g Includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage.

Source: Mekinist (trametinib) tablets prescribing information. May 2013. a

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Drug Update

Tafinlar and Mekinist: Two Oral Targeted Kinase Inhibitors... Continued from page 53 highly effective contraception during trametinib therapy and for 4 months after treatment.9 Table 6 summarizes these warnings and precautions associated with the use of trametinib, as well as recommendations for monitoring and appropriate drug use.

Conclusion For adults with BRAF-mutated metastatic melanoma, the new kinase inhibitors dabrafenib and trametinib have demonstrated clinically and statistically significant efficacy and manageable toxicity profiles.

Although dabrafenib and trametinib are currently approved as single agents, clinicians have expressed interest in their potential value when used in combination for the treatment of advanced melanoma.19 Based on data from a phase 1/2

Table 6 Warnings and Precautions for Trametinib Clinical trial findings Cardiomyopathy, cardiac failure, left-ventricular dysfunction, or decreased LVEF

Recommendations regarding the monitoring and use of trametinib

•M edian time to onset of cardiomyopathy with trametinib is 63 days (range, 16-156 days) •A t the recommended dose, approximately 11% of patients receiving trametinib had evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥10% compared with baseline); 5% had a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline

• Perform LVEF assessments using echocardiogram or multigated acquisition scan before trametinib initiation, 1 month after initiation, and then at 2- to 3-month intervals • Withhold trametinib if absolute LVEF value decreases by 10% from pretreatment and is less than the lower limit of normal • Permanently discontinue trametinib for symptomatic cardiomyopathy or persistent, asymptomatic LVEF dysfunction

Retinal pigment epithelial detachment

• In the phase 3 study, 1 patient developed RPED •R PED was seen in 14 of the 1749 patients across all clinical trials of trametinib •A reduction in visual acuity secondary to RPED resolved after a median of 11.5 days (range, 3-71 days) after interruption of trametinib; abnormal­ ities in ocular coherence tomography persisted beyond 1 month in at least several cases

•P erform ophthalmologic evaluations when a patient reports visual disturbances •W ithhold trametinib for up to 3 weeks when RPED is diagnosed • I f resolution of RPED is documented on repeat ophthalmologic evaluation within 3 weeks, resume trametinib at a reduced dose

Retinal vein occlusion

RVO can lead to macular edema, decreased visual function, neovascularization, and glaucoma; RVO was seen in 4 (0.2%) patients in all clinical trials of trametinib

• Any patient-reported vision loss or other visual disturbances should undergo urgent (within 24 hrs) ophthalmologic evaluation • Permanently discontinue trametinib in patients with documented RVO

Interstitial lung disease

• In the phase 3 study, 5 of the 211 patients who were treated with trametinib were hospitalized for ILD or pneumonitis • The first presentation of ILD or pneumonitis occurred at a median of 160 days (range, 60-172 days) • ILD or pneumonitis occurred in 6 of 329 patients who received trametinib at the recommended dose in clinical trials

• Withhold trametinib in patients with new or progressive pulmonary symptoms (ie, cough, dyspnea, hypoxia, pleural effusion, infiltrates) pending clinical investigations • Patients diagnosed with treatment-related ILD or pneumonitis should discontinue trametinib permanently

Skin toxicity

• Skin toxicity (ie, rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, erythema) was 87% in patients treated with trametinib •S evere skin toxicity occurred in 12% of patients treated with trametinib •S kin toxicity was observed in patients treated with trametinib after 15 days (median), with a range of 1 to 221 days; the median time to skin toxicity resolution was 48 days (range, 1-282 days) •O f patients with skin toxicity, 12% required trametinib dose reductions and 1% permanently discontinued trametinib

•P atients receiving trametinib should be monitored for skin toxicities and for secondary infections

Embryofetal toxicity

Trametinib can cause fetal harm when administered to a pregnant woman

• Female patients of reproductive potential should use highly effective contraception during therapy with trametinib and for 4 mo after treatment • Patients who are taking trametinib should contact their provider if pregnancy is suspected • If trametinib is used during pregnancy, or if the patient becomes pregnant while taking trametinib, she should be apprised of the potential hazard to a fetus

ILD indicates interstitial lung disease; LVEF, left-ventricular ejection fraction; RPED, retinal pigment epithelial detachment; RVO, retinal vein occlusion.

Sources: Mekinist (trametinib) tablets prescribing information. May 2013; Flaherty KT, Robert C, Hersey P, et al. N Engl J Med. 2012;367:107-114.

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study comparing dabrafenib monotherapy with the combination, in July 2013, GlaxoSmithKline submitted a supplemental New Drug Application to the FDA for the use of dabrafenib in combination with trametinib for the treatment of adults with unresectable or metastatic melanoma with a BRAF V600E or BRAF V600K mutation.20 The addition of these 2 oral agents to the armamentarium of immunotherapies, targeted agents, and chemotherapy for the treatment of advanced melanoma offers hope for improved outcomes. n References

1. Skin Cancer Foundation. What is melanoma? www. skincancer.org/skin-cancer-information/melanoma.

Accessed July 24, 2013.

2. National Cancer Institute. SEER cancer statistics review 1975-2010. Updated June 14, 2013. http://seer. cancer.gov/csr/1975_2010/. Accessed July 7, 2013.

3. Reed KB, Brewer JD, Lohse CM, et al. Increasing incidence of melanoma among young adults: an epidemiological study in Olmsted County, Minnesota. Mayo Clin Proc. 2012;87:328-334.

4. Wong JR, Harris JK, Rodriguez-Galindo C, Johnson KJ. Incidence of childhood and adolescent melanoma in the United States: 1973-2009. Pediatrics. 2013;131:846-854.

5. Davis KL, Mitra D, Kotapati S, et al. Direct economic burden of high-risk and metastatic melanoma in the elderly: evidence from the SEER-Medicare linked database. Appl Health Econ Health Policy. 2009;7:31-41.

6. US Food and Drug Administration. Drugs: dabraf­ enib. Updated May 30, 2013. www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm354477. htm. Accessed July 7, 2013.

7. US Food and Drug Administration. Drugs: trametinib. Updated May 30, 2013. www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm354478. htm. Accessed July 7, 2013.

8. Tafinlar (dabrafenib) capsules [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; May 2013.

9. Mekinist (trametinib) tablets [prescribing information].

Research Triangle Park, NC: GlaxoSmithKline; May 2013.

10. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954.

11. Jakob JA, Bassett RL Jr, Ng CS, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012;118:4014-4023.

12. IMNG Medical Media. Melanoma advances make chemo third-tier therapy. YouTube. Posted by ElsGlobalMedicalNews. June 1, 2013. www.youtube. com/watch?v=Vw2GmsgT620. Accessed July 24, 2013.

13. Wong KK. Recent developments in anti-cancer agents targeting the Ras/Raf/MEK/ERK pathway.

Recent Pat Anticancer Drug Discov. 2009;4:28-35.

14. McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance.

Adv Enzyme Regul. 2006;46:249-279.

15. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet.

2012;380:358-365.

16. American Society of Clinical Oncology. Dabrafenib extends progression-free survival in metastatic melanoma, has high clinical activity in brain metastases. ASCO Annual Meeting. ASCO News Daily: LBA8500. http:// chicago2012.asco.org/ASCODailyNews/LBA8500. aspx. Accessed July 31, 2013.

17. Hauschild A, Grob JJ, Demidov LV, et al. An update on BREAK-3, a phase III, randomized trial: dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM). J Clin Oncol. 2013;31(15 suppl):Abstract 9013.

18. Flaherty KT, Robert C, Hersey P, et al; for the METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-114.

19. CurrentMedicine.TV. Phase 2 studies of BRAF plus MEK inhibitors to treat melanoma. YouTube. October 4, 2012. www.youtube.com/watch?v=UG2pX98X2z4.

Accessed July 24, 2013.

20. Grogan K. GSK files melanoma combo, signs Immunocore pact. PharmaTimes. July 9, 2013. www. pharmatimes.com/Article/13-07-09/GSK_files_ melanoma_combo_signs_Immunocore_pact.aspx.

Accessed July 16, 2013.

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4TH ANNUAL CONFERENCE

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

F. Randy Vogenberg, PhD, RPh

Partner Health Policy Strategies, LLC

Principal Institute for Integrated Healthcare

Personalized Medicine and Payers Co-Chairs Michael Kolodziej, MD

National Medical Director, Oncology Solutions Aetna

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

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

President Wilshire Oncology Medical Group

Vicki Kennedy, LCSW

Vice President, Program Development and Delivery Cancer Support Community

AVBCC Leadership Burt Zweigenhaft, BS President and CEO OncoMed

Gary M. Owens, MD

President Gary Owens Associates

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

www.AVBCConline.org AVBCC2014chairs Ksize_91313

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

CONTINUING EDUCATION

Faculty Perspectives

SEPTEMBER 2013 • VOLUME 4 • NUMBER 2

™

ADVANCES IN THE TREATMENT OF HEMATOLOGIC MALIGNANCIES

PUBLISHING STAFF

LETTER

Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com

FROM THE

EDITOR

Progress in the treatment of hematologic malignancies has been remarkable over the past decade, primarily due to the introduction of targeted agents, a better understanding of prognostic indicators, and new data on biomarker analysis. There is no doubt that these advances have great potential for improving outcomes; however, hematologists and oncologists who seek to provide state-of-the-art therapy for their patients may be challenged by the rapidly shifting paradigm of care. In 2013, a wealth of new data regarding the treatment of chronic lymphocytic leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndromes, myelofibrosis, and multiple myeloma has been presented at major scientific meetings throughout the world. In this “Faculty Perspectives” newsletter series, we will continue to feature highlights from several of these meetings, along with perspectives from highly respected thought leaders in the field, which will provide valuable practice implications for the management of your patients with hematologic malignancies.

Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen Grants/Project Associate Susan Yeager The Lynx Group President/CEO Brian Tyburski

Sincerely,

Chief Operating Officer Pam Rattananont Ferris

Paul Richardson, MD RJ Corman Professor of Medicine Harvard Medical School Clinical Director Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute Boston, Massachusetts

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

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Director, Production & Manufacturing Alaina Pede

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Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean

Stephanie A. Gregory, MD The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/ Rush University Chicago, Illinois

Ruben A. Mesa, MD, FACP Professor and Chair Division of Hematology and Medical Oncology Deputy Director Mayo Clinic Cancer Center Professor of Medicine Scottsdale, Arizona

David P. Steensma, MD, FACP Leukemia Program, Dana-Farber Cancer Institute Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston

Supported by educational grants from Millennium: The Takeda Oncology Company, Celgene Corporation, and Incyte Corporation.

Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski

This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

Office Coordinator Robert Sorensen Center of Excellence Media, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512

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FACULTY PERSPECTIVES Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

patient characteristics for MF, MDS, CLL, MM, NHL, and HL and apply the results to create an individualized approach to managing each patient

Commercial Support Acknowledgment This activity is supported by educational grants from Millennium: The Takeda Oncology Company, Celgene Corporation, and Incyte Corporation.

Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships.

Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with hematologic malignancies.

Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of hematologic malignancies.

Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.5 contact hours.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this applicationbased activity provides for 1.5 contact hours (0.15 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-017-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss emerging data and recent advances in the personalized treatment of patients with hematologic malignancies, and integrate key findings into clinical practice • Outline contemporary prognostic and predictive biomarkers and

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months.

Planners’ and Managers’ Disclosures Karen Cooksey, Medical Writer, has nothing to disclose. She does intend to discuss either non-FDA-approved or investigational use for the following product/devices: brentuximab vedotin, elotuzumab, ibrutinib, idelalisib, lenalidomide, MLN9708, mocetinostat, obinutuzumab, ofatumumab, panobinostat, rigosertib, ruxolitinib, SAR302503, and SGI-110.

William J. Wong, MD, MLI Reviewer, has nothing to disclose.

Nancy Nesser, JD, PharmD, MLI Reviewer, has nothing to disclose.

Pamela Vlahakis, RN, MSN, CBCN, MLI Reviewer, has nothing to disclose.

Faculty Disclosures Jennifer Brown, MD, PhD, is a Consultant for Celgene Corporation, Genentech, Novartis, Onyx, Pharmacyclics, Inc., Sanofi, and Vertex, and has received research funding from Celgene Corporation and Genzyme. She does intend to discuss either non-FDA-approved or investigational use for the following products/devices: idelalisib and obinutuzumab.

Stephanie A. Gregory, MD, is on the Speakers’ Bureau for Celgene Corporation and Janssen and is Chair of the Data Safety Monitoring Board for Genentech (Protocol GAO4753g). She does not intend to discuss any non-FDA-approved or investigational use for any products/devices.

Ruben A. Mesa, MD, FACP, has received research funding from Celgene Corporation, Genentech, Gilead Sciences, Inc, Incyte

Corporation, and Sanofi. He does intend to discuss either non-FDAapproved or investigational use for the following products/devices: SAR302503.

Paul Richardson, MD, is on the Advisory Board for Bristol-Myers Squibb, Celgene Corporation, Genmab, Johnson & Johnson, Millennium: the Takeda Oncology Company, Novartis, and Onyx.

He does not intend to discuss any non-FDA-approved or investigational use for any products/devices.

David P. Steensma, MD, FACP, is a Consultant for Celgene Corporation and is on the Advisory Committee for Amgen, Astex, and Boehringer Ingelheim. He does intend to discuss either nonFDA-approved or investigational use for the following products/ devices: EPO, mocetinostat, rigosertib, and SGI-110 for MDS and lenalidomide for non-deletion 5q MDS. Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred.

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13005B.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

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Estimated time to complete activity: 1.5 hours Date of initial release: September 13, 2013 Valid for CME/CPE/CE credit through: September 13, 2014

Updates from ASCO, EHA, and ICML 2013 Introduction Recently, researchers from around the world gathered at 3 key meetings: (1) the Annual Meeting of the American Society of Clinical Oncology (ASCO), held in Chicago, Illinois, on May 31–June 4, 2013; (2) the 18th Congress of the European Hematology Association (EHA), held in Stockholm, Sweden, on June 13–16, 2013; and (3) the 12th International Conference on Malignant Lymphoma (ICML), held in Lugano, Switzerland, on June 19–22, 2013. After the meetings, Paul Richardson, MD, David P. Steensma, MD, FACP, and Jennifer Brown, MD, PhD, from Dana-Farber Cancer Institute, Stephanie A. Gregory, MD, from Rush University Medical Center, and Ruben A. Mesa, MD, FACP, from the Mayo Clinic reviewed important data from abstracts and presentations regarding the treatment of myelofibrosis (MF), chronic lymphocytic leukemia (CLL), myelodysplastic syndromes (MDS), multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL). This supplement provides these experts’ key take-home messages for community oncology practices.

MYELOFIBROSIS

MF, which belongs to the class of hematologic malignancies known as myeloproliferative neoplasms, may be primary, secondary to polycythemia vera (PV), or secondary to essential thrombocythemia (ET).1 The disease is typically characterized by splenomegaly, burdensome symptoms, progressive bone marrow fibrosis, and shortened survival, and has a poor prognosis with limited treatment options.2,3 Although allogeneic stem cell transplant (allo-SCT) may cure MF, the procedure is associated with significant morbidity and transplant-related mortality and is feasible only in young individuals with poor prognostic factors.4 The enlarged spleen and debilitating symptoms of MF are linked to dysregulated signaling in the Janus kinase (JAK) pathway. This dysregulation may be caused by various mechanisms and mutations, such as the JAK2 V617F mutation.5,6 In 2005, the 2 V617F mutation was discovered in approximately 50% of patients with primary MF, as well as in 95% of patients with PV and 50% of patients with ET.7

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Ruxolitinib In November 2011, the US Food and Drug Administration (FDA) approved ruxolitinib, an oral JAK1 and JAK2 inhibitor, for the treatment of patients with intermediate or high-risk MF, including primary MF, post–PV MF, and post-ET MF.8 In the two phase 3 COMFORT (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment) trials, ruxolitinib was shown to reduce spleen volume and improve MF-related symptoms and quality of life, and prolonged survival compared with placebo (COMFORT-I)9 and best available therapy (COMFORT-II), which included hydroxyurea, interferon-alpha, or various sequential therapies.10,11 The primary and key secondary end points were both met: the proportion of patients achieving a response (defined as a ≥35% reduction in spleen volume) at week 48 (ruxolitinib, 28.5%; best available therapy, 0%; P<.0001) and week 24 (31.9% and 0%; P <.0001), respectively.11 Ruxolitinib 3-Year Update. At EHA, a 3-year update of the efficacy and safety findings of the COMFORT-II study was presented by Vannucchi and col-

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CONTINUING EDUCATION

Figure 1. Change in bone marrow fibrosis grade: ruxolitinib vs hydroxyurea.15 Ruxolitinib Hydroxyurea 80

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leagues. The long-term follow-up data showed that ruxolitinib provided rapid reductions in splenomegaly that were sustained for â&#x2030;Ľ3 years of treatment in the majority of patients. Overall, 75 patients (51.4%) treated with ruxolitinib achieved a â&#x2030;Ľ35% reduction from baseline in spleen volume, and reductions in spleen volumes were sustained with continued ruxolitinib therapy. At the time of data cutoff, the median duration of spleen response had not yet been reached. Ruxolitinib was well tolerated, with 45.2% of patients remaining on study after >3 years of therapy, and no newly reported or unexpected adverse events (AEs) have occurred. Longer follow-up (median, 151 weeks) continues to suggest a survival advantage with ruxolitinib treatment compared with best available therapy. Despite the fact that approximately half the patients initially randomized to best available therapy crossed over to ruxolitinib, there was a 52% reduction in risk of death in the ruxolitinib arm compared with best available therapy (HR=0.48; 95% CI, 0.28-0.85; log-rank P=.009).12 Perspective The COMFORT II trial compared ruxolitinib to best alternative therapy, which largely employed all of the current therapies we had used for MF, or all the therapies that had been used prior to JAK2 inhibition. What was quite interesting is that they continue to see the indication of a survival benefit for these patients, now 3 years out from the conclusion of the trial. In addition, there was nothing suggesting cumulative toxicity for patients receiving this agent. This is very important in terms of long-term management of patients with this therapy. It is also encouraging that many patients remained on ruxolitinib and showed signs of durable responses this far out. Overall, I would say these results are quite favorable, especially since the comparison group had received best alternative therapy.

-Ruben A. Mesa, MD, FACP

Ruxolitinib and Bone Marrow Fibrosis. Bone marrow fibrosis (ie, accumulation of reticulin and/or collagen fibers, possibly mediated by clonal cell-derived cytokines and inflammatory stromal reactions) is a key marker of worsening disease in patients with MF. Standard pharmacotherapy has not been shown to improve bone marrow fibrosis; the only proven treatment option is bone marrow transplantation.13,14 Data presented both at ASCO and at EHA by Kvasnicka and colleagues suggest that long-term treatment with ruxolitinib may stabilize or reverse bone marrow fibrosis.15,16 Results from an exploratory analysis (N=68) of bone marrow fibrosis data from an ongoing phase 1/2 single-arm, open-label trial showed

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that fibrosis of the bone marrow was stabilized or reversed after 24 and 48 months of ruxolitinib treatment in the majority of patients with MF (Figure 1).15 For comparison, bone marrow fibrosis grading was also determined in a separate set of biopsy specimens from 41 patients treated with hydroxyurea monotherapy. A comparable effect on bone marrow fibrosis was not seen with hydroxyurea treatment.

In another comparative analysis, bone marrow fibrosis grading was determined in a set of biopsy specimens from 160 patients treated with best available therapy, which included not only hydroxyurea monotherapy (48%), but also watchful waiting (21%), interferon-alfa (7%), or various other therapies as monotherapy or in combination (corticosteroids, androgens, melphalan, busulfan, thalidomide, splenic irradiation).16 Results were similar to those with hydroxyurea monotherapy. At 24 and 48 months, 62% and 75% of patients receiving best available therapy showed worsening of bone marrow fibrosis, respectively.

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Since the start of testing of JAK2 inhibitors, the issue of whether these agents can have an impact on bone marrow changes has been an important subject of discussion. In other words, is there evidence that these drugs are impacting the natural history of the disease in other biological ways in addition to the demonstrated improvement in splenomegaly symptoms and even survival? This analysis was very interesting because it demonstrated that with long-term use of ruxolitinib, there is a clear signal that patients could potentially experience either a stabilization or improvement in bone marrow fibrosis. Furthermore, compared with a historical control group of patients treated with other MF therapies, ruxolitinib seemed to have a more significant impact on reduction of bone marrow fibrosis and a greater degree of stabilization of fibrosis.

Overall, these results imply that ruxolitinib has a meaningful benefit for the long term and that there is a biological effect that is demonstrable in the bone marrow. It is important to note, however, that this is a lengthy process.

Given the fact that it may take up to 1 year for allo-SCT to produce significant improvements in marrow fibrosis, it is expected that medical therapy may take 2 to 3 years to significantly impact marrow histology.

-Ruben A. Mesa, MD, FACP

SAR302503 SAR302503 (previously TG101348) is an oral, selective JAK2 inhibitor under investigation for the treatment of MF. SAR302503 is being evaluated in a phase 2 study (N=31) of the efficacy and safety of daily oral doses of 300 mg (n=10), 400 mg (n=10), and 500 mg (n=11) in patients with intermediate-2 or high-risk MF. Results after 3 cycles, which were reported previously,17 showed that a spleen response (defined as spleen reduction of at least 35%) was seen in 30% of patients (3/10) in the 300-mg group, 50% (5/10) in the 400-mg group, and 64% (7/11) in the 500-mg group. Updated results were reported at both ASCO and EHA by Pardanani and colleagues, and showed that spleen response rates at the end of 6 cycles of treatment were 30% (3/10) in the 300-mg group, 60% (6/10) with 400 mg, and 55% (6/11) with 500 mg.18,19 SAR302503 reduced baseline constitutional symptoms at the end of cycle 3 in all dose groups, with the greatest symptom responses seen for night sweats in 14/15 patients (93%), itching 10/14 (71%), early satiety 10/18 (56%), and abdominal pain 10/18 (56%). The most commonly reported AEs across all doses were grade 3/4 anemia (58%), grade 3/4 diarrhea (13%), and grade 3/4 thrombocytopenia (16%). No cases of grade 3/4 neutropenia were seen.18,19 Perspective SAR302503 is the JAK2 inhibitor that is the most developed after ruxolitinib for the treatment of MF. Pardanani and colleagues reported on the efficacy and tolerability of SAR302503 at 3 different doses in this phase 2 trial, and reported that it was active in terms of both splenomegaly and symptomatic control. The safety profile was most prevalently impacted by gastrointestinal toxicity. However, the incidence of grade 3/4 toxicities was low and these AEs were frequently manageable. As with other JAK2 inhibitors, treatment-

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FACULTY PERSPECTIVES related cytopenias were prevalent, hence, the effort to best characterize the dose/response by dosing intensity treatment group.

-Ruben A. Mesa, MD, FACP

CHRONIC LYMPHOCYTIC LEUKEMIA

The American Cancer Society estimates that in 2013, approximately 15,680 patients will be diagnosed with CLL and 4580 will die from the disease.20 Although CLL remains incurable, over the past decade there have been major advances in the understanding of the disease pathophysiology and its treatment.21,22 The most important advances in CLL outcomes have been with combination chemotherapy and then with chemoimmunotherapy.22,23 Idelalisib Phosphatidylinositol 3-kinase delta (PI3Kδ) is a molecular target that is critical for the activation, proliferation, and survival of B lymphocytes. PI3Kδ signaling is hyperactive in many B-cell leukemias and lymphomas and drives proliferation, survival, and trafficking to lymphoid tissue.24 Final results of a phase 1 study of idelalisib (GS-1101), an oral, selective inhibitor of PI3Kδ, as monotherapy in 54 patients with relapsed or refractory CLL were reported by Brown and colleagues at ASCO. Patients were treated continuously for up to 48 weeks with idelalisib as a single agent from a 50- to 350-mg/dose once or twice daily in 28-day cycles, although 10 patients received the 300-mg dose once daily in 28-day cycles. Patients had received a median of 5 prior therapies (range, 2-14), and 70% of patients were refractory to their most recent prior regimen. Patients were exposed to idelalisib for a median of 9 months (0-41+), with 25 patients (46%) completing the primary study and 23 patients (43%) enrolling in an extension study. The overall response rate (ORR) was 72% (including 33% who had nodal response with lymphocytosis). The median time to first response was 1.9 months (range, 0.9-12.9). The median progression-free survival (PFS) was 17.1 months and the median duration of response was 18 months. Idelalisib was generally well tolerated. AEs associated with the drug included elevated liver function tests that were asymptomatic and resolved, diarrhea, and rash. Low neutrophil counts and infections, particularly pneumonia, were also observed.25 Perspective Idelalisib was the first PI3Kδ inhibitor to be tested in CLL and has shown very promising activity in relapsed/refractory patients. The population in this study was extremely heavily pretreated, and 70% were refractory to their last regimen, which is more refractory than we see in most studies. However, the response rate was still quite high, and the PFS, even in the phase 1 study, was 17 months. If you look just at patients treated at what was selected as the phase 2 dose, the PFS is even longer at about 29 months. This drug is now in 3 randomized registration trials.

-Jennifer Brown, MD, PhD

Idelalisib was the first PI3Kδ inhibitor to be tested in CLL and has shown very promising activity in relapsed/refractory patients.

Results of a phase 2 study of idelalisib in combination with rituximab in 64 treatment-naive patients (≥65 years of age) with CLL or small lymphocytic lymphoma were presented by O’Brien and colleagues at ASCO 2013. Patients received idelalisib 150 mg twice daily for 48 weeks and rituximab 375 mg/m2 once weekly for 8 weeks. A primary assessment was conducted during the 8th week, and 62 patients with improving or responding disease were enrolled for the extension study. After the completion of a 24-month period, results indicated an ORR of 97%, including complete responses (CRs) in 19% and partial responses (PRs) in 78%. In addition, among the 9 patients with reported chromosome abnormalities, 3 patients reported CRs and 6 reported PRs. A 93% PFS rate was reported in all patients, and a 100% PFS in 9 patients who had high-risk cytogenetics. Overall, 33% of patients in the primary and extension studies experienced grade 3 diarrhea and/or colitis. Grade 3 or higher pneumonia occurred in 17%, transaminase elevations in 23%, and neutrope-

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nia in 28%. Of the patients who discontinued therapy due to AEs, 5 did so because of respiratory events in the first 24 weeks, and 5 did so because of diarrhea/colitis during the extension study. Other causes of discontinuation were anemia and elevated transaminases.26 Perspective O’Brien and colleagues provided us with the first upfront data on idelalisib, which was given in combination with rituximab in this study. These were previously untreated patients with CLL, and the response rate to therapy was very high at 97%. The investigators also evaluated the impact of treatment on patients with high-risk cytogenetics (del [17p]) and found that these individuals responded as well as the rest of the population. This is not typical for current CLL therapies, so the results of this study are very encouraging. In general, idelalisib is well tolerated; it may cause some diarrhea and elevated liver function, but these AEs are typically manageable.

-Jennifer Brown, MD, PhD

Obinutuzumab (GA101) is a glycoengineered, type II anti-CD20 antibody that is being investigated in combination with chlorambucil for the treatment of CLL. Obinutuzumab Plus Chlorambucil Obinutuzumab (GA101) is a glycoengineered, type II anti-CD20 antibody that is being investigated in combination with chlorambucil for the treatment of CLL. Updated results of a phase 3 multicenter, open-label, randomized three-arm study (CLL11) of obinutuzumab were reported by Goede and colleagues at ASCO. In CLL11, the combination of obinutuzumab plus chlorambucil was compared with the combination of rituximab plus chlorambucil (a standard chemotherapy) and with chlorambucil alone in 589 patients with CLL who had preexisting comorbidities. Responses are shown in Figure 2.27 The addition of obinutuzumab to chlorambucil led to a statistically significant reduction in the risk of disease progression or death of 86% (HR=0.14; P≤.0001). The median PFS improved by more than 1 year from 10.9 months for chlorambucil alone to 23 months for obinutuzumab plus chlorambucil.

The addition of rituximab to chlorambucil significantly reduced the risk of disease progression or death during study follow-up by 68% (HR=0.32; P≤.0001). Median PFS was 10.8 months for chlorambucil versus 15.7 months for rituximab plus chlorambucil. The most common grade 3/4 AEs seen with the combination of obinutuzumab and chlorambucil were neutropenia (34%), infusion-related reactions (IRRs, 21%), and infections 6%. The incidence and severity of IRRs decreased dramatically after the first infusion and no serious reactions have been reported beyond the first infusion. The most common toxicities seen with the combination of rituximab and chlorambucil were neutropenia (25%), infections (8%), and IRRs (4%).27 Perspective Obinutuzumab is a novel CD20 antibody that works by a different mechanism of action than the CD20 antibodies already approved for CLL (rituximab and ofatumumab). This agent is glycoengineered, which results in enhanced antibody-dependent cellular cytotoxicity. It also has a type-2 mechanism that is not dependent on the patients’ immune system, which is often impaired in CLL. This was the first report from the phase 3 registration trial of obinutuzumab. Although the investigators did not make a direct comparison between rituximab and obinutuzumab, a report on this is expected later this year. However, the CR rate with obinutuzumab was greatly improved over the CR rate seen with chlorambucil alone. An interesting observation is that a significant number of patients in this trial treated with obinutuzamab plus chlorambucil showed no minimal residual disease, which is not commonly seen with chlorambucil alone. The data from this trial are not yet mature, so we would expect that the PFS rates will be even better in later reports.

-Jennifer Brown, MD, PhD

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Figure 2. Responses observed with obinutuzumab plus chlorambucil vs rituximab plus chlorambucil vs chlorambucil alone.27 80

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CR indicates complete response; ORR, objective response rate.

Ofatumumab Ofatumumab is a CD20-directed cytolytic monoclonal antibody approved by the FDA in 2009 for the treatment of patients with CLL refractory to fludarabine and alemtuzumab. At ASCO, Castro and colleagues presented results of a phase 2, single-arm study evaluating ofatumumab in combination with high-dose methylprednisolone for the treatment of 21 patients (median age, 63 years [range, 46-76], median of 3 prior therapies, 24% had unfavorable cytogenetics, 76% had CLL cells that expressed unmutated IgVH genes or high levels of ZAP-70, 24% were fludarabine refractory) with relapsed or refractory CLL. At 2 months after completion of therapy, the ORR was 81% (17/21) including 5% CR (1/21), 10% nodular PR (2/21), and 67% PR (14/21). The median follow-up time was 12 months (range, 5-23). The median PFS time was 9.1 months and the median treatment-free survival time was 11.5 months.

Treatment was well tolerated. The majority of AEs were grade 1 or 2, including insomnia, anxiety, fatigue, and infusion reactions. Grade 3 AEs included neutropenia (19%), thrombocytopenia (5%), hyperglycemia (71%), nonmelanoma skin cancer and other skin lesions (19%), as well as acute coronary syndrome, atrial fibrillation, renal calculi, pneumonia, and hypocalcemia (1 patient each). There were no grade 4 toxicities.28 Perspective Methylprednisolone is a drug that has activity in relapsed/refractory and high-risk CLL. This drug is typically given in combination with rituximab, so these investigators took a novel approach by combining methylprednisolone with ofatumumab. The patients in this study had a median of 3 prior therapies and about 25% had unfavorable cytogenetics. Thus far, the data look pretty good; the PFS rate seen with this regimen is fairly long for a relapsed/refractory, high-risk CLL population. In general, one advantage to using a steroid-antibody combination such as this is that it can often be given to patients who could not tolerate standard chemotherapy.

-Jennifer Brown, MD, PhD

MYELODYSPLASTIC SYNDROME

The MDSs are a collection of myeloid malignancies characterized by one or more peripheral blood cytopenias that progress to acute myeloid leukemia (AML) with myelodysplastic features when blood or bone marrow blasts reach or exceed 20%. Approximately 50% of patients with MDS have a detectable cytogenetic abnormality, most commonly a deletion of all or part of chromo-

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some 5 or 7, or trisomy 8.29 Patients with MDS are classified by the International Prognostic Scoring System (IPSS) into low-, intermediate-1 (int-1)–, intermediate-2 (int-2)–, and high-risk groups based on the percentage of marrow blasts, number of cytopenias, and bone marrow cytogenetic findings.

Among patients with lower-risk (low or int-1) MDS, refractory anemia is the principal therapeutic challenge.30 Therefore, the mainstay of treatment for MDS has traditionally been supportive care, including the use of erythropoiesis-stimulating agents (ESAs) to improve anemia.29 However, ESAs yield only 40%-50% response rates.30 In recent years, several therapeutic agents have been approved for the treatment of patients with MDS, including lenalidomide and the azanucleosides (azacitidine and decitabine), with several promising new agents also under investigation.

Lenalidomide Lenalidomide is FDA approved for the treatment of patients with transfusion-dependent anemia due to low- or int-1–risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Previous studies have shown that lenalidomide allows independence from red blood cell (RBC) transfusions in about 25% of patients with ESA-resistant (or ESA-relapsing), transfusion-dependent, lower-risk MDS without deletion 5q,30 and that a gene expression signature can predict response.31 At both ASCO and EHA, Toma and colleagues presented results from a randomized, open-label phase 2 study of lenalidomide plus erythropoietin versus lenalidomide alone in RBC transfusion-dependent patients (N=132) with lower risk (ie, IPSS scores low or int-1) MDS who did not have deletion 5q and who were resistant to erythropoietin.32,33 The primary end point was erythroid response (hematologic improvement–erythroid [HI-E]), as defined by the 2006 International Working Group response criteria in myelodysplasia.34 Among the 129 patients evaluable for response, 23.4% of patients receiving lenalidomide alone achieved HI-E versus 40.0% of patients receiving lenalidomide plus erythropoietin. In addition, 14.1% of patients receiving lenalidomide alone achieved RBC transfusion independence versus 24.6% of patients receiving lenalidomide plus erythropoietin. Among the 99 patients who completed 4 treatment cycles, 30.6% of patients receiving lenalidomide alone achieved HI-E versus 52.0% of patients receiving lenalidomide plus erythropoietin. Furthermore, 18.4% of patients receiving lenalidomide alone achieved RBC transfusion independence versus 32.0% of patients receiving lenalidomide plus erythropoietin (Figure 3).32,33 AEs were similar in the 2 groups. A 29-gene expression profile signature predicting HI-E to lenalidomide plus erythropoietin versus lenalidomide alone was identified and a polymorphism in the CRBN gene was significantly associated with HI-E in the entire cohort (P=.034).

Perspective This was a randomized trial of lenalidomide with or without erythropoietin in patients who did not have deletion 5q. The reason this is important is because while lenalidomide works really quite well in those patients with lower-risk MDS who have this deletion, outside of that population, there’s a subset of patients who respond, but it is difficult to predict who those patients will be in advance.

This study was conducted for 2 reasons: (1) to ascertain whether lenalidomide could resensitize patients to erythropoietin and (2) to determine whether there was some sort of gene signature that predicted which patients without deletion 5q would respond better to lenalidomide. The investigators found that with lenalidomide alone, there was a transfusion independence rate of 14%, which is low but meaningful in lower-risk patients who often have few options. When patients were given a combination of lenalidomide plus erythropoietin, responses were a little better.

There was, in fact, a gene signature that predicted response to the combination therapy, as well as a cereblon polymorphism that predicted response to lenalidomide. That is interesting biologically, but there is not currently a clinically available test for either the gene expression pattern or the polymorphism. Also, these are not practice-changing results because even though the cereblon polymorphism was associated with significantly better responses, there were still patients who did not have the polymorphism who responded, as well as patients who had it and did not respond. So the mys-

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Azanucleosides Two azanucleosides, azacitidine and decitabine, are FDA approved for the treatment of MDS; however, azanucleoside treatment is limited by prohibitive AEs (mainly myelosuppression, as manifested by thrombocytopenia, neutropenia, and anemia) or the lack of sustained benefit. In 2008, Borthakur and colleagues published results of 14 patients with MDS who achieved a 28% ORR (including 3 CRs) with decitabine after lack of response to azacitidine.35 At ASCO, Komrokji and colleagues presented results of their retrospective investigation of cases of sequential azanucleoside treatment that were identified through the Moffitt Cancer Center MDS database. Two groups of patients were identified; Group 1 (32%) had received decitabine after azacitidine failure and Group 2 (68%) had received azacitidine after decitabine failure. A total of 39 MDS patients who received treatment with both azanucleosides were identified. Complete records were available in 31 patients, including 21 patients in Group 1 (decitabine after azacitidine) and 10 patients in Group 2 (azacitidine after decitabine). Results showed that response rates were higher in patients who received decitabine followed by azacitidine (40% vs 19%) and that the rate of transformation to AML was lower for patients who received decitabine followed by azacitidine (20% vs 29%). The median overall survival was also higher for patients who received decitabine followed by azacitidine (100 months from diagnosis), compared with patients who received azacitidine followed by decitabine (48 months).36 Perspective Most patients with higher-risk MDS are treated at some point with azacitidine or decitabine. These drugs are very similar chemically and have virtually the same intracellular effects on gene expression and DNA methyltransferase binding. This study sought to answer the question: if you use one of these 2 agents and it doesn’t work, is there a role for trying the other? In my own clinical experience, I have not seen a patient respond to a second azanucleoside after the first one failed, whether going from azacitidine to decitabine or vice versa. A French study also suggested that this was not a useful strategy. However, the investigators from Moffitt, like those from MD Anderson who looked at this issue 5 years ago, did report that there were a significant number of patients that responded to one agent after the other one had

This study sought to answer the question: if you use one of these 2 agents and it doesn’t work, is there a role for trying the other? failed. Among the patients who received decitabine followed by azacitidine in this study, 40% of them showed a response, which is high enough that it may make us rethink this strategy. It is important to note, however, that the duration of response to the second drug was generally only a few months. This is not a curative therapy, but it might give a little bit of extra mileage out of an azanucleoside. The bottom line is that when azacitidine or decitabine fails, we don’t have a lot of other good options for our patients who are not eligible for transplant. The results of this study at least suggest that it may be worth it, in some patients, to do a trial of a second azanucleoside if the first one fails and if the patient is not a candidate for transplant and doesn’t have access to a clinical trial.

-David P. Steensma, MD, FACP

Rigosertib Rigosertib, a novel small molecule inhibitor of both PI3K and polo-like kinase, is being developed in both oral and intravenous (IV) forms as a treatment for hematologic diseases and solid tumors. Interim data from the randomized phase 2 ONTARGET study, which is evaluating oral rigosertib as a single agent (administered either intermittently [for 2 of 3 weeks] or continu-

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Figure 3. RBC transfusion independence after 4 cycles: lenalidomide plus erythropoietin vs lenalidomide alone.32,33

40 32.0%

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tery of which patients without del 5q will respond to lenalidomide remains partly unsolved.

-David P. Steensma, MD, FACP

18.4%

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ously) in transfusion-dependent lower-risk MDS patients, were presented at ASCO. In the ONTARGET study, 50% (13/26) of the evaluable patients in the intermittent-dosing group and 25% (2/8) of the evaluable patients in the continuous-dosing group achieved transfusion independence (defined as no RBC transfusions for at least 8 consecutive weeks). None of the responders had a deletion 5q upon cytogenetic evaluation. Onset of transfusion independence ranged from 1 to 24 weeks following the initiation of rigosertib dosing, and the duration of transfusion independence ranged from 8 to >48 weeks, with 2 patients continuing to benefit from therapy >9 months after initiating rigosertib treatment. Eleven of the 13 transfusion-independent patients in the intermittent-dosing arm received ≥1 injection of ESAs during the time of oral rigosertib administration, and the patterns of hemoglobin responses observed in a few patients suggest a possible synergy between oral rigosertib and ESAs. Rigosertib was generally well tolerated except for a high incidence of grade ≥2 urinary AEs. In the continuous-dosing arm of the study, grade ≥2 urinary AEs (dysuria, hematuria, cystitis, and urinary urgency) were observed in 5 of the first 9 patients. Therefore, the study protocol was amended to allow for all patients to be treated with intermittent dosing, with the option of dose interruption/reduction resulting in a much lower frequency of urinary AEs. The most frequent urinary AEs in the intermittent-dosing arm were grade ≥2 urinary urgency/frequency (38%), grade ≥2 dysuria (15%), and hematuria (15%).

Intermittent grade 3/4 neutropenia (n=2) was also observed (1 patient per grade). Median onset of grade ≥2 AEs in the intermittent-dosing group was 28 weeks versus 12 weeks in the continuous-dosing group. Median duration of treatment in the intermittent-dosing group has not yet been reached (>48 weeks vs 24 weeks in the continuous-dosing group). Renal function was unaffected and gastrointestinal AEs and fatigue were infrequently observed.37 Perspective There is a 300-patient randomized trial under way in which IV rigosertib is being administered as a 72-hour infusion every 2 weeks in patients who were treated with azacitidine or decitabine and either didn’t respond or lost their response to the azanucleoside. The control group in that study is either supportive care or low-dose cytarabine. It will be interesting to see the results, which will hopefully determine whether rigosertib can improve survival when given to higher-risk MDS patients in a second-line setting.

In this ONTARGET trial, the investigators chose to use a more convenient oral form of rigosertib in patients with lower-risk MDS. They reported that in a relatively small number of patients, there was some hematologic improvement. However, this agent appeared to be very irritating to the bladder, so partway through the trial, they amended the protocol so that patients could receive intermittent dosing rather than continuous dosing, which did reduce the incidence of this AE. This oral drug could turn out to be helpful for some patients with lower-risk MDS. Still, I think the urinary toxicity is somewhat con-

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CONTINUING EDUCATION cerning because many MDS patients are older men with prostate problems who already have urinary difficulties.

-David P. Steensma, MD, FACP

Mocetinostat Mocetinostat, an oral isotype-selective histone deacetylase inhibitor, is being evaluated in an open-label phase 2 study in combination with the demethylating agent azacitidine in 28 patients with MDS (median age, 72 years; 54% had marrow blast counts >10%; 64% were intermediate or high risk; 50% had received >1 prior therapy [none had received prior azacitidine]). The ORR was 61%, including 50% who achieved a CR or a CR with incomplete recovery (CRi), and 11% who achieved HI. Of the patients with int-2 or highrisk MDS, 9/14 (64%) achieved CR or CRi. The median OS was 12.9 months (range 1.9-62.0). On-study transfusion independence was achieved in 36% (8/22) of patients. Clinically meaningful reductions in bone marrow blasts were seen by cycle 2, with continued improvement in cycle 3. The most common severe side effects among all study participants included fatigue (23%), nausea (22%), diarrhea (17%), and vomiting (14%).38 Perspective There is a number of deacetylase inhibitors that are being, or have been, evaluated in MDS, including mocetinostat, which used to be known as MGCD0103. In this trial, because everyone received combination therapy, it is difficult to ascertain how many of the responses seen were due to azacitidine versus the combination regimen. However, the investigators did observe that 50% of patients achieved a reduction in bone marrow blasts and some also had hematopoietic recovery. That’s a pretty high rate. I think that mocetinostat needs to be compared in a randomized fashion to azacitidine alone to get a better idea of its clinical activity, just like the vorinostatazacitidine combination that is being compared with azacitidine alone in the US/Canadian S1117 Intergroup trial. Right now, we don’t know if mocetinostat will be any more effective than vorinostat, panobinostat, pacrinostat, or any of the other histone deacetylase inhibitors currently under investigation in MDS. -David P. Steensma, MD, FACP

The investigational agent MLN9708 (ixazomib citrate) is the first oral proteasome inhibitor in the boronate peptide class with reported clinical activity in MM. SGI-110 SGI-110 is a second-generation hypomethylating agent (formulated as a dinucleotide of decitabine and deoxyguanosine) delivered as a subcutaneous injection that allows a longer half-life and more extended decitabine exposure than IV decitabine infusion. At EHA, O’Connell and colleagues presented results of a randomized phase 1 dose escalation study with 2 different regimens of SGI-110 in 15 intermediate- or high-risk MDS patients (median 74 years of age [range, 46-82]; median of 2 prior therapies) who had previously failed treatment with azacitidine or decitabine. Responses were observed in 5 patients for an ORR of 33% with reported response duration of 28 to 224 days.

Patients who responded had higher baseline median bone marrow blast counts (16.5%) than patients who did not respond (5%). Treatment was well tolerated; the most commonly reported nonhematologic AEs (mostly grade 1) were injection site pain and diarrhea.39 Perspective SGI-110 is interesting in that it is almost like a precursor drug of decitabine.

Basically, it is decitabine conjugated to another nucleoside, which seems to allow for longer drug exposure, prolonged half-life, and deeper methylation changes across the genome. Whether that’s going to translate into a clinical benefit over existing azanucleosides, however, remains to be seen. I think

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one take-home from this study is that there were patients who had previously been treated with decitabine who in fact did respond to SGI-110, suggesting that this investigational agent may be a little more potent than decitabine itself.

-David P. Steensma, MD, FACP

MULTIPLE MYELOMA

The American Cancer Society estimates that this year, MM will be diagnosed in 22,350 individuals (12,440 men and 9910 women), and will result in 10,710 deaths.20 Novel and active combination regimens that are well tolerated as long-term therapy are required for elderly patients with MM, including many who are ineligible for autologous stem cell transplantation (ASCT).

MLN9708, Lenalidomide, and Dexamethasone The investigational agent MLN9708 (ixazomib citrate) is the first oral proteasome inhibitor in the boronate peptide class with reported clinical activity in MM. At EHA, Richardson and colleagues presented subset analysis results (comparing elderly vs younger patients) of a phase 1/2 study of oral MLN9708 (dosed weekly) plus lenalidomide-dexamethasone in both transplant-eligible and transplant-ineligible patients with previously untreated MM. Preliminary response data showed clinical activity across the age groups (Table 1). A total of 3 patients had disease progression, including 0, 3, and 2 patients aged <65, ≥65, and ≥75 years, respectively.40 The incidences of common (≥30% of patients overall), all-grade, all-cause AEs at the recommended phase 2 dose were similar across the age groups (Table 2). There were 2 on-study deaths, 1 due to cardiorespiratory arrest after abdominal surgery in an 86-year-old patient (considered unrelated to the study drug by the investigator) and 1 due to drug-related respiratory syncytial virus pneumonia in a 68-year-old patient.40 Perspective The combination of ixazomib citrate and lenalidomide and dexamethasone in the upfront treatment of myeloma demonstrated very exciting results with encouraging response rates for this “all oral” regimen, an ORR of approximately 90% and the very high quality of responses seen as well. In this analysis of our multicenter phase 1/2 study, clinical activity across all age groups and a broadly manageable set of side effects was demonstrated. Encouragingly, rates of peripheral neuropathy were remarkably low and whilst fatigue and gastrointestinal upset remain important side effects of this combination, the overall tolerability of this oral regimen was favorable. Phase 3 studies of this combination are now under way in both the relapsed and upfront settings, with accrual proceeding well. Given the remarkably high quality of responses seen in the upfront setting, it is anticipated that this will be an important combination for myeloma patients in general. Finally, this particular platform of a proteasome inhibitor combined with an immunomodulator demonstrates clinical synergy and further validates this approach, as originally seen with the combination of lenalidomide and bortezomib. It also emphasizes the convenience of an all oral combination, as well as important differences in overall tolerability compared with other regimens.

-Paul Richardson, MD

Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone Carfilzomib is FDA approved for the treatment of MM in patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent. Jakubowiak and colleagues previously published 13-month results of a phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for MM.41 At ASCO, they presented updated (25-month) results (Table 3) from 53 patients who had received a median of 22 cycles (range, 2-24).42 Immunophenotypic CR was achieved in 22/26 of evaluated patients.

Among the patients who achieved stringent CR (sCR), 25% had high-risk cytogenetics. Among the patients who did not proceed to transplant (n=46), the sCR was 59%, CR 70%, ≥near complete response (nCR) 78%, ≥very good partial response (VGPR) 91%, and ≥PR 100%. Over the course of treatment,

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Table 1. Responses to MLN9708 Plus Lenalidomide Plus Dexamethasone by Age Group40 Patients <65 Years of Age (n=31)

Patients ≥65 Years of Age (n=34)

Patients ≥75 Years of Age (n=12)

ORR

94%

91%

82%

CR+VGPR

43%

70%

CR

29%

24%

VGPR

13%

45%

Patients <65 Years of Age (n=31)

Patients ≥65 Years of Age (n=34)

Patients ≥75 Years of Age (n=12)

Fatigue

56%

64%

60%

73%

Diarrhea

44%

54%

60%

18%

Nausea

52%

32%

50%

55%

Constipation

44%

32%

20%

Peripheral edema

36%

36%

20%

Upper respiratory tract infection

32%

32%

10%

Vomiting

32%

21%

40%

CR indicates complete response; ORR, overall response rate, VGPR, very good partial response.

the depth of response improved. Median time to ≥VGPR was 4 cycles (range, 2-17), ≥nCR 4.5 cycles (range, 2-15), and sCR 10 cycles (range, 4-30). Two patients converted to sCR during lenalidomide maintenance. At 2 years, for all patients, the estimated PFS rate was 94% and the overall survival (OS) was 98%. For the subset of patients that achieved an sCR, the PFS rate was 96% and the OS rate was 100%. AE types, rates, and dose modifications during extended treatment were comparable to those previously reported at 13 months, follow-up. There was 1 death off-study due to disease progression.42 Perspective Jakubowiak and colleagues updated at ASCO the results in 53 patients of their highly active combination of carfilzomib, lenalidomide, and low-dose dexamethasone with newly diagnosed myeloma. In this analysis, updated information regarding the quality of response was presented, with the high rate of sCRs seen in patients not proceeding to transplant being especially noteworthy. Consistent with other regimens in this setting, over the course of treatment, depth of response improved. A particularly striking aspect of this analysis was the high quality of responses achieved even as patients proceeded to maintenance with lenalidomide alone, suggesting a durable effect from carfilzomib and commensurate with its pharmacodynamics as a very potent proteasome inhibitor. Importantly, tolerability was favorable with rates of treatment-emergent neuropathy stable at approximately 25% and the incidence of cardiopulmonary toxicity remaining low. Comparative studies of this regimen versus lenalidomide, bortezomib, and low-dose dexamethasone are planned and should provide greater insights into both its activity and tolerability in newly diagnosed patients. Once more, the concept of proteasome inhibition plus immunomodulatory therapy as a synergistic combination in the clinical setting has been validated by these remarkable results.

-Paul Richardson, MD

Elotuzumab, Lenalidomide, and Low-Dose Dexamethasone The humanized monoclonal antibody elotuzumab targets CS1, a protein that is highly expressed on the surface of MM cells, mediates their adhesion to bone marrow stromal cells, and enhances natural killer cell-mediated killing of MM cells primarily via antibody-dependent cell–mediated cytotoxicity.43 Updated results from a small, randomized, open-label phase 1/2 study of elotuzumab (either at a 10-mg/kg dose or a 20-mg/kg dose) in combination with lenalidomide and low-dose dexamethasone in 73 patients with relapsed or refractory MM were reported by Lonial and colleagues at both ASCO and EHA. In the phase 2 cohort, after a median follow-up of 20.8 months, the median PFS was 33 months and the ORR was 92% for patients who received 10 mg/kg (n=36) and the median PFS was 18.6 months and the ORR was 76% for those who received 20 mg/kg (n=37). The most common grade 3/4 toxicities for the 10-mg/kg and 20-mg/kg arms, respectively, were lymphopenia (26% and 9%), neutropenia (21% and 22%), thrombocytopenia (21% and 17%), anemia (13% and 12%), leukopenia (8% and 7%), hyperglycemia (5% and 12%), pneumonia (8% and 5%), diarrhea (10% and 5%), fatigue (8% and 9%), and hypokalemia (8% and 5%). Most treatment-emergent AEs occurred within 18 months of initiating therapy. Across all patients in the study, 15 patients discontinued due to AEs (none after 18 months of treatment). Four second primary malignancies occurred (none were reported after 18 months of treatment).44,45

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Table 2. Toxicities* Reported With MLN9708 Plus Lenalidomide Plus Dexamethasone by Age Group40 Adverse Event

*Common (≥30% of patients overall), all-grade, all-cause AEs at the recommended phase 2 dose.

Table 3. Responses With Carfilzomib, Lenalidomide, and LowDose Dexamethasone: 13-Month vs 25-Month Follow-Up41,42 13-Month Follow-Up

25-Month Follow-Up

sCR

42%

53%

CR

62%

64%

nCR

62%

72%

VGPR

81%

87%

PR

98%

98%

CR indicates complete response; nCR, near complete response; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.

Perspective Lonial and colleagues updated the results both at ASCO and EHA of this important study in which the combination of elotuzumab, lenalidomide, and low-dose dexamethasone have previously shown striking results in a phase 1 trial. This subsequent randomized, open-label phase 2 study evaluated elotuzumab either at a 10-mg/kg dose or a 20-mg/kg dose in combination with lenalidomide, and low-dose dexamethasone in 73 patients with relapsed or refractory MM and demonstrated encouraging PFS, with a median of 33 months (vs approximately 11 months in a similar study of comparable patients previously with lenalidomide and dexamethasone alone) and a remarkably high ORR of 92%. Interestingly, median PFS and ORR were less in those receiving higher-dose elotuzumab. Side effect profiles were nonetheless similar and this combination was generally well tolerated with manageable toxicity.

This combination continues to show considerable promise as an exciting platform for combination therapy utilizing monoclonal antibodies. Elotuzumab is currently a front-running monoclonal antibody in myeloma now being evaluated in phase 3 trials, both in the relapsed and refractory setting as well as in the newly diagnosed setting. The synergy with immunomodulatory therapy is particularly noteworthy. Moreover, current clinical trials are exploring its activity with bortezomib and studies evaluating elotuzumab in combination with both immunomodulatory therapy and proteasome inhibitors (eg, lenalidomide, bortezomib, and dexamethasone plus elotuzumab) are either planned or soon to be under way.

-Paul Richardson, MD

Bortezomib, Panobinostat, and Dexamethasone In a phase 2 single-arm, open-label, multicenter study known as PANORAMA 2, Richardson and colleagues previously evaluated oral panobinostat in combination with bortezomib and dexamethasone in 55 patients with relapsed and bortezomib-refractory MM (PANORAMA 2) and found an ORR of 34.5%, a clinical benefit rate (CBR) of 52.7%, and a median PFS time of 5.4 months.46 At both ASCO and EHA, these investigators presented further results from PANORAMA 2, in which they evaluated clinical response by baseline patient characteristics. With few exceptions, the efficacy

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CONTINUING EDUCATION end points were similar regardless of baseline demographics. A trend was seen toward a higher response rate in patients whose prior bortezomib therapy was not their last line of therapy. However, the numbers are small and did not reach statistical significance. While no trend in response rate was noted, PFS appeared to be longer in those who had progressed within 60 days of their last bortezomib-containing regimen than in those who had progressed while on their last bortezomib-containing regimen. Among patients with adverse cytogenetics (n=14) the ORR was 42.9% and the CBR was 71.4%. The authors concluded that panobinostat, when combined with bortezomib and dexamethasone, recaptured responses in heavily pretreated, bortezomib-refractory MM patients; demonstrated activity regardless of baseline demographics; and was tolerable, with manageable toxicities. While the small patient subgroups limit more definitive conclusions, it appears that patients with high-risk cytogenetics had similar outcomes to the patient population as a whole.

Symptoms of peripheral neuropathy remained relatively unchanged throughout the study.47,48

Brentuximab vedotin is a CD30-targeted antibody-drug conjugate that is FDA approved for the treatment of HL and for the treatment of systemic anaplastic large cell lymphoma (ALCL).

Perspective In the setting of relapsed and refractory MM, in which all patients were bortezomib-resistant, we were encouraged by the results of this relatively large, single-arm multicenter phase 2 trial which observed a response rate of approximately 35%, with 53% of patients enjoying minimal response or better, and an overall median PFS in excess of 5 months. In our updated analyses, the efficacy end points appeared similar regardless of baseline demographics. Of particular note was the activity of the combination in patients with adverse cytogenetics, where we saw an ORR of 43% and a clinical benefit rate of 71%. Recognizing that the size and single arm design of this trial limits interpretation, the construct of a histone deacetylase inhibitor combined with dexamethasone and bortezomib being active in this population is nonetheless supported by these favorable results. Moreover, given that newer histone deacetylase inhibitors with a more manageable side effect profile are now in development, these results do suggest that this approach warrants further study, and results from ongoing phase 3 trials with panobinostat as well as other agents are awaited with great interest.

-Paul Richardson, MD

NON-HODGKIN LYMPHOMA

The American Cancer Society estimates that in 2013, NHL will be diagnosed in 69,740 individuals (37,600 men and 32,140 women), and will result in 19,020 deaths.20

Lenalidomide Plus Rituximab Follicular lymphoma (FL) is the most common indolent NHL and the second most common form of NHL.49 Previously reported results showed activity of lenalidomide plus rituximab in patients with recurrent FL.50 At ICML, Martin and colleagues presented the results of a multicenter, phase 2 study (CALGB 50803; ALLIANCE) of lenalidomide plus rituximab in 66 patients with previously untreated FL. Among the 54 patients evaluable for response, the ORR was 92.6%, including 72.2% CRs and 20.4% PRs. Grade 3/4 AEs included neutropenia (20%), lymphopenia (8%), rash (8%), fatigue (6%), and leukopenia (5%). Grade â&#x2030;Ľ2 AEs included fatigue (25%), infusion reaction (17%), upper respiratory reaction (13%), nausea (8%), constipation (7%), increased ALT (7%), hyperglycemia (7%), hypophosphatemia (7%), pain (6%), oral mucositis (5%), and myalgia (5%). Febrile neutropenia occurred in 1 patient (2%).51 Perspective Although many individuals still die from FL, the life span of patients has increased dramatically over the past several years, to the point where we can

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almost consider this a chronic illness. Going forward, I think that we need to focus on novel, less toxic approaches to treating this subtype of NHL, such as the regimen of lenalidomide plus rituximab evaluated in this trial by Martin and colleagues. It is important to note that the inclusion criteria were for patients with Follicular Lymphoma International Prognostic Index (FLIPI) scores of 0 to 2. Therefore, this was a low-risk group of patients and the question arises whether they even needed treatment. There are other studies looking at lenalidomide plus rituximab in patients who have higher tumor burden and higher FLIPI scores. With that being said, the high CR rate seen with this combination was very impressive for a nonchemotherapeutic regimen.

-Stephanie A. Gregory, MD

Ibrutinib Plus Bendamustine-Rituximab Mantle cell lymphoma (MCL) is an aggressive type of B-cell NHL that usually occurs in older adults.52 In the United States, approximately 5000 new cases of MCL are diagnosed each year; this subtype accounts for approximately 6% to 8% of NHL diagnoses. The average survival time with MCL is significantly shorter than with other types of indolent lymphomas.53 Currently, bortezomib is FDA approved as treatment for patients with MCL who have received at least 1 prior therapy, and lenalidomide is approved for patients whose disease has relapsed or progressed after 2 prior therapies, one of which included bortezomib. Ibrutinib is an investigational, oral Brutonâ&#x20AC;&#x2122;s tyrosine kinase (BTK) inhibitor that has previously demonstrated promising singleagent activity in a phase 2 study in relapsed or refractory MCL: 68% ORR, including 22% CRs.54 In addition, ibrutinib was combined with bendamustine and rituximab in a phase 1 study in relapsed or refractory NHL and results indicated that ibrutinib enhanced the activity of bendamustine-rituximab: in 5 evaluable patients, the ORR was 100%, including 80% CRs.55 At ICML, Dreyling and colleagues described a phase 3 double-blind, placebo-controlled study (SHINE) of ibrutinib in combination with bendamustine-rituximab versus bendamustine-rituximab without ibrutinib that began enrolling patients in the first quarter of 2013. At approximately 200 sites globally, the investigators aim to enroll 520 patients 65 years of age or older who are ineligible for high-dose chemotherapy. Key exclusion criteria include diagnosis or treatment for malignancy other than MCL, requirement for treatment with warfarin or equivalent vitamin K antagonists, and treatment with strong CYP3A4/5 inhibitors. All patients will receive bendamustine-rituximab therapy for 6 cycles; those patients achieving a CR or PR will receive rituximab maintenance for 2 years. In addition to bendamustine-rituximab and rituximab, all patients will receive an oral daily dose of 560 mg ibrutinib or placebo concomitant with the chemotherapy and ongoing as a single agent until disease progression or unacceptable toxicity. The primary objective is to evaluate if the addition of ibrutinib to bendamustine-rituximab will result in prolongation of PFS, with secondary objectives of evaluation of OS, ORR, CR, duration of response, and safety.56 Perspective The regimen being evaluated by Dreyling and colleagues in the SHINE study is a very novel approach to treating newly diagnosed MCL. We already know that bendamustine plus rituximab produces very high ORR and CR rates in patients with MCL who are not eligible for transplant. We also know that rituximab maintenance prolongs OS in these individuals. The addition of the novel BTK inhibitor ibrutinib, which appears to be a promising strategy, will hopefully lead to even better patient outcomes, and we are anxiously awaiting PFS and OS results from this trial.

-Stephanie A. Gregory, MD

Brentuximab Vedotin Brentuximab vedotin is a CD30-targeted antibody-drug conjugate that is FDA approved for the treatment of HL and for the treatment of systemic anaplastic large cell lymphoma (ALCL). The most common initial treatment for mature T-cell lymphomas is CHOP, a combination of the drugs cyclophosphamide, doxorubicin, vincristine, and prednisone. At ICML, Oâ&#x20AC;&#x2122;Connor and colleagues described a randomized, double-blind, placebo-controlled, multicenter, global phase 3 study (ECHELON-2) comparing CHOP versus the

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FACULTY PERSPECTIVES combination of brentuximab vedotin and CHP (cyclophosphamide, doxorubicin, and prednisone) in the frontline treatment of patients with CD30+ mature T-cell lymphomas that began enrolling patients in early 2013. The investigators aim to randomize approximately 300 patients 1:1 to receive either brentuximab vedotin and CHP or CHOP for 6 to 8 cycles. Randomization will be stratified by anaplastic lymphoma kinase (ALK)+ sALCL versus other histologic subtypes and International Prognostic Index score (0-1, 2-3, or 4-5).

The target proportion of patients with a diagnosis of systemic ALCL (sALCL) will be 75%. The primary objective is PFS; secondary objectives include safety, OS, and CR. After completion of treatment, patients will be followed for disease progression, medical resource utilization, quality of life, and survival.

Post-treatment stem cell transplant is permitted.57 Perspective CHOP is not the treatment of choice for any T-cell lymphomas with the exception of anaplastic ALK+ T-cell lymphomas. O’Connor and colleagues’s approach of substituting brentuximab for vincristine, thereby creating a novel CHOP-like regimen, is exciting. Although the toxicity profile of brentuximab is typically very good, neurotoxicity can be an issue, which is why the cohort of patients who received this agent did not receive vincristine as part of their treatment. We are hopeful that the results of this trial will provide us with a new, more effective strategy for this hard-to-treat patient population with CD30+ T-cell lymphomas.

-Stephanie A. Gregory, MD

HODGKIN LYMPHOMA

The American Cancer Society estimates that this year, HL will be diagnosed in approximately 9290 individuals (5070 men and 4220 women), and will result in 1180 deaths.20

BEACOPP, which is a very aggressive regimen, is typically used to treat patients with high-risk advanced-stage HL. ABVD vs BEACOPP An intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), has been advocated as the new standard of treatment for advanced HL, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). In 2011, Viviani and colleagues conducted a study in which 331 patients with previously untreated and unfavorable HL received either BEACOPP or ABVD. They found that treatment with BEACOPP resulted in better initial tumor control than ABVD, but the long-term clinical outcome did not differ significantly between the 2 regimens, and severe AEs occurred more frequently in the BEACOPP group than in the ABVD group.58 Given the higher treatment-related morbidity, whether or not BEACOPP should be given to low-risk patients has been a matter of debate. At ICML, Mounier and colleagues presented final results from the LYSA H34 study, which compared 8 cycles of ABVD (n=80) with 4 escalated cycles of BEACOPP (n=70) in 150 patients with low-risk (Interntaional Prognostic Index score of 0-2) HL. They found that 85% of patients receiving ABVD and 90% of patients receiving BEACOPP achieved a CR. Relapses occurred more frequently in the ABVD group (14 in the ABVD group vs 3 patients in the BEACOPP group). Second malignancies occurred in 5 ABVD patients and 1 BEACOPP patient. With a median follow-up of 5.5 years, 7 patients died: 6 in the group receiving ABVD and 1 in the group receiving BEACOPP. Five-year survival outcomes are shown in Table 4.59 Perspective BEACOPP, which is a very aggressive regimen, is typically used to treat patients with high-risk advanced-stage HL. In the LYSA H34 study, the investigators chose to compare the safety and efficacy of this regimen with ABVD (the standard of care in the US) for low-risk advanced-stage patients.

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Table 4. Outcomes at 5 Years: ABVD vs BEACOPP59 ABVD Group (n=80)

BEACOPP Group (n=70)

Hazard Ratio

P Value

62%

77%

0.6

.07

EFS PFS

75%

93%

0.3

.007

OS

92%

99%

0.18

.06

ABVD indicates doxorubicin, bleomycin, vinblastine, and dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; EFS, eventfree survival; OS, overall survival; PFS, progression-free survival.

It is interesting that the results showed higher response rates and lower relapse rates with BEACOPP compared with ABVD. I do question the increased incidence of secondary malignancies reported with ABVD over BEACOPP. This is unusual, as these events are rarely reported with the use of ABVD. The OS rates at 5 years were not significantly different between the 2 regimens in this trial, so given the higher toxicity associated with BEACOPP in general, ABVD is still the treatment of choice for low-risk advanced-stage patients in the US. -Stephanie A. Gregory, MD

Brentuximab Vedotin In 2011, the FDA granted accelerated approval to brentuximab vedotin (a CD30-targeted antibody-drug conjugate) for the treatment of (1) patients with HL after failure of ASCT or after failure of ≥2 prior multiagent chemotherapy regimens in patients who are not candidates for ASCT, and (2) patients with sALCL after failure of ≥1 prior multiagent chemotherapy regimen.

At ICML, Radford and colleagues presented results from a post hoc analysis comparing PFS achieved with brentuximab vedotin versus PFS achieved with the last prior therapy for each of these patient populations in 2 phase 2 studies (SGN35-003 and SGN35-004). SGN35-003 enrolled 102 patients (median age, 31 years [range, 15-77]; median 3.5 prior therapies [range, 1-13]. At the data cut-off (median follow-up 27 months), 62% of patients achieved longer durations of PFS with brentuximab vedotin than with their most recent prior therapy. SGN35-004 enrolled 58 patients (median age, 52 years [range, 1476]; median 2 prior therapies [range, 1-6]. At the data cut-off (median follow-up 22 months), 66% of patients achieved longer PFS with brentuximab vedotin than with their most recent prior therapy.60 Perspective In the study by Radford and colleagues, single-agent brentuximab was shown to be effective in patients with relapsed HL who were either transplant-ineligible or who had relapsed after transplant, as well as in patients with sALCL. I think the results of this study were interesting and this is a novel approach to treatment in 2 rather unusual patient situations.

-Stephanie A. Gregory, MD

CONCLUSIONS

In the arena of MF, long-term treatment with ruxolitinib is well tolerated and provides rapid, sustained reductions in splenomegaly, may stabilize or reverse bone marrow fibrosis, and may provide a survival advantage compared with best available therapy. SAR302503 also shows promise in the treatment of MF, with response rates at the end of 6 cycles as high as 60%. In CLL, idelalisib has shown activity both as a single agent and in combination with rituximab. Chemoimmunotherapy with obinutuzumab/chlorambucil or with rituximab/chlorambucil significantly prolongs PFS versus chlorambucil alone, and the combination of high-dose methylprednisolone plus ofatumumab is an effective, tolerable, nonmyelosuppressive treatment regimen. For patients with MDS, lenalidomide plus erythropoietin yielded a significantly better erythroid response than lenalidomide alone in lower-risk MDS patients with anemia resistant to ESA treatment alone; intermittent dosing of rigosertib is well tolerated and active in producing transfusion independence in approximately 50% of transfusion-dependent, lower-risk MDS patients. Other promising therapies for MDS include mocetinostat, decitabine followed by azacitidine, and SGI-

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CONTINUING EDUCATION 110. In MM, a number of novel combination regimens are showing activity, including MLN9708-lenalidomide-dexamethasone, carfilzomib-lenalidomidedexamethasone, elotuzumab-lenalidomide-dexamethasone, and bortezomib-panobinostat-dexamethasone. In the NHL arena, combinations including lenalidomide-rituximab, ibrutinib-bendamustine-rituximab, and brentuximab vedotin in combination with CHP are under investigation. In HL, results suggest that both ABVD and BEACOPP are effective in prolonging survival, but more progressions/relapses were observed with ABVD than with BEACOPP. In addition, in heavily pretreated patients with HL, treatment with brentuximab vedotin was associated with a longer duration of remission than that achieved with the last prior therapy in more than 60% of patients.

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24. Fung-Leung WP. Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signaling and function. Cell Signal. 2011;23(4):603-608.

25. Brown JR, Furman RR, Flinn I, et al. Final results of a phase I study of idelalisib (GS-1101) a selective inhibitor of PI3Kδ, in patients with relapsed or refractory CLL. J Clin Oncol.

2013;31(suppl). Abstract 7003.

26. O’Brien SM, Lamanna N, Kipps TJ, et al. A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor idelalisib (GS-1101) in combination with rituximab

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(R) in treatment-naive patients (pts) ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). J Clin Oncol. 2013;31(suppl). Abstract 7005.

27. Goede V, Fischer K, Humphrey K, et al. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): Final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol. 2013;31(suppl). Abstract 7004.

28. Castro JE, Choi MY, Carvajal T, et al. Ofatumumab in combination with high-dose methylprednisolone for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2013;31(suppl). Abstract 7124.

29. National Cancer Institute. Myelodysplastic Syndromes Treatment (PDQ®). http://www. cancer.gov/cancertopics/pdq/treatment/myelodysplastic/HealthProfessional/ Accessed July 30, 2013.

30. Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1–risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008;111(1):86-93.

31. Ebert BL, Galili N, Tamayo P, et al. An erythroid differentiation signature predicts response to lenalidomide in myelodysplastic syndrome. PLoS Med. 2008;5(2):e35.

32. Toma A, Chevret S, Kosmider O, et al. A randomized study of lenalidomide (LEN) with or without EPO in RBC transfusion dependent (TD) IPSS low and int-1 (lower risk) myelodysplastic syndromes (MDS) without del 5q resistant to EPO. J Clin Oncol. 2013;31(suppl).

Abstract 7002.

33. Toma A, Chevret S, Kosmider O, et al. A randomized study of lenalidomide (LEN) +/- EPO in RBC transfusion dependent (TD) IPSS low and Int-1 (lower risk) myelodysplastic syndromes (MDS) without del 5q resistant to EPO. Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract S1107.

34. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia.

Blood. 2006;108(2):419-425.

35. Borthakur G, Ahdab SE, Ravandi F, et al. Activity of decitabine in patients with myelodysplastic syndrome previously treated with azacitidine. Leuk Lymphoma. 2008;49(4):690-695.

36. Komrokji RS, Apuri S, Ali NA, et al. Evidence for selective benefit of sequential treatment with azanucleosides in patients with myelodysplastic syndromes (MDS). J Clin Oncol.

2013;31(suppl). Abstract 7113.

37. Raza A, Mukherjee S, Eisenberger A, et al. Phase II study of orally administered rigosertib (ON 01910.Na) in transfusion-dependent lower-risk myelodysplastic syndrome (MDS) patients. J Clin Oncol. 2013;31(suppl). Abstract 7031.

38. Luger SM, O’Connell CL, Klimek V, et al. A phase II study of mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in patients with myelodysplastic syndrome (MDS) J Clin Oncol. 2013;31(suppl).

Abstract 7116.

39. O’Connell C, Tibes R, Walsh K, et al. Outcomes of intermediate or high risk myelodysplastic syndromes (MDS) patients post azacitidine and/or decitabine treatment failures with SGI-110, a novel second generation hypomethylating agent (HMA). Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P189.

40. Richardson PG, Berdeja JG, Niesvizky R, et al. Weekly oral investigational proteasome inhibitor MLN9708 plus lenalidomide-dexamethasone in elderly patients (Pts) with previously untreated multiple myeloma (MM): subset analysis of a phase 1/2 study. Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P236.

41. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120(9):1801-1809.

42. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up. J Clin Oncol. 2013;31 (suppl).

Abstract 8543.

43. Tai YT, Dillon M, Song W, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 2008;112(4):1329-1337.

44. Lonial S, Jagannath S, Moreau P, et al. Phase (Ph) I/II study of elotuzumab (Elo) plus lenalidomide/dexamethasone (Len/dex) in relapsed/refractory multiple myeloma (RR MM): Updated Ph II results and Ph I/II long-term safety. J Clin Oncol. 2013;31. (suppl).

Abstract 8542.

45. Facon T, Richardson P, Jagannath S, et al. Phase (Ph) I/II study of elotuzumab plus lenalidomide/dexamethasone (Len/Dex) in relapsed/refractory multiple myeloma (RR MM): updated ph ii results and ph I/II long term safety. Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P764.

46. Richardson PG, Schlossman RL, Alsina M, et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013 Aug 15. [Epub ahead of print].

47. Alsina M, Richardson PGG, Schlossman RL, et al. Clinical response by baseline characteristics in patients (pts) with relapsed and bortezomib (BTZ)-refractory multiple myeloma treated with panobinostat (PAN), BTZ, and dexamethasone (DEX; PANORAMA 2). J Clin Oncol. 2013;31(suppl). Abstract 8531.

48. Richardson PG, Schlossman R, Alsina M et al. Clinical response by baseline characteristics in patients with relapsed and bortezomib-refractory multiple myeloma treated with panobinostat, bortezomib, and dexamethasone (PANORAMA 2). Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P775.

49. American Cancer Society. Non-Hodgkin Lymphoma. http://www.cancer.org/acs/groups/cid/ documents/webcontent/003126-pdf.pdf. Accessed August 4, 2013.

50. Leonard J, Jung S-H, Johnson JL, et al. CALGB 50401: A randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma. J Clin Oncol. 2013;31(suppl). Abstract 8000.

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FACULTY PERSPECTIVES 51. Martin P, Jung S, Johnson J, et al. CALGB 50803(ALLIANCE): a phase 2 trial of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma. Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2013; Lugano, Switzerland. Abstract 063.

52. Cancer.Net. Lymphoma—Non-Hodgkin. http://www.cancer.net/cancer-types/lymphomanon-hodgkin/subtypes. Accessed August 5, 2013.

53. Know Cancer. Mantle Cell Lymphoma. http://www.knowcancer.com/oncology/mantlecell-lymphoma/. Accessed August 5, 2013.

54. Wang M, Rule SA, Martin P, et al. Interim results of an international, multicenter, phase 2 study of Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), in relapsed or refractory mantle cell lymphoma (MCL): durable efficacy and tolerability with longer follow-up. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 904.

55. Blum KA, Christian B, Flynn JM, et al. A phase I trial of the Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), in combination with rituximab (R) and bendamustine in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL). Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 1643.

56. Dreyling M, Gordon L, Rule S, et al. A phase 3 study of ibrutinib in combination with

bendamustine and rituximab (BR) in elderly patients with newly diagnosed mantle cell lymphoma (MCL). Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2013; Lugano, Switzerland. Abstract 137.

57. O’Connor OA, Pro B, Illidge T, et al. ECHELON-2: phase 3 trial of brentuximab vedotin and CHP versus CHOP in the frontline treatment of patients (pts) with CD30+ mature T-cell lymphomas (MTCL). Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2013; Lugano, Switzerland. Abstract 138.

58. Viviani S, Zinzani PL, Rambaldi A, et al. ABVD versus BEACOPP for Hodgkin’s lymphoma when high-dose salvage is planned. N Engl J Med. 2011;365(3):203-212.

59. Mounier N, Brice P, Bologna S, et al. ABVD (eight cycles) versus BEACOPP (4 escalated cycles to 4 baseline) in stages III-IV low risk Hodgkin lymphoma (IPS 0–2): final results of LYSA H34 trial. Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2013; Lugano, Switzerland. Abstract 127.

60. Radford J, Younes A, Pro B, et al. Progression-free survival analyses of two pivotal phase 2 studies of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma or systemic anaplastic large-cell lymphoma. Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2013; Lugano, Switzerland. Abstract 303.

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