Value-Based Cancer Care by The Lynx Group

www.ValueBasedCancer.com

Cost of Drugs and Affordability Don’t Always Jibe By Phoebe Starr

By Wayne Kuznar

n international collaborative pilot study found large differences by country in retail prices for 23 cancer drugs, with the highest retail prices in the United States and the lowest in India and South Africa. Higher prices, however, did not mean that the drugs were less affordable, according to lead investigator Daniel Goldstein, MD, Rabin Medical Center, Petach Tikvah, Israel, who presented the results at the 2016 ASCO annual meeting. When monthly drug pricing was expressed as a percentage of gross domestic product per capita at purchasing power parity (GDPcap),

ith the exception of resistance mutations, somatic alterations in circulating tumor (ct) DNA (ie, a liquid biopsy) are consistent with alterations found in tissue biopsies of patients with advanced solid tumors, said Philip C. Mack, PhD, Director of Molecular Pharmacology, University of California Davis Comprehensive Cancer Center, Sacramento, at the 2016 American Society of Clinical On-

Trials and Tribulations: Reporting Clinical Trial Results Is a Legal and Ethical Duty By Kristen Chanley usan Gubar, an ovarian cancer survivor whose life has been extended by a clinical trial, was shocked to read a recent article published online by Charles Piller on the lack of reporting of clinical trial results.1,2

cology (ASCO) annual meeting. This finding comes from the largest study to date involving a genomic analysis of blood samples from more than 15,000 patients with 50 different tumor types, and suggests that tumor DNA shed into a patient’s blood may be informative when tissue biopsy is Continued on page 32

Continued on page 10

Liquid Biopsies Show High Correlation with Tissue Biopsy for Genetic Mutations

Responding to his report with dismay and concern via her blog in the New York Times, “Living with Cancer: A Broken Covenant with Patients,” Ms Gubar said, “My first response was to ask: Is he a reputable journalist? Is the online Continued on page 34

New Oncology Care Model Focuses on Payment Reform and Value-Based Care By Jessica Miller

Diana K. Verrilli, MS

new payment and delivery model introduced by the Center for Medicare & Medicaid Innovation aims to align financial incentives to improve oncology care and outcomes. Ex-

Continued on page 15

INSIDE MULTIPLE MYELOMA . . . . . . . . . . . 11 Daratumumab extends progression-free survival EMPLOYERS’ PERSPECTIVE . . . . . 12 Patient and employer perspectives in cancer care HEALTH POLICY . . . . . . . . . . . . . . . . Proposed reductions to Medicare drug payments

IN THE LITERATURE . . . . . . . . . . . . . 21 3 new AML subtypes uncovered Risk-based lung cancer CT screening could save lives

pected to begin in July 2016, the program will target patients from the start of their chemotherapy through 6 months of care. Practices that are participating in the program will be required to:

GENITOURINARY CANCERS . . . . . . Adjuvant chemoradiotherapy for bladder cancer

PATIENT ADVOCACY . . . . . . . . . . . . FDA advisors reject new drug and value of hope PANCREATIC CANCER . . . . . . . . . . New soft-tissue tumor therapy PERSONALIZED MEDICINE . . . . . . New biomarker improves diagnostic accuracy CLINICAL TRIALS . . . . . . . . . . . . . . . RAF inhibitor active in multiple tumor types COLORECTAL CANCER . . . . . . . . . . Stool DNA test performs well

28 30 32 34 36

DRUG UPDATE . . . . . . . . . . . . . . . . . 37 Defitelio for patients with hepatic VOD

EDITORIAL BOARD SECTION EDITORS EDITOR-IN-CHIEF Burt Zweigenhaft, BS Managing Director, BioPharma Partners, LLC, President, National Association Specialty Pharmacy, Co-Chairman, Association Value, Based Cancer Care, Chairman, CureVax, LLC

BIG DATA & HEALTH INFORMATION EXCHANGE Bruce S. Pyenson, FSA, MAAA Principal & Healthcare Consultant Milliman, Inc. New York, NY

CLINICAL EVIDENCE, GUIDELINES, & VALUE William McGivney, PhD Managing Partner McGivney Global Advisors Philadelphia, PA

EMERGING THERAPIES Ray Tancredi, RPh, MBA, CSP Divisional Vice President Specialty Pharmacy Development Walgreens Boots Alliance Deerfield, IL

HEMATOLOGY & ONCOLOGY COMMUNITY PRACTICE John D. Sprandio, MD, FACP Chief Physician, Consultants in Medical Oncology and Hematology Chairman, Oncology Management Services Drexel Hill, PA

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

EMPLOYERS

PATIENT ADVOCACY

SPECIALTY PHARMACY

F. Randy Vogenberg, PhD, RPh, FASHP Partner, National Institute of Collaborative Healthcare, and Access Market Intelligence Greenville, SC

Robert Goldberg, PhD President and Co-Founder Center for Medicine in the Public Interest Springfield, NJ

Eric Sredzinski, PharmD, AAHIVP EVP Clinical and Quality Assurance Avella Specialty Pharmacy Phoenix, AZ

GOVERNMENT & POLICY

PERSONALIZED MEDICINE

SURVIVORSHIP

Jayson Slotnik, JD, MPH Partner Health Policy Strategies, Inc. Bethesda, MD

Sanjiv S. Agarwala, MD Professor of Medicine Chief, Oncology & Hematology St. Luke’s University Hospital and Temple University Philadelphia, PA

Julie Silver, MD Associate Professor and Associate Chair for Strategic Initiatives Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA

EDITORS-AT-LARGE 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 Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute New York, NY

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

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

Linda D. Bosserman, MD, FACP Clinical Assistant Professor Medical Oncology and Hematology City of Hope Medical Group Rancho Cucamonga, CA

Philip E. Johnson, MS, RPh, FASHP Pharmacy, Oncology, Healthcare, and School Health Consulting Tampa, FL

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN

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

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

Barbara L. McAneny, MD Chief Executive Officer New Mexico Oncology Hematology Consultants, Ltd Albuquerque, NM

Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX

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

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

Lee Newcomer, MD, MHA UnitedHealthcare Group Minnetonka, MN

Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA

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

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

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

G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA

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

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

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

ENGAGE

IN THIS ISSUE

HEALTHCARE COMMUNICATIONS, LLC

VALUE IN ONCOLOGY

PATIENT ADVOCACY

Cost of drugs and affordability don’t always jibe More…

DA advisors reject new drug and value of F hope

FDA NEWS

MULTIPLE MYELOMA Daratumumab extends progression-free survival

EMPLOYERS’ PERSPECTIVE atient and employer perspectives in drug P therapy decision-making

HEALTH POLICY DA streamlines expanded access application F process

Market competition increases for biosimilars

PALLIATIVE CARE

PANCREATIC CANCER urvival benefit with new soft-tissue tumor S therapy

Importance of reporting clinical trial results

Production Manager Cara Nicolini

Senior Vice President/Group Publisher John W. Hennessy jhennessy2@the-lynx-group.com Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com

COLORECTAL CANCER tool DNA test performs well in communityS based setting

Vice President, Finance Andrea Kelly Senior Financial Assistant Audrey LaBolle Director, Human Resources Jennine Leale Medical Director Julie Strain

GENITOURINARY CANCERS More…

Editorial Assistant Cara Guglielmon

Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com

More… djuvant chemoradiotherapy for bladder A cancer

Associate Editor Lara J. Lorton

President/CEO Brian Tyburski

IN THE LITERATURE More…

Managing Editor Kelsey Moroz kmoroz@the-lynx-group.com

Liquid biopsies comparable to tissue biopsy

More… isk-based lung cancer CT screening could R save lives

Senior Editorial Director Dalia Buffery dbuffery@the-lynx-group.com

PERSONALIZED MEDICINE

CLINICAL TRIALS

Palliative care requires a team approach

Publisher Cristopher Pires cpires@the-lynx-group.com

Senior Associate Editor Lilly Ostrovsky

More…

Senior Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com

DRUG UPDATE

Director, Strategy & Program Development John Welz

efitelio approved for patients with hepatic D veno-occlusive disease

Editorial Director Susan Berry Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 11 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2016 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 ValueBased 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

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Director, Production & Manufacturing Alaina Pede President Abigail Adair Account Group Supervisor Karie Gubbins Account Supervisors Alex Charles Deanna Martinez Senior Account Executive Jeremy Shannon Meg Spencer Business Development Advisor Saher Almaita

ASSOCIATION & CONGRESS DIVISION Association Director Patrice Melluso Meeting & Event Planner Linda Mezzacappa Senior Account Executive George Fuller Project Manager Rachael Baranoski Senior Project Coordinator Gretchen Dann Project Administrator Sara Mohamed

Director, Creative & Design Robyn Jacobs Design Managers Chris Alpino Lora LaRocca Director, Digital Marketing Samantha Weissman Digital Content Manager Anthony Trevean Digital Editor John Parkinson Digital Media Specialist Charles Easton IV Jr Digital Content Manager Walford Guillaume Junior Digital Developer Christina Bethencourt Executive Administrative Assistant/Office Manager Dana Rivera Administrative Assistant Colette Puhalski IT Manager Kashif Javaid Office Coordinator Robert Sorensen

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.

VALUE IN ONCOLOGY

Cost of Drugs and Affordability Don’t Always... cancer drugs appeared to be less affordable in low-income countries despite the lower retail prices. Although the study is informative, the authors were not able to obtain discount prices from the drug manufacturers to factor into their computations. “The study provides a glimpse into prices and affordability of cancer drugs around the world and sets the stage for further research. However, the implications of our findings are limited, because we were not able to take discounts and rebates into account, which would better predict affordability,” said Dr Goldstein. “Until now it hasn’t been clear what the magnitude of difference in prices is, or how prices in each country relate to affordability. The differences in prices are not proportional to ability to pay,” he noted. Of the 23 cancer drugs, 15 were generic and 8 were proprietary drugs. These drugs are used to treat a range of cancer types and stages. The 6 countries analyzed were Australia, China, India,

“We need open access to discount prices and transparency—which we did not have. This study raises significant questions, and shows us that knowing the price of drugs is not all we need to know to determine value. Some drugs save lives, while others benefit patients for weeks.” —Daniel Goldstein, MD

South Africa, the United Kingdom, and the United States (Table). The United States had the highest prices for drugs—generic and patented—as well as the highest affordability per capita. Of note, drugs in Australia cost only 50% as much as in the United States, but affordability was second to the United States. China had the third highest cost of drugs, but affordability fell in the middle range, whereas India and South Africa had the lowest drug prices. India had the lowest affordabili-

Table M onthly Cost of 15 Generic and 8 Proprietary Cancer Drugs by Country Australia

China

India

South Africa

United Kingdom

United States

Median generic monthly price, $a

228

532

159

120

458

654

Median patented monthly price, $a

2741

3173

1515

1708

2587

8694

46,550

13,324

5808

13,094

39,826

54,370

Median generic monthly price, %b

Median patented monthly price, %b

288

313

157

192

GDPcap, $a

US dollars. Percentage of gross domestic product per capita at purchasing power parity (GDPcap). Source: Goldstein D, et al. J Clin Oncol. 2016;suppl; abstr LBA6500. a

Continued from the cover

at a glance he United States had the T highest retail prices for 23 cancer drugs as well as the highest affordability per capita ancer drugs were less C affordable in low-income countries despite lower retail prices he 6 countries analyzed were T Australia, China, India, South Africa, the United Kingdom, and the United States

“The concept of affordability is novel and adds another dimension to the discussion of the price of drugs, the value of drugs, and whether they are affordable.” —Patricia Ganz, MD

ty, whereas South Africa’s affordability was on par with China’s. Prices were low-to-middle for the United Kingdom, but affordability was the third highest. The study did not take into account the health insurance systems in the dif-

ferent countries. Depending on the insurance system, the patient may have to bear some or all of the cost of the drugs. “We need open access to discount prices and transparency—which we did not have. This study raises significant questions, and shows us that knowing the price of drugs is not all we need to know to determine value. Some drugs save lives, while others benefit patients for weeks,” Dr Goldstein said. “This is an interesting international comparative study. The concept of affordability is novel and adds another dimension to the discussion of the price of drugs, the value of drugs, and whether they are affordable,” said Patricia Ganz, MD, Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, who commented on the study. “The prices of drugs are putting a significant burden on the healthcare system and on patients. More needs to be done to make treatments more affordable and accessible for all patients,” Dr Ganz said. s

Opportunities for Shared Decision-Making in Clinical Practice By Chase Doyle

he National Academy of Medicine recommends a shared decision-making approach when discussing medical treatments; however, an overview of evidence presented by Terrance Lynn Albrecht, PhD, Associate Center Director, Population Sciences, Karmanos Cancer Institute, and Chief of Oncology, Wayne State University School of Medicine, Detroit, at the 2016 American Society of Clinical Oncology annual meeting suggests that clinicians

are not very effective in following this recommendation. Shared decision-making requires equal investment by the patient and the oncologist. Communication about the reasons, values, and preferences for different treatment options is needed between the 2 parties, Dr Albrecht said. “Doctors should be pragmatic about what shared decision-making means before and after the decision is made,” she said.

Dr Albrecht summarized the 4 basic steps to collective decision-making: 1. Outline treatment options for a patient to consider, which should include no treatment or stopping treatment. This is especially important for patients looking for end-of-life options 2. Describe the probabilities of the benefits and risks for each option 3. Elicit and help patients express their questions, thoughts, opinions, concerns, and expectations about treatment options, benefits, and side effects.

Although it takes a lot of time, this is what the formal process involves 4. Share responsibility for decisions, and assess each partner’s preferred roles in the partnership. Pragmatic Approaches to Sharing Treatment Decisions

Most patients say they want to share in the decision-making with their doctors, said Dr Albrecht, but it depends on how you ask the question. Thus, it is important for doctors to

Continued on page 11

MULTIPLE MYELOMA

Adding Daratumumab to the Treatment Regimen Improves Progression-Free Survival in Patients with Multiple Myeloma By Jessica Miller

aratumumab in combination with lenalidomide and dexamethasone achieved a 63% reduction in progression-free survival (PFS) compared with lenalidomide and dexamethasone alone in patients with multiple myeloma who had received at least 1 previous line of therapy, according to study results presented at the 2016 European Hematology Association Annual Congress meeting. The open-label, phase 3 POLLUX study randomized 569 patients (median age, 65 years) to treatment with daratumumab in combination with lenalidomide and dexamethasone (ie, the treatment group) or to treatment with lenalidomide and dexamethasone alone (ie, the control group). All patients received 25 mg of lenalidomide daily for the first 21 days of the 28-day cycle and 4 mg of dexamethasone weekly. The patients in the treatment group also received daratumumab 16 mg/kg once weekly during treatment cycles 1 and 2; every 2 weeks during treatment cycles 3 to

6; and once on the first day of treatment cycles 7 and onward. The treatment was continued until disease progression, unacceptable toxicity, or patient withdrawal. The patients received previous treatment with proteasome inhibitors

overall response rate compared with the control group (93% vs 76%, respectively; P <.0001). The time to progression in the treatment group was also significantly delayed compared with the control group (P <.0001). In addition, the rates of complete re-

Daratumumab combined with lenalidomide and dexamethasone could potentially represent a new standard of care for patients with multiple myeloma who have received at least 1 previous therapy. (86%); immunomodulatory agents (55%); or a proteasome inhibitor and immunomodulatory agents (44%), with 27% of all patients refractory to their last line of previous therapy. At a median follow-up of 13.5 months, the treatment group had a significantly improved median PFS (63%) and a significantly increased

sponses or better and very good partial responses or better were doubled in the treatment group (43% vs 19%, respectively; P <.0001 and 76% vs 44%, respectively; P <.0001). The trial was unblinded after meeting its primary end point of improved PFS. After recommendations from an independent data monitoring com-

mittee, the patients in the control group were offered the option to receive daratumumab after confirmed disease progression. The most common adverse events were neutropenia, diarrhea, fatigue, upper respiratory tract infection, anemia, constipation, cough, thrombocytopenia, and muscle spasms. The most common grade 3/4 treatment adverse events were neutropenia, thrombocytopenia, and anemia. The rates of discontinuation as a result of adverse events were similar for the treatment and control groups (7% and 8%, respectively). The safety of daratumumab in combination with lenalidomide and dexamethasone was consistent with the safety profile of daratumumab alone and the safety profiles of each drug. The investigators concluded that daratumumab combined with lenalidomide and dexamethasone could potentially represent a new standard of care for patients with multiple myeloma who have received at least 1 previous line of therapy. s

VALUE IN ONCOLOGY

Opportunities for Shared Decision-Making... emphasize a therapeutic alliance with their patients early in the relationship. “You need to signal to your patient upfront that your relationship is a partnership. Let them know that their values are important and need to be a part of the discussion,” Dr Albrecht advised. “Also, don’t just focus on the decision itself, but on patients’ preference for the outcomes they want to see happen,” she added. According to Dr Albrecht, the second pragmatic issue is that perceptions matter. After the decision is made, doctors and patients do not necessarily agree that shared decision-making has occurred, even though they have gone into the process with that in mind. “Doctors and patients often need to have a sense of personal control, which is about feeling heard and feeling a sense of influence over the course of the discussion,” said Dr Albrecht, who stressed

that acknowledging the roles each party will play is an important step in strengthening the alliance.

“You need to signal to your patient upfront that your relationship is a partnership. Let them know that their values are important and need to be a part of the discussion.” —Terrance Lynn Albrecht, PhD

In addition, because uncertainty is inherent in the estimated benefits and risks, shared decisions based on patient values are essential. “Risks and benefits are never so easily

Continued from page 10

portrayed, particularly for individual patients,” she said. “They vary by type, probability, degree, timing, and frequency for each patient and need to be adapted as such.” There are also costs to be considered. With everything that happens in treatment, said Dr Albrecht, there is a tolerable price: the amount a patient is willing to pay for a positive outcome or to minimize a negative one. Finally, this approach is not without controversy. According to Dr Albrecht, critics have argued that it could lead to requests for needless, expensive, and risky procedures. Although this certainly could happen, she said, a central tenet of shared decision-making is “the ethical right of patients to make requests, to ask questions, and to express needs and concerns.” To promote trust, clinicians should address questions and requests with evidence and sensitivity to the patient’s

fears, as well as recognize the patient’s need for understanding and resources, Dr Albrecht concluded. s

EMPLOYERS’ PERSPECTIVE

Incorporating Patient and Employer Perspectives into Value-Based Cancer Therapy Decision-Making Joseph P. Fulginiti, PharmD; and Melissa S. Pavilack, PharmD Drs Fulginiti and Pavilack are Postdoctoral Fellows, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway

Currently, the majority of frameworks aim to help payers with formulary decision-making and may leave out the patient perspective when deciding value. Assessing Current Value Frameworks

In a webinar hosted by the Academy of Managed Care Pharmacy, speakers from a health policy research organization discussed the clinical factors of

Figure Key Features Incorporated into Select Value Frameworks National Comprehensive Cancer Network American Society of Clinical Oncology Memorial Sloan Kettering Cancer Center Institute for Clinical and Economic Review

Intended for patient use

Population burden

Rarity

Novelty

American Heart Association Toxicity

The consensus among the medical community is that instituting frameworks as guidance for determining the appropriateness of therapy on a case-by-

often overshadow the patient perspective, patient assessment and preference are lacking in the design of therapeutic value frameworks.

Clinical benefit/ efficacy

Addressing 2 Key Perspectives

to market is costly, so it is no surprise that pharmaceutical companies are seeking optimal pricing models that satisfy return on investment.3 However, justifying an expensive drug that can extend life by a few months has been challenging to sell to consumers and to some healthcare providers, and is a topic of much public debate.3 When a patient consents to undergo cancer treatment, a burden is placed on all major stakeholders in terms of cost and therapy management. Providers have to manage the patient’s disease and expectations, as well as work with the patient to select the most cost-effective treatment options. Payers may push back on diagnostic and treatment selections based on hospital system and outpatient setting reimbursements. With increasing research and advances in drug development, the price of innovative cancer treatments

Budget impact

The challenges in navigating these frameworks include understanding the methodology behind determining value, defining the strengths and limitations of the framework, and interpreting the results. Another challenge is defining the target audience for each framework. Currently, the majority of frameworks aim to help payers with formulary decision-making and may leave out the patient perspective when deciding value. Some frameworks that assist payers and providers in determining value claim to incorporate benefits and shortcomings that are important to patients, but it is often unclear how this information is used in the final determination of value. Other frameworks are intended to assist patients in choosing therapy, but the terminology used in these frameworks can be confusing for patients. This article discusses gaps within existing frameworks to define value from the patient and employer perspectives.

has doubled in the past decade.3 In some instances, payers are charged an annual cost of $100,000 per treatment for breakthrough cancer drugs.3 Because issues related to pricing and affordability

When a patient consents to undergo cancer treatment, a burden is placed on all major stakeholders in terms of cost and therapy management. Providers have to manage the patient’s disease and expectations, as well as work with the patient to select the most cost-effective treatment options.

Cost per qualityadjusted life-year

Challenges of National Frameworks

case fashion is a step forward.2 Cancer drug prices are often deemed “unsustainable,” and determining their fair value is a major concern among stakeholders.3 The expense of bringing a drug

Affordability

“V

alue” in healthcare has been defined as outcomes relative to cost.1 Determining the value of a healthcare benefit remains difficult and complex for many stakeholders. With the increasing cost of cancer therapies, value has become an important topic of conversation for patients, healthcare providers, self-funded plan sponsors (employers), and payers. Several national health organizations have designed value frameworks (guidelines or to determine value) to assist stakeholders in the decision-making process to ensure that high-quality care is provided.2 These organizations have developed criteria to determine which prescription drug therapy has the highest clinical value and is the most cost-effective under certain scenarios. Quantifying value for clinical assessment is a step in the right direction, but the details of each framework leave significant room for improvement in incorporating all important stakeholder perspectives, including those related to cancer.

various frameworks.4 Patient-centric metrics of frameworks were found to be excluded from current treatment guidelines, with the exception of those developed by the Institute for Clinical and Economic Review (ICER). Indirect benefits, unmet needs, and the burden of illness were other clinical factors that were found to be lacking from the framework design.4 The Figure shows some of the key factors that were included (and missing) from established value frameworks that are discussed in this article. NCCN’s Evidence Blocks

Several national organizations have designed frameworks, with variability in what factors each organization considers necessary for assigning value. For example, the National Comprehensive Cancer Network (NCCN) focuses on 5 key measures in its Evidence Blocks for the efficient interpretation of clinical treatment decision-making.5,6 Although the NCCN’s measures include assessments of efficacy, safety, affordability, quality, and consistency of evidence, there are no clear explanations for how these measurements assess disease-specific data.5,6 The NCCN panel experts incorporate clinical experience and knowledge of the landscape to rank each category on a scale from 1 to 5.7 However, the individual rankings and the methods used to reach consensus are not disclosed. The NCCN characterizes the criteria for scores in qualitative measures, which can be difficult for patients to understand. For example, in terms of characterizing affordability, a score of 4 is classified as “inexpensive” and a 3 is classified as “moderately expensive.” 7 These classifications are difficult to assess, because coverage and out-of-pocket expenses may vary widely based on individual insurance. In addition, the Evidence Blocks do not evaluate novel mechanisms of action of therapies or the current burden of disease. Although the NCCN’s Evidence Blocks system is visually appealing and intuitive at face value for patients to understand, it is still lacking in practicality. Navigating the specifics and applying the Evidence Blocks can be confusing and overwhelming for patients individually. For example, multiple treatment regimens are listed for each cancer type, and Evidence Blocks Continued on page 14

EMPLOYERS’ PERSPECTIVE

Incorporating Patient and Employer Perspectives... are listed for each therapy, with no clear-cut recommendations on how to choose one therapy over another. In addition, the size of the scale for each category is not defined, making distinguishing a therapy with an efficacy score of 3 of 5 versus a score of 4 of 5 mean very little to a patient who does not know how to quantify the difference. A patient may decide that a therapy with an affordability score of 4 of 5 and an efficacy score of 3 of 5 is a better option than a therapy with better efficacy and greater cost. Is enough information provided with the Evidence Blocks for patients to make that decision? Furthermore, limited data are available on the time providers spend explaining these frameworks and extraneous data to patients to allow for joint decision-making.7,8 ASCO’s Value Framework

The value framework developed by the American Society of Clinical Oncology (ASCO) weighs individual components to determine a drug’s value.8 For example, clinical benefit and toxicity, as well as bonus points for palliation and treatment-free survival, are calculated, with a maximum score of 130 points, allowing clinicians to differentiate between the value of multiple therapy options.8 The scores in each category are determined according to a selection of quantified data, which clarifies how scores are defined and simplifies patient and provider decision-making.

at a glance he majority of frameworks T leave out the patient perspective when deciding value of therapy here is variability in what T factors organizations consider necessary for assigning value when designing frameworks I ssues related to pricing and affordability often overshadow the patient perspective ore weight needs to be M added to the patient and employer perspectives for a complete healthcare decision vercoming disparities O in framework design will increase their utility, leading to high-quality cancer care

One unique feature of the ASCO framework is that cost is scored separately from the clinical value of a therapy, although some experts are concerned that the cost of therapy is not

Revisions to frameworks should be considered by their respective organizations to better account for the stakeholders that are most affected by them. properly scored. The National Pharmaceutical Council issued comments on ASCO’s framework, including on the proper communication of cost to patients, noting that the framework’s current inclusion of drug acquisition cost has many associated shortcomings, including not capturing additional treatment-related services (eg, diagnostics), markup pricing by hospitals and clinics, and variance of cost by site of care (ie, inpatient vs community clinics).9 Population-specific differences in treatment response are another important issue to patients who are considering individualized therapy options.9 MSKCC’s Drug Abacus

Memorial Sloan Kettering Cancer Center (MSKCC)’s Drug Abacus is a value decision tool that incorporates a drug’s efficacy, toxicity, novelty, cost of development, rarity, and population burden.10 However, there is no clear target audience. Inputting information into the tool allows the user to adjust multipliers for each factor, including the cost per quality-adjusted life-year (QALY), but doing so limits the patient friendliness of the tool, because patients would not be able to set a cost per QALY threshold or determine how high a multiplier to set for novelty, rarity, and population burden.10 ICER Value Framework

The ICER Value Assessment Framework uses all publicly available data to determine a drug’s value on the basis of its budget impact and cost per QALY. Modifications are made to account for clinical effectiveness, contextual factors, and other considerations; however, it is unclear how other benefits and disadvantages are weighted in the final budget impact calculation. Care value and health system value are determined from the previously mentioned factors,

but these values do not reflect economic benefits, such as improvements in worker productivity or reductions in caregiver burden.11 Revisions Needed to Improve Current Frameworks

Revisions to frameworks should be considered by their respective organizations to better account for the stakeholders that are most affected by them. Adding more weight to the patient and employer perspectives is necessary to properly incorporate a complete healthcare decision. This can be accomplished by readjusting scoring methods and by adding metrics to the current layouts, giving all stakeholders an outlook on treatment variables that matter most to them. Universal areas to revise include increasing the transparency of the methodologies that are used to determine each value score, creating a closer link between cost and outcomes,

Because issues related to pricing and affordability often overshadow the patient perspective, patient assessment and preference is lacking in the design of therapeutic value frameworks. and improving patients’ understanding of difficult concepts. These changes will enable value frameworks to be more patient-centered and will include the employer perspective, a stakeholder that is often overlooked in decision tools. In addition to weaknesses in methodology addressing patients’ concerns regarding the role in decision-making, the opinion of the employer is often overlooked. Employers are key stakeholders when considering the burden of illness in cancer survivors. Data from the 2000 National Health Interview Survey, which was administered by the US Census Bureau, revealed that cancer survivors experienced increased rates of productivity loss compared with people without cancer when controlled for age, sex, and education.12 There were 5 statistically significant measures of productivity loss in the study, including the percent of people working in the past 12 months, the percent unable to work as a result of health problems, the percent limited

Continued from page 12

in the amount or type of work they performed because of health problems, and the mean (reported and modified) number of days lost from work in the past 12 months. The study demonstrates the burden of illness of patients with cancer relevant to lost productivity that impacts employers and is not currently addressed in any of the existing frameworks.12 Conclusion

Because drug pricing in cancer therapy has been an intensely scrutinized issue, there is an increased focus on new value assessment tools. Healthcare organizations will face several challenges when creating future versions of value frameworks to better incorporate patient and employer perspectives. Although limited, this review could jump-start efforts to improve value frameworks, as well as increase their use and effectiveness in the marketplace. Because frameworks are still being instituted in common clinical practice, resolving their disparities will increase their utility and move closer to achieving value-based decision-making and high-quality cancer care. s

References

1. Porter ME. What is value in health care? N Engl J Med. 2010;363:2477-2481. 2. Neumann PJ, Cohen JT. Measuring the value of prescription drugs. N Engl J Med. 2015;373:2595-2597. 3. Experts in Chronic Myeloid Leukemia. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood. 2013;121:4439-4442. 4. Fazio L, Drummond MF, Dubois RW. Developing and using value frameworks: part I & II. Webinar; December 16, 2015. www.amcp.org/Newsletter.aspx?id= 20457. Accessed June 27, 2016. 5. National Comprehensive Cancer Network. NCCN unveils Evidence Blocks for CML and multiple myeloma. Press release; October 16, 2015. www.nccn.org/ about/news/newsinfo.aspx?NewsID=546. Accessed March 1, 2016. 6. Goldberg R. The NCCN new tool to assess value discourages patients’ hope. Value-Based Cancer Care. 2015;6(10):7. 7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) with NCCN Evidence Blocks. www.nccn. org/evidenceblocks/. Accessed June 27, 2016. 8. Schnipper LE, Davidson NE, Wollins DS, et al. American Society of Clinical Oncology statement: a conceptual framework to assess the value of cancer treatment options. J Clin Oncol. 2015;33:2563-2577. 9. Dubois RW. NPC comments on ASCO framework. National Pharmaceutical Council; August 21, 2015. www.npcnow.org/commentary/npc-comments-ascoframework. Accessed June 27, 2016. 10. Memorial Sloan Kettering Cancer Center. Evidence driven drug pricing project. www.drugabacus.org/. Accessed March 15, 2016. 11. Institute for Clinical and Economic Review. Evaluating the value of new drugs and devices. Webinar presented by Steven Pearson, September 15, 2015. www. icer-review.org/wp-content/uploads/2014/01/Slides-onvalue-framework-for-national-webinar1.pdf. Accessed March 15, 2016. 12. Yabroff KR, Lawrence WF, Clauser S, et al. Burden of illness in cancer survivors: findings from a population-based national sample. J Natl Cancer Inst. 2004; 96:1322-1330.

HEALTH POLICY

New Oncology Care Model Focuses on Payment... • Provide patient navigation • Document a care plan • Have a clinician with access to current medical records available to patients 24 hours a day, 7 days a week • Utilize nationally recognized clinical treatment guidelines • Monitor data to improve quality • Use an electronic health record that is certified by the Office of the National Coordinator for Health Information Technology. The multipayer model will include Medicare fee for service and will use a 2-part payment approach that includes a care management payment of $160 per beneficiary per month and a performance-based payment for episodes of care. The new model will require a change in the way practices think about healthcare delivery. Patients and their family will be the center of care, with activities designed around what is most efficacious for them instead of healthcare revolving around the provider and the care facility, explained Diana K. Verrilli, MS, Vice President and General Manager, Payer & Provider Solutions, McKesson Specialty Health. In collaboration with the US Oncology Net-

“This new model…is a change not only for physicians, but the entire spectrum of how we deliver outpatient care, from proactive nursing calls and education of patients to how the back office bills visits to quality and —Diana K. Verrilli, MS performance improvement.”

work, McKesson Specialty Health sponsored a project to design and pilot the needed care delivery changes to meet the requirements of the Oncology Care Model (OCM). “This new model…is a change not only for physicians, but the entire spectrum of how we deliver outpatient care, from proactive nursing calls and education of patients to how the back office bills visits to quality and performance improvement with measure and continued redesign of care,” she said. According to Ms Verrilli, the OCM has the potential to decrease healthcare costs while improving patient-reported outcomes. “We can look at a Health Policy Brief published by the Institute of Medicine in 2012 [Ca-

“Up to 30% of [Medicare] healthcare [spending] may be wasteful, citing failures in care delivery, failure of care coordination, unhelpful overtreatment, administrative complexity, pricing failures, and fraud and abuse.”

—Diana K. Verrilli, MS

farella Lallemand N. Health Aff. December 13, 2012] that suggested up to 30% of [Medicare] healthcare [spend-

Continued from the cover

ing] may be wasteful, citing failures in care delivery, failure of care coordination, unhelpful overtreatment, administrative complexity, pricing failures, and fraud and abuse,” she said. The OCM program’s design specifically addresses a number of these areas, including care delivery and care coordination, pushing practices to focus on improving them. Success will be measured in a number of ways, according to Ms Verrilli, including chemotherapy prescribed in accordance with national standards and guidelines, patient-reported outcomes of symptoms, the total cost of care per episode, and important outcome measures, such as survival and end-of-life measures. To help practices better succeed, McKesson recently held an intensive 2-day training program for personnel from practices within the US Oncology Network that will be participating in the OCM. Using data and experiences from 3 pilot sites that tested McKesson Specialty Health’s comprehensive OCM solutions, attendees at the training program were able to learn more about what is needed to successfully transition to the OCM program. s

Proposed Reductions to Medicare Drug Payments Will Hurt Patients, Small Practices By Jessica Miller

pposition to proposed changes to the Medicare Part B payment for prescription drugs

at a glance roposed Medicare payment P rule would lower the add-on price paid to physicians from 6% to 2.5% of average sales price of drugs, plus a flat fee of $16.80 per drug daily ncology stakeholders, such O as ACS CAN, are concerned that the proposed rule will limit patient access to life-saving drugs and appropriate care he second phase of the T payment model would implement value-based pricing tools

continues to grow since the Centers for Medicare & Medicaid Services (CMS) announced its plan in March 2016. Bipartisan support from every member of the Senate Committee on Finance and more than 300 members of the House of Representatives have joined clinicians, patient advocates, and drug makers in questioning the new rule, which, CMS anticipates, will slow spending on prescription drugs. The proposed rule would lower the current add-on payment to physicians and hospital outpatient departments for prescribed drugs from the 6% average sales price to 2.5%, plus a flat fee of $16.80 per drug daily. CMS contends that under the current system, physicians are rewarded for selecting higher-cost drugs when equivalent lower-cost drugs are available. However, oncology stakeholders worry that the proposed cuts in payment will limit patient access to individualized targeted cancer treatments,

“We are concerned that, as currently proposed, the demonstration does not protect cancer patients’ access to the life-saving drugs needed to treat their disease.” —American Cancer Society Cancer Action Network

which often do not have lower-cost alternatives. “We are concerned that, as currently proposed, the demonstration does not protect cancer patients’ access to the life-saving drugs needed to treat their disease,” the American Cancer Society Cancer Action Network (ACS CAN) wrote in a letter to Sylvia Mathews Burwell, Secretary of Health & Human Services.1 The proposed

rule “focuses more on the potential for cost savings” rather than on ensuring that “the quality of care for Medicare beneficiaries is preserved or enhanced,” ACS CAN added.1 ACS CAN also fears that a significant reduction in reimbursement for some cancer drugs under the new payment system will be difficult for small practices to absorb, potentially forcing patients to seek care at larger, more expensive hospital systems. House Members Weigh In on Medicare Payment Proposal

House Republicans echoed this sentiment at the House Committee on Energy and Commerce, Subcommittee on Health hearing that was held in May 2016, where they suggested that the proposed model would disproportionately impact small and rural providers who do not have the same drug negotiating powers as larger practices. This first phase of the new payment Continued on page 16

HEALTH POLICY

FDA Streamlines Expanded Access Application for Patients to Get Investigational Drugs By Nick Bryant

he Individual Patient Expanded Access Application, which is designed to streamline the application procedure for individual patients who apply for expanded access to investigational therapeutics, including expanded access to drugs that are not in clinical trials, was recently updated by the FDA. Form FDA 3926 authorizes expanded access to investigational drugs for patients with serious or life-threatening conditions who have no therapeutic options. “Access to investigational treatments requires the active cooperation of the FDA, industry, and health care professionals in order to be successful,” said FDA Commissioner Robert Califf, MD, in a statement. “But we know that navigating that process can be challenging and time consuming, and we are com-

“Access to investigational treatments requires the active cooperation of the FDA, industry, and health care professionals in order to be successful. ”

—Robert Califf, MD

mitted to reducing the procedural burdens on physicians and patients whenever possible.” The FDA anticipates that the new application will take 45 minutes to complete, instead of the approximate 100 hours that the previous form required. Along with the new application, the FDA released step-by-step instructions detailing how to complete the applica-

Proposed Reductions to Medicare Drug...

Continued from page 15

system could take effect as early as August 2016. The second phase of the proposed rule could begin in early January 2017, and would implement value-based pricing (VBP) tools, such as eliminating patient cost-sharing, testing indication-based drug pricing, and setting reference pricing for therapeutically similar drugs. Phase 2 has similarly drawn concern from stakeholders. “As CMS considers implementing the VBP tools, we urge the agency to balance the impact of the tools with advancements in treatments based on personalized medicine, including treatments based on genetic information, and issues related to side-effects and drug-to-drug interactions,” 1 ACS CAN wrote. CMS will actively evaluate the proposed model to ensure that it is working as intended. “The criteria for a successful model will be whether it reduces net Medicare spending, without limiting coverage or benefits, while maintaining or improving patient care. CMS plans to implement a concurrent real-time claims monitoring program to track utilization, spending, and prescribing patterns as well as changes in site of service delivery, mortality,

hospital admissions, and several other high-level claims-based measures,” 2 CMS stated. Although opposition is wide, the proposal is not without endorsement. At the May hearing, Jan Schakowsky, representative from the state of Washington, highlighted the need to address high drug prices. “Every time we attempt to do anything to rein in drug costs we are met with fierce opposition. We are actively reforming every other aspect of our health care system to pay for value except pharmaceuticals,” he said.3 s References

1. US House of Representatives. American Cancer Society Cancer Action Network letter to Sylvia Mathews Burwell. http://docs.house.gov/meetings/IF/ IF14/20160517/104931/HHRG-114-IF14-20160517SD005.pdf. Accessed June 21, 2016. 2. Centers for Medicare & Medicaid Services. CMS proposes to test new Medicare Part B prescription drug models to improve quality of care and deliver better value for Medicare beneficiaries. March 8, 2016. www. cms.gov/Newsroom/MediaReleaseDatabase/Factsheets/2016-Fact-sheets-items/2016-03-08.html. Accessed June 21, 2016. 3. US House of Representatives, Energy and Commerce Subcommittee on Health. Hearing on Medicare drug experiment: the patient and doctor perspective. May 17, 2016. https://democrats-energycommerce. house.gov/sites/democrats.energycommerce. house.gov/files/Transcript-051716-HE-Hrg-Med icare%20Drug%20Experiment.pdf. Accessed June 22, 2016.

tion, as well as a final guidance document outlining when and how to request expanded access. In addition, a document explaining how drug sponsors or manufacturers can charge when investigational drugs are used indicated that they will not be able to charge for indirect costs; indirect costs include those associated with developing treatment protocol, reporting to the FDA, or corresponding with the Institutional Review Board (IRB) or the drug manufacturer.

Although the vast majority of expanded access requests are approved, the FDA is often criticized for how long it takes to move applications through the process. Over the years, the FDA has been supportive of patients receiving expanded access medications. Between 2010 and 2014, the FDA granted 5962 of 5995 requests for expanded access, which is a 99% approval rate. Although the vast majority of expanded access requests are approved, the FDA is often criticized for how long it takes to move applications through the process. Although the updated form will mitigate some of these criticisms, there are still additional FDA requirements in place that may delay or prevent patients from receiving time- sensitive treatments. Before patients can apply for expanded access, their physician must first obtain an authorization letter from the drug manufacturer. However, drug manufacturers are not required to offer expanded access to their drugs that are in clinical trials, and possible lawsuits may dissuade them from allowing access to these and other medications with a Risk Evaluation and Mitigation Strategies program. Once an application is submitted, the FDA must first determine that there is no “comparable” or “satisfactory alternative” therapy to grant expanded access. Next, the FDA mandates that a patient’s prospective administration of a medication be reviewed by an IRB to confirm that the risks posed by the medication are commensurate with its possible benefits. Last, the FDA’s expanded access

at a glance atients who apply for P expanded access to investigational therapeutics, including drugs that are not in clinical trials, must have no “comparable” or “satisfactory alternative” therapy available to them he new application will T take 45 minutes to complete; the previous form took approximately 100 hours uthorization from the A drug manufacturer must be received before submitting an application etween 2010 and 2014, the B FDA had a 99% approval rate for expanded access rug manufacturers will not D be able to charge for indirect costs when investigational drugs are used

program allows pharmaceutical manufacturers to charge patients for their drugs. The latter FDA proviso could represent a significant barrier for patients, especially if third-party payers decline to reimburse patients for experimental medications. The Individual Patient Expanded Access Application comes in the wake of several states drafting “Right to Try” guidelines, which are intended to circumvent FDA restrictions and provide terminally ill patients with access to experimental treatments. Opponents of Right to Try, including the American Society of Clinical Oncology, have posited that Right to Try exposes patients to possibly toxic drugs that have an unproven medical benefit and have the potential to hinder patient enrollment in clinical trials. Unlike Right to Try, the FDA expanded access criteria are more restrictive concerning the drugs a patient may receive, and the FDA also requires an IRB to oversee the expanded access process. Consequently, the FDA will continue to offer safer guidelines than the states’ Right to Try initiatives, but the Individual Patient Expanded Access Application will concomitantly expedite patients’ requests for experimental program. s

PALLIATIVE CARE

Palliative Care Requires a Team Approach By Wayne Kuznar If not for Dr Malekpour’s husband, a hematologist at the same hospital where her mother was being treated and who knew of the available resources, palliative care would have

3. Tertiary palliative care means referral to expert-level palliative care services when a patient’s palliative care needs go beyond regular appointments.

“Her medical team was underprepared for our needs in palliative care issues. We were never offered palliative care, or any of the other resources but chemotherapy.”

arly intervention utilizing a team approach is important to successful palliative care, agreed a multidisciplinary panel convened at the 2016 National Comprehensive Cancer Network (NCCN) annual conference. The panel offered insight into the value of palliative care in the cancer care continuum, emphasizing the importance of open, continuous dialogue. The transition from active treatment to palliative care can be challenging, because patients may misperceive palliative care as “giving up,” panel members noted, and palliative care planning is difficult to achieve in the typical time allotted to patient appointments.

—Shirin Malekpour, PhD

at a glance alliative care planning is P difficult to achieve in the typical time allotted to patient appointments o-show rates for referrals to N palliative care specialists are approximately 50% program funded by the A NCCN and Pfizer aims to increase shared decisionmaking between the patient and provider alliative care providers often P discuss the emotional and psychological symptoms their patients are experiencing n educational curriculum A around shared decisionmaking is being developed at Duke for patients receiving end-of-life care

The roundtable opened with a personal anecdote from Shirin Malekpour, PhD, Family Member Advocate, University of Wisconsin-Madison, who described her mother’s experience with palliative care after being diagnosed with stage III ovarian cancer. “Her medical team was underprepared for our needs in palliative care issues. We were never offered palliative care, or any of the other resources but chemotherapy,” Dr Malekpour said. “Here is another surgery, and so forth.”

Personal Experience with Palliative Care

“Only 15% of our patients who died within the past 2 years had documented directives.” —Sophia K. Smith, PhD, MSW

“The team approach to [palliative] care is not a substitution, it is an addition” to the care already being provided in a clinic.” —Maria Dans, MD

gone unnoticed. Through him, Dr Malekpour was able to connect with Toby C. Campbell, MD, Chief, Palliative Care program, University of Wisconsin School of Medicine and Public Health, Madison, and his team. They worked with Dr Malekpour’s family to identify her mother’s priorities and end-of-life values. Dr Campbell advised that palliative care be practiced on 3 levels: 1. Primary palliative care is the care provided by clinicians who do not often practice palliative care, such as primary care providers 2. Secondary palliative care refers to the routine circumstances involved in managing seriously ill patients; this type of palliative care is integral to everyday practice in oncology

Whereas oncologists discuss physical symptoms, palliative care providers tend to talk about emotional and psychological symptoms, which are issues that may be considered part of advance care planning, said Dr Campbell. “You can reassure yourselves that your patients will not be spending time going over the same stuff that they have already been over,” he added. “Four Conversations”

Sophia K. Smith, PhD, MSW, Department of Nursing, Duke Cancer Institute, Durham, NC, described palliative care work at her institution. Duke is developing and testing a pro-

gram called “Four Conversations.” “It is an educational curriculum around shared decision-making,” Dr Smith said. The program hopes the conversations will clarify a patient’s personal values and promote solution-focused thinking. A 2-year study of the program is being funded together by the NCCN and Pfizer. The Four Conversations program represents: 1. The patient–provider interactions 2. The patient’s discussions with his or her loved ones 3. The patient’s spiritual life 4. The patient’s discussion with self (self-care). The program provides online content and offers group-facilitated meetings led by a social worker who is trained in the curriculum. “Patients are able to get together with their peers in a confidential online format,” said Dr Smith. The program has evolved from a face-to-face format to online to make it more accessible and cost-effective. The program was developed for patients with metastatic breast cancer who are receiving end-of-life care to enhance quality of life and the relationship with the care team, including family members. Mind–body exercises and relaxation training are taught to patients, and patients are encouraged to complete advance directives. “We found that only 15% of our patients who died within the past 2 years had documented directives,” Dr Smith said. Barriers to Palliative Care

A barrier to palliative care planning is the current shortage of palliative care specialists, because clinics are only now building palliative care programs. The traditional model of referral “has not worked particularly well,” said Dr Campbell, with noshow rates of approximately 50%, making scheduling difficult. “The next move has been toward integrated, or embedded, palliative care,” which places palliative care providers with oncology providers, he said. Home-based palliative care may be the next generation of palliative care, Dr Campbell believes. “The team approach to [palliative] care is not a substitution, it is an addition” to the care already being provided in a clinic, said Maria Dans, MD, Clinical Director, Palliative Care Services, Siteman Cancer Center at Barnes-Jewish Hospital, St Louis, MO. s

IN THE LITERATURE Researchers Discover 3 New Subtypes of Acute Myeloid Leukemia

After studying the genetic makeup of acute myeloid leukemia (AML), researchers determined that this malignancy exists in at least 11 different forms, each with its own distinguishing clinical features (Papaemmanuil E, et al. N Engl J Med. 2016;374:22092221).

Using data from 1540 patients participating in 3 different prospective multicenter clinical trials for AML (AML-HD98A, AML-HD98B, and AMLSG-07-04), scientists looked at patterns between gene mutations. Patients in the AML-HD98A trial were aged 18 to 65 years, and induction chemotherapy consisted of idarubicin, cytarabine, and etoposide (ICE). High-risk patients received allogeneic

stem-cell transplantation, intermediate-risk patients received stem-cell allograft or intensive chemotherapy, and low-risk patients received intensive chemotherapy. The patients in the AML-HD98B trial were aged 58 to 84 years, whereas the patients in the AMLSG-07-04 trial were 18 to 61 years of age. Both cohorts were randomly assigned to induction therapy with ICE or ICE plus all-trans

retinoic acid, with patients in the AMLSG-07-04 trial receiving additional therapy as dictated by response. Previous research had suggested that AML could be classified into 8 subgroups, but a large number of patients with AML in the current study did not fall into any of them. When the 3 new subgroups were added to the already identified 8 subgroups, 80% of patients overall were able to be classified. Continued on page 22

IN THE LITERATURE Researchers Discover 3 New Subtypes of... Continued from page 21

The 3 newly identified subgroups included patients with AML with gene mutations that regulate RNA splicing, chromatin, or transcription (18%); AML with the TP53 mutation, complex karyotype alterations, cytogenetically visible copy-number alterations (aneuploidies), or a combination of both (13%); and AML with IDH2R172 mutations (1%).

The investigators hope that these findings will help develop more targeted, individualized treatments for patients with AML.

Risk-Based Lung Cancer CT Screening Could Prevent More Deaths

Lung cancer screening based on individualized risk could prevent more lung cancer deaths over 5 years compared

â&#x20AC;&#x153;On the policy side, there will always be a trade-off between screening efficiency and preventing as many lung cancer deaths as possible.â&#x20AC;? Michael K. Gould, MD, MS

with the current US Preventive Services Task Force (USPSTF) recommendations, according to new recommendations (Katki HA, et al. JAMA. 2016;315:2300-2311). The USPSTF currently recommends annual computed tomography (CT) lung cancer screening for current smokers (aged 55-80 years) and former smokers (aged 55-77 years) with at least 30 pack-years of smoking and no

IN THE LITERATURE more than 15 years since quitting. Researchers at the National Cancer Institute examined data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a large randomized trial to determine the effects of screening on cancer-related mortality, and developed and validated empirical risk models for lung cancer incidence and death when no CT screening is performed.

Over 5 years, an estimated 46,488 deaths from lung cancer could be avoided by using the USPSTF recommendations for lung cancer screening, whereas an estimated 55,717 deaths could be prevented by using a riskbased model, which translates to a 20% increase in screening-avertable deaths. In an accompanying editorial, Michael K. Gould, MD, MS, Department

of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, questioned who gets the final say in lung cancer screening (JAMA. 2016; 315:2279-2281). “There is a difference between clinical and policy-level decision making,” he said. “On the policy side, there will always be a trade-off between screening efficiency and preventing as many lung cancer deaths as possible. In clinical practice, the decision to

screen is very personal and should be individualized for each patient.”

ASCO Releases New Treatment Guidelines for Pancreatic Cancer

The American Society of Clinical Oncology (ASCO) issued new guidelines for the management of patients with potentially curable, locally advanced, unresectable pancreatic cancer. Continued on page 24

IN THE LITERATURE ASCO Releases New Treatment... Continued from page 23

A systematic review of the literature from January 2002 to June 2015 was undertaken by a panel that included oncology, gastroenterology, palliative care, and advocacy experts. The panel recommendations are in part based on evidence from 26 randomized controlled trials that met the in clusion criteria (Balaban EP, et al. J

Clin Oncol. 2016 May 31. Epub ahead of print). According to the new recommendations, clinicians should perform a multiphase computed tomography scan of the abdomen and pelvis using a pancreatic protocol or magnetic resonance imaging to evaluate the anatomic relationships of the primary tumor and to assess for the presence of intra- abdominal metastases.

Patients should be assessed for baseline performance status, symptom burden, and comorbidities. The goals of care and patient preferences should be discussed before establishing a multi‑ disciplinary treatment plan. Patients should also be informed of any relevant clinical trials that may be available. Preoperative therapy should be offered as an alternative treatment strategy for patients who have radiographic

findings that are suspicious for extrapancreatic disease but who have not been diagnosed; radiographic interference between the primary tumor and mesenteric vasculature; and cancer antigen 19-9 level suggestive of disseminated disease. Patients with a performance status or comorbidity that is not conducive for major abdominal surgery should also be considered for preoperative therapy. The guidelines recommend 6 months of adjuvant therapy for patients who receive preoperative therapy. The guidelines also recommend that after preoperative therapy, patients should undergo a complete restaging before surgical planning. For patients with resected pancreatic cancer who did not undergo preoperative therapy, 6 months of adjuvant chemotherapy with either gemcitabine or fluorouracil plus folinic acid should be offered and should be initiated 8 weeks after surgery. Patients with microscopically positive margins and/or node-positive disease after the completion of 4 to 6 months of systemic adjuvant chemotherapy should be offered adjuvant chemoradiation. Finally, the guidelines recommend that patients who have completed treatment should be followed every 3 to 4 months during the first 2 years, with the interval increasing to every 6 months thereafter once stability is achieved. s

By the Numbers 53,070—Estimated number of people who will be diagnosed with pancreatic cancer in 2016

41,780—Estimated deaths from pancreatic cancer in 2016

29%

—1-year survival rate for all stages of pancreatic cancer combined

≤20%

—Proportion of patients with pancreatic cancer who are candidates for surgery

7%—5-year survival rate for all stages of pancreatic cancer combined

1.2%—Annual increase in

pancreatic cancer incidence from 2000 through 2012

0.4%—Increase in

pancreatic cancer deaths since 2000

Source: American Cancer Society.

GENITOURINARY CANCERS

No Benefit from Nephrectomy in High-Risk Renal-Cell Carcinoma with Thrombus By Charles Bankhead

Survival Benefits of Surgery Unclear

Approximately 10% of patients with RCC have tumors that produce throm-

at a glance igh-risk patients with H metastatic RCC and venous tumor thrombus do not benefit from cytoreductive nephrectomy pproximately 10% of patients A with RCC have tumors that produce thrombus in the venous system, which increases the complexity of surgery It is unclear whether surgery in patients with RCC and tumor thrombus improves survival, but identifying patients with poor overall survival could help patients avoid unnecessary risks for complications

bus in the venous system. The presence of thrombus increases the complexity of and risk for surgery, but few studies have systemically evaluated the outcomes of cytoreductive nephrectomy in patients with thrombus, said Dr Abel. One multi-institutional review of nephrectomy and thrombectomy in patients with RCC showed a 90-day mortality rate of 5%. The trial included

Predicting Poor Survival Risk with Risk Models

To address the issues, Dr Abel and colleagues reviewed the data on patients with metastatic RCC and tumor thrombus who were treated at 4 different centers from 2000 to 2014. They sought to determine whether thrombus location or level and risk models could predict poor survival.

“Poor overall survival following cytoreductive nephrectomy in metastatic renal-cell carcinoma patients with tumor thrombus can be predicted. Patients who have level 3/4 thrombus and are poor risk by prognostic criteria are high-risk patients and should be considered for upfront systemic therapy in clinical trials.”

Photo by © ASCO/Todd Buchanan 2016

igh-risk patients with metastatic renal-cell carcinoma (RCC) and venous tumor thrombus derived no benefit from cytoreductive nephrectomy and should be evaluated for clinical trials of systemic therapy, suggested a retrospective multicenter review. Patients with thrombus above the diaphragm had a median overall survival of 6.8 months after surgery, which is approximately 33% of the median survival for patients with thrombus in the renal veins only or in the inferior vena cava (IVC) below the hepatic veins. In addition, patients classified as unfavorable according to M.D. Anderson criteria had a 9-month mortality rate of 63%, according to E. Jason Abel, MD, Assistant Professor of Urology, University of Wisconsin, Madison, at the 2016 Genitourinary Cancers Symposium. “Poor overall survival following cytoreductive nephrectomy in metastatic renal-cell carcinoma patients with tumor thrombus can be predicted,” said Dr Abel. “Patients who have level 3/4 thrombus and are poor risk by prognostic criteria are high-risk patients and should be considered for upfront systemic therapy in clinical trials.” Patients with IVC thrombus below the hepatic veins “probably should undergo surgery and be treated similarly to other patients undergoing cytoreductive nephrectomy,” he said.

—E. Jason Abel, MD

patients with metastatic and nonmetastatic disease and tumor thrombus at all levels (Abel EJ, et al. J Urol. 2013;190: 452-457). A recent review of 162 patients with RCC and IVC thrombus above the hepatic veins showed a 90-day mortality rate of 10% and a 34% rate of major complications. The study included patients with metastatic and nonmetastatic disease, and the surgery included cardiac bypass or intervention for hepatic ischemia in some cases (Abel EJ, et al. Eur Urol. 2014; 66:584-592). “The rationale for complex surgery in nonmetastatic renal-cell carcinoma is simple—50% of the patients are cured,” said Dr Abel. “In patients with metastatic disease, are the risks of surgery justified for patients who have limited life expectancies?” Whether surgery in patients with RCC and tumor thrombus improves survival remains unclear, Dr Abel noted. However, surgery can provide local disease control and can prevent thrombus extension, leading to hepatic or cardiac failure. Moreover, systemic alternatives have limited impact on the tumor and on disease progression. Identifying patients with metastatic RCC and venous thrombus who have poor overall survival could help patients avoid unnecessary risks for complications and morbidity while more efficiently using resources.

The risk models evaluated were from Memorial Sloan Kettering Cancer Center (MSKCC), M.D. Anderson, and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). The MSKCC and IMDC criteria were developed to stratify patients according

“The rationale for complex surgery in nonmetastatic renal-cell carcinoma is simple—50% of the patients are cured. In patients with metastatic disease, are the risks of surgery justified for patients who have limited life expectancies?” —E. Jason Abel, MD

to overall survival from systemic treatment to death. The M.D. Anderson criteria were developed specifically to determine whether patients might benefit from cytoreductive nephrectomy. Of the 293 patients investigators identified, 29 (10%) had thrombus above the diaphragm (level IV) and 45 (15%) had thrombus between the hepatic veins and the diaphragm; the remainder had thrombus below the he-

patic veins, including 39% that were primarily limited to the renal veins. Overall, the study population had a 30-day mortality rate of 6.1%; however, 35.5% of the patients died within the first year after surgery, suggesting that many patients did not benefit from surgery and leading Dr Abel to conclude that maybe patients can be selected better. Comparing thrombus location and mortality, the investigators found that patients with thrombus in the renal veins or below the hepatic veins had similar survival of approximately 19 months, but those with thrombus above the hepatic veins (level 3/4) fared significantly worse (14.5 months for thrombus between hepatic veins and diaphragm vs 6.8 months for thrombus above the diaphragm; P = .0048). An evaluation of the risk models showed that the MSKCC and IMDC criteria showed a separation in survival curves for patients with favorable, intermediate, and poor risks (P = .0027 and P = .0053, respectively). The M.D. Anderson criteria were derived from a comparison of 566 patients who underwent cytoreductive nephrectomy and 110 patients who had medical therapy only. The model is based on preoperative variables that influenced survival after surgery: serum albumin below the lower limit of normal; serum lactate dehydrogenase above the upper limit of normal; liver metastasis; metastasis-associated symptoms; retroperitoneal lymph node involvement; supradiaphragmatic nodal involvement; and clinical stage T3/4. The model demonstrated that patients with ≤3 risk factors had better survival with cytoreductive nephrectomy than medically or surgically treated patients with ≥4 risk factors (Culp SH, et al. Cancer. 2010;116:3378-3388). Applying risk criteria, thrombus location, and mortality, Dr Abel and colleagues found that patients with unfavorable M.D. Anderson risk criteria had a 25% mortality rate at 3 months and a 63% mortality rate at 9 months, and with level 4 thrombus, a 35% mortality rate at 3 months and 56% at 9 months. Using the IMDC criteria, for patients who were classified as poor risk, the 3-month and 9-month mortality rates were 17% and 50%, respectively. Using MSKCC risk grouping, poor-risk patients had 3-month and 9-month mortality rates of 18% and 49%, respectively, and for patients with level 3 thrombus, the rates were 21% and 41%, respectively. s

GENITOURINARY CANCERS

Adjuvant Chemoradiotherapy May Provide Benefit in Locally Advanced Bladder Cancer By Phoebe Starr

n the United States, the standard of care for locally advanced bladder cancer after radical cystectomy is to “consider” adjuvant chemotherapy and adjuvant radiation. Results of a 3-arm randomized clinical trial showed that adjuvant radiation therapy alone or combined with chemotherapy (ie, chemoradiotherapy) did not significantly improve disease-free survival compared with adjuvant chemotherapy alone. However, the findings hint at benefits for chemoradiotherapy that should be studied further. Brian Baumann, MD, a radiation oncology resident at the University of Pennsylvania, Philadelphia, presented the findings at the 2016 Genitourinary Cancers Symposium. The study included 2 main comparisons of adjuvant chemoradiotherapy versus radiation and adjuvant chemoradiotherapy versus chemotherapy alone. The 3-year disease-free survival rate was 68% for adjuvant chemoradiotherapy versus 53% for radiation alone, but this 5% difference was not statistically significant. The 3-year disease-free survival rate in the second comparison was 68% for chemoradiotherapy versus 56% for chemotherapy alone, a numer-

at a glance mong patients with locally A advanced bladder cancer, adjuvant radiation therapy alone or chemoradiotherapy did not show significant improvement in diseasefree survival compared with adjuvant chemotherapy alone he disease-free survival T rates were 68% in the chemoradiation arm and 63% in the radiation arm he distant metastases-free T survival rates were 73% for chemoradiation and 72% for radiation, and the overall survival rates were 64% and 48%, respectively he only significant T difference between the arms was the rate of local recurrence, which was significantly reduced with adjuvant chemoradiation versus chemotherapy

ical trend toward improved survival with chemoradiotherapy. The rate of local recurrence was significantly reduced with adjuvant chemoradiation versus chemotherapy, which was the only significant difference between the arms in this trial.

ECOG performance status, and adequate organ function. Patients with evidence of distant metastasis or second malignancies were excluded from the study. The patients were randomized 3 to 6 weeks after radical cystectomy to adju-

“This is one of the largest trials to be presented, and it provides more evidence that adjuvant chemoradiation may have some benefit in locally advanced bladder cancer.” —Brian Baumann, MD

However, the improved control of local recurrence did not lead to improved disease-free survival or metastasis-free survival. The study was conducted in Egypt, where adjuvant radiation therapy is the standard of care for pelvic failure after radical cystectomy. Also, Egyptian patients have more mixed histology, with a higher percentage of squamous-cell bladder cancer than in the United States, explained Dr Baumann. Investigators from the University of Pennsylvania provided help in analyzing and interpreting the data. “This is one of the largest trials to be presented, and it provides more evidence that adjuvant chemoradiation may have some benefit in locally advanced bladder cancer. Chemoradiation led to improvement in local control in the second randomization. We think the results are intriguing, and larger studies are needed. Four organizations [worldwide] are currently considering such trials adding radiation to neoadjuvant chemotherapy,” Dr Baumann said. Study Details

The study enrolled 198 patients with bladder cancer who were treated between 2002 and 2008 at the National Cancer Institute in Cairo. The patients were treated with radical cystectomy and pelvic node dissection with negative margins and at least 1 high-risk feature for local failure (ie, stage pathologic T3b disease or higher, grade 3 tumors, and positive lymph nodes). The patients were aged <70 years (median age, 54 years), had adequate

“The small size of these arms limits the ability to detect clinically meaningful differences between the chemotherapy and chemoradiation arms.”

By the Numbers 76,960—Estimated new

cases of bladder cancer in 2016

16,390—Estimated deaths from bladder cancer in 2016

—Average age at time of bladder cancer diagnosis

90%

—Cases of bladder cancer treated with surgery

77%—5-year survival

rate for all stages of bladder cancer combined

50%

—Patients diagnosed with noninvasive bladder cancer

0.5%—Decrease in

bladder cancer incidence from 2003 to 2012

Source: American Cancer Society.

—Brian Baumann, MD

vant radiation 45 Gy given twice daily over 3 weeks or chemotherapy with 2 cycles of gemcitabine (Gemzar, Eli Lilly) plus cisplatin (Platinol, Corden Pharma Latina S.p.A.), followed by adjuvant radiation and then by 2 more cycles of gemcitabine plus cisplatin. There were 78 patients in the radiation-alone arm and 75 patients in the chemoradiation arm. A total of 45 patients were later enrolled in the chemotherapy-alone arm and received 4 cycles of gemcitabine plus cisplatin. Overall, 53% of patients had urothelial carcinoma, and 41% had squamous-cell carcinoma. The median follow-up was 19 months. In the initial randomization, the disease-free survival rate was 68% for the chemoradiation arm and 63% for the radiation arm, a nonsignificant difference. The rate of freedom from local disease-free recurrence was 96% at 3 years with chemoradiation versus 87% for radiation, which was again a nonsignificant difference. The rate of distant metastases-free survival was 73% for chemoradiation

versus 72% for radiation, and the overall survival rate was 64% versus 48% respectively, which were nonsignificant differences. In the second comparison between chemoradiation and chemotherapy alone, a trend was seen toward improved disease-free survival with chemoradiation versus chemotherapy alone (68% vs 56%, respectively), and a significant benefit was seen for chemoradiation on local recurrence-free survival (96% vs 69%, respectively; P <.001). No significant differences were found between these 2 arms in patients with 3-year metastasis-free survival (64% for chemoradiation vs 51% for chemotherapy alone) or overall survival; however, the overall survival analysis numerically favored chemoradiation over chemotherapy alone (64% vs 51%, respectively). “The small size of these arms limits the ability to detect clinically meaningful differences between the chemotherapy and chemoradiation arms,” Dr Baumann said, which is “something that has plagued many adjuvant chemotherapy trials.” s

PATIENT ADVOCACY

FDA Advisors Vote Against Duchenne Muscular Dystrophy Drug, Reject Value of Hope for Patients By Robert Goldberg, PhD President and Co-Founder, Center for Medicine in the Public Interest, Springfield, NJ

n April 25, 2016, an FDA advisory committee voted not to recommend the approval of eteplirsen, an experimental drug that targets one of many genetic mutations causing Duchenne muscular dystrophy (DMD), a deadly degenerative disease that has no cure.1 After agreeing to study the real-world effects of eteplir sen, the FDA advisory committee rejected findings that patients who have been taking eteplirsen since 2011 were still able to walk because the clinical data did not meet the FDA requirements for a well-controlled study. The FDA committee noted that the study in question involved only 12 patients without an adequate placebo control. Patients were also very knowledgeable about the drug, the FDA said, which could have led to patients inventing positive findings just to get the drug approved. The committee recommended new studies that randomly assigned patients to eteplirsen or placebo. This rejection by the committee is even more remarkable because it had hammered out the study design with the drug manufacturer to rely less on randomized clinical trials and more on measures of patient response, which were developed in cooperation with patient groups and DMD experts. Because randomized clinical trials assume that every patient is the same and will have the same response to therapy, they can miss individual differences in responses that drugs for rare diseases target. Studies need to measure benefit in combination with real-world experiences and the biologic diversity that new drugs target.2 Therefore, the study was designed, as Janet Woodcock, MD, Director of the FDA’s Center for Drug Evaluation and Research, stated, to “take the views of the patient community into account in determining the benefit and the risks of treatments.” 3 That is what the FDA review team, as well as those who applauded the FDA advisor’s decision, rejected. Michael Carome, MD, Director of Public Citizen’s Health Research Group, said, “It would be a mistake for the FDA to approve this….It would be giving in to political pressure and essentially eviscerating their standard for approval....To put out a drug that’s not effective isn’t helping anyone.” 4 Objections to the use of evidence from real-world use of a drug compared with historical controls of randomized clinical trials have nothing to do with concern about patients being harmed

populations.” 6 Therefore, ICER must decide “orphan drug coverage decisions to ensure that an undue burden is not placed on others for the sake of a few.” 6 Patient Involvement in Approvals

Underlying this approach is the belief that patients cannot be trusted to make such decisions, because hope clouds their judgment. and has everything to do with the belief that patient involvement will lead to an increase in the development and use of new medicines, and, by extension, benefit drug companies that have a financial interest in getting drugs approved. Rationing Access to New Drugs

The financial stakes of drug approvals are significant. Health insurance companies, hospitals, the government, and other groups are seeking to create defensible ways to ration access to new drugs. Public Citizen and other groups have sprung up to “objectively” measure value in an effort to suppress the patient input they regard as biased. For example, the Institute for Clinical and Economic Review (ICER) claims that it is a “trusted non-profit organization that evaluates evidence on the value of medical tests, treatments and delivery system innovations and moves that evidence into action to improve the health care system.” 5 ICER, funded by health insurance companies, defines value and determines what drugs should be used. ICER wants the public to believe that the choice of how to measure effectiveness and value of drugs is simply a technical matter that is best left to the “experts.” But that is a way to guarantee that insurers and other health organizations are free to ration access to drugs. ICER President Steven D. Pearson, MD, MSc, emphasized, “The resource allocation problems posed by orphan drugs are therefore a harbinger of things to come. Tomorrow’s medical care will feature a growing number of expensive therapies that offer benefit only to small

Underlying this approach is the belief that patients cannot be trusted to make such decisions, because hope clouds their judgment. According to the American Society of Clinical Oncology, the use of more expensive diagnostic and therapeutic interventions is driven by “unrealistic patient and family expectations that lead clinicians to offer or recommend some of these services, despite the lack of supporting evidence of utility or benefit.” 7 However, economist Tomas J. Philipson, PhD, notes, “Hope for new innovations increases demands and a willingness to pay for existing innovations. This

Ordinary citizens—those who are potential patients and the friends and relatives of such patients—have as much to say about these innovations as any so-called expert. hope is realistic: the first anti-AIDS treatments added ‘only’ two months of life in 1987. By 2006 a combination of new drugs added 15 years of life.” 8 Similarly, children taking eteplirsen are able to stay alive long enough for future drugs to be developed; the father of one of the children with DMD echoed this sentiment, saying, “Eteplir sen has given us a reason to hope.” 9 As one analyst said, “Sarepta has plans to begin work on seven additional exon-skipping drugs that, in a perfect world where every one hit the mark, would combine with eteplirsen to provide a therapeutic benefit for nearly half of all DMD patients.” 10 Increasingly, medical advances determine not only whether we live or die, but also how we will live and die. Ordinary citizens—those who are potential patients and the friends and relatives of such patients—have as much to say about these innovations as any so-called expert. To be sure, on June 2, 2016, the FDA announced a streamlined process for phy-

sicians to request “compassionate use” to investigational drugs. This initiative should not be regarded as a fix to the failure to open access to drugs established as safe. Compassionate use data are not included in the body of evidence used to approve a drug. Companies cannot charge for the product since it is not on the market. If patients apply for access to investigational drugs en masse it would not be financially sustainable. So why not simply allow patients with fatal diseases that have no other medical alternative access to medicines that are safe? Who or what are we protecting when we let people die by denying access to treatments? When there is no effective treatment, any progress is a quantum leap from the cost and burden of disease, which, in the absence of any medicine, is infinite. DMD advocate Christine McSherry, Executive Director of the Jett Foundation, Kingston, MA, stated that the DMD community’s involvement in drug approvals “will change the way people confront barriers to justice in society. This will be historic not just in Duchenne, not just in rare disease, but for every ordinary individual who has felt the need to change a broken system but never knew how to do it.” 11 s References

1. Pollak A. Advisers to F.D.A. vote against Duchenne muscular dystrophy drug. New York Times. April 25, 2016. www.nytimes.com/2016/04/26/business/musculardystrophy-drug-fda-sarepta-eteplirsen.html?_r=0. Accessed May 17, 2016. 2. Goldberg R, Kauffman S, Topol EJ. Study design and the drug development process. JAMA. 2014;311:2023. 3. The Jett Foundation. April 25, 2016 Advisory Committee Meeting – Clarifying Question and FDA Response. http://jettfoundation.org/blog/april-25-2016advisory-committee-meeting-clarifying-question-andfda-response/. Accessed May 16, 2016. 4. Rubin R. Could desperate pleas sway the FDA to approve a drug even if evidence it works is lacking? Forbes. April 24, 2016. http://onforb.es/1typwzL. Accessed May 16, 2016. 5. Institute for Clinical and Economic Review. About. http://icer-review.org/about/. Accessed May 19, 2016. 6. Largent EA, Pearson SD. Which orphans will find a home? The rule of rescue in resource allocation for rare diseases. Hastings Center Report. 2012;42:27-34. 7. Schnipper LE, Davidson NE, Wollins DS, et al; for the American Society of Clinical Oncology. American Society of Clinical Oncology statement: a conceptual framework to assess the value of cancer treatment options. J Clin Oncol. 2015;33:2563-2577. 8. Philipson TJ, Becker GS, Goldman DP, et al. Terminal care and the value of life near its end. The National Bureau of Economic Research. MFI Working Paper No. 2010-005. January 8, 2010. 9. Anderson E; for Parent Herald. FDA advisers say no to Duchenne muscular dystrophy drug. April 29, 2016. www.parentherald.com/articles/39202/20160429/fdaadvisers-duchenne-muscular-dystrophy-drug.htm. Accessed May 17, 2016. 10. Investopedia. Sarepta Therapeutics’ 3 biggest risks (SRPT). www.investopedia.com/stock-analysis/032315/ sarepta-therapeutics-3-biggest-risks-srpt.aspx#ixzz47G 2N39by. Accessed May 16, 2016. 11. McSherry C. Jett Foundation statement: to be attributed to Christine McSherry, Executive Director, Jett Foundation. April 22, 2016. http://jettfoundation.org/ blog/jett-foundation-statement-to-be-attributed-to-execu tive-director-christine-mcsherry/. Accessed May 16, 2016.

FDA NEWS FDA Regulator Says Too Much Focus Is on PD-1 Drugs

Developing a new type of drug to disable the PD-1 proteins that tumors use to evade the immune system has become the focus of too many drug makers, according to one FDA regulator. Speaking to Reuters during the annual American Society of Clinical Oncology meeting, Richard Pazdur, MD, Head of the FDA’s Office of Oncology Products, explained that although a few companies have already seen success in developing drugs that target PD-1 proteins, other companies that are in the early stages of developing their own PD-1 drugs may potentially be considered niche indications.

“People should ask themselves...would we be better off spending those resources into looking at more novel drugs?” —Richard Pazdur, MD

The FDA has already approved the immunotherapies pembrolizumab (Keytruda) and nivolumab (Opdivo), but as many as 5 other companies are developing similar treatments. “People should ask themselves...would we be better off spending those resources into looking at more novel drugs,” Dr Pazdur noted. Industry leaders, however, argue that with the future of cancer treatments leaning toward combination therapy, having their own PD-1 drugs will give them flexibility in clinical trials.

As Biosimilars Gain FDA Approval, Market Competition Increases

On April 5, 2016, the FDA approved the biosimilar infliximab-dyyb (Inflectra; Janssen Biotech) for multiple indications, including moderate-to- severe rheumatoid arthritis and chronic severe plaque psoriasis. Infliximab-dyyb is the second biosimilar to be approved. The first biosililar, filgrastim-sndz (Zarxio), was approved in March 2015. Biosimilars must be shown to be highly similar, although not identical, to an already approved biologic (reference) drug. There can be no clinically meaningful difference in safety or effectiveness between the biosimilar and the reference drug. As many biologic patents expire over the next few years, biosimilars have the potential to enter the market and impact drug costs. Although only recently approved in the United States, biosimilars have been available in Europe since 2006 and often cost less than 33% of the price of biologics

(Hede K. J Natl Cancer Inst. 2015; 107:djv191). That trend appears to be carrying over to the United States. When Novartis launched filgrastim-sndz, a biosimilar to Amgen’s filgrastim (Neupogen), it did so at a 15% discount. As other biosimilars enter the market (eg, Apotex’s filgrastim biosimilar, Grastofil, is expected to be approved by the FDA in 2016), prices may decrease even further.

When Novartis launched filgrastim-sndz... it did so at a 15% discount. As other biosimilars enter the market prices may decrease even further.

With applications submitted by Apotex and Sandoz for biosimilars to pegfilgrastim (Neulasta) as the reference drug (both expected to be accepted in 2016), increased competition in the oncology drug space is likely to drive down costs. Other oncology biosimilars that are expected to be approved this year include rpoetin alfa (Retacrit; Pfizer), which is a biosimilar to Amgen Epogen and Janssen Procrit. s

PANCREATIC CANCER

Irreversible Electroporation Boosts Soft-Tissue Cancer Survival, but with Significant Morbidity and Cost By Rosemary Frei, MSc

new article by a New York surgical team confirms that there is a survival benefit from an emerging therapy for difficult-to-treat soft-tissue tumors, but that it is not without a steep price for some patients (Kluger MD, et al. Ann Surg Oncol. 2016;23:1736-1743). Michael D. Kluger, MD, MPH, Assistant Professor of Gastrointestinal and Endocrine Surgery, New York-Presby terian Hospital, Columbia University, New York, NY, and colleagues summarized the results for their first 50 patients with T4 pancreatic cancer who received treatment with irreversible electroporation (IRE; NanoKnife; AngioDynamics). This is the largest single-institution series ever published. Overall, 6 (12%) patients died in the first 90 days after the procedure, and another 10 (20%) experienced other major complications. An earlier article examined the outcomes from 200 patients with stage III (T4) pancreatic cancer who received treatment at 6 centers (Martin RCG II, et al. Ann Surg. 2015;262:486-494). There was a 37% complication rate. However, there are some inconsistencies in the article, which makes it more difficult to interpret the data. For example, a table in the article on complications lists 2 grade 5 complications (ie, death), but the investigators state in the text that there were 3 deaths. The researchers reported a 3% local recurrence rate at a median follow-up of 29 months. The median overall survival was 24.9 months.

stage pancreatic cancer, as well as for those with renal, liver, prostate, or lung cancer. A very high current is passed between probes across the tumor tissue for brief bursts of approximately 90 millionths of a second, interspersed with 2- to 5-second breaks, and repeated up to 180 times. This punches tiny holes in the cell walls and leads to cell death, but not to tissue necrosis. The NanoKnife is the only device on the market for IRE. It costs between $250,000 and $300,000, plus approximately $2000 for each probe, accord“There is benefit from the ing to Robert C. G. Martin, II, MD, treatment, either used PhD, University of Louisville School alone or in combination of Medicine, KY, in a question and answer section at the end of his article. with resection or formal Dr Martin reported a total hospital pancreatectomy.” charge per procedure of between —Michael D. Kluger, MD, MPH $75,000 and $80,000. Dr Kluger and colleagues reported that 5 of the 6 patients who died had “We feel in our center, based on our IRE ablation of the primary tumor, results, that there is benefit from the whereas 1 patient had IRE of only the treatment, either used alone or in combi- tumor margins after pancreatectomy. nation with resection or formal pancre- Another 5 patients had grade 3 or 4 atectomy,” Dr Kluger said in a telephone complications. The median overall interview. “So I agree with everyone survival after IRE was 7.71 months in about that, but we need to parse out the primary tumor IRE group and >8.7 what the survival benefit is, because it is months in the margin IRE group. Howalso coming at a time when we have ever, as Dr Kluger told Value-Based more effective chemotherapy than we Cancer Care, these patients were folhave ever had for pancreatic cancer. I see lowed for only 33% of the time that the NanoKnife as an adjunct treatment the patients in the study by Dr Martin in the most difficult cases that have the and colleagues were followed. Some of highest complication rate in general.” the patients continued receiving cheIRE is used for the curative-intent motherapy after IRE treatment. treatment of patients with advanced- Dr Kluger and colleagues are now

at a glance he data from 50 patients T with pancreatic cancer who had irreversible electroporation showed there is a survival benefit but with high cost and increased rates of morbidity and mortality verall, 6 (12%) patients O died in the first 90 days after the procedure, and another 10 (20%) experienced other major complications se of the NanoKnife costs U $250,000 to $300,000, plus approximately $2000 for each probe, and has a total hospital charge per procedure of $75,000 to $80,000 urther investigation of this F novel treatment is warranted because of its importance in the treatment of difficultto-treat cancers with few effective therapy options

mostly performing IRE for margin extension rather than for unresectable tumors. The researchers also use IRE for some cases of liver metastases from colo rectal cancer. Other centers use IRE for renal, liver, prostate, and lung cancers. s

PERSONALIZED MEDICINE

Liquid Biopsies Show High Correlation with Tissue... insufficient for genotyping, Dr Mack said. “It’s actually very typical for tissue biopsies to be insufficient for comprehensive molecular analysis,” he said. In addition, liquid biopsy may serve as a reliable method to periodically monitor disease progression, response to therapy, and the development of drug resistance, said Dr Mack. The following observations from the genomic analysis provide insight into the clinical utility of plasma ctDNA: • 49% of the cases had alterations for which FDA-approved targeted therapies exist • 27% of the cases had actionable resistance mutations • The ability of ctDNA to enhance and complement the initial biomarkers analysis in tissue was exemplified by an increase in the yield of 42% in tissue-insufficient or partially genotyped non–small-cell lung cancer (NSCLC). Liquid Biopsy Detects Mutations in Multiple Cancers

In this analysis, DNA was isolated from blood, and fragmented DNA was barcoded using a high-efficiency molecular tagging approach. Target capture was conducted to identify regions of interest in 70 key cancer-associated genes. Sequence analysis was subsequently performed, followed by variant calling that included missense mutations, small insertions and deletions, amplification events, and a limited number of fusions. “One of the advantages of using next-generation sequencing in plasma is that it reports a fairly precise mutated

“It’s actually very typical for tissue biopsies to be insufficient for comprehensive molecular analysis.” —Philip C. Mack, PhD

with advanced NSCLC (37%), breast cancer (14%), colon or rectum cancer (6%), or other cancers (14%). Each patient provided blood samples for ctDNA analysis. The accuracy of liquid biopsies in identifying mutations was assessed using tumor tissue samples. Overall, 83.4% of alterations were detected by ctDNA analysis compared with 94% of alterations identified using data from The Cancer Genome Atlas (TCGA). DNA was isolated from blood samples when a patient’s cancer was in the advanced stage of the disease, typically during a second-line treatment or later. In 49% of the cases, the identified mutations were associated with at least 1 FDA-approved therapy. The patterns of genomic changes in ctDNA were compared with those found in 398 patients who had genetic testing.

“One of the advantages of using next-generation sequencing in plasma is that it reports a fairly precise mutated allele frequency. This allows you to easily discriminate the presence of germline polymorphisms from the somatic mutations, with a germline polymorphism occurring at 50% or 100% —Philip C. Mack, PhD allele frequencies.” allele frequency. This allows you to easily discriminate the presence of germline polymorphisms from the somatic mutations, with a germline polymorphism occurring at 50% or 100% allele frequencies,” said Dr Mack. This study included 15,191 patients

The predictive value for key abnormalities in EGFR, BRAF, KRAS, ALK, RET, and ROS1 genes by ctDNA ranged from 94.1% to 100%. This was not the case for subclonal mutations, which are associated with resistance mutations. Discordant resis-

Continued from the cover

tance cases likely reflect the evolution of disease on therapy after the initial tissue biopsy. “Circulating tumor DNA alteration patterns were highly similar, in terms of the frequency and distribution of mutations, between TCGA tissue and this series, with correlations of variant patterns ranging from 0.85 to 0.99,” Dr Mack said. One exception was the detection of EGFR T790M resistance mutations in plasma in patients with NSCLC receiving EGFR inhibitor therapy that was absent in the tissue-based population data, because the latter group had yet to receive treatment. Overall, 27% of the cases had potentially actionable resistance targets detected in ctDNA. In a subset of 362 patients with NSCLC, 63% had tissue that was partially tested or insufficient for testing. Of the 362 patients, 120 had primary activating mutations in the tumor tissue. When plasma ctDNA analysis was conducted, an additional 51 patients were identified with actionable biomarkers, an increase of 42%. Clinical Implications

Dr Mack noted that at the moment liquid biopsy is not an alternative to traditional tissue biopsy for an initial diagnosis of cancer, and should be used for patients who do not have sufficient tissue for tissue biopsy. “At this point, we cannot dispense with that initial tumor biopsy. The initial biopsy and subsequent pathology are what allow us to determine what type of cancer it is.” s

New Biomarker Holds Promise to Discriminate Between High-Grade and Low-Grade Prostate Cancer By Wayne Kuznar

hen combined with other clinically relevant parameters, a novel protein biomarker called IsoPSA can improve selection of patients with prostate cancer for biopsy. IsoPSA holds promise for improved diagnostic accuracy, said Eric A. Klein, MD, Chairman, Glickman Urological and Kidney Institute, Cleveland Clinic, OH, at the 2016 American Urological Association annual meeting. In an ongoing multinational study comparing the clinical performance of IsoPSA with serum prostate-specific antigen (PSA) measurement, “using Iso

“Using IsoPSA reduced unnecessary biopsies by 52%, missed no high-grade cancers, and correctly identified 97% of low-risk patients….This is an add-on to standard total PSA/free PSA assays; it’s done very cheaply without requiring an —Eric A. Klein, MD additional blood draw.” PSA reduced unnecessary biopsies by 52%, missed no high-grade cancers, and correctly identified 97% of low-risk patients,” said Dr Klein.

To be clinically useful, a biomarker must be specific to tissue type and to cancer. PSA is prostate-specific but not prostate cancer–specific, which limits

its ability to distinguish between prostate cancer, prostatitis, benign prostatic hyperplasia, and urinary tract infection accurately, Dr Klein explained. The diagnostic accuracy, predictive value, and clinical utility of current biomarkers are limited by a lack of cancer specificity and by relatively poor sensitivity. PSA has multiple structural isoforms that can be detected in the serum and that are cancer-specific. Current screening assays measure only the concentration of a limited number of prespecified isoforms. By contrast, IsoPSA measures

Continued on page 33

PERSONALIZED MEDICINE

Molecular Targeted Therapy or Immunotherapy Recommended as Initial Therapy in BRAF Mutation–Positive Melanoma By Walter Alexander

olding what was essentially a one-person debate, Michael B. Atkins, MD, Deputy Director of the Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, described strong cases for immunotherapy or molecularly targeted therapy as initial treatment for patients with advanced BRAF mutation–positive melanoma. The survival probability curves cross over at a little past 2 years; BRAF inhibition was superior initially, but ipilimumab maintained a higher survival plateau from there onward past 5 years, said Dr Atkins at the 2016 HemOnc Today Melanoma and Cutaneous Malignancies meeting. Offering the case for frontline immunotherapy, Dr Atkins noted, “Immunotherapy produces treatment-free tumor responses, while BRAF inhibitors do not.” In addition, the 3-year overall survival (OS) rate with ipilimumab of 21% in a 2015 pooled analysis compares well with his own research finding of a high-dose interleukin-2 rate of 11% at >5 years, and a median OS with BRAF inhibition of approximately 26 months (median progression-free survival [PFS], approximately 10-13 months). Although combined BRAF/MEK inhibition has produced the best outcomes in patients with normal lactate dehydrogenase (LDH), the benefit is strongest in patients with elevated LDH, a more advanced disease stage (M1c vs IIIc/M1a/ M1b), and greater tumor burden (≥3 disease sites). Immunotherapy, however, works as well against BRAF V600 mutation–positive melanoma as it does against wild-type tumors. In a previous poster, Mangana and colleagues reported a similar 1-year

“Immunotherapy produces treatment-free tumor responses, while BRAF inhibitors do not.” —Michael B. Atkins, MD

Dr Atkins also pointed out that although BRAF inhibitors work as well in patients who previously received immunotherapy, the converse is not supported by the evidence. In the 2011 BRIM2 trial, an objective response rate of approximately 53% with vemurafenib was observed regardless of previous interleukin-2 treatment. However, there were no tumor responses among 34 patients when single-agent immunotherapy with ipilimumab was given after MAPK inhibition, and the median OS was 5 months (all surviving patients at a year were again receiving MAPK inhibitors). “Patients progressing on BRAF inhibitors appear unlikely to respond to ipilimumab,” Dr Atkins said. In a trial comparing ipilimumab and BRAF inhibitor sequencing, when ipi

For many patients with BRAF V600E mutation–positive melanoma, starting with immunotherapy “offers a chance for long-term benefit without compromising benefit from subsequent BRAF inhibition.” —Michael B. Atkins, MD

survival rate in patients receiving ipilimumab who were BRAF V600 mutation–positive or –negative; NRAS mutation status, as well, did not have a significant effect on survival. In the CheckMate 069 trial comparing nivolumab with or without ipilimumab, complete responses were reported in 22% of patients with the combination for BRAF wild type and BRAF mutation–positive patients (Postow MA, et al. N Engl J Med. 2015;372: 2006-2017).

limumab was given first, the median OS was 14.5 months compared with 9.9 months for BRAF inhibition followed by ipilimumab. The implication is that for many patients with BRAF V600E mutation–positive melanoma, starting with immunotherapy “offers a chance for long-term benefit without compromising benefit from subsequent BRAF inhibition,” Dr Atkins noted. The immunotherapy-first strategy is further supported by data from the 2015 Keynote-006 trial, which showed supe-

rior 1-year OS with the PD-1 inhibitor pembrolizumab, with longer PFS and a nearly tripled overall response rate. Combining ipilimumab with the PD-1 inhibitor nivolumab produced a median PFS of 11.5 months compared with 6.9 months for ipilimumab alone (Larkin J, et al. N Engl J Med. 2015;373:23-34). The grade 3/4 serious adverse event rate for the combination was 16% versus 55% with ipilimumab alone. Although the overall antitumor activity appears similar between BRAF inhibitors and the newer immunotherapies, durability (3-year OS of 68% with nivolumab plus ipilimumab in the CheckMate 004 trial) is greater with the immunotherapies. Even with all of this said for the immunotherapies, there is still a case for the use of molecularly targeted therapies, according to Dr Atkins. The BRAF/MEK inhibitor combination produces responses in a majority of patients, and, in the subgroup of patients with M1a/b disease, high response rates, median OS rates, and complete response rates are being observed. In patients with the BRAF V600 mutation and metastatic melanoma who were receiving dabrafenib combined with trametinib, the 3-year OS rates were 68% in patients with stage IIIc, M1a, or M1b disease and 62% in patients with normal LDH (Long GV, et al. J Clin Oncol. 2016;34:871-878) and fewer disease sites. When resistance to BRAF/MEK inhibitor therapy does arise, responses are being observed with PD-1 pathway blockers. Because toxicity with a BRAF/ MEK inhibitor may be worse after immunotherapy, initial therapy with this treatment is preferred. s

New Biomarker Holds Promise to Discriminate Between... Continued from page 32 the concentration of all isoforms. “That’s important, because in different patients there may be different PSA isoforms that are associated with cancer that are not detectable by the current assays,” Dr Klein said. “Furthermore, there may be different isoforms of PSA in the same patient over the course of time that are also not captured by current assays.” IsoPSA is a novel assay that uses aqueous-based solvents to detect overall changes in the structure or isoform mixtures of biomarkers.

The IsoPSA assay interrogates the entire PSA isoform distribution in serum, as opposed to preselecting individual protein biomarkers. “This is an add-on to standard total PSA/free PSA assays; it’s done very cheaply without requiring an additional blood draw,” said Dr Klein. “The way it will be reported…is the percent likelihood for an individual patient for the presence of Gleason 7 cancer.” Preliminary studies showed excellent discrimination between cancerous

and benign prostate diseases. Dr Klein’s study included 132 patients with PSA values of 2 ng/mL to 26 ng/mL. The objective was to assess the clinical performance (ability to predict for Gleason 7 cancer) of Iso PSA against PSA with 12-core ultrasound-guided prostate biopsy. Compared with PSA alone, which had an area under the curve (AUC) of 0.61 for prediction of Gleason grade ≥7 cancer, adding IsoPSA to the model improved the AUC to 0.85.

The positive predictive value for aggressive cancer was very high, and the negative predictive value (negligible chance for aggressive cancer) was also very high, said Dr Klein. In patients at very low risk for aggressive disease, the negative predictive value was 97%; in those at high risk for high-grade disease, the positive predictive value was 86%. “So IsoPSA has a very high ability to correctly discriminate clinical outcome,” Dr Klein said. s

CLINICAL TRIALS

Trials and Tribulations: Reporting Clinical Trial... venue in which the article appears legit? When the answer to each of these questions came back a resounding yes, I began worrying that cancer doctors and patients have been imperiled by irresponsible researchers.” 1 According to Mr Piller, “Most research institutions—including leading universities and hospitals in addition to drug companies—routinely break a law that requires them to report the results of human studies of new treatments to the federal government’s ClinicalTrials. gov database.” 2 During interviews with researchers, university administrators, and hospital executives, it became clear to Mr Piller that these professionals were not intentionally undermining the law, but instead were waylaid by intense scheduling and a lack of administrative funding. Interviewees also said that some clinical trial results are disclosed in medical journals and at conferences, but are not making it to the government database, where visibility would be the greatest. Anchoring her response in her own experience, Ms Gubar reminded readers that “the often debilitated participants in clinical cancer trials decide on their own accord to put their lives on the

line, usually with no resulting personal health benefit.” 1 A Grueling Experience

After recalling her own exhausting first days of a clinical trial, Ms Gubar noted that what kept her going was the knowledge that her participation would help researchers ascertain the effectiveness of the drug she was taking. Howev-

“Thousands of patients have kept our side of the covenant. The researchers and the institutions for which they work should keep theirs.” —Susan Gubar

“Most research institutions—including leading universities and hospitals in addition to drug companies—routinely break a law that requires them to report the results of human studies of new treatments to the federal government’s ClinicalTrials.gov database.” —Charles Piller

er, she wrote, “the knowledge they [researchers] gain from this study remains barren, if it does not circulate among other researchers, cancer doctors, and patients.” Ms Gubar emphasizes that the results need to be promptly reported, not only in a medical journal, but also on the site constructed to disseminate this information.

Mr Piller points out that the timely and accurate reporting of data is the main source of information for physicians who are trying to understand the efficacy and safety of the new drugs. According to the American Society of Clinical Oncology, only 5% of adults with cancer currently participate in

Continued from the cover

clinical trials, and 60% of children with cancer receive treatment through clinical trials. Overall, 75% of children with cancer survive long-term compared with 50% of adults with cancer. Doctors attribute these higher survival rates in children to their more frequent participation in clinical trials over a long period of time. Ms Gubar firmly believes that she lives and breathes today because of cutting-edge research, but she wants to make sure that other patients can say the same thing. “Thousands of patients have kept our side of the covenant,” she wrote. “The researchers and the institutions for which they work should keep theirs.” To improve accountability and transparency of clinical trials, researchers can begin by visiting www.alltrials.net, which promotes reporting the results of all clinical trials. s References

1. Gubar S. Living with cancer: a broken covenant with patients. New York Times Blog. January 15, 2016. http:// well.blogs.nytimes.com/2016/01/15/living-with-cancera-broken-covenant-with-patients/. Accessed February 5, 2016. 2. Piller C. Failure to report: a STAT investigation. STAT. December 13, 2015. www.statnews.com/2015/ 12/13/clinical-trials-investigation/. Accessed February 5, 2016.

RAF Family Inhibitor Has Preliminary Activity in Multiple Tumor Types By Charles Bankhead

he multitargeted RAF inhibitor BGB-283 demonstrated activity in several types of advanced solid tumors associated with different mutations in the RAF family of genes, results of a preliminary clinical trial showed. Of the 29 evaluable patients who received BGB-283, 3 had confirmed partial responses, 1 had an unconfirmed response, and 14 had stable disease. The responses are durable, and several patients have had prolonged periods of stable disease, according to Jayesh Desai, MBBS, a medical oncologist at the Royal Melbourne Hospital in Australia, who presented the results at the 2016 American Association for Cancer Research annual meeting. “These results are very encouraging, especially seeing antitumor activity against RAS-mutant cancers, which are challenging to treatment,” said Dr Desai. The RAF family of gene proteins—

“These results are very encouraging, especially seeing antitumor activity against RAS-mutant cancers, which are challenging to treatment.” —Jayesh Desai, MBBS

which includes BRAF, KRAS, and NRAS—are drivers of multiple types of cancer, including melanoma, thyroid, colorectal, and lung cancers. The BRAF V600E mutation predominates in melanoma, and several specific BRAF inhibitors have been developed to target this mutation. In contrast to agents that target the BRAF protein, BGB-283 inhibits the activity of all RAF family proteins, including the BRAF V600E mutation. Because the oncogenic effects of RAS

mutations involve BRAF signaling, the investigators hypothesized that BGB283 would have activity against cancers driven by RAS mutations and signaling, said Dr Desai. According to the National Cancer Institute, approximately 33% of all cancers are driven by RAS mutations. To date, however, no effective inhibitors of RAS have been developed. BGB-283 Demonstrates Safety and Efficacy

Overall, 31 patients with previously treated advanced solid tumors and documented mutations in the BRAF, NRAS, or KRAS genes enrolled in this phase 1 study. The primary objectives of this clinical trial included BGB283 safety, tolerability, pharmacokinetics, recommended phase 2 dose, and preliminary clinical activity. The patients received 1 of 7 doses evaluated in the study.

BGB-283 was well-tolerated, and the maximum tolerated dose was 40 mg once daily, said Dr Desai. Thrombocytopenia was the dose-limiting toxicity. The most frequent treatment-associated adverse events (all grades) were fatigue, anorexia, constipation, nausea, vomiting, dermatitis, handfoot syndrome, hypertension, and dysphonia (all in ≥30% of patients). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (13%), fatigue (10%), and elevation in liver enzyme levels (alanine transaminase, 10%). Confirmed partial responses occurred in 1 patient with BRAF V600E– associated melanoma, 1 patient with endometrial cancer and a KRAS mutation, and 1 patient with thyroid cancer and a BRAF V600E mutation. The unconfirmed response occurred in a patient with KRAS mutation– positive non–small-cell lung cancer. Continued on page 38

COLORECTAL CANCER

Cologuard: Stool DNA Test Performs Well in Community-Based Setting Among Medicare Beneficiaries By Charles Bankhead

he multitarget stool DNA test, a noninvasive screening tool for colorectal cancer (CRC), demonstrated potential for identifying cancer and advanced adenomas in community-based individuals who had previously not followed national screening recommendations, reported Mark Prince, MD, MBA, Director of Gastroenterology, USMD Health System, Arlington, TX, at the 2016 American Association for Cancer Research annual meeting. Nearly 90% of patients completed the Cologuard stool DNA test when offered the option, and 15% had positive test results that led to a referral for diagnostic colonoscopy. Although none of the 393 patients in the study had undergone screening colonoscopy within the previous 10 years, 90% of those with a positive stool DNA test result followed through with the colonoscopy referral. “The availability of the multitargeted stool DNA test provided significant medical benefit to our previously screening noncompliant Medicare population,” said Dr Prince. “Patients with clinically critical advanced colorectal neoplasia were identified in this cohort due to high compliance with both stool DNA screening and fol-

test as a screening tool for CRC. The pivotal clinical trial involving 10,000 patients showed that the multitarget stool DNA test had a 92% sensitivity for detecting CRC, a 42% sensitivity for detecting colonic adenomas, and an 87% specificity (Imperiale TF, et al. N Engl J Med. 2014;370:1287-1297). The number-needed-to-treat values were 154 with colonoscopy, 166 with the multitarget stool DNA test, and 208 with the fecal immunochemical test.

“The availability of the multitargeted stool DNA test provided significant medical benefit to our previously screening noncompliant Medicare population.” —Mark Prince, MD, MBA

low-up diagnostic colonoscopy.” Although derived from a retrospective chart review, the results provided real-world support for the pivotal multicenter clinical trial that led to the FDA approval of the multitarget stool DNA

Good Adherence Rate in the Community Setting

To investigate whether the results of this pivotal clinical trial could be extrapolated to the community, Dr Prince and colleagues reviewed medical records of patients in the USMD Health System, and identified 393 Medicare beneficiaries who had not undergone screening colonoscopy in the previous 10 years, or who had completed a fecal occult blood test more than 1 year ago. All participants had an average risk for CRC. Overall, 77 providers offered the multitargeted stool DNA test to the 393 screening-noncompliant individuals, and 347 completed the test, representing an 88.3% adherence rate. The test yielded positive results in 51 partic-

ipants; all patients with positive test results were referred for colonoscopy, and 46 patients followed this recommendation. Of the remaining 5 patients, 3 refused colonoscopy, and 2 were lost to follow-up. Overall, 4 patients had CRC, 21 patients had advanced adenomatous polyps, 9 patients had nonadvanced adenomas, and 12 patients had neither polyps nor cancer. None of the patients had symptoms before testing positive on the multitargeted stool DNA test. These results indicate good adherence to the test in the community setting and provide additional evidence that “colon cancer screening saves lives,” said Dr Prince. “Colonoscopy is the best form of colon cancer screening, but for patients who will not have a colonoscopy, a noninvasive screening test like Colo guard is needed,” he said. Dr Prince cautioned that every patient with a positive stool DNA test result should be referred for colonoscopy, which remains the definitive method for detecting CRC and advanced adenomas of the colon. He added that the applicability of these results to patients with private insurances remains unclear. s

USPSTF Issues New Colorectal Cancer Screening Recommendations By Jessica Miller

ew recommendations issued by the US Preventive Services Task Force (USPSTF) focus on increasing colorectal cancer screening, which, according to the task force, is “a substantially underused preventive health strategy.” Previous USPSTF guidelines recommended specific screening approaches, including colonoscopy, fecal occult blood testing, or sigmoidoscopy, for adults aged 50 through 75 years (USPSTF. JAMA. 2016 June 15. Epub ahead of print). Colorectal cancer is the second leading cause of death related to cancer in the United States. It is the most frequently diagnosed cancer in adults aged 65 to 74 years. After reviewing the effectiveness of

“There is convincing evidence that colorectal cancer screening substantially reduces deaths from the disease among adults aged 50 to 75 years and that not enough adults in the United States are using this effective preventive intervention.” —US Preventive Services Task Force

different screening methods and the harms related to each, the USPSTF concluded “with high certainty” that for average-risk, asymptomatic adults aged 50 to 75 years, colorectal cancer screening is of “substantial net benefit.” The task force found that no specific screening method was better than the others. The screening modalities that

were reviewed included colonoscopy, flexible sigmoidoscopy, computed tomography colonography, guaiac-based fecal occult blood test, fecal immunochemical test, multitargeted stool DNA test, and the methylated SEPT9 DNA test. “In the current recommendation, instead of emphasizing specific screen-

ing approaches, the USPSTF has instead chosen to highlight that there is convincing evidence that colorectal cancer screening substantially reduces deaths from the disease among adults aged 50 to 75 years and that not enough adults in the United States are using this effective preventive intervention,” the researchers noted. “The reasons for this gap between evidence and practice are multifaceted and will require sustained effort among clinicians, policy makers, advocates, and patients to overcome.” Screening for colorectal cancer in adults aged 76 to 85 years should be an individualized decision that takes into account the patient’s health and previous screening history. s

DRUG UPDATE

Defitelio (Defibrotide Sodium): First Drug Approved for Patients with Hepatic Veno-Occlusive Disease By Laura Morgan

epatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, is a rare and life-threatening liver condition that is characterized by rapid weight gain, ascites, painful hepatomegaly, and jaundice.1 It is often observed in patients after allogeneic or autologous hematopoietic stem-cell transplantation (HSCT), and has also been reported during the treatment of Wilms tumor, rhabdomyosarcoma associated with actinomycin D, and acute lymphoblastic leukemia.1 Hepatic VOD is thought to be caused by damage to sinusoidal endothelial cells and hepatocytes in the area surrounding the central veins.2 The pathogenesis of hepatic VOD involves cy tokine release, endothelial injury, hemostatic activation, and hepatic drug detoxification through the glutathione pathway. Hepatocellular necrosis, fibrosis, and vascular occlusion lead to liver failure, hepatorenal syndrome, multiorgan failure, and death.2 A liver biopsy is the gold standard for diagnosing hepatic VOD; however, the majority of cases are diagnosed clinically because of the invasive nature of a biopsy.1 Hepatic VOD is more common after allogeneic HSCT than after autologous HSCT, and is usually triggered by the administration of conditioning therapy for HSCT.2-7 It has been reported in ≤60% of patients after HSCT, ranging in severity from a mild, reversible disease to a severe syndrome associated with a high mortality rate and progression to multiorgan failure; however, there is no consensus on how to evaluate the severity of hepatic VOD. Overall, <2% of patients have severe hepatic VOD, and approximately 80% of these patients do not survive.8 The primary goal of treating hepatic VOD is to normalize the flow in the sinusoidal vessels and veins by controlling the vasculitis and fibrin deposition.9 Although no specific treatment modality has been recognized for patients with VOD, several methods have been used to normalize flow in sinusoidal blood vessels and veins, including low-dose tissue plasminogen activators to increase fibrin degradation, antithrombin III replacement, and antithrombin III in combination with heparin and low-dose tissue plasminogen activators. Other anticoagulant therapies have also been used, but yielded mixed results.9-13

Table 1 Survival Rates with Defibrotide Sodium After HSCT Study description

Patients receiving defibrotide sodium, N

Survival rate 100+ days after HSCT, %

Study 1

Phase 3 prospective

102

38 (95% CI, 29-48)

Study 2

Phase 2 prospective

44 (95% CI, 33-55)

Study 3

Expanded access

351

45 (95% CI, 40-51)

Study

CI indicates confidence interval; HSCT, hematopoietic stem-cell transplantation. Sources: References 14-17.

FDA Approves Defitelio for Hepatic VOD

On March 30, 2016, the FDA approved defibrotide sodium (Defitelio; Jazz Pharmaceuticals) for the treatment of adults and children with hepatic VOD with renal or pulmonary dysfunction after HSCT. Defibrotide sodium is the first therapy to receive FDA approval for patients with severe hepatic VOD.8 The FDA approval was based on 3 clinical trials showing its treatment benefits in 528 patients with severe hepatic VOD and with liver or kidney abnormalities after HSCT.8 The studies measured the percentage of patients who were still alive 100 days after undergoing HSCT.8

modulin expression, and decreases expression of von Willebrand factor and plasminogen activator inhibitor-1 in endothelial cells, leading to the reduction of endothelial-cell activation and increased endothelial-cell–mediated fibrinolysis. In addition, defibrotide sodium protects endothelial cells from damage associated with chemotherapy, tumor necrosis factor-α, serum starvation, and perfusion.14 Dosing and Administration

Defibrotide sodium is administered for 2 hours via a continuous intravenous infusion; defibrotide sodium should be diluted before infusion. The recommended dosage is 6.25 mg/kg every 6 hours; the dose should be based on the

“The approval of Defitelio fills a significant need in the transplantation community to treat this rare but frequently fatal complication in patients who receive chemotherapy and HSCT,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products.8 Defibrotide sodium was approved under the FDA’s priority review status, which enables the FDA to expedite the review of certain drugs because of their potential to benefit patients with serious conditions.8 In addition, defibrotide sodium received an orphan drug designation.8 Mechanism of Action

Although its mechanism of action is not fully understood, defibrotide sodium has been shown to enhance the enzymatic activity of plasmin to hydrolyze clots of fibrin.14 Defibrotide sodium increases tissue plasminogen activator and thrombo-

patient’s baseline body weight. Defibrotide sodium should be administered for a minimum of 21 days, and continued until the signs and symptoms of VOD have resolved, or up to a maximum of 60 days.14 Defibrotide sodium is available in a 200-mg/2.5-mL (80-mg/mL) single-use vial, containing light yellow to brown, sterile, preservative-free solution.14 Clinical Trials

The approval of defibrotide sodium for the treatment of adults and children with hepatic VOD and renal or pulmonary dysfunction after undergoing HSCT was based on the results of 3 clinical trials.14-17 Survival rates reported with defibrotide sodium in the 3 studies are outlined in Table 1.

Study 1: Phase 3 Trial

In the first study, a phase 3, prospec-

tive clinical trial, investigators evaluated the efficacy and safety of defibrotide sodium in 134 patients with hepatic VOD and multiorgan failure.14,15 Patients in the treatment group (N = 102) received defibrotide sodium 25 mg daily, and the control group (N = 32) comprised historical-control patients who underwent HSCT and were identified from 6867 medical charts. The primary outcome measure was the difference in survival rate at day 100 or more (100+) after HSCT between the treatment group and the control group; the secondary outcome measures were (1) the difference in the complete response rate at 100+ days after HSCT in the treatment group versus the control group, and (2) survival at 180+ days after HSCT.15 The survival rate at 100+ days after HSCT was 38.2% in the treatment group versus 25% in the control group (P = .0109). The complete response rate at the same time point was 25.5% in the defibrotide sodium group, and 12.5% in the control group (P = .0160; Table 1).15 Study 2: Phase 2 Trial

The second study was a phase 2, dose-finding clinical trial in which investigators prospectively evaluated adult and pediatric patients with hepatic VOD and multiorgan dysfunction after HSCT.14,16 Overall, 75 patients received defibrotide sodium 6.25 mg/kg, and 74 patients received defibrotide sodium 10 mg/kg infused every 6 hours for ≥14 days or until the signs of hepatic VOD resolved.16 The survival rate at 100+ days after HSCT was 44% for patients who received the 6.25-mg/kg dose, and 39% for patients who received the 10-mg/kg dose (P = .619). In addition, the complete response rate was 49% in the 6.25mg/kg group, and 43% in the 10-mg/kg group (P = .613; Table 1).14,16

Study 3: Expanded Access Trial

The third study was an expanded access analysis in 351 adult and pediatric patients with hepatic VOD and renal or pulmonary dysfunction after HSCT who received 6.25-mg/kg infusions of defibrotide sodium every 6 hours.14,17 The survival rate at day 100+ after HSCT was 45% (Table 1).14,17 Adverse Reactions

The safety of defibrotide sodium was evaluated in 176 patients who participated in the 3 clinical trials. The most common (≥10%) adverse reactions of Continued on page 38

DRUG UPDATE

Defitelio (Defibrotide Sodium): First Drug Approved for Patients with Hepatic Veno-Occlusive... Continued from page 37

any grade reported with defibrotide sodium were hypotension (37%), diarrhea (24%), vomiting (18%), nausea (16%), and epistaxis (14%). The most common serious adverse events were hypotension (7%) and alveolar hemorrhage (11%). Table 2 lists grade 4 or 5 adverse events occurring in 3% of the patients.14 Data from 102 patients with VOD showed that 34% of patients had adverse events that resulted in the permanent discontinuation of defibrotide sodium. Adverse events that led to the permanent discontinuation of defibro‑ tide sodium included pulmonary alveolar hemorrhage (5%), pulmonary hemorrhage (3%), hypotension (3%), catheter-site hemorrhage (3%), multiorgan failure (3%), cerebral hemorrhage (2%), and sepsis (2%).14 Specialty Pharmacy Distributors

Defibrotide sodium is distributed through McKesson Plasma and Biologics. Institutions should verify they have a contract with this distributor or set up a contract before ordering the drug, according to the drug manufacturer (https://defitelio.com).

Contraindications

The use of defibrotide sodium concomitantly with systemic anticoagulants or fibrinolytic therapy is contraindicated. In addition, defibrotide sodium is contraindicated in patients with a hypersensitivity to any of its excipients.14

Warning and Precautions

Bleeding. Defibrotide sodium should not be used in patients with persistent, severe or potentially life-threatening bleeding. Increased activity of fibrino-

Table 2 Grade 4 or 5 Adverse Reactions in ≥3% Patients Adverse reaction

Grade 4 or 5, N (%)

Hypotension

12 (7)

Pulmonary alveolar hemorrhage

12 (7)

Gastrointestinal hemorrhage

5 (3)

Sepsis

9 (5)

Graft versus host disease

7 (4)

Lung infiltration

5 (3)

Pneumonia

5 (3)

Source: Reference 14.

lytic enzymes may increase the risk for bleeding in patients with VOD after HSCT. Patients should be monitored for the signs of bleeding, and defibrotide sodium should be permanently discontinued in patients with recurrent, significant bleeding. The risk for bleeding may be increased with the concomitant use of defibrotide sodium and a systemic anticoagulant or fibrinolytic therapy.14 Hypersensitivity reactions. Hypersensitivity reactions, including rash, urticaria, and angioedema, have occurred in <2% of patients who received defibrotide sodium; anaphylactic shock was reported in 1 patient who had received defibrotide sodium. Patients should be monitored for hypersensitivity reactions, especially if they have been exposed to defibrotide sodium; the drug should be discontinued if a hypersensitive reaction occurs.14 Use in Specific Populations

Pediatric patients. The safety and

efficacy of defibrotide sodium have been established in pediatric patients aged 1 month to 17 years, and were consistent across pediatric and adult patients in the clinical trials.14 Pregnant or lactating women. The safety and efficacy of defibrotide sodium therapy have not been established in pregnant patients. It is advised that women should not receive defibrotide sodium while breast-feeding.14 Geriatric patients. Insufficient data were collected in older patients (aged ≥65 years) to determine whether they respond differently to defibrotide sodium compared with younger patients.8 Conclusion

Defibrotide sodium is the first treatment to receive FDA approval in the United States for patients with severe hepatic VOD, a rare but life-threatening condition occurring in patients who receive chemotherapy after HSCT. Evidence from 3 clinical trials shows that this new medication is generally safe and well-tolerated, and is an effective treatment option for patients with hepatic VOD associated with renal or with pulmonary dysfunction after HSCT. s

References

1. Kotecha RS, Buckland A, Phillips MB, et al. Hepatic sinusoidal obstruction syndrome during chemotherapy for childhood medulloblastoma: report of a case and review of the literature. J Pediatr Hematol Oncol. 2014;36: 76-80. 2. Coppell JA, Richardson PG, Soiffer R, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010;16:157-168. 3. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85: 3005-3020. 4. Carreras E, Bertz H, Arcese W, et al. Incidence and outcome of hepatic veno-occlusive disease after blood or

marrow transplantation: a prospective cohort study of the Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood. 1998;92:3599-3604. 5. Richardson P, Guinan E. The pathology, diagnosis, and treatment of hepatic veno-occlusive disease: current status and novel approaches. Br J Haematol. 1999; 107:485-493. 6. McDonald GB, Hinds MS, Fisher LD, et al. Veno- occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255-267. 7. Bearman SI, Anderson GL, Mori M, et al. Veno-occlusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation. J Clin Oncol. 1993;11:1729-1736. 8. US Food and Drug Administration. FDA approves first treatment for rare disease in patients who receive stem cell transplantation from blood or bone marrow. www.fda.gov/NewsEvents/Newsroom/PressAnnounce ments/ucm493225.htm. Published March 30, 2016. Accessed May 31, 2016. 9. Harper JL, Willert JR. Veno-occlusive hepatic disease treatment & management. http://emedicine.medscape. com/article/989167-treatment. Updated March 31, 2016. Accessed April 19, 2016. 10. Kulkarni S, Rodriguez M, Lafuente A, et al. Recombinant tissue plasminogen activator (rtPA) for the treatment of hepatic veno-occlusive disease (VOD). Bone Marrow Transplant. 1999;23:803-807. 11. Bearman SI, Lee JL, Barón AE, McDonald GB. Treatment of hepatic venocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients. Blood. 1997;89: 1501-1506. 12. Bajwa RP, Cant AJ, Abinun M, et al. Recombinant tissue plasminogen activator for treatment of hepatic veno-occlusive disease following bone marrow transplantation in children: effectiveness and a scoring system for initiating treatment. Bone Marrow Transplant. 2003;31:591-597. 13. Baglin TP, Harper P, Marcus RE. Veno-occlusive disease of the liver complicating ABMT successfully treated with recombinant tissue plasminogen activator (rt-PA). Bone Marrow Transplant. 1990;5:439-441. 14. Defitelio (defibrotide sodium) [package insert]. Palo Alto, CA: Jazz Pharmaceuticals; 2016. 15. Richardson PG, Riches ML, Kernan NA, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016;127:1656-1665. 16. Richardson PG, Soiffer RJ, Antin JH, et al. Defibro‑ tide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biol Blood Marrow Transplant. 2010;16:1005-1017. 17. Richardson PG, Smith AR, Triplett BM, et al. Early initiation of defibrotide in patients with hepatic veno- occlusive disease/sinusoidal obstruction syndrome following hematopoietic stem cell transplantation improves day +100 survival. Presented at the American Society of Hematology 57th Annual Meeting; December 5-8, 2015; Orlando, FL.

CLINICAL TRIALS

RAF Family Inhibitor Has Preliminary Activity... All the responses had a duration of >200 days; several patients with stable disease have ongoing stability after >300 days. The patient with endometrial cancer had an ongoing response at 411 days and progression-free survival of 455 days. In addition to assessing clinical activity, the researchers evaluated the metabolic activity of BGB-283 using 18F-fluorodeoxyglucose–positron emission tomography imaging performed

“We will likely need to understand the biology of each individual patient’s tumor to determine whether BGB-283 would be an appropriate —Jayesh Desai, MBBS treatment option.” before treatment and at the end of the first cycle of treatment. The results showed that 13 patients had partial metabolic responses.

Evaluation of BGB-283 is ongoing in an expansion study involving patients with several types of molecularly defined tumors.

Continued from page 34

“Emerging evidence suggests that RAS-mutant cancers are not all the same, and that the signaling networks driving cancer cell proliferation and survival can be different for different RAS mutations and for different types of cancer. This has huge implications for using BGB-283 in the clinical, as we will likely need to understand the biology of each individual patient’s tumor to determine whether BGB-283 would be an appropriate treatment option,” said Dr Desai. s