VBCC August 2014 Vol 5, No 6

AUGUST 2014 VOL 5 NO 6

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

Medication Costs Impact Patient Determining the Value Adherence Even in Oncology, of Cancer Therapies: A Affecting Quality Care Paradigm Shift Focused on Financial toxicity more common than you think

By Eileen Koutnik-Fotopoulos

Quality, Outcomes, and Cost

By Winston Wong, PharmD President, W-Squared Group, Longboat Key, FL, and former Associate Vice President of Pharmacy Management, CareFirst BlueCross BlueShield, Baltimore, MD

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ccording to the 2013 Annual Report on Progress Against Cancer published in 2014 by the American Society of Clinical Oncology (ASCO), cancer death rates have declined by 21% among men and by 12% among women since the 1990s, and

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Continued on page 6

2014 Oncology Pipeline Looks Impressive

By Wayne Kuznar

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Lung Cancer

Anti–PD-1 Antibodies The future looks particularly bright

© 2014 Engage Healthcare Communications, LLC

Continued on page 30

Fourth Conference

onadherence to medication has been associated with financial burden; however, little is known about the association between the discussion of cancer treatments between patients and oncologists regarding out-of-pocket cost and medication adherence. In a new study, researchers sought to explore the relationship between nonadherence, financial distress, and patient–physician discussions of costs related to the

he cancer drug pipeline continues to boast many new therapies, reinforcing the recent trends of new and improved monoclonal antibodies and other classes of targeted therapies for different types of tumors. At ASCO 2014, researchers presented findings for many of these drugs, with immunotherapies leading the way in current drug development in oncology.

more than 13 million cancer survivors are alive in the United States today (Patel JD, et al. J Clin Oncol. 2014;32:129160). This is in part thanks to the growing understanding of cancer at the molecular level, which enables the development of new targeted thera-

for the anti–programmed death (PD)1 monoclonal antibodies, which are being evaluated in several solid tumors. Strong results were reported for both nivolumab and pembroliz­umab (MK-3475; formerly lambroliz­ umab) in phase 1 and 2 studies of patients with non–small-cell lung cancer, melanoma, and renal-cell carcinoma. The durability of responses to these agents is perhaps more impressive than the response rates themselves. The majority of responders continue to demonstrate responses at the time of the study analyses.

Continued on page 19

Patients with Cancer Need Psychosocial Support, Expression of Caring

By Wayne Kuznar

Los Angeles, CA—Patient comfort and emotional support are part of the quality components in value-based cancer care. However, hospitals and caregivers are not always up to the

task, said Lee Tomlinson, an author, educator, and speaker from Santa Monica, CA, as well as a cancer survivor; he presented the patient’s perspective at the Fourth Annual Continued on page 35

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

The 340B program dilemma

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POLICY MATTERS . . . . . . . . . . . . . . 21 How to fix the 340B program

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VALUE PROPOSITIONS . . . . . . . . . . 5 Simple blood test can identify 3 cancers

REIMBURSEMENT . . . . . . . . . . . . .

Value-based care, payment models

FDA APPROVALS . . . . . . . . . . . . . . . . 5 Belinostat for peripheral T-cell lymphoma

4TH CONFERENCE . . . 35 Value concerns lead to payer scrutiny of new cancer drugs

ECONOMICS OF CANCER CARE . . . .

Newer cancer drugs also more expensive

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LUNG CANCER . . . . . . . . . . . . . . . . 46 Two new drugs improve survival

THE PATIENT PERSPECTIVE . . . . . . . . 20 DRUG UPDATE . . . . . . . . . . . . . . . . 48 Sandra Wade’s long road to rehabilitation Zykadia for crizotinib-resistant ALK-positive NSCLC

VISIT THE NEW ONLINE RESOURCE FOR THE ENTIRE MULTIPLE MYELOMA CARE TEAM

“Better informed teams provide better care.”

Matthew P. Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth Murray, UT

Value-Based Care IN Myeloma

™

RESOURCE CENTER FOR PAYERS, PROVIDERS, AND THE ENTIRE CANCER CARE TEAM

Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues.

Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.

www.ValueBasedMyeloma.com Value-Based Care in Myeloma is a publication of Engage Healthcare Communications, a member of The Lynx Group. © 2014 All rights reserved.

VBMKsize_Mitchell_81214

In This Issue INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM

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

FROM THE EDITOR

IN THE LITERATURE

The 340B program: the good, the bad, the ugly

Ibrutinib outperforms ofatumumab, extends survival in CLL New payment model saves money, maintains outcomes More…

VBCC PAYERS’ PERSPECTIVE Determining the value of cancer therapies

VALUE PROPOSITIONS

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

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

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

Upfront docetaxel markedly improves survival

4TH CONFERENCE

FDA APPROVALS

Oncology pipeline bustling, but value concerns increase payer scrutiny Big data can optimize outcomes in oncology More…

Belinostat for peripheral T-cell lymphoma Idelalisib for 3 types of hematologic cancers More…

ECONOMICS OF CANCER CARE

LUNG CANCER

Costs impact patient adherence, care quality More…

Necitumumab, ramucirumab improve survival

DRUG UPDATE

EHA MEETING HIGHLIGHTS Patients with AML live longer with azacitidine More…

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

PROSTATE CANCER

Blood test can identify 3 types of cancer More…

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

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

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

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN

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

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

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

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

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

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

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

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

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

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

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

Lee Newcomer, MD, MHA UnitedHealthcare Group Minnetonka, MN

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

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

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

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

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

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

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

Vol. 5

Zykadia for crizotinib-resistant ALK-positive non–small-cell lung cancer

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

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

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

august 2014

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From the Editor

The 340B Program Dilemma: The Good, the Bad, and the Ugly

By Craig Deligdish, MD

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

he 340B Drug Pricing Program was a result of Public Law 102585, the Veterans Health Care Act of 1992, which was codified as Section 340B of the Public Health Service Act. This program is managed by the Health Resources and Services Administration (HRSA) Office of Pharmacy Affairs. Section 340B limits the costs of outpatient drugs to qualified health centers (ie, community-based healthcare providers that receive funds from the HRSA Health Center Program to provide primary care services in underserved areas), federally qualified health center lookalikes (ie, community-based healthcare providers that meet the requirements of HRSA, but do not receive funding from it), and other federal grantees, including community health centers, migrant health centers, health centers for residents of public housing, and health centers managed by the Office of Family Assistance’s Tribal programs or urban Indian organizations. Other organizations eligible for 340B pricing include black lung clinics (which provide services to coal miners and their families), comprehensive hemophilia diagnostic treatment centers, certain entities receiving assistance under Title XXVI of the Social Security Act, disproportionate share hospitals, free-standing cancer hospitals, critical access hospitals and sole community hospitals, in addition to a number of other organizations. The Affordable Care Act further expanded the number of organizations that were eligible for the program.

The program covers outpatient drugs, but does not cover drugs that are administered on an inpatient basis.

The discount that organizations receive is significant and varies between 20% and 50%, but generally can be estimated to be 50% of the average wholesale price of a drug.1 In recent years, the 340B program has grown dramatically, allowing for eligible institutions to benefit and to provide important drug treatments to qualified patients. The financial benefits of the 340B discount can be significant for healthcare institutions. The 340B program has an important impact on patients with cancer and their providers because of the high costs of oral therapies and other drugs that are given in the outpatient setting.2 In recent years, there has been a

4

great deal of debate as to whether the expansion of this program is consistent with the original intent of the legislation that created it.3 There has also been much written about the benefits of the program to patients and to eligible institutions. Advocates of the program have argued that the program allows eligible institutions to expand the services they offer and to provide appropriate care to individual patients who otherwise would not have had access to or have received this care.2 Alternatively, there has been criticism of the program because institutions have abused it to expand their provider networks and take advantage of the discounts for the benefit of the institution.4 It has also been suggested that some institutions have taken the discounts for inpatient care when the program was intended only for use in the outpatient care setting.4

ing the costs of outpatient services.

The expansion by these hospital-based cancer programs has significantly increased the overall cost of care in some communities. Others have been critical of nonprofit hospitals that do not align the 340B discount program with the delivery of indigent care.4 Organizations that have suggested that the program be reformed include the American Society of Clini­ cal Oncology and the Community Oncology Alliance, both of which have written position statements and white papers in the past year on this topic.2,4 Advocates of the program, such as the Safety Net Hospitals for Pharmaceutical Access (SNHPA), have promoted bipartisan legislation to expand and maintain the program’s original intent.8 It is increasingly clear that the cost of drugs for the treatment of cancer

There needs to be reform in the 340B program, and the time for enhanced supervision is now. The government should take action to address the abuses in this program that contribute to increased costs for care.

more than $27 billion, on marketing and advertising.10 For many years, the pharmaceutical industry has benefited from the support of the federal government.

The expansion of pharmaceutical spending resulting from the Medicare Modernization Act, which created Medicare Part D, is one such example.

The time has come for the government to restore the free market in the pharmaceutical industry, while simultaneously addressing the conduct of 340B-eligible organizations that abuse the intent of the 340B programs to attain competitive advantages in their markets.

There needs to be reform in the 340B program, and the time for enhanced supervision is now. The government should take action to address the abuses in this program that contribute to increased costs for care. It is important that lawmakers consider alternative approaches that will ensure that all patients have access to affordable drugs, while pharmaceutical companies continue to generate the resources they need to support research and innovation. n Reference

The expansion in the size of the 340B Drug Pricing Program has resulted from policy changes made by the HRSA and Congress and the use of contracted pharmacies that distribute drugs at sites other than at 340B-covered sites.

In March 2010, HRSA issued guidance that allows 340B-covered entities to create arrangements that permit them to increase the number of prescriptions filled through contracted pharmacies.5 During the past several years, there has been concern whether this program has been adequately managed.

These concerns have been examined by the Government Accountability Office6 and the Office of Inspector General,7 and Congress has taken a role in investigating the potential abuse of the program.

Although they appreciate the noble intentions of the 340B Drug Pricing Program, oncologists in private practice have also recognized that some hospitals have used the program to expand their number of employed oncologists.4 Many of these hospitals bill for services at higher rates than physicians in the community, thereby increas-

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and other chronic diseases is not sustainable. It is inconsistent that federal laws allow many organizations to be eligible for substantial discounts, including state Medicaid programs and the Veterans Administration that can negotiate drug pricing with pharmaceutical companies, yet Medicare does not. Of note, European governments pay significantly less for many medications than patients in the United States and our own government.

Although the pharmaceutical industry has taken a position and has sued the US Department of Health & Human Services regarding providing 340B coverage for orphan drugs,9 pharmaceutical companies do not appear to be as publicly critical of the expansion of the 340B Drug Pricing Program as may be expected.

This debate was recently put in perspective by Ted Slafsky, President and Chief Executive Officer of the SNHPA, who indicated that only 2% of the $325 billion in annual US pharmaceutical spending is attributable to 340B purchases, yet pharmaceutical companies spend 8% of this revenue,

1. Richardson K; for Medicine for People in Need. The bridge to 340B: comprehensive pharmacy services solutions in underserved populations. April 2004. www. hrsa.gov/opa/files/bridgeto340b.pdf. Accessed August 7, 2014.

2. American Society of Clinical Oncology. Policy statement on the 340B Drug Pricing Program by the American Society of Clinical Oncology. J Oncol Pract. 2014;10:259263.

3. Alliance for Integrity and Reform of 340B. The impact of growth in 340B contract pharmacy arrangements.

Summer 2014. http://340breform.org/userfiles/FINAL. The%20Impact%20of%20Growth%20in%20340B%20 Contract%20Pharmacy%20Arrangements.%20AIR%20 340B.%20July%2014,%202014.pdf. Accessed August 7, 2014.

4. Community Oncology Alliance. 340B Drug Discount Program: position statement. July 21, 2014. http:// blog.communityoncology.org/userfiles/76/COA_ Position_340B_7-14.pdf. Accessed August 7, 2014.

5. Notice Regarding 340B Drug Pricing Program— Contract Pharmacy Services. Fed Regist. 2010;75:1027210279.

6. Government Accountability Office. Manufacturer discounts in the 340B Program offer benefits, but federal oversight needs improvement. September 23, 2011. www.gao.gov/new.items/d11836.pdf. Accessed August 7, 2014.

7. Office of Inspector General. Memorandum report: contract pharmacy arrangements in the 340B program.

February 4, 2014. www.oig.hhs.gov/oei/reports/oei-0513-00431.pdf. Accessed August 7, 2014.

8. Safety Net Hospitals for Pharmaceutical Access.

Statement from SNHPA President and CEO Ted Slafsky on the bipartisan 2014 budget agreement. Press release.

January 14, 2014. www.snhpa.org/files/SNHPA_bud get_statement_1_28_14.pdf. Accessed August 7, 2014.

9. Health Resources and Services Administration.

Orphan drugs exclusion. www.hrsa.gov/opa/program requirements/orphandrugexclusion/. Accessed August 7, 2014.

10. Slafsky T. More of the same from Big Pharma.

Congress Blog. April 1, 2014. http://thehill.com/blogs/ congress-blog/healthcare/202210-more-of-the-samefrom-big-pharma. Accessed August 7, 2014.

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Advance Care Planning

VALUE PROPOSITIONS Value of Low-Dose Aspirin for the Prevention of Pancreatic Cancer

Results of a new study by the American Association for Cancer Research suggest that the long-term use of low-dose aspirin lowers the risk for developing pancreatic cancer (Streicher SA, et al. Cancer Epidemiol Biomarkers Prev. 2014;23:1254-1263).

“We found that the use of low-dose aspirin was associated with cutting the risk of pancreatic cancer in half, with some evidence that the longer low-dose aspirin was used, the lower the risk,” said Harvey A. Risch, MD, PhD, Professor of Epidemiology, Yale School of Public Health. A dose of 75 mg to 325 mg daily was defined as low dose in this study. The risk reduction was 39% for patients who took low-dose aspirin for ≤6 years and 60% for those who took the drug for >10 years.

“Because about one in 60 adults will get pancreatic cancer and the fiveyear survival rate is less than 5 percent, it is crucial to find ways to prevent this disease,” said Dr Risch. American Association for Cancer Research press release; June 26, 2014

A Simple Blood Test Can Accurately Identify 3 Types of Cancer

A new blood test, the Lymphocyte Genome Sensitivity (LGS) test, was developed at the University of Bradford, United Kingdom, and may soon offer a new, noninvasive way of diagnosing 3 types of cancer—melanoma, colon cancer, and lung cancer. If the results are confirmed in an ongoing clinical trial, this simple blood test could be an alternative to invasive procedures, such as colonoscopies or biopsies, in determining whether a person has 1 of these types of cancer, and can save the costs of these more invasive procedures.

The LGS test measures potential damage in the DNA of white blood cells that are subjected to different intensities of ultraviolet (UV) A light. Early results (Anderson D, et al. FASEB J. 2014 Jul 25. Epub ahead of print) suggest that the test has a high degree of accuracy in diagnosing melanoma, lung cancer, and colon cancer, said lead investigator Diana Anderson, PhD, of the School of Life Sciences and School of Health Sciences, University of Bradford, United Kingdom.

“These are early results completed on three different types of cancer and we accept that more research needs to be done; but these results so far are remarkable,” said Dr Anderson. “Whilst the numbers of people we tested are, in epidemiological terms, quite small, in molecular epidemiological terms, the results are powerful.”

The study included blood samples from 208 persons, including 94 healthy individuals and 114 blood samples from individuals suspected of having cancer. The samples were coded, deidentified, and were then ran-

domly exposed to UVA light through 5 different depths of agar.

“We’ve identified significant differences between the healthy volunteers, suspected cancer patients, and confirmed cancer patients of mixed ages at a statistically significant level of P <0.001. This means that the possibility of these results happening by chance is 1 in 1000. We believe that this confirms the test’s potential as a diagnostic tool,” said Dr Anderson.

The test ultimately diagnosed 58 patients with cancer, 56 individuals with precancerous conditions, and 94 healthy individuals. If approved, the test can help to quickly rule out or confirm the 3 types of cancer, saving time and costs. The test may eventually be useful for other types of cancer. As Dr Anderson notes, “We found that people with cancer have DNA which is more easily damaged by ultraviolet light than other people, so the test shows the sensitivity to damage of all the DNA—the genome—in a cell.”

The University of Bradford has filed patents for this new test, and a new company, Oncascan, has been established to prepare the test for use in clinical practice. University of Bradford, United Kingdom, press release; July 28, 2014

New Collaboration Highlights Value of Immunotherapy in Lung Cancer

Dana-Farber Cancer Institute has announced a new collaboration between its Belfer Institute for Applied Cancer Science, Johnson & Johnson Innovation, and Janssen Biotech to identify which patients with lung cancer are most likely to benefit from new-generation immunotherapies, which immunotherapy combinations would be most effective in lung cancer, and look for new biomarkers.

This new collaboration brings together researchers from Janssen and the Belfer Institute’s lung cancer research platform to maximize innovation efforts for this type of cancer. “Harnessing the immune system to fight common and deadly cancers is one of the most exciting areas in oncology,” said Barrett Rollins, MD, PhD, Chief Scientific Officer at Dana-Farber Cancer Institute and Linde Family Professor of Medicine at Harvard Medical School. “Belfer Institute scientists have unique tools for figuring out how to do this. Through their work with Janssen, a leader in therapeutic innovation, we expect to see the rapid development of new drugs that will help cancer patients,” Dr Rollins said.

“Immunotherapies have yielded dramatic and durable responses in subsets of cancer patients. In lung cancer there is a tremendous opportunity to enhance patient outcome by understanding why some patients respond to immunotherapy agents while others don’t,” said Kwok-Kin Wong, MD, PhD, Co-Scientific Director of the Belfer Institute. “Our partnership with Janssen will focus on elucidating response and resistance mechanisms so that new therapies can be used to extend lung cancer patients’ lives.”

Dana-Farber Cancer Institute press release; June 24, 2014

FDA Drug Approvals Lymphoseek Injection Receives Expanded Indication for Head and Neck Cancer SLN Biopsy

The FDA approved technetium Tc 99m tilmanocept (Lymphoseek In­ jection; Navidea Biopharmaceuticals) for an expanded use for guiding sentinel lymph node (SLN) biopsy in patients with head and neck cancers with squamous-cell carcinoma of the oral cavity. This is the first approval

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for a radiopharmaceutical agent for the diagnosis of SLN. The approval was done under the agency’s priority review process.

In 2013, the FDA approved Tc 99m for lymphatic mapping in patients with breast cancer or with melanoma. The new indication was approved based on data from a prospective phase 3 study showing that Tc 99m had a significantly greater ability to correctly identify patients with pa-

thology-positive SLN compared with lymph node dissections or pathologic evaluations.

In addition, the use of multiple levels of lymph node dissection in the trial resulted in the removal of 38 lymph nodes per patient compared with only 4 lymph nodes, on average, with Tc 99m, which represents a substantial reduction in potential morbidity in patients undergoing SLN biopsy.

(June 13, 2014)

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Belinostat Approved for Peripheral T-Cell Lymphoma, an Aggressive Form of NHL

The FDA approved belinostat (Beleodaq; Spectrum Pharmaceuticals) for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), a rare and fast-growing type of non-Hodgkin lymphoma (NHL). The approval was done under the agency’s accelerated approval program. PTCL comprises a

Continued on page 44

www.ValueBasedCancerCare.com

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Economics of Cancer Care

Medication Costs Impact Patient Adherence... treatment of cancer. The findings of a cross-sectional survey show that many of today’s high-cost cancer drugs impose out-of-pocket costs on patients that affect their treatment decisions (Bestvina CM, et al. J Oncol Pract. 2014; 10:162-167).

“A growing body of evidence suggests that insured cancer patients are suffering under mounting healthcare bills,” study coinvestigator S. Yousuf Zafar, MD, MHS, Associate Professor and Gastrointestinal Oncologist at Duke Cancer Institute, Durham, NC, told Value-Based Cancer Care. “Our findings suggest that patients might wait to talk about costs until they are already financially burdened. We need to work harder at identifying patients at risk for financial toxicity before they experience it.”

The survey included 300 insured respondents diagnosed with solid tumors who had received at least 1 month of anticancer therapy at the time of enrollment. The most common malignancy was colorectal (81%). The median income of the group was approximately $60,000 annually; 49 (16%) respondents reported a state of “high” or “overwhelming” financial distress. A total of 56

By the Numbers 50%—average rate of adherence to long-term treatment for chronic illnesses in developed countries worldwide 33%—approximate proportion of patients with cancer who delay or omit many prescribed doses Nearly 75%—rate of patients with advanced cancer who experience pain, with nonadherence a main cause leading to undertreatment of their pain 89%—rate of patients adhering to around-the-clock treatment among patients with cancer versus only approximately 25% of patients adhering to prescribed “as needed” treatment Source: World Health Organization.

Adherence to long-term therapies: evidence for action.

2003. http://whqlibdoc.who.int/ publications/2003/9241545992.pdf.

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(19%) patients had talked with their oncologist about out-of-pocket costs, and 155 (52%) patients reported some desire to have cost discussions with their oncologist.

“Whether we are talking about cost, quality, or satisfaction, the patient– physician relationship is at the epicenter of how we define delivery of best possible care,” said Dr Zafar about why patient–physician communica-

motherapy doses, approximately 2% took less chemotherapy drugs than prescribed, and 3% did not fill a prescription for a chemotherapy agent because of cost.

Discussing Costs with Your Patients Dr Zafar said that there are strategies oncologists can use in their conversations with patients to help allevi-

“

Our findings suggest that patients might wait to talk about costs until they are already financially burdened. We need to work harder at identifying patients at risk for financial toxicity before they experience it.

”

—S. Yousuf Zafar, MD, MHS

tion is vital in preserving quality of care. “A great deal of work has been— and is being—done around how to optimize that relationship. We are learning more about how cost can harm the patient experience. Just like we have learned to communicate and teach patients about how to manage physical toxicity related to chemotherapy, we must foster patient–physician communication around financial toxicity.

Importantly, not everyone wants to talk about costs. Part of the challenge is identifying those who might benefit most from such a discussion.”

Medication Cost and Nonadherence Patient-reported nonadherence parameters in this study included: • Skipping doses • Taking less medication than prescribed to make it last longer • Or simply not filling a prescription because of cost.

Of the 300 patients in the study, 80 patients reported nonadherence to their medication. Of the nonadherent patients, 66 (22% of the total patients) did not fill a prescription because of cost, 42 (14%) skipped doses, and 33 (11%) took less medication.

When asked about adherence with chemotherapy drugs, 14 (approxi­ mately 5%) patients reported nonadherence to their chemotherapy. To make a prescription last longer, 1% of the study patients skipped che-

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ate any financial concerns before they become a barrier to adherence.

“Keep it simple. We know that in the outpatient setting, prescription medications are the biggest culprit in terms of out-of-pocket costs. A simple

“

We can no longer afford to ignore the impact of financial burden on the quality of care and patient well-being. We need to find ways to integrate value and costs to patients into decision-making.

”

—S. Yousuf Zafar, MD, MHS

question like, ‘Do you have prescription drug coverage?’ can save a patient thousands of dollars, especially as we prescribe more oral chemotherapy,” he said.

“Also, I engage the help of others.

Our pharmacist in the clinic evaluates the insurance plans of my patients before they leave with their expensive prescription. This avoids problems down the road.”

The study findings raise important questions for oncologists regarding shared decision-making, said Dr Zafar.

“First, we have to find ways to address

Continued from the cover

at a glance ➤ The patient–physician relationship is at the center of delivering best possible care for patients with cancer ➤ Financial concerns can be a barrier to medication adherence even when dealing with cancer ➤ Physicians must begin to engage their patients in cost discussions and involve team members for help ➤ Find out if the patient has drug coverage, and if cost is an issue of concern ➤ Identifying patients at risk for financial toxicity will improve proper medication adherence ➤ More research is needed on how to promote discussion of costs of therapy to improve adherence the cost of care in decision-making without getting too bogged down in details of insurance plans and nontransparent pricing,” he advised.

“Most oncologists want to avoid adding to their patients’ financial burden, but we have little education as to how we can help. Second, we need more effective ways to educate patients about the risks and benefits of treatment. Only then can patients make informed decisions regarding the value of their cancer care.”

Dr Zafar emphasized, “We can no longer afford to ignore the impact of financial burden on the quality of care and patient well-being. We need to find ways to integrate value and costs to patients into decision-making.

Again, not everyone wants or needs to discuss costs, but in the status quo, we are missing even the ones who do want to have that discussion.”

Dr Zafar acknowledged the study’s limitations. “These data suggest correlation but not evidence of direction.

In other words, we could not tell specifically if nonadherence was a result of cost discussion or vice versa.

Furthermore, details of the cost discussions between patients and physicians were not recorded. Specifically, it is unclear what event triggered the discussion or whether the patient or provider initiated the conversation. Future research should focus on whether promoting cost discussion can improve treatment adherence,” he suggested. n

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Economics of Cancer Care

Even When Adjusting for Improved Survival, Newer Anticancer Drugs Are More Expensive than Older Ones

By Wayne Kuznar

Chicago, IL—Even after adjusted for improved outcomes, newer anticancer drugs are more expensive than older agents, said Rena Conti, PhD, Assistant Professor of Health Policy and Economics, University of Chicago, at the 2014 American Society of Clinical Oncology meeting.

This conclusion came from an examination of the prices of 56 anticancer drugs approved between 1995 and 2013. The analysis measured the launch prices of the drugs using Medicare prices for oral and intravenous drugs, and adjusted the price (in 2013 dollars) based on survival data obtained from phase 3 clinical trials. For drugs approved on the basis of single-arm trials, modeling studies were used to estimate the survival benefit. The prices of the drugs represent the cost of a course of therapy based on the median duration of treatment in the clinical trials submitted to gain approval.

“The reason we did this study was to examine exactly how and if the launch prices of these were increasing at a rate over and above inflation, and also over and above their benefit in terms of survival,” said Dr Conti.

For each drug, the annual price of additional survival was calculated as the price per course of therapy divided by the survival benefit in years.

The average drug price in the sample was $78,600, and the average survival benefit was 0.45 years. Therefore, the average annual price of survival benefit was $185,000.

“We found that drug prices, after adjusting for survival, appear to be going up approximately 5% to 7% per year over time. These are inflation-

“

the same drug launched in 2010 would have been $84,000. A sensitivity analysis found no change in the results when controlling for side effects or quality of life.

Manufacturers are pricing their anticancer drugs as high as the market is willing to bear, with little pushback from insurers, hospitals, or physicians,

Drug prices, after adjusting for survival, appear to be going up approximately 5% to 7% per year over time.

adjusted prices,” she said. “The only other consumer goods that we see that have this type of price trajectory appear to be luxury products, such as art and jewelry, but also college tuition.”

The price of an additional month of survival increased by $600 annually, Dr Conti noted. The model predicted that the launch price of a drug that extended median survival by 5 months would be $37,000 in 1995, but

”

—Rena Conti, PhD

Dr Conti said. “These are list prices,” she pointed out. “It reflects what insurers will pay, and also what patients will pay for these therapies. This is not what physicians, hospitals, and pharmacies pay to acquire these drugs, and we believe that there are quite substantial discounts in the marketplace for these therapies that are then baked into the list price over time.”

Expansion of the 340B Drug Pricing

at a glance ➤ New cancer drugs are more costly than older agents, even after adjusting for improved outcomes ➤ Manufacturers are pricing these drugs at the highest possible market prices, with little pushback from insurers, hospitals, or physicians ➤ The cost of cancer drugs increases annually by approximately 5% to 7%, after adjusting for survival ➤ Using current drug costs, this model calculated that a drug launched in 1995 and extended median survival by 5 months would have been priced at $37,000 versus $84,000 if launched in 2010 ➤ The price of an additional month of survival for a cancer drug is $600 annually

Program, which requires manufacturers to give discounts to eligible buyers, may have contributed to price increases for noneligible buyers, she added. n

Oncologists Want More Education on How to Discuss Cost of Treatment with Patients Chicago, IL—Oncologists responding to a national electronic survey believe that discussing out-of-pocket (OOP) costs of therapy with patients is important, and that OOP costs and societal cost of therapy will play a larger role in cancer treatment decisions over the next 5 years. These results were reported by Laura L. Tenner, MD, a hematologist/oncologist at Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, at the 2014 American Society of Clinical Oncology meeting.

US oncologists’ attitudes and perceptions about the cost of cancer care in the wake of the implementation of the Affordable Care Act (ACA) were assessed through an electronic questionnaire deployed over 4 months in 2013.

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“Back in 2008, about 40% of physicians said that they communicated to their patients about costs of therapy

“

cause of the ACA coming in,” Dr Tenner said.

“Because of the competing obliga-

Under the ACA, physicians will only be able to do what has proven to be efficacious, so they’re going to have to start having those difficult discussions with patients.

”

—Laura L. Tenner, MD

most of the time or always, and we wanted to see if that has changed be-

tions placed on physicians by the ACA, physicians may have to become

august 2014

I

adept at engaging in shared decision-making and communication concerning cost and resource distribution,” said Dr Tenner.

Survey Results A total of 135 (16%) of the oncologists contacted in 50 states responded to the survey, representing 35 states.

Of these, 41% of the oncologists are in private practice, 30% are employed at a university medical center, 17% at a community hospital, and 5% at an HMO. “Under the ACA, physicians will only be able to do what has proven to be efficacious, so they’re going to have to start having those difficult discussions with patients,” she added.

Dr Tenner and colleagues found

Continued on page 8

www.ValueBasedCancerCare.com

7

Economics of Cancer Care

Most Hospital Readmissions Not Preventable for Patients with Cancer

By Wayne Kuznar

Chicago, IL—Hospital readmissions in patients with cancer reflect the high burden of this disease, which is often refractory and, therefore, readmission is not reasonably preventable. Consequently, applying readmission penalties to this population, as is being done with noncancer index admissions, is not appropriate, said Andrew S. Epstein, MD, Division of Gastrointestinal Medical Oncology, Memorial Sloan Kettering Cancer Center (MSKCC), at the 2014 American Society of Clinical Oncology meeting.

“The vast majority of readmissions in this population do not represent lapses in care, judgment, or discharge management during the index admission and are not reasonably preventable,” he said.

In an effort to improve patient care and reduce costs, the Centers for Medicare & Medicaid Services has initiated the Hospital Readmissions Reduction Program. This currently applies to certain noncancer index admissions and defines readmission as an admission occurring within 30 days of a discharge. Reimbursement penalties are incurred for readmissions deemed preventable.

Readmissions for cancer are not included in the program, but there is concern among oncologists that these could soon be targeted. This study was

conducted at MSKCC to determine whether readmissions for cancer may be reasonably preventable.

From a database of 876 patients with cancer who had been discharged and then readmitted between September 2008 and March 2013 within 30 days to the Gastrointestinal Oncology

“

The vast majority of readmissions in this population do not represent lapses in care, judgment, or discharge management during the index admission and are not reasonably preventable.

”

—Andrew S. Epstein, MD Service of MSKCC, Dr Epstein and colleagues randomly selected 50 cases.

Two study authors manually reviewed each case to assess reasons for index admission and readmission, the nature of the index admission discharge plan, and whether the readmission was preventable.

“We were hypothesizing that our patients with this disease are so sick and vulnerable that the readmissions

are not preventable,” Dr Epstein said.

“Preventable” was defined prestudy as a readmission that could probably have been avoided by either prolonging the index admission until a realistically attainable medical improvement had occurred, or by making agreed on practical changes in the index admission discharge plan.

Cases identified as potentially preventable readmissions were then critically reviewed by 3 study authors to reach a consensus.

Of the 50 cases, the most common diagnosis categories for either index admission or readmission were infection, pain, or gastrointestinal issues.

The readmission diagnoses differed from index admission diagnoses in 64% of the cases.

In 5 cases, there was disagreement between the care team and the patient or family about the index admission discharge plan. Although the disagreements did not result in preventable readmissions, “it is an extremely important minority of patients to try to deliver care to in the future through… better communication about the risks, benefits, and alternatives of certain treatments or discharge plans,” acknowledged Dr Epstein.

Review of the records revealed the fragile health and/or refractory admitting diagnoses of all patients. Diagno-

Oncologists Want More Education... that physicians are communicating with patients about cost at a similar rate as they did 5 years ago, 43% in 2008 versus 48% in 2013. “What has changed is that physicians want more cost-effectiveness and comparative effectiveness data to be able to make those decisions,” she said. “They feel like they don’t have the resources right now to be able to effectively communi-

cate with patients about cost of therapies and decision-making.”

A total of 89% of respondents strongly or somewhat strongly agreed that it was important to discuss OOP costs with patients, and 66% strongly or somewhat strongly agreed that discussing healthcare system costs with patients was important.

In all, 70% of respondents reported

at a glance ➤ Discussing costs with patients will play a larger role in cancer treatment decisions over the next 5 years ➤ In a survey of 135 oncologists, 70% reported that patient OOP costs influence their treatment decisions

8

Value-Based Cancer Care

➤ Also, 60% said cancer care costs were likely to have a larger effect on their treatment decision-making ➤ Approximately 66% thought physicians should decide the value of certain drugs, but 4% said the government should decide

I

august 2014

at a glance ➤ Most readmissions of patients with cancer do not result from lapses in care, judgment, or discharge management ➤ The majority of hospital readmissions for patients with cancer reflect the challenges of the disease and are overall not preventable ses may have improved or resolved and then recurred despite appropriate treatment, he indicated.

Only 1 readmission of the 50 cases was found to have been preventable.

This readmission involved a patient who was discharged with a recommendation for an outpatient procedure that was not scheduled. The findings indicate that readmissions for patients with cancer are not reasonably preventable in the vast majority of cases. In this population, readmissions are common as a result of the devastating nature of the disease. “We hope that if cancer patients are ever considered for inclusion under this readmission reduction program, these data would refute the inclination to include them,” Dr Epstein said. n

Continued from page 7

that OOP costs of therapy influence their treatment decisions, and 60% agreed that OOP costs and healthcare system costs of treatment for cancer were likely or extremely likely to have a larger effect on their decisions regarding which cancer treatments to recommend to patients in the future under the ACA. Some 87% of the oncologists said more comparative effectiveness research is needed, and 91% desired more cost-effectiveness research. In all, 85% of the respondents agreed that communicating the cost of therapies with patients was needed.

Approximately 66% of respondents noted that physicians are the ones who should decide the value of certain drugs, whereas only 4% said that government should decide good value. A total of 53% favored more government price controls of health resources, and 62% of

“

These data suggest that educational efforts aimed at improving oncologists’ tools for communication about the costs of cancer care would be valuable.

”

—Laura L. Tenner, MD

respondents thought that the health system cost of therapy would have a larger effect on treatment decisions.

“These data suggest that educational efforts aimed at improving oncologists’ tools for communication about the costs of cancer care would be valuable,” said Dr Tenner. n

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The first and only FDA-approved combination therapy Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

2 AGENTS. 1 THERAPY.

DEMONSTRATED DURABLE RESPONSE RATE IN A PHASE II STUDY 1,2

Investigator-assessed analysis

TAFINLAR + MEKINIST

150 mg twice daily

2 mg once daily

in combination TAFINLAR

as a single agent

overall response rate1 overall response rate1

76 54%

% (95% CI: 62, 87)

median duration of response1

(95% CI: 40, 67)

median duration of response1

10.5 5.6

months

(95% CI: 7, 15)

months

(95% CI: 5, 7)

Important Safety Information for TAFINLAR and MEKINIST when used in combination New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.

Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.

New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of

TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.

Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies.

Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

TAFINLAR + MEKINIST demonstrated a 76% overall response rate1 Major efficacy outcome: Investigator-assessed response rate1 Overall Response

54%

(95% CI: 40, 67)

Overall Response

76%

(95% CI: 62, 87)

67%

80 70

50%

60

Response Rates

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutationpositive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible.

Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1

50 40 30 20 10 0

9%

4

%

Complete Response

Partial Response

TAFINLAR as a single agent (N=54)

Complete Response

TAFINLAR

150 mg twice daily

+

Partial Response

MEKINIST

2 mg once daily

(N=54)

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST

and in none of the patients treated with TAFINLAR as a single agent.

The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55).

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of â&#x2030;Ľ20% below baseline.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749).

RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances.

Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent. Retinal detachments resulting from MEKINIST are often

TAFINLAR + MEKINIST achieved a median duration of response of 10.5 months1 Efficacy outcome: Investigator-assessed median duration of response1

TAFINLAR

+ MEKINIST

150 mg twice daily 2 mg once daily (N=54)

10.5

months

(95% CI: 7, 15)

Months Months TAFINLAR as a single agent (N=54)

5.6

months

(95% CI: 5, 7)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1 • 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1 – Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39% • Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.

Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1.

If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.

If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination

with MEKINIST compared with TAFINLAR as a single agent.

In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.

In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

®

(dabrafenib) 50 mg, 75 mg capsules

®

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202).

Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications.

Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.

Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination.

Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective.

Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST. Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg

twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%).

The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%).

Drug Interactions Effects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

Effects of the Combination of Dabrafenib with Trametinib.

Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions.

To learn more, visit TAFINLARMEKINISTHCP.com Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Please see full Prescribing Information and Medication Guide for TAFINLAR and full Prescribing Information and Patient Information Leaflet for MEKINIST.

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Flaherty KT, Infante JR, Daud A, et al.

N Engl J Med. 2012;367:1694-1703.

TAFINLARMEKINISTHCP.com TAFINLAR and MEKINIST are registered trademarks of the GSK group of companies. ©2014 GSK group of companies. All rights reserved.

Printed in USA. MEL156R0 July 2014

®

(dabrafenib) 50 mg, 75 mg capsules

®

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

BRIEF SUMMARY TAFINLAR® (dabrafenib) capsules, for oral use MEKINIST® (trametinib) tablets, for oral use The following is a brief summary only; see Full Prescribing Information for each product to view the complete product information 1 INDICATIONS AND USAGE TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate.

Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent.

The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.

Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.

New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.

Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)].

5.3 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

5.4 Venous Thromboembolism Venous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

5.5 Cardiomyopathy Cardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with

MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55).

Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

5.6 Ocular Toxicities Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749).

RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose.

Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina.

In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202).

Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.

Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops.

Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. 5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days).

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations.

Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.

If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. 5.7 Serious Febrile Reactions The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].

In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.

In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202).

Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. 5.8 Serious Skin Toxicity Serious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.

Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity.

TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

5.9 Hyperglycemia Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.

Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5.10 Glucose-6-Phosphate Dehydrogenase Deficiency TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

5.11 Embryofetal Toxicity TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman.

Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label: • New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST. BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white.

Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent.

In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination.

Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 All All Grades Adverse Reactions Gradesa 3 and 4 Gradesa General disorders and administrative site conditions Pyrexia 71 5 69 Chills 58 2 50 Fatigue 53 4 57 b 31 0 28 Edema peripheral Skin and subcutaneous tissue disorders 45 0 43 Rashc Night Sweats 24 0 15 Dry skin 18 0 9 Dermatitis acneiform 16 0 11 Actinic keratosis 15 0 7 Erythema 15 0 6 Pruritus 11 0 11 Gastrointestinal disorders Nausea 44 2 46 Vomiting 40 2 43 Diarrhea 36 2 26 33 2 24 Abdominal paind Constipation 22 0 17 Dry mouth 11 0 11 Nervous system disorders Headache 29 0 37 Dizziness 16 0 13 Respiratory, thoracic, and mediastinal disorders Cough 29 0 11 Oropharyngeal pain 13 0 7 Musculoskeletal, connective tissue, and bone disorders Arthralgia 27 0 44 Myalgia 22 2 24 Back pain 18 5 11 Muscle spasms 16 0 2 Pain in extremity 16 0 11 Metabolism and nutritional disorders Decreased appetite 22 0 30 Dehydration 11 0 6 Psychiatric Disorders Insomnia 18 0 11 Vascular disorders 16 5 11 Hemorrhagee Infections and infestations Urinary tract infection 13 2 6 Renal and urinary disorders 7 7 2 Renal failuref

Grades 3 and 4

All Gradesa

Grades 3 and 4

9 2 2 0

26 17 40 17

0 0 6 0

2 0 0 0 0 0 0

53 6 6 4 9 2 13

0 0 0 0 0 0 0

6 4 0 2 2 0

21 15 28 21 11 6

0 0 0 2 0 0

2 0

28 9

0 0

0 0

21 0

0 0

0 0 0 0 2

34 23 11 4 19

0 2 2 0 0

0 2

19 2

0 0

0

8

2

0

2

0

0

9

2

0

0

0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.

Includes the following terms: peripheral edema, edema, and lymphedema. c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular. d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. f Includes the following terms: renal failure and renal failure acute.

Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were: Eye Disorders: Vision blurred, transient blindness.

Gastrointestinal Disorders: Stomatitis, pancreatitis.

General Disorders and Administration Site Conditions: Asthenia.

Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.

Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.

Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis.

Vascular Disorders: Hypertension.

Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 a

b

All Grades

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4a Tests Hematology Leukopenia 62 5 46 4 21 0 Lymphopenia 55 22 59 19 40 6 Neutropenia 55 13 37 2 9 2 Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0 Liver Function Tests Increased AST 60 5 54 0 15 0 Increased alkaline 60 2 67 6 26 2 phosphatase Increased ALT 42 4 35 4 11 0 Hyperbilirubinemia 15 0 7 4 0 0 Chemistry Hyperglycemia 58 5 67 6 49 2 Increased GGT 56 11 54 17 38 2 Hyponatremia 55 11 48 15 36 2 Hypoalbuminemia 53 0 43 2 23 0 Hypophosphatemia 47 5 41 11 40 0 Hypokalemia 29 2 15 2 23 6 Increased creatinine 24 5 20 2 9 0 Hypomagnesemia 18 2 2 0 6 0 Hyperkalemia 18 0 22 0 15 4 Hypercalcemia 15 0 19 2 4 0 Hypocalcemia 13 0 20 0 9 0 a No Grade 4 events were reported in patients receiving TAFINLAR as a single agent.

ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.

QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent.

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Dabrafenib Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

Grades 3 and 4

7.2 Effects of Dabrafenib on Other Drugs Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

7.3 Trametinib Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy TAFINLAR Pregnancy Category D Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)].

Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

MEKINIST Pregnancy Category D Risk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)].

Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss.

In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in postimplantation loss, including total loss of pregnancy, compared with control animals.

8.3 Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. 8.5 Geriatric Use One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1.

Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older.

8.6 Females and Males of Reproductive Potential TAFINLAR Contraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)].

Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients.

Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)].

MEKINIST Contraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)].

Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)].

Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR. 8.7 Hepatic Impairment TAFINLAR No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].

MEKINIST No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)].

The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment.

8.8 Renal Impairment No formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR. There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) for TAFINLAR. See FDA-approved patient labeling (Patient Information) for MEKINIST. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated.

• TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)].

• TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)].

• TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)].

• TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)].

• TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to

contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)].

• MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)].

• TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)].

• TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)].

• TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)].

• TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)].

• MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness.

• MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment.

• TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].

• Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)].

• Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)].

• TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal.

TAFINLAR is a registered trademark of GlaxoSmithKline.

MEKINIST is a registered trademark of GlaxoSmithKline.

GlaxoSmithKline Research Triangle Park, NC 27709

© 2014, GlaxoSmithKline group of companies. All rights reserved.

Revised: 01/2014 TFR:4BRS © 2014 GSK group of companies.

All rights reserved. Printed in USA. MEL156R0 July 2014

Economics of Cancer Care

Patients with Cancer Are Not Asking for Low-Value Tests or Therapies Educating patients can enhance value-based care

By Wayne Kuznar

“

The frequency of requested testing was unusual in itself. In only about 9% of 3800 encounters did a patient ask for something….When we asked the providers to rank the appropriateness of that request, it was pretty infrequent that even they thought it was an inappropriate request, and even less likely that they would act on an inappropriate request.

Photo by © ASCO/Todd Buchanan 2013

Chicago, IL—Contrary to common belief, there appears to be little demand on the part of patients with cancer for unsuitable, high-cost, low-value tests or therapies. Furthermore, oncologists and nurse practitioners (NPs) are not ordering such services often, according to Keerthi Gogineni, MD, MSHP, an oncologist at the Abramson Cancer Center, University of Pennsylvania, Philadelphia. He presented his findings at the 2014 American Society of Clinical Oncology meeting.

Data from a large survey of oncologists and NPs revealed that “the frequency of requested testing was unusual in itself. In only about 9% of 3800 encounters did a patient ask for something,” she said. “The likelihood of acting on inappropriate requests was even lower. When we asked the providers to rank the appropriateness of that request, it was pretty infrequent that even they thought it was an inappropriate request, and even less likely that they would act on an inappropriate request.”

Dr Gogineni and colleagues assessed whether and how often patients are seeking expensive or low-value therapies and treatments from their providers. Past studies have indicated that many patients with cancer, as well as oncologists and the public, believe

”

—Keerthi Gogineni, MD, MSHP

that healthcare costs are, to some extent, propelled by patients seeking unnecessary treatments, she said.

For the study, oncologists and NPs at 2 sites affiliated with an academic cancer center were questioned soon after patient visits to measure how often patients demanded potentially unnecessary treatments, whether the demands were acceptable to providers, whether physicians followed through on the requests, and why the providers chose to agree to certain tests.

Of the 2050 encounters assessed, 73.1% of patients were white, 42% had stage IV or refractory disease, and

66.3% were receiving active therapy.

A total of 26 clinicians were surveyed.

In 177 (8.6%) encounters, the patients requested some form of testing.

Clinicians were recommended to rank the appropriateness of patient requests on a 10-point Likert scale (1 = not at all appropriate, 10 = extremely appropriate).

Study Results More than 80% of the requests were categorized as appropriate. These included requests for imaging, blood work, and treatments for pain or nausea. Providers denied patients’ re-

quests in 32 (18.1%) cases; for 27 of these instances, physicians reported that they declined the test or therapy, because they viewed it as unnecessary or saw no clinical advantage to doing it. In 4 of the 2050 (<1%) encounters, the provider requested a test or therapy that was considered unsuitable.

Clinicians viewed requests by patients as inappropriate in only 24 (13.6%) encounters.

Patients with early-stage cancer were more likely to make an inappropriate request, said Dr Gogineni. Patients with late-stage disease who were undergoing surveillance were nearly twice as likely to make an inappropriate request compared with patients receiving treatment.

Of note, patients who were being treated with a goal to cure were more often seeking unnecessary treatments than patients who received palliative care.

To limit low-value care, the researchers suggest educating patients on evidence-based surveillance, because patients with early-stage cancer who are under observation are often more likely to seek inadvisable treatments or therapies. In this survey, patients undergoing observation were 9 times more likely to make inappropriate requests than patients with advanced-stage cancer. n

Secondary Oncology Pathways Can Have Big Cost Impact

By Kate O’Rourke

Chicago, IL—The implementation of collaborative, secondary clinical pathway programs can improve outcomes and can lower costs when providers are already participating in another payer-sponsored pathway program.

This conclusion comes from a study published online in conjunction with the 2014 American Society of Clinical Oncology meeting.

“Patients who enroll with providers who use pathway programs get more definitive outcomes-based treatment with more holistic care, because the providers are reminded to do not just the regimen-based prescribing, but also some of the other important care interventions that make a difference in

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Patients who enroll with providers who use pathway programs get more definitive outcomes-based treatment with more holistic care, because the providers are reminded to do not just the regimen-based prescribing, but also some of the other important care interventions.

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—Ira M. Klein, MD, MBA, FACP keeping patients out of the hospital and giving you a better outcome,” said Ira M. Klein, MD, MBA, FACP,

National Medical Director, Clinical Thought Leadership, Aetna.

Clinical pathways that guide evi-

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dence-based healthcare decisions have been shown to change practice patterns and improve health outcomes. In 2011, Aetna and Cardinal Health implemented an oncology pathway in which the dominant regional commercial payer, Blue Cross Blue Shield, had previously implemented a similar pathway program.

“The clinical criteria of the 2 pathways were closely matched, and ours lined up with Aetna’s Clinical Policy Bulletins,” said Dr Klein.

In this new study, Aetna investigators compared the impact of the second-to-market pathway on cost of care.

Claims data from July 1, 2010, through June 30, 2012, were used to evaluate

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Economics of Cancer Care

Telephone-Based Cancer Care Support Program Saves Big Bucks

By Kate O’Rourke

T

elephone-based support programs are capable of reducing cancer-related medical costs by 10% to 30%, according to results of the first nurse-led study of the cost impact of telephonic case management in oncology (Wu C, et al. J Oncol Pract. 2014; 10:178-186). This cancer support program was offered to self-insured employers with 3000 or more employees.

Patients with cancer could choose to participate in the program or not.

The goals of the program were to help patients understand their treatment goals, whether palliative or curative, and to facilitate informed decision-making about treatment; to reduce emergency department visits and hos-

at a glance ➤ A telephone-based cancer support program can reduce cancer-related medical costs by 10% to 30% and increase use of palliative care ➤ Over 6 months, the average medical costs were lower in participants compared with nonparticipants, whether they received active treatment ($10,363 vs $11,491) or not ($1306 vs $1448) ➤ The average cancer-related medical costs were also 28.2% lower for decedents ($14,684) who had participated in the program in their last month of life versus nonparticipants ($20,713)

pitalizations; and to enhance the effective management of symptoms, complications, and adverse effects.

“

We have abundant data that says that if people don’t have good effective management, they will be rehospitalized. We can’t be reactionary anymore, or we will go broke.

Nurses assisted patients with navigating the healthcare system and provided referrals to specialists as needed.

Nurses took an active role in managing costs by reviewing medications and comparing them with evidencebased standards.

The investigators compared outcomes in 3991 patients with cancer who chose to participate in the program and 4842 patients who did not participate.

Study Results The average cancer-related medical costs were 9.8% lower over 6 months of follow-up in patients with cancer who participated in the program than in those who did not participate (P <.01), with 57.8% of the savings attributable to lower inpatient costs, 32.2% attributable to reduced chemotherapy use, and 5.4% attributable to fewer nonchemotherapy-infused drugs.

The mean cancer-related medical

Secondary Oncology Pathways... the costs of managing patients with breast, lung, or colon cancer.

Chemotherapy, supportive care, emergency department, and hospital admission costs were compared for patients managed by providers participating in the secondary pathway program with patients managed by providers in only the primary pathway program.

Improved Outcomes After adjusting the data to account for variations in tumor type and age, the cost per patient for chemotherapy and supportive-care drugs decreased

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costs over 6 months per patient per month (PPPM) were lower in survivors who received active treatment

by 18.3% in the group that was using primary and secondary pathways, and increased by 3.8% in the physician group that was only impacted by the primary clinical pathway. The average number of emergency department admissions also decreased by 0.8% among providers participating in the secondary pathway and increased by 8.5% among secondary pathway nonparticipating providers.

The difference in the drug-cost trend between participating and nonparticipating providers was 22%, resulting in a savings of $7037 per patient annually. The aggregated savings

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—Betty Ferrell, RN, PhD, MA

and participated in the program ($10,363) compared with those who did not ($11,491). Similarly, the mean medical costs PPPM were lower among patients who participated in the program but did not receive active treatment ($1306) compared with those who did not participate in the program ($1448; P = .002).

The mean cancer-related medical costs were 28.2% lower for decedents in the last month of life if they had participated in the program ($14,684) than for those who did not participate in the program ($20,713; P <.01), with 81.3% of the cost-savings attributable to reduced inpatient costs, 9.8% attributable to reduced radiation therapy, and 5% attributable to less surgery.

Patients who participated in this telephonic support program spent more days in hospice in the last month of life than those who did not participate (16.4 days vs 12.8 days, respectively; P = .04).

Continued from page 17 for drug costs and emergency department admissions was $7402 per patient annually.

“It is interesting to look at pre- and postbehavior when implementing an additional pathway to see whether your entry in as a contracted pay for value payer changes behavior a lot or whether some of the people are already doing a little of this,” said Dr Klein. “We postulate that it is very hard for 1 payer to get maximal savings out of this, but generally if 2 or more payers elect to enter a market, you tend to leverage behavior change to the max.” n

Betty Ferrell, RN, PhD, MA, Director and Professor, Division of Nursing Research and Education, City of Hope, Duarte, CA, who was not involved with the study, said that this study is “significant” and adds to the growing body of evidence that telephone-based cancer support can reduce costs and can increase the use of palliative care.

“One of the significant things about this paper is that it was in a large group of people,” Dr Ferrell said.

She said that in a true cost-benefit analysis, the researchers would have tallied up the costs of running the telephone-based support, but she had no doubt that the program was cost-effective. “The investigators didn’t provide

Charlotte Wu, MBBS, MS

Average cancer-related medical costs were 9.8% lower over 6 months of follow-up in survivors who participated in the program. the length of the phone calls and the minutes of nursing time, which you would need to figure out how much time the nurses spent on average with each patient to put a price tag on the program, but I think even though they didn’t go into the cost of the program, [telephone-based care] is not very costly,” Dr Ferrell said.

According to Dr Ferrell, oncology care has to keep moving toward providing cancer support programs at the beginning of cancer treatments to keep patients out of the emergency department and reduce hospitalizations. “We have abundant data that says that if people don’t have good effective management, they will be rehospitalized,” she said. “We can’t be reactionary anymore, or we will go broke.” n

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Emerging Therapies

2014 Oncology Pipeline Looks Impressive The monoclonal antibody ramucirumab, which is already approved for the treatment of advanced gastric cancer, is being investigated in NSCLC. Ramucirumab improved overall survival (OS) when added to docetaxel versus chemotherapy alone in a phase 3 trial of 1253 patients with stage IV NSCLC, although the median OS was prolonged by only 1.4 months (see article, page 46).

Other Agents CO-1686 is a selective, oral tyrosine kinase inhibitor (TKI) that specifically targets EGFR mutations in patients with NSCLC. The efficacy of other EGFR inhibitors has been limited by acquired resistance, most frequently a second T790M mutation. The proposed solution to this challenge is to create drugs that can inhibit these newly mutated targets.

At ASCO 2014, investigators reported early data on 3 drugs that successfully target T790M. In a phase 1/2 dose-finding trial of CO-1686, responses were achieved by 58% of 72 heavily pretreated patients with T790M mutations; in a phase 2 extension study of 40 patients, median progression-free survival (PFS) was not reached and was estimated to exceed 12 months. Activity against metastases in the central nervous system was observed. The most common toxicity was elevated glucose, which was well-managed with oral hypoglycemic and/or dose reduction.

In a phase 1 trial of AZD9291 in 199 heavily pretreated patients with EGFR mutation, the objective response rate (ORR) was 51%, rising to 64% among the 89 patients with a T790M mutation. Among T790M-negative patients, the response rate was 23%. Nearly all patients were still responding at the data cutoff, with the longest response lasting more than 8 months. AZD9291 is also associated with less skin toxicity than other EGFR inhibitors. Because greater efficacy is seen in patients with the T790M mutation, future studies of this drug will be limited to this subgroup.

Although they are still in clinical testing, AZD9291 and CO-1686 have already received breakthrough therapy designation from the FDA. Both drugs are in phase 3 clinical trials.

The oral CDK 4/6 inhibitor abemaciclib (LY2835219), given twice daily, showed evidence of single-agent activity in heavily pretreated patients with NSCLC in a phase 1 study.

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disease progressed or relapsed after a median of 4 previous treatments.

KRAS mutations were present in 29 of the patients. The disease control rate was 49%, including 2 partial responses and 26 patients with stable disease.

The disease control rate was higher for patients with KRAS mutation (55%) compared with the wild-type KRAS (38%).

The human anti-EGFR monoclonal antibody necitimumab improved median OS by approximately 2 months when added to standard chemotherapy in a phase 3 trial of patients with stage IV NSCLC of squamous histology (see article, page 46).

Myeloma In the international phase 3 PANORAMA 1 trial in multiple myeloma (MM), the addition of the oral pan-histone deacetylase (HDAC) inhibitor panobinostat to a bortez­­ omib-containing regimen led to a statistically and clinically significant 4-month increase in median PFS, meeting the study’s primary end point. The study enrolled 768 patients who had received 1 to 3 previous lines of treatment but their disease was not refractory to bortezomib.

The ORRs were similar between the arms—60.7% with panobinostat and 54.6% with placebo (P = .087)—but the active combination was associated with almost a doubling in the rate of complete responses (CRs) and near CRs—27.6% versus 15.7%, respectively (P = .006). The median PFS was significantly improved, from 8.1 months with placebo to 12 months with panobinostat (P <.001), a 37% reduction in risk. After 28 months of follow-up, the median OS remained comparable at 33.6 months in the panobinostat arm and 30.4 months in the placebo arm (P = .87).

In May 2014, the FDA granted priority review status to panobinostat. Other panobinostat-containing combinations and additional HDAC inhibitors are currently in clinical trials.

The ORR was 58% but rose to 63% among patients receiving the highest dose (10 mg/kg given every other week), with 25% of patients achieving a very good partial response.

Antitumor activity for the second monoclonal antibody, daratumumab, as a single agent was shown in a phase 2 study of 50 heavily pretreated patients with relapsed/refractory MM. The ORRs for the single agent were 35% with the 16-mg/kg dose and 10% with the 8-mg/kg dose. The median PFS times were 23 weeks in the 16-mg/kg group and 15 weeks in the 8-mg/kg cohort, although the investigators noted that the PFS analysis is still immature.

Lymphoma Favorable findings from the STARLYTE phase 2 trial were reported for coltuximab ravtansine (SAR3419), a CD19-targeting antibody drug conjugate, in diffuse large B-cell lymphoma.

Study investigators reported achievement of proof of concept, with a 43.9% ORR in 55 patients with relapsed and/ or refractory disease who received the single agent, including responses among patients whose disease had not responded to previous therapy. There were few treatment-related grade 3/4 adverse events. This was a “Best of ASCO” abstract.

Leukemia Blinatumomab is an investigational bispecific T-cell–engaging antibody developed using bispecific T-cell engager technology designed to bring the T-cells into closer contact with the tumor cells, thereby promoting T-cell– mediated lysis of tumor cells.

A large phase 2 study presented at the meeting confirmed the antileukemic activity of single-agent blinatumomab in a difficult-to-treat population of 189 patients with relapsed and/or refractory acute lymphocytic leukemia. Treatment with blinatumomab resulted in a 43% CR/complete hematologic response rate during the first 2 cycles. The median relapse-free surAnti-CD38 Monoclonal Antibodies vival was 5.9 months, and the median Impressive data from small early-­ OS was 6.1 months. phase studies were presented for 2 ABT-199 (GDC-0199), an investimonoclonal antibodies that target the gational B-cell lymphoma 2–selective CD38 protein—SAR650984 and da- inhibitor, in combination with rituxratumumab. In a phase 1b study, the imab produced an ORR of 84% in an combination of SAR650984 and lena- open-label phase 1b study of 45 palidomide plus dexamethasone in 31 tients with relapsed and/or refractory patients with refractory disease who chronic lymphocytic leukemia (CLL). had received 6 previous treatments for In a separate phase 1 study of ABTMM showed strong antitumor activity 199/GDC-0199 as monotherapy in paand good tolerability. tients with relapsed and/or refractory

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CLL, the ORR was 77% in 78 evaluable patients, with 23% of the patients achieving a CR. The ORRs for the 19 patients with 17p deletion and the 41 patients with fludarabine-refractory CLL were 79% and 76%, respectively. The median duration of response has not been reached. This same monotherapy trial enrolled 124 patients with various subtypes of non-Hodgkin lymphoma, where the ORR was 48% in the 59 patients who were evaluable for efficacy.

Thyroid Cancer For the treatment of metastatic differentiated radioiodine-refractory thyroid cancer, treatment with the multi-TKI lenvatinib reduced disease progression by 79% versus placebo in the phase 3 SELECT trial. The median PFS (the primary end point) was improved by 14.7 months. Patients receiving lenvatinib had a median PFS of 18.3 months, whereas in patients receiving placebo the PFS was only 3.6 months (P <.001). Toxicity could be challenging, and 6 treatment-related deaths were reported. Disease progression at 2 years was reported in 41% of patients in the lenvatinib arm versus 86% of patients in the placebo arm.

The ORR was 65% with lenvatinib versus 2% with placebo (P <.001). The median OS has not been reached in either arm; because of the expected crossover on disease progression, this end point may be hard to interpret.

Receipt of previous anti–vascular endothelial growth factor therapy did not adversely affect outcomes.

Breast Cancer The poly (ADP-ribose) polymerase inhibitor veliparib demonstrated activity in a phase 2 trial of 41 patients with metastatic breast cancer and BRCA1 or BRCA2 mutation. At enrollment, the patients received a median of 3 previous chemotherapy regimens. The partial remission rate in patients receiving at least 4 cycles of follow-up was 17% (2 of 12 patients) with BRCA1 mutations and 23% (3 of 13 patients) with BRCA2 mutations. The time to failure while receiving veliparib was 2 months and 5.1 months, respectively. In all, 20 patients are still alive from the group receiving veliparib; 10 patients proceeded to postprogression therapy with veliparib and carboplatin, with 1 partial response in a patient with a BRCA1 mutation. n

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The Patient Perspective

The Long Road to Rehabilitation: Sandra Wade’s Story on Surviving Breast Cancer

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

S

andra Wade first e-mailed me on July 15, 2011. As you can see in the excerpts from her correspondence with me below, she asked me to contact her oncologist and let her know that as a breast cancer survivor, Sandra had suffered more than she should have, because she was not referred for rehabilitation services. I told her that I did not feel comfortable with contacting the oncologist, but with her permission, I would share her message with others who were not directly involved in her care. No cancer survivor should be told to “accept a new normal” without first being offered cancer rehabilitation services.

The evidence-based need for cancer rehabilitation services in the majority of survivors is well documented.1 Sandra’s story is similar to those of many survivors who have not been screened for physical impairments and treated with appropriate rehabilitation interventions. Over the past few years, I have had the privilege of sharing her story (at my lectures) with thousands of healthcare professionals who have told me how compelling it was to hear the patient’s perspective. I hope her story will encourage you in your oncology work to better understand and support rehabilitation for high-quality cancer care.

The following letters are excerpts from Sandra’s e-mails to me over a period of several years.

July 15, 2011 Dear Dr Julie Silver, My heart is overwhelmed with emotion learning of the STAR [Survivorship Training and Rehabilitation] Program. My story is long and painful, so I will not go into my cancer journey thus far. I just want you to know that I have suffered unbelievably for 9 years with stage IV metastatic inflammatory breast cancer. I Dr Silver is the founder of Oncol­ ogy Rehab Partners (www.Oncology RehabPartners.com), which developed the STAR Program Certi­fi­cation, a service-line model for high-quality cancer rehabilitation care that has been adopted by more than 200 hospitals and cancer centers and is now available at nearly 1000 sites throughout the United States.

Sandra Wade is a breast cancer sur-

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truly love my oncologist and therapist, but they need to know about your work. I have come close to suicide, because of my “experts’” lack of

God is good; I just discovered the Jupiter Medical Center and their newly initiated STAR Program. I have my first appointment this Monday.

No cancer survivor should be told to “accept a new normal” without first being offered cancer rehabilitation services. The evidence-based need for cancer rehabilitation services…is well documented.

—Julie K. Silver, MD

knowledge and inability to listen to me and to try to find help for me (and many others, I’m sure).

When I researched whether there was help for me, I was dumbfounded by how much help was available for patients with cancer, and had been for years. First I was relieved, then felt hurt, and now I’m unbelievably angry. I felt instinctively that there had to be help for people like me, I just was too sick to look or ask for it before now.

I can’t believe my “experts” did not know or even bother to look. I have suffered needlessly; it’s almost unforgivable. If I didn’t love my doctor so much, I’d probably start an awareness campaign to ensure some changes in the “business as usual: cut ‘em, burn ‘em, and poison ‘em.”

I don’t like being angry, especially with people who are great, and have saved my life. I’m too hurt, and I have too many other neglected issues; I can’t broach this topic with them.

Could you just send them some information? I know there are other patients who will be eternally grateful. vivor and cancer rehabilitation advocate. She has written about her experience in the book, Chicken Soup for the Soul: Hope & Healing for Your Breast Cancer Journey, and has been interviewed by various media outlets.

Her willingness to share her story and educate healthcare professionals about cancer rehabilitation from the patient’s perspective has had a considerable impact on advancing the field.

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October 19, 2011 (Sandra wrote the following note after the announcement of a statewide STAR Program initiative in Rhode Island.) Congratulations!

You’ve just taken a huge step in making oncology rehab available to patients in our country. I pray for you and wish you the greatest success! I will be paying it forward.

“

I can’t believe my ‘experts’ did not know or even bother to look. I have suffered needlessly; it’s almost unforgivable.

Sometimes I think my oncologist didn’t do a lot of things for me, because she and everyone else have been waiting for me to die.

”

—Sandra Wade

October 23, 2012 If not for cancer rehabilitation, I would still be an invisible, voiceless person fighting cancer (and death), struggling alone, and probably still desperate for help. I’ve decided to spend the rest of my life writing about my journey—sharing the knowledge I learned and being an advocate for breast cancer survivors.

I have confronted my oncologist and demanded help that I needed.

September 21, 2013 I think “congratulations” are in order. I see the STAR Program popping up all over the place. I feel like I’m keeping in touch with you through all the announcements. What a wonderful thing you are doing for patients with cancer.

July 3, 2014 For 8.5 years I lived as if on “death row.” I was alive, but not living, almost an invalid, and there wasn’t much hope of my life ever getting better, according to my doctor(s).

Sometimes I think my oncologist didn’t do a lot of things for me, because she and everyone else have been waiting for me to die. I’m not afraid of dying, but I don’t want to suffer. If I’m alive, I want to be engaged in and participate in life. I’ve gone from death row to having a life, a life worth living, because I found the STAR Program and other support.

I have so much love in my life. I am truly blessed.

Epilogue, by Sandra Wade Oncology treatment has kept me alive—for that I am grateful. However, the ongoing and collateral damage has resulted in myriad medical conditions complicating my suffering and increasing my rehabilitation needs.

Not surprisingly, I suffered from clinical depression, and was anxious and frustrated. I struggled with loss of independence, isolation, loneliness, and was bed-bound, unable to care for myself and needing help to do everything, including sitting up, getting out of bed, walking, bathing, and simple life activities.

I learned of the STAR Program online. Cancer rehabilitation validated my thoughts and feelings, and gave me the hope for a better quality of life.

I have great respect for my oncologist, but I will love my physiatrist for the rest of my life. She has helped reduce my pain (and pain medication) and improve my quality of life. I am eternally grateful. n Reference

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

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Policy Matters

ASCO Issues Recommendations on How to Fix the 340B Drug Pricing Program

By Lilly Ostrovsky

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n April, the American Society of Clinical Oncology (ASCO) released a policy statement recommending how to fix the 340B Drug Pricing Program (ASCO. J Oncol Pract.

2014;10:259-263).

Established in 1992, the 340B Drug Pricing Program was intended to provide resources and incentives for uninsured, underinsured, and lowincome patients. Under the 340B program, manufacturers must provide substantial discounts for the sales of covered drugs to covered entities as a prerequisite to qualifying for Medicaid reimbursement.

Covered entities are defined as those that provide high levels of uncompensated or undercompensated care. This program is particularly important in oncology, considering the high cost of cancer drugs.

Since its enactment, policymakers have questioned whether the 340B program is accomplishing its goals to benefit vulnerable patient populations. The ASCO committee identified factors that may be hindering the program, including its rapid growth, insufficient oversight and regulation, and inattention to the effects on outpatient oncology care.

Compliance Issues Over the past decade, the number of 340B covered entities has approxi-

at a glance ➤ Many are questioning whether the 340B drug program is achieving its goal of benefiting vulnerable patient populations ➤ Concern is mounting that the growth of the program does not reflect the goals of the program ➤ Inadequate compliance and lack of oversight have resulted in abuse and confusion ➤ ASCO has recently issued new recommendations on how to fix the 340B program ➤ Congress should introduce a new formula to define eligibility, clarify funding oversight, improve the program’s transparency, and better respond to unintended consequences of the program

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mately doubled. The disproportionate share hospital adjustment percentage defines eligibility for the program by inpatient services rather than by outpatient drug prescrip-

“

Our concern became that 340B was tilting the balance such that it made it very difficult, especially in some communities, for patients to be able to go to community oncologists, and were being in some ways forced into the hospital system.

”

—Blase N. Polite, MD, MPP tions. Consequently, concern is mounting that the growth of the program does not accurately reflect the proportion of prescription drugs used to help low-income or vulnerable patient populations.

Inadequate compliance with the 340B program is another concern, and current “oversight standards make it particularly susceptible to confusion, misinterpretation, and abuse.” ASCO members noted that existing regulatory definitions are unclear––contributing to the lack of compliance and preventing meaningful oversight.

For example, the program defines eligible individuals as “patients” based only on whether they are treated by a covered entity and not on whether they are uninsured or underinsured. This ambiguity may lead some covered entities to divert discounted prescription drugs away from unqualified patients.

Another concern is whether cancer

care merits special attention by policymakers. For example, because outpatient oncology practices do not qualify as stand-alone entities for the 340B program, many hospitals acquire practices to allow more patients access to 340B cancer drugs. This can lead to reimbursement problems and increased out-of-pocket costs for patients.

“Our concern became that 340B was tilting the balance such that it made it very difficult, especially in some communities, for patients to be able to go to community oncologists, and were being in some ways forced into the hospital system,” Blase N. Polite, MD, MPP, Chair of ASCO’s Government Relations Committee and member of the ASCO 340B Workgroup, told Value-Based Cancer Care (VBCC).

“To use discount purchase agreements to increase the profitability of chemotherapy infusions on well-insured patients is an unjustified corruption of the program’s intent. As a community oncologist, I applaud ASCO’s important work on providing equity for all of our patients,” said Kevin B. Knopf, MD, MPH, California Pacific Medical Center Sutter Health, San Francisco, and VBCC editorial board member.

ASCO’s Recommendations to Fixing the Program Improve transparency. Congress, Health Resources and Services Administration (HRSA), and other policymakers should mandate each eligible entity to report on its 340B savings and the percentage of savings reinvested into the care of low-income and vulnerable patients annually.

Adopt safeguards. To accommodate the changing demographics of oncology care and to evade some of the adverse consequences of the growth of the program, Congress should replace the use of inpatient data to determine eligibility with a formula that considers the percentage of underinsured and uninsured patients treated in the outpatient setting.

“This will improve the accountability for the program and address concerns that some entities could profit from the 340B Drug Pricing Program without a commitment to providing outpatient drugs to vulnerable populations,” the authors noted.

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Clarify definitions and fund oversights. Congress and HRSA should define and clarify the term “patient” to be consistent with the program’s overarching principle, stating that

“

To use discount purchase agreements to increase the profitability of chemotherapy infusions on well-insured patients is an unjustified corruption of the program’s intent.

As a community oncologist, I applaud ASCO’s important work on providing equity for all of our patients.

”

—Kevin B. Knopf, MD, MPH such efforts would “promote the goals of the program and permit meaningful oversight.” Furthermore, HRSA should be sufficiently funded and staffed to properly conduct oversight activities.

Understand and respond to adverse impacts of the program. In light of the expansion of the 340B program, policymakers are urged to focus on understanding and responding to intended and unintended impacts of the program, including patient access to care through the availability of community-based physician oncology practices. Policymakers need to be aware that community-based physician oncology practices increase patient access and choice, and the adverse consequenc­ es of their potential termination or acquisition. n

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EHA Meeting Highlights

Older Patients with AML Live Longer with Azacitidine

By Robert Osborne

Milan, Italy—Older patients with acute myeloid leukemia (AML) gained a “clinically significant,” if not statistically significant improvement in survival when treated with azacitidine (Vidaza) rather than with conventional therapy, reported Hervé Dombret, MD, hematologist, Hôpital Saint Louis in Paris, France, at the European Hematology Association meeting.

Azacitidine therapy led to a median overall survival (OS) of 10.4 months compared with 6.5 months with conventional treatment. An analysis that ended with a switch to a new therapy led to a 5-month difference in survival, which was statistically significant, said Dr Dombret.

“Although this study did not reach statistical significance for its primary end point of overall survival, azacitidine demonstrated a clinically meaningful improvement in median overall survival,” said Dr Dombret.

OS with censoring at subsequent AML therapy did demonstrate a clinically significant benefit for azacitidine, and patients had substantial improvement in 1-year survival.

Historically, older patients with AML have a poor prognosis with standard therapy and a median survival of

2 to 8 months, said Dr Dombret. Poor health status and comorbid conditions rule out treatment with intensive chemotherapy for many older patients.

Building on earlier positive results with this drug, Dr Dombret and col-

“

Azacitidine demonstrated a clinically meaningful improvement in median overall survival.

”

—Hervé Dombret, MD

leagues conducted a phase 3, multicenter, randomized trial involving patients aged ≥65 years with newly diagnosed AML associated with >30% blasts in bone marrow; patients had intermediate- or poor-risk cytogenetics and were not eligible for stem-cell transplantation.

All patients received best supportive care and were randomized to azacitidine, low-dose chemotherapy, intensive chemotherapy with cytarabine and an anthracycline, or to best supportive care alone.

The primary end point was OS, but investigators also planned a survival analysis with data censoring at the start of subsequent therapy for AML. The secondary end points included 1-year survival, event-free survival, and relapse-free survival. The final analysis included 488 patients (median age, 75 years) with a median blast involvement of 70%.

The difference in the primary (unstratified) analysis translated into a 16% reduction in the hazard for survival, which failed to reach statistical significance. The investigators prespecified a survival analysis stratified

by Eastern Cooperative Oncology Group performance status and cytogenetic risk. That analysis yielded a 15% reduction in the hazard, which also failed to achieve statistical significance.

The censored survival analysis resulted in median OS times of 12.1 months in the azacitidine arm and 6.9 months in the conventionally managed patients. The difference represented a 25% reduction in the survival hazard and was a significant outcome.

With respect to secondary end points, the data showed an absolute 12% difference in 1-year survival in favor of the azacitidine arm (46.5% vs 34.2%, re-

spectively). The difference retained significance in a stratified analysis.

The subgroup analysis showed a consistent benefit of azacitidine versus conventional therapy: larger benefits were seen in patients under age 75 years, and in women.

Overall, 69 patients in the azacitidine arm and 75 patients in the conventional arm received subsequent therapy.

Patients in the azacitidine arm lived longer with subsequent therapy. The median OS from first subsequent treatment was approximately 8 months with azacitidine and 3 to 4 months with conventional therapy.

Secondary outcomes included an event-free survival of 6.7 months with azacitidine versus 4.8 months with conventional therapy, and relapse-free survival times of 9.3 months and 10.5 months for the groups, respectively.

Complete responses were reported in 28% of patients with azacitidine versus 25% of patients with conventional treatments; the rates of stable disease were also similar.

“The safety profile was consistent with that previously observed with azacitidine.” Grade 3/4 hematologic toxicity was similar among the groups. n

Stopping TKIs Safe after Deep Molecular Response The depth of molecular response before TKI withdrawal affects relapse-free survival Milan, Italy—More than 60% of patients with chronic myeloid leukemia (CML) were free of relapse 6 months after stopping tyrosine kinase inhibitor (TKI) therapy that led to deep molecular remission, according to the interim results from an ongoing trial reported by Susanne Saussele, MD, of Universitätsmedizin Mannheim, Germany, at the 2014 European Hematology Association meeting.

A majority of the 200 patients from 47 European centers remained relapse free at 12 months. The 6-month data allowed investigators to reject the null hypothesis of a relapse-free survival (RFS) rate of ≤40% (P <.001) and to continue enrollment to an accrual goal of 700 patients.

The results also showed that the depth of molecular response (MR) achieved before the withdrawal of TKIs affects RFS. “With less strict inclusion and relapse criteria than was used in [previous trials], stopping is safe, and we can continue with the trial,” said Dr Saussele.

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These results are consistent with previous studies, showing that select patients with CML can stop long-term TKI therapy after achieving deep MR, she added. TKI therapy has improved the survival of patients with CML, and more patients achieve durable deep MRs (ie, ≥MR4).

The effectiveness of TKIs has given patients and clinicians a reasonable expectancy of improved survival and cure, said Dr Saussele. A critical first step toward cure is to increase the proportion of patients who achieve durable deep molecular remission after the withdrawal of treatment.

Previous studies showed that 40% to 65% of patients maintained deep MR for up to 36 months after TKI therapy discontinuation. However, the trials used stringent definitions of deep remission. In addition, some of the trials had a relatively small sample size.

Other key objectives of the study were to determine the minimal duration of TKI therapy required before

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withdrawal, the minimal duration of MR4 before stopping, and prognostic factors for RFS. Eligible patients had completed at least 3 years of TKI therapy and had maintained MR4 for at least 1 year. Patients with previous or planned allogeneic stem-cell transplantation because of TKI therapy failure were excluded.

After a screening phase to confirm MR4, patients stopped the TKI therapy and began follow-up for 3 years. They had MR status evaluated by polymerase chain reaction every 4 to 6 weeks during the first year after discontinuation and then every 3 months.

The trial’s primary end point is duration of deep molecular remission after stopping TKI therapy (defined by the loss of major MR). The null hypothesis is a molecular RFS of ≤40% at 6 months.

The median duration of TKI therapy was approximately 8 years, and the duration of MR4 before discontinuation was 5 years. All but 6 patients re-

ceived imatinib as first-line TKI therapy. Of the 24 patients who received second-line TKI therapy, dasatinib was the choice in 16 cases.

Overall, 86 patients relapsed, including 77 patients in the first 6 months after stopping TKI therapy. Subsequently, 13 patients who relapsed regained MR4 status.

RFS was 87% at 3 months, 61% at 6 months, 58% at 9 months, and 55% at 12 months.

Of 197 evaluable patients, 74 attained MR4, 79 attained MR4.5, and 44 attained MR5. Subsequently, 37 patients in MR4 relapsed, as did 31 in MR4.5, and 17 in MR5.

“In the setting of standardized molecular testing within a stopping trial in CML, it seems that the level of molecular remission has an impact on relapse-free survival,” said Dr Saussele.

A total of 57 adverse events (all grades) occurred in 31 patients, including 3 patients who had a total of 9 grade 3/4 adverse events.—RO n

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In the Literature Ibrutinib Outperforms Ofatumumab, Extends Survival in Patients with CLL

In a head-to-head study comparing ibrutinib (Imbruvica) and ofatumu­ mab (Arzerra) for the second-line treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), ibrutinib significantly improved progression-free survival (PFS) time, overall survival (OS), as well as response rate (Byrd JC, et al. N Engl J Med. 2014;371:213-223). These results came from the phase 3 randomized RESONATE trial. The results of this trial were also presented at the 2014 American Society of Clinical Oncology (ASCO) annual meeting.

”

—John C. Byrd, MD

Ibrutinib is a first-in-class, oral covalent inhibitor of Bruton’s tyrosine kinase, whereas ofatumumab is a monoclonal antibody that binds to the CD20 antigen on the CLL or SLL cells.

In the multicenter, open-label RESONATE trial, 391 patients with relapsed or refractory CLL or SLL in whom 1 or more therapies had failed were randomized in a 1:1 ratio to receive ibrutinib (N = 195) 420 mg once daily or ofatumumab (N = 196) 300 mg intravenously, at week 1, followed by 2000 mg weekly for 7 weeks and then every 4 weeks for 16 weeks.

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(hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.15-0.32; P <.001).

Furthermore, ibrutinib significantly improved OS duration (HR for death, 0.43; 95 CI, 0.24-0.79; P = .005), with the risk of death reduced by 57%. The OS rate was 90% at 12 months in the in 81% in the ofaibrutinib group B:7.625 versus tumumab group.

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Overall, 57 patients in the ofatumumab group whose disease had progressed had crossed over and began receiving ibrutinib at the time this analysis. The partial response rate was much higher for patients in the ibrutinib group than for patients in the ofatumumab group—43% vs 4%, respectively.

Continued on page 24

In mCRPC therapy…

Is there more to the story?

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

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

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

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.

Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken.

Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

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

Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. mCRPC=metastatic castration-resistant prostate cancer; AST=aspartate aminotransferase; ALT=alanine aminotransferase.

Please see additional Important Safety Information on the next page.

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

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www.ValueBasedCancerCare.com

Customer Code: 016819-140612

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“

Ibrutinib beat a standard comparator in CLL for the first time. If I were a patient with CLL, I would want this drug. In the relapsed and refractory setting after 1 prior therapy, there is no good reason not to give this drug outside of a few circumstances.

The primary end point was PFS, with secondary end points evaluating OS and response rate. The median follow-up time was 9.4 months.

Ibrutinib significantly extended PFS, with the median not reached (88% at 6 months) at the follow-up compared with a median PFS of 8.1 months in the ofatumumab group

In the Literature Ibrutinib Outperforms Ofatumumab, Extends Survival... Continued from page 23

In the ibrutinib group, 20% of the patients showed partial response with lymphocytosis: if these patients are included, the resulting response rate is 63%. Similar effects were observed in patients with chromosome 17p13.1

deletion or those with resistance to purine analogs.

More patients in the ibrutinib group than in the ofatumumab group had at least 1 adverse event of grade ≥3 (57% vs 47%, respectively). Adverse events (grade ≥3) that occurred more often in the ibrutinib group than in the ofatumumab group included diarrhea (4%

vs 2%, respectively) and atrial fibrillation (3% vs 0%, respectively). Bleeding-related adverse events of any grade were also more common in the ibrutinib group (44%) than in the ofatumumab group (12%).

These results support ibrutinib as an effective single-agent therapy for B:7.625 in difficult-to-treatT:7.375 patients with CLL in

or SLL, given its positive effect on PFS, OS, and response rate. The improvement in survival was observed across all subgroups that were examined. Phase 3 trials examining the effect of ibrutinib in previously untreated patients with CLL or SLL are ongoing.

Commenting on the study at ASCO

For men with mCRPC who progressed on ADT

In a clinical trial, patients had a median overall survival on ZYTIGA® (abiraterone acetate) of…*

More than 1,000 days.

And every day tells a story.

35.3 IMPROVEMENT IN MEDIAN OVERALL SURVIVAL 5.2 MONTHS compared with placebo plus prednisone.

MONTHS MEDIAN OVERALL SURVIVAL FOR ZYTIGA® plus prednisone† vs 30.1 MONTHS with placebo plus prednisone (active compound).‡

Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached.

Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

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IMPORTANT SAFETY INFORMATION (cont) Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken.

Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter.

Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were overall survival (OS) and radiographic progression-free survival.

ADT=androgen-deprivation therapy.

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In the Literature 2014, lead investigator John C. Byrd, MD, said, “Ibrutinib beat a standard comparator in CLL for the first time.

If I were a patient with CLL, I would want this drug. In the relapsed and refractory setting after 1 prior therapy, there is no good reason not to give this drug outside of a few circumstances.”

Interinstitutional Variations in Cancer Treatment Identified

Little is known about why patient care varies greatly for patients with similar illnesses, such as in patients with different types of cancer. VariaB:7.625 in tion in the care of patients with cancer signals a lack T:7.375 of consensus about in

what constitutes optimal care; this suggests important gaps in the evidence base in which research may have an effect. In a new study, researchers sought to systemically assess interinstitutional variation in the management decisions for 4 common cancers using the National Comprehensive Cancer Network (NCCN)

Outcomes Database (Weeks JC, et al.

Ann Intern Med. 2014;161:20-30).

This multi-institutional, observational cohort study included patients with 1 of 4 types of cancer who were diagnosed between July 2006 and May 2011 at 18 cancer centers participating in the formulation of treatment guidelines and systematic outcomes Continued on page 26

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003307-130924

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

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). †At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone compared with 43% (234/542) of patients treated with placebo plus prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

Learn more today at

www.zytigahcp.com.

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In the Literature Interinstitutional Variations in Cancer Treatment...

Continued from page 25

assessment through the NCCN. The investigators identified 25,589 patients with incident of breast cancer (N = 11,293), colorectal cancer (N = 4564), lung cancer (N = 6718), or non-Hodgkin lymphoma (NHL; N =

3014). They measured interinstitutional variation for 171 binary management decisions with varying levels of supporting evidence. For each decision, variation was characterized by the median absolute deviation of the center-specific proportions.

Important management decisions for patients with the 4 types of cancer

varied greatly among the major cancer centers. Interinstitutional variation was high (median absolute deviation, >10%) for 35 of 171 (20%) oncology management decisions, including 41% for NHL, 21% for breast cancer, 15% for lung cancer, and 12% for colorectal cancer. Overall, 46% of high-variance decisions involved imaging or diag-

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

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

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

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

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

Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

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

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

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

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

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

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA

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nostic procedures, and 37% involved the choice of chemotherapy regimen.

The evidence grade underpinning the 35 high-variance decisions was category 1 for 0%, category 2A for 49%, and category 2B or other for 51% of the decisions.

The findings showed that high interinstitutional variation in common de-

ZYTIGA® (abiraterone acetate) Tablets is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

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

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

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

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

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

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

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

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

Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders 4 Edema 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract 11.5 infection 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0

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In the Literature cisions regarding oncology management reveals opportunities to health systems to prioritize comparative effectiveness research, patient–provider education, or pathway development.

Also, careful attention should be given to customized decision-making that includes patient preferences, concluded the researchers.

G-CSF Pathways Compliance Reduces Emergency Department Visits, Hospitalizations

Clinical pathways have been suggested as a good method to implement guidelines into clinical practice and to reduce treatment variability. Although oncology clinical pathways have been

studied previously, a new study looked at supportive care services and their effect on reducing emergency department visits and hospitalizations associated with chemotherapy toxicities (Kreys ED, et al. J Oncol Pract.

2014;10:168-173).

This retrospective cohort study analyzed the effects of compliance to

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

Table 1: Adverse Reactions due to ZYTIGA in Study 1 (continued) ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest 7 discomfort 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

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

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2

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cancer supportive care pathways on emergency department visits and hospitalizations associated with neutropenia, anemia, and chemotherapy-induced nausea and vomiting (CINV). Pathways for supportive care services encompassed the utilization of granulocyte colony-stimulating factors (G-CSFs), erythroContinued on page 28

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In the Literature G-CSF Pathways Compliance Reduces Emergency Department...

Continued from page 27

cyte-stimulating agents (ESAs), and antiemetics.

The evaluated data, spanning the initial 2 years of the Cardinal Health

Specialty Solutions and the CareFirst BlueCross BlueShield multistate oncology clinical pathways program, were obtained from the CareFirst claims database.

A total of 3191 patients from 46 practice sites across 3 states received 4144 lines of therapy. Of these pa-

tients, 51% received treatments for breast cancer, 27% for lung cancer, and 22% for colorectal cancer. Among the chemotherapy regimens, 28% were potentially at high risk for causing febrile neutropenia; 56% of the regimens included cisplatin (Platinol), oxaliplatin (Eloxatin), cyclophosphamide (Cy-

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%.

Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

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

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

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

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose.

ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss.

Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

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

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

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information.

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

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

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

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

Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

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

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

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

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

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

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

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

toxan), or carboplatin (Paraplatin).

Overall, 472 emergency department visits/hospitalizations were reported for neutropenia, 34 visits for anemia, and 799 visits for CINV. Compliance with the G-CSF pathway was associated with a significant reduction in neutropenia emergency department visits/hospitalizations compared with pathway noncompliant treatment (10.5% vs 25.9%, respectively; odds ratio [OR], 0.34; 95% confidence interval [CI], 0.25-0.45; P <.001).

Compliance with ESAs and antiemetic medication was not associated with significant differences in corresponding emergency department visits/hospitalizations for anemia. When adjusting for cancer type and G-CSF drug expenditure, a similar reduction was observed in neutropenia-related emergency department visits/hospitalizations (OR, 0.42; 95% CI, 0.30-0.58; P <.001). However, the adjustment did not greatly alter the results when applied to analogous comparisons of ESAs or antiemetics.

The total expenditures for emergency department visits/hospitalizations as a result of neutropenia, anemia, and CINV were $2.8 million, $0.1 million, and $3.6 million, respectively, resulting in average expenditures of $687, $34, and $877, respectively, per line of therapy.

Compliance with G-CSF therapy was also associated with an average decrease of $1085 in emergency department visit/hospitalization costs per line of therapy, whereas ESA and antiemetic medication compliance was associated with average cost increases of $60 and $7, respectively, per line of therapy.

This study underscores the importance of adhering to evidence-based medicine to prevent adverse events of chemotherapy and to optimize treatment for cancer as a whole. The analysis appears to demonstrate an association between pathway compliance for the use of G-CSFs and a reduction in emergency department visits/hospitalizations resulting from neutropenia.

Although this association cannot be made regarding ESAs or antiemetics, the researchers suggest that studies that incorporate more comprehensive clinical data would be valuable. They also recommend further study of the implications of adherence to guidelines for supportive care.

New Payment Model Saves Money, Maintains Outcomes

New payment models that reward cost-effective, high-quality cancer care are needed. An experimental Continued on page 50

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Reimbursement in Oncology

New Payment Models in Oncology Must Consider Value

By Kate O’Rourke

E

conomists predict that, in less than 3 years, the average household in the United States will use 50% of its income on health insurance and out-of-pocket medical bills. According to Lee N. Newcomer, MD, MHA, Senior Vice President, Oncology, Genetics and Women’s Health, UnitedHealthcare, Minnetonka, MN, creating payment models that can reimburse physicians for cost-effective care is difficult in itself, but demonstrating that the new models are indeed cost-effective involves another set of hurdles.

“Payers and physicians must continue searching for better payment methods. Today’s methods do not work well enough, and more experiments are necessary to find ways to reduce costs and preserve quality,” said Dr Newcomer in a recent commentary (Newcomer LN. J Oncol Pract.

2014;10:187-189).

One of the prevalent reimbursement models used today is the pay-for-performance (P4P) approach. With this model, it is difficult to accumulate a sufficient number of patients to prove that an outcome is statistically significant. To prove a significant 10% difference in the cost of care, studies must include hundreds of patients; however, aside from Medicare, each payer usually only accounts for 5% or 15% of the patients in the practice. For example, UnitedHealthcare, one of the nation’s largest payers in the country,

See also page 28

“

Payers and physicians must continue searching for better payment methods. Today’s methods do not work well enough, and more experiments are necessary to find ways to reduce costs and preserve quality.

”

—Lee N. Newcomer, MD, MHA with more than 29 million members, has only 37 medical oncology groups that see more than 10 patients covered

by UnitedHealthcare monthly.

P4P programs provide financial rewards to physicians for meeting prespecified goals, but according to Dr Newcomer, the rewards are often too small to provide an incentive. For example, in a hypothetical P4P program that saves 5% on chemotherapy drug costs or hospitalizations, physicians would receive an annual payment of $2008 for reduced hospitalizations and $7366 for reduced chemotherapy costs. “These sums are quite small when one considers the work effort required to obtain them,” commented Dr Newcomer.

Reimbursing for Value Increased costs for funding a program that improves outcomes must take into account the increase in value.

According to Dr Newcomer, an unnamed cancer center recently requested a payment from UnitedHealthcare as a reward for its superior survival rates, but often the center’s rates were only a few percentage points better for a given tumor.

The center’s 5-year survival rates were 19% better than the national average for myeloma and 15% better for lung cancer, but much smaller gains were seen for pancreatic cancer (9%), breast cancer (3%), prostate cancer (2%), colon cancer (1%), and liver cancer (1%).

The reimbursement the cancer center requested was not in line with the savings that were actually achieved.

A recent study involving 5 medical groups that treated 810 patients with cancer demonstrated that modifying the fee-for-service payment system for therapy for cancer with feedback data and financial incentives that rewarded outcomes and cost-efficiency

reduced the predicted total medical costs by 34% (Newcomer LN, et al. J Oncol Pract. 2014 Jul 8. Epub ahead of print). This study, however, was not designed to determine what expenses caused the difference in the total medical cost (see article on page 28).

Dr Newcomer suggests that “it may be time to measure something new.

Measuring the effectiveness of specific chemotherapy regimens rather than physician groups may have more value.” This will allow Medicare and some commercial payers to more quickly accumulate large numbers of patients with certain types of tumor in their data sets for comparative effectiveness analyses to compare different regimens in terms of their benefits and total costs.

“Regimens could be compared for total costs, toxicities and most importantly outcomes,” he noted.

This will allow payers to give preferential status to superior regimens or nonpreferential status to inferior regimens. This strategy will allow payers to pay for value.

In the search for new payment models, “payers and physicians should remember that the same scientific method which was used to test new therapies and improve processes of care—particularly adherence to statistical rigor when making efficacy claims—should be used to provide equally important insights in the affordability and value of care,” emphasizes Dr Newcomer. n

Shifts to Value-Based Care and Payment Models Are Improving Quality of Care

By Wayne Kuznar

B

lue Cross Blue Shield (BCBS) is implementing value-based care and payment models across the country to reward quality and improve outcomes, and these are amounting to billions of dollars in cost-savings and reduced hospitalizations. According to a company press release (“Blue Cross and Blue Shield companies direct more than $65 billion in medical spending to value-based care programs”; July 9, 2014), these programs “shift payment away from the fee-for-service model... to one that links reimbursement to the quality of care and improved patient outcomes.”

These programs include account-

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able care organizations (ACOs), patient-centered medical homes (PCMHs), pay-for-performance programs, and episode-based payment programs.

“Through these innovative, valuebased care models, Blue Cross and Blue Shield companies provide patients with access to improved care while also creating value for our members, employers and taxpayers supporting public healthcare programs,” said Scott P. Serota, MHA, President and Chief Executive Officer of the BCBS Association, in the press release. “Studies estimate that 30 cents of every healthcare dollar goes to care that is ineffective or redundant.”

PCMHs Cut Healthcare Utilization According to 2013 data, practices participating in the BCBS PCMH program show a 19.1% lower hospital admission rate; 8.8% and 17.7% lower emergency department visit rates for adults and children, respectively; and 7.3% lower use of high-tech radiology services.

Data from 2012 from a PCMH program in New Jersey showed a 23% lower inpatient admissions rate, a 12% reduced emergency department visits rate, a 5% higher rate of improved control of diabetes, and a 3% higher rate of breast cancer screenings.

In a PCMH pilot from Anthem, practices had 15% lower medical and pharmaceutical costs than in the control practices. In Connecticut, PCMH pilot practices had 18% and 29% fewer hospital admissions and readmissions,

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“

Through these innovative, valuebased care models, Blue Cross and Blue Shield companies provide patients with access to improved care while also creating value for our members, employers and taxpayers.

”

—Scott P. Serota, MHA respectively, than nonparticipating practices. Similarly, in Colorado, 18% reduced hospital admissions and 15% Continued on page 30

www.ValueBasedCancerCare.com

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VBCC Payers’ Perspective

Determining the Value of Cancer Therapies... pies. The question remains, however, at what cost did we achieve these improvements?

The economic environment within the healthcare sector presents challenges from the perspective of all stakeholders. Those stakeholders who are at financial risk for the provision of patient care are facing constant challenges. No other medical specialty is more sensitive to this financial struggle than oncology. The value of technology is more easily understood in some areas of oncology practice, such as genomic profiling. Genomic profiling provides the oncologist with the necessary information to manage the patient with cancer more effectively, and to select the most appropriate treatment regimens, whether targeted or nontargeted therapies.

Commenting on the recent ASCO annual report, ASCO past president Clifford A. Hudis, MD, Chief, Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, New York City, noted, “We are witnessing the acceleration of our shift into a new era of medicine in which our knowledge of the molecular basis and activity of cancers leads to ever more precise treatments that offer increased efficacy and reduced toxicities.…Precision medicine is now a reality for an increasing number of patients.”

Thus, genomic profiling provides value in its potential to improve outcomes, improve the patient experience, and reduce healthcare cost. The inefficiency of not being able to administer targeted therapies leads to variability in the clinical outcome, as well as adds unnecessary toxicities to patients, and increases overall care costs to healthcare stakeholders and the en-

tire US healthcare system. The value of these tests remains largely unrecognized by payers.

Personalized medicine, however, comes at a cost. Discussing the “State of Cancer Care in America: 2014,” Lowell E. Schnipper, MD, Chair,

healthcare stakeholders that this cost trend is unsustainable.

According to the World Health Organization, the healthcare costs per capita in the United States are ranked the highest compared with other countries; however, the quality of our health-

By defining value, we will be able to differentiate between regimens that only provide an incremental benefit and those that significantly improve outcomes, as well as taking into consideration the question, “at what cost?”

Winston Wong, PharmD

ASCO’s Value in Cancer Care Task Force, outlined the goals of the task force, citing the report’s finding that the US annual cost of providing cancer care is projected to reach $173 billion by 2020, representing a 40% increase from 2010 (Mariotto AB, et al. J Natl Cancer Inst. 2011;103:117-128). Clearly, we cannot sustain this cost trend.

The cost of new treatment regimens is a major contributor to this ever-rising cost trend. Results of a new study presented at ASCO 2014 (see article in this issue, page 7) by Rena Conti, PhD, Assistant Professor of Health Policy and Economics, University of Chicago, show that even after adjusting for inflation and improved survival, the cost of antineoplastic drug prices has increased 5% to 7% annually between 1995 and 2013 ($1200 vs $9700 monthly). There is little disagreement by

care system is ranked number 37 among 191 countries. The reasons for this are beyond the scope of this discussion, but as an industry, we must work to develop a process by which we can evaluate the value of treatment regimens objectively, and with transparency.

The value determination of a treatment regimen should be based on clinical efficacy, safety and tolerability, and cost, and should encompass the interests of all stakeholders, including patients, providers, and payers. All too often, one stakeholder significantly influences the treatment decision-making process, frequently with little regard to other stakeholders.

Determining “value” will force us to evaluate treatment regimens in a very different way. By defining value, we will be able to differentiate between regimens that only provide an incre-

Continued from the cover

mental benefit and those that significantly improve outcomes, as well as taking into consideration the question, “at what cost?”

The question is—how do we define and determine value? Earlier this year, ASCO announced its effort to develop a working definition of “value” based on clinical benefit, toxicity, and cost of treatment regimens. The goal of that initiative is to develop a standard methodology by which treatment options can be assessed. The goal is that oncologists should be well versed in the methodology of value assessment, and be able to explain and present the value of treatment options to their patients. It is expected that patients will then be able to make an informed decision regarding their treatment direction.

As payers gradually begin to accept this methodology, payers will then be able to assess the value of treat­ ment options from their perspective, through the use of claims data, to help guide their policy decisions and benefit designs. Ideally, upfront collaboration among payers and providers would bring together the clinical expertise of the oncologist and the utilization and financial data of payers to form the “value score” that could be assessed by the patients.

The barriers to success in oncology, as noted by ASCO, include the need to show quality, efficiency, and transparency, and the challenge of addressing the rising costs of new cancer treatments, related tests, and services.

Although many in the oncology team would consider these goals lofty, it is a much needed paradigm shift away from focusing on cost alone, and instead refocusing on outcomes, quality, and cost combined. n

Shifts to Value-Based Care and Payment Models... fewer emergency department visits were reported compared with nonparticipant practices, according to a BCBS report (“Blue plans improving healthcare quality and affordability through innovative partnerships with clinicians”; February 13, 2014).

ACOs Contribute to Cost-Savings BCBS’s ACO arrangements, which offer financial incentives for improvements in care, have seen similar success. BCBS of Illinois has a 4-year agreement with 10 hospitals in the Advocate Health Care. “This ACO is

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driving compelling quality and cost impact including a decline of 4.7 percent in the inpatient admission rate per 1000 for Advocate facilities versus an increase of 2.2 percent for the control facilities, a decline of 0.9 percent for length of stay for Advocate facilities versus an increase of 2.7 percent for the control facilities and better results for outpatient utilization,” according to BCBS. In Minnesota, BCBS has aligned with providers to transition from fee for service to performance incentives that are tied to measurable improve-

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ments in quality outcomes and to managing the total cost of care. In this “aligned incentive contracting,” BCBS of Minnesota provides a riskadjusted per-member per-month payment along with an allowed trend for attributed members’ total cost of care.

If the provider’s actual per-member per-month cost is below the target, the provider is eligible to receive a share of the savings. In 2011, 75% of the aligned incentive contracting providers earned incentives, and approximately $13 million in net savings against the expected claims costs were achieved.

Continued from page 29

In Massachusetts, performance stan­­dards tied to nationally accepted quality standards are combined with a population-based global budget adjusted annually for health status and inflation in what is called an “alternative quality contract.” Practice pattern analyses are provided to participating physician groups to provide feedback to clinicians and to identify opportunities for improvement. An independent analysis showed that these contracts led to slower growth in medical spending—2% slower growth in 2009 and 3% slower growth in 2010. n

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Breast Cancer

ALTTO: Dual Anti-HER2 Adjuvant Therapy No Better than Trastuzumab Alone Largest trial ever in this setting provides new insights

By Phoebe Starr

Photo by © GMG/Phil McCarten 2011

“”

The study’s failure tells us, at a simple level, that we won’t be using lapatinib in the adjuvant setting.

—George W. Sledge, Jr, MD

cart-Gebhart, MD, PhD, Chair, Breast International Group, Brussels, Belgium, at a plenary session at the 2014 American Society of Clinical Oncology (ASCO) meeting.

More than 8000 patients with early

breast cancer were randomized after surgery to concurrent use of trastuzumab and lapatinib, to the sequential use of trastuzumab followed by lapatinib, or to trastuzumab alone for 1 year.

A lapatinib-only arm was closed early because of futility. The majority (N = 4613) of patients received anti-HER2 agents after completing chemotherapy. Patients with hormone receptor– positive disease also received appropriate hormonal therapy.

At a median follow-up of 4.5 years, dual targeting, either concurrently or sequentially, was associated with slight numerical (but insignificant) reductions in progression versus trastuzumab alone.

“The ALTTO trial did not meet its end points,” Dr Piccart-Gebhart said.

The disease-free survival rates at 4 years were 86% with trastuzumab, 88% with concurrent HER2-directed treatment, and 87% in the sequential arm. Similarly, the median overall survival rates were 94%, 95%, and 95%, respectively.

These results were unexpected, because the previous NeoALTTO trial, which evaluated the combination in the neoadjuvant setting, showed improved pathologic complete response rates with 2 agents versus 1 agent, which correlated with better clinical outcomes.

However, “The doubling in pathologic complete response observed with lapatinib plus trastuzumab in NeoALTTO did not translate into im-

vant clinical trial in HER2-positive breast cancer, involving 8381 women from 946 centers in 44 countries.

Photo by © ASCO/Silas Crews 2014

T

he addition of lapatinib (Tykerb) to trastuzumab (Herceptin) to create dual HER2 blockade was no better than trastuzumab alone in the adjuvant treatment of patients with HER2 breast cancer in the global phase 3 ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial, reported Martine J. Pic-

“

Another way of looking at this study is that the patients overall did pretty well—better than anticipated.

”

—Edith A. Perez, MD

proved survival outcomes in ALTTO,” Dr Piccart-Gebhart said.

Furthermore, “lapatinib was also associated with significant increases in adverse events of special interest— diarrhea, skin rash or erythema, and hepatobiliary problems,” Dr PiccartGebhart added. Only 60% to 78% of patients in the lapatinib-containing arms received at least 85% of the protocol-specified dose. The rates of serious cardiotoxicity, however, were less than 1%, although 97% of women received anthracyclines.

ALTTO was the largest-ever adju-

A Disappointment ASCO past president George W. Sledge, Jr, MD, Chief, Division of Oncology, Stanford University Medical Center, CA, called the findings “a serious disappointment, not only to investigators but for the entire field….The study’s failure tells us, at a simple level, that we won’t be using lapatinib in the adjuvant setting.”

Dr Sledge added that the fact that ALTTO did not corroborate findings from the NeoALTTO trial seriously calls into question the use of pathologic complete response rate as a surrogate end point for survival and as an end point that can be used in drug approvals, suggesting the need to “rethink our approach to the development of new drugs for early breast cancer.”

A Different Perspective The one aspect of good news to come from ALTTO, according to coprincipal investigator Edith A. Perez, MD, Deputy Director at Large, Mayo Clinic Cancer Center, Jacksonville, FL, was that the 555 relapse events that occurred at 4.5 years were far less than the 850 events that were anticipated.

“Another way of looking at this study is that the patients overall did pretty well—better than anticipated,” said Dr Perez. n

Guidelines Target Brain Metastases in HER2-Positive Breast Cancer

By Eileen Koutnik-Fotopoulos

A

pproximately 15% to 20% of patients with breast cancer have HER2-positive disease.

Brain metastases are relatively common in patients with HER2-positive metastatic breast cancer, with up to 50% of patients developing metastases over time. The American Society of Clinical Oncology (ASCO) recently issued an updated guideline for the management of brain metastases in patients with HER2-positive breast cancer (Ramakrishna N, et al. J Clin Oncol. 2014;32:2100-2108).

The main recommendations from ASCO are: Ø Patients with brain metastases

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should receive appropriate local therapy and systemic therapy, if indicated • Local therapies include surgery, whole-brain radiotherapy (WBRT), and stereotactic radiosurgery (SRS) • Treatments depend on factors such as patient prognosis, presence of symptoms, resectability, number and size of metastases, previous therapy, and whether metastases are diffuse Ø WBRT may be offered in patients with diffuse disease or extensive metastases and a more favorable prognosis, and in patients with symptomatic leptomeningeal metastasis in the brain Ø Options for patients with poor

prognosis include WBRT, best supportive care, and/or palliative care Ø For patients with progressive intracranial metastases despite initial radiation therapy, options include SRS, surgery, WBRT, a trial of systemic therapy, or enrollment in a clinical trial, depending on initial treatment.

For patients in this group who also have diffuse recurrence, best supportive care is an additional option Ø Systemic therapy should not be switched in patients whose systemic disease is not progressive at the time of a brain metastasis diagnosis Ø Clinicians should offer HER2-targeted therapy according to the algo-

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rithms for the treatment of HER2positive metastatic breast cancer in patients whose systemic disease is progressive at the time of a diagnosis of brain metastasis Ø Because patients with HER2positive advanced breast cancer have a high incidence of brain metastases, clinicians should not perform routine brain magnetic resonance imaging (MRI) to screen for brain metastases, but rather should have a low threshold for brain MRI. The original panel and another group of experts subjected the draft recommendations to 2 rounds of formal ratings before approval. n

www.ValueBasedCancerCare.com

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Web-Based Care

Web-Based Patient Portals Improve Patient Care

By Kate O’Rourke

Boston, MA—Across the country, many hospitals have begun to use web-based patient portals in their healthcare delivery, but are these portals improving care? According to Kaiser Permanente representatives who spoke at the 2014 Medical Informatics World Conference, they are, and the numbers show it. Although not specific only to oncology, this new approach can have a beneficial impact on managing patients with cancer, improving medication adherence, and preventive services.

Terhilda Garrido, Vice President, Health Information Technology Transformation and Analytics, Kaiser Permanente, said that roughly 10 years ago, Kaiser made a $4-billion investment in their electronic health record. “Today, out of 9.3 million members, 4.4 million are now KP.org members,” said Ms Garrido. “About 60% of our adult members are members of KP.org. The KP.org functionality is a patient portal that sits on top of the electronic health record. It exposes part of the electronic health record to the patient.”

Kaiser has approximately 611 medical offices and 17,000 physicians.

Through Kaiser Permanente’s web portal, patients can communicate with their doctors, view test and laboratory results, schedule appointments, and refill prescriptions, among other tasks.

In 2003, Kaiser essentially had no interactions that involved secure e-mails.

Secure e-mail through the web portal now represents 32% of primary care patient encounters. On average, physicians receive roughly 5 e-mails daily from patients, some of which can be answered by other members of the care team.

According to Ms Garrido, patient satisfaction with the portal is high, with approximately 85% of patients rating portal encounters an 8 or a 9 on a 9-point scale, with 9 being highly satisfied. In 2010, the average registration rate was 52%; the registration rate 60% (highest) in patients aged 60 to 69 years, and 46% among patients aged >70 years.

A personal action plan is a KP.org view of a member’s preventive and chronic conditions, screenings, tests,

“

We think this is helping out our screening rates for cancer and all sorts of cardiovascular diseases immensely. We have people signing up for weight management programs at a higher rate.

”

—Michael Kanter, MD and immunizations. It reminds members of actions that will help maintain their health. Michael Kanter, MD, Regional Medical Director, Quality and Clinical Analysis, Southern California Permanente Medical Group, said the personal action plans have had an impact. People who registered and visited the patient portal were slightly more likely to have preventive care (eg, Pap smear, flu shot) than other patients.

“We think this is helping out our screening rates for cancer and all sorts

of cardiovascular diseases immensely.

We have people signing up for weight management programs at a higher rate,” said Dr Kanter.

In an evaluation of 35,000 Kaiser patients, portal use at Kaiser was associated with a 2% to 6.5% improvement in health data. Patient adherence to statins, as well as measures of low-density lipoprotein levels, improved by 6% among patients with diabetes who exclusively used the patient portal for prescription refills compared with users of the web-based portal who did not refill their medications on­line. This indicates that adoption of online refills may improve medication adherence.

Dr Kanter pointed out that the online registration at Kaiser varied by race and ethnicity, with approximately 61% white patients, 55% Asian patients, 43% black patients, and 37% Hispanic patients registering for the site. In an attempt to decrease health disparities, Kaiser has launched a Spanish language version of the web portal, which is rapidly growing in popularity. n

breast cancer

Adjuvant Exemestane More Effective than Tamoxifen in Early-Stage Breast Cancer

By Wayne Kuznar

Chicago, IL—Adjuvant exemestane is more effective at preventing breast cancer recurrences than tamoxifen when given with ovarian function suppression (OFS) in young women with hormone receptor–positive early breast cancer, reported Olivia Pagani, MD, Clinical Director, Breast Unit, Oncology Institute of Southern Switzerland, Bellinzona, at the 2014 American Society of Clinical Oncology meeting.

In a joint analysis of the Tamoxifen and Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT), the relative risk for any cancer recurrence was reduced by 28%, and for breast cancer recurrence 34%, with exemestane plus OFS. “For years, tamoxifen has been the standard hormone therapy for preventing breast cancer recurrences in young women with hormone-sensitive disease. These results confirm that exemestane with ovarian function suppression constitutes a valid alternative,” said Dr Pagani.

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“

Our findings indicate that exemestane is better than tamoxifen when given with ovarian function suppression, but longer follow-up of these young women will be important to assess survival and any long-term side effects and fertility.

”

—Olivia Pagani, MD

The 2 Studies The 2 protocols enrolled more than 5600 premenopausal women (2672 women from TEXT and 3066 from SOFT) who had hormone receptor– positive early breast cancer. They were randomly assigned to exemestane and OFS or to tamoxifen and OFS in the TEXT study or to exemestane plus

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OFS, tamoxifen plus OFS, or tamoxifen monotherapy in the SOFT study.

The joint analysis included 4690 women (average age, 43 years).

At a median follow-up of 5.7 years, the disease-free survival rates were 91.1% with exemestane and 87.3% with tamoxifen, corresponding to a hazard ratio (HR) of 0.72 (P = .002).

More than 96% of women were alive at 5 years. No difference was observed in overall survival between adjuvant exemestane and tamoxifen therapy.

Dr Pagani noted that “some premenopausal women may have excellent prognosis with highly effective endocrine therapy alone.” A total of 1996 women in the joint analysis did not receive chemotherapy. They tended to be older (aged ≥40 years) and had smaller tumors and no nodal involvement. “More than 97% were free of breast cancer at 5 years when treated with exemestane plus ovarian function suppression,” Dr Pagani said.

This compared with approximately 95% of the tamoxifen plus OFS group,

for an HR of 0.41 to 0.53.

Exemestane plus OFS was also more effective than tamoxifen plus OFS for women who received chemotherapy.

Musculoskeletal complaints, osteoporosis, and fractures were more common in the exemestane group, and thrombotic or embolic events were more common in the tamoxifen group.

The frequency of severe side effects and self-reported quality of life did not differ between the groups.

Only 14% of the patients overall stopped the protocol-assigned treatments before 5 years—an adherence rate that exceeds that in everyday practice, said Dr Pagani. The early cessation of treatment was 16% in the exemestane group and 11% in the tamoxifen group.

“Our findings indicate that exemestane is better than tamoxifen when given with ovarian function suppression, but longer follow-up of these young women will be important to assess survival and any long-term side effects and fertility,” Dr Pagani concluded. n

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

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

Indication

» GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colonystimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

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

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

Prostate Cancer

Upfront Docetaxel Markedly Improves Survival

By Wayne Kuznar

Chicago, IL—The upfront addition of docetaxel to androgen deprivation therapy (ADT) adds more than 1 year to overall survival (OS) compared with ADT alone in men with newly diagnosed hormone-sensitive prostate cancer, according to findings from a phase 3 study presented at the 2014

American Society of Clinical Oncology meeting.

The survival benefit was even greater for the subset of men with high-volume disease, reported Christopher Sweeney, MBBS, Lank Center for Genitourinary Oncology at the DanaFarber Cancer Institute, Boston. “The

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

4 CONTRAINDICATIONS None.

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

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

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

Discontinue GRANIX in patients undergoing a sickle cell crisis.

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

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

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

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

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benefit is substantial and warrants this being a new standard treatment for men who have high-extent disease and are fit for chemotherapy,” he said.

Docetaxel is typically initiated only after disease progression despite ADT. The study randomized 790 men with newly diagnosed metastatic prostate

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

august 2014

“

The benefit is substantial and warrants this being a new standard treatment.

”

—Christopher Sweeney, MBBS

cancer to either ADT alone or to ADT with docetaxel over 18 weeks. Approximately 66% of patients had high-volume disease. At a median follow-up of 29 months, 136 deaths occurred in the ADT-alone group compared with 101 in the group receiving ADT plus docetaxel. OS was improved by 13 months with upfront docetaxel: 44 months in the ADT group versus 57.6 months in the group receiving ADT plus docetaxel, for a relative improvement of 39% (P = .003).

In men with high-volume disease, the median OS was 49.2 months with docetaxel plus ADT compared with 32.2 months with ADT, corresponding to a 40% reduction in the risk of death (P = .006). In men with low-volume disease, the median OS had not been reached at the time of the analysis.

Docetaxel also delayed disease progression, assessed by either a rise in the level of prostate-specific antigen (PSA) or the appearance of new metastases or symptom worsening. At 1 year, the proportion of patients with PSA levels of <0.2 ng/mL was 11.7% in the ADT group versus 22.7% in the group receiving ADT plus docetaxel.

The median time to clinical progression was 19.8 months in the ADT group compared with 32.7 months in the combination group (P <.001). The median time to castration-resistant prostate cancer was also significantly improved with docetaxel compared with ADT alone (20.7 months vs 14.7 months; P <.001).

Immediate past president of ASCO, Clifford A. Hudis, MD, remarked, “In prostate cancer, I’m not aware of a historical study that ever offered up this magnitude of improvement in survival. Across all solid tumors, this is all almost unprecedented improvement in median survival.”

Michael J. Morris, MD, Memorial Sloan Kettering Cancer Center, New York City, said. “Docetaxel is going to cost less than our newer therapies. I estimate that using docetaxel in castration-resistant prostate cancer gains 81 days of life for $15,000 of drug costs at wholesale prices. If docetaxel is applied in castration-sensitive disease, it gains 476 days of life at a cost of $9000 for 6 cycles.” n

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No. 6

4th Conference

Patients with Cancer Need Psychosocial Support...

Conference of the Association for Value-Based Cancer Care.

An anticipated routine visit to his ear, nose, and throat physician turned into something more than the allergies that he had been diagnosed with when his physician recommended that he have an endoscopy. The physician told him she found evidence of advanced esophageal cancer, and suggested that his wife come to her office. The physician then patiently answered all their questions, gave them her cell phone number, referred Mr Tomlinson to Beverly Hills Cancer Center, and hugged him as he was leaving, saying, “We’re in this together—the 3 of us are going to beat this… together,” he reported.

“It was easily, next to the death of family members, the worst day of my life, but I left that office somehow

at a glance ➤ There are simple ways of improving the experience of patients with cancer, and these do not cost much money ➤ Basic psychosocial care consists of offering patients and their families emotional support and communication in a patientcentered and sensitive manner ➤ Patients with cancer want treatment, and they want comfort ➤ Expressions of caring are important to the patient; unexpressed care is useless

comforted, somehow empowered, somehow feeling optimistic, despite the crushingly bad news that I had just been given,” said Mr Tomlinson.

“Well, I would love to tell you that it was all hats and horns after that.”

“

I knew that I was a paycheck….I clearly had no value as a human beyond $10,500 a day.

”

—Lee Tomlinson

While undergoing treatment, along with the kind gestures from caregivers and even a parking lot attendant who carried him up the steps and placed him into a wheelchair, Mr Tomlinson described a slew of severe side effects from his chemotherapy and radiation, a dead gecko in his hospital room, a bout of coagulase-negative Staphylococcus epidermidis, dead orchids at the reception desk, a physician–nurse verbal confrontation in

the hall, a hospital “thank you” note with his gender misidentified and his name misspelled, and more.

“I knew that I was a paycheck,” Mr Tomlinson said. “I wanted to die. I clearly had no value as a human beyond $10,500 a day.”

Some of his pain was self-inflicted, such as his decision to forgo parenteral nutrition, and he delayed entering the cancer support community, which he called one of his biggest regrets.

Mr Tomlinson is now 2 years out and is “100% cancer free,” with no evidence of disease. “I owe it to people who do exactly what you do,” he said to the oncologists and payers present at the conference. “I am alive today because of you. Without the research, without the treatment, without the care, without all of what you’ve been talking about, without my insurance company, without my employer, I would be dead,” he emphasized.

“That’s thrilling to me. However, what you don’t know is the fight was harder than it needed to have been. There were parts of it that were unnecessarily difficult, that caused me enormous pain, enormous suffering—caused my family and friends the same,” Mr Tomlinson continued.

What Constitutes Value to the Patient?

There are ways of improving a patient’s experience, and they do not cost much money, Mr Tomlinson said. Basic psychosocial care is crucial. As defined by the World Health Organization, psychosocial care consists of offering patients and their families emotional support and com-

Continued from the cover

munication in a person-centered and sensitive manner.

Patients want treatment, and they want comfort. “Nobody told me it was important,” said Mr Tomlinson.

“Remind us—stress the importance.”

Expressions of caring are impor­ tant, he said. “I get that you care, but unexpressed care is useless,” Mr Tomlinson said.

“

I am alive today because of you.

However, what you don’t know is the fight was harder than it needed to have been. There were parts of it that were unnecessarily difficult, that caused me enormous pain, enormous suffering.

”

—Lee Tomlinson

Patients want their caregivers to be at their best, he said, noting that 38% of oncologists experience burnout.

They want well-rested, well-compensated oncologists who put themselves first, so they could be at their best.

“Whatever time I have left, I’m committed to creating a deeper, mutual understanding between medical professionals and patients to enable all of us to work better as a team, rather than adversaries, or in our silos,” Mr Tomlinson said. n

Oncology Pipeline Bustling, But Value Concerns Lead to Increased Payer Scrutiny

By Wayne Kuznar

Los Angeles, CA—Targeted therapies have dramatically increased their share of global oncology sales over the past decade. But concerns over value have led to more payer scrutiny of targeted therapies and other oncology drugs, suggested Doug Long, Vice President, Industry Relations, IMS Health, at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

These data come from the IMS Institute study on cancer care between 2003 and 2013. For most cancers, “the

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No. 6

survival rate is improving as detection and treatment improve,” said Mr Long. But many of the improved outcomes come from a variety of things.

“In our study, 23% of the improvement was attributed to behavioral changes, 35% is due to screening, 20% to advances in treatment, and the remaining 22% to other factors,” he said.

Oncology Drug Spending “Oncology is what we spend the most on in the United States,” said Mr Long. Global spending on oncology

“

Oncology is what we spend the most on in the United States.

”

—doug long

drugs has increased from approximately $40 billion in 2003 to approximately $90 billion in 2013. So the spending on oncology drugs has more than doubled in 10 years. Spending

august 2014

I

on cancer drugs in the United States is projected to reach $74 billion to $84 billion in 2017.

Global spending in oncology therapies has grown much faster than that for other therapeutic categories, but global growth for oncology spending has slowed since 2008, to <10% annually. In the United States, the annual growth rate in oncology drug spending has been 3.5% over the past 5 years, reaching $37 billion in 2013.

Approximately 41% of the global oncology spending was in the United

Continued on page 40

www.ValueBasedCancerCare.com

35

NEW PHASE 3 DATA

IMBRUVICA® demonstrated single-agent survival in previously treated CLL INDICATIONS: IMBRUVICA® is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with: • Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy • CLL with 17p deletion

Significantly improved overall survival (OS)—secondary endpoint • 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA® arm (HR=0.43; 95% CI: 0.24, 0.79) • Median OS not yet reached in either treatment arm • 29% of ofatumumab patients crossed over to receive IMBRUVICA® upon progression

Significantly extended progression-free survival (PFS)—primary endpoint 78% statistically significant reduction in the risk of death or progression (independent review) 100

PFS (%)

80 60 40 Hazard ratio (HR) for progression or death: 0.22 (95% CI: 0.15, 0.32) P<0.0001 by log-rank test

20 0

0

3

6

183 161

116 83

Number at risk IMBRUVICA® 195 Ofatumumab 196

Months

Ofatumumab 9

12

15

38 15

7 1

0 0

Results from the randomized, multicenter, open-label, Phase 3 RESONATE™ trial of IMBRUVICA® vs ofatumumab in patients with previously treated CLL. Patients (N=391) were randomized 1:1 to receive either IMBRUVICA® 420 mg orally daily until disease progression or unacceptable toxicity or IV ofatumumab at an initial dose of 300 mg, followed 1 week later by a dose of 2000 mg weekly for 7 doses, and then every 4 weeks for 4 additional doses. Fifty-seven patients randomized to ofatumumab crossed over following Independent Review Committee-confirmed progression to receive IMBRUVICA®. Primary endpoint: PFS as assessed by an Independent Review Committee (IRC) according to modified International Workshop on CLL Criteria.

Significantly improved PFS in patients with previously treated del 17p CLL • 75% reduced risk of progression or death (HR=0.25; 95% CI: 0.14, 0.45) — Median PFS not reached with IMBRUVICA® vs 5.8 months with ofatumumab

In CLL studies, approximately 5% of patients discontinued due to adverse events Please review the Important Safety Information on adjacent page.

ORAL, ONCE-DAILY DOSING

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage - Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®.

The mechanism for the bleeding events is not well understood.

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

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA®. Twenty-six percent of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly.

Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation.

Periodically monitor patients clinically for atrial fibrillation.

Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification.

Second Primary Malignancies - Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in

© Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 07/14 PRC-00483

patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%).

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA®. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS The most common adverse reactions (≥20%) in the clinical trials were thrombocytopenia (56%), neutropenia (51%), diarrhea (51%), anemia (37%), fatigue (28%), musculoskeletal pain (28%), upper respiratory tract infection (28%), rash (26%), nausea (25%), and pyrexia (24%). Approximately 5% of patients receiving IMBRUVICA® discontinued treatment due to adverse events. These included infections, subdural hematomas, and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients.

DRUG INTERACTIONS CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.

CYP3A Inducers - Avoid co-administration with strong CYP3A inducers.

SPECIFIC POPULATIONS Hepatic Impairment - Avoid use in patients with baseline hepatic impairment.

Please review the Brief Summary of full Prescribing Information on the following page.

To learn more, visit us at

www.IMBRUVICA.com

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

IMBRUVICA® (ibrutinib) capsules

INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Accelerated approval was granted for this indication based on overall response rate. Improvements in survival or disease-related symptoms have not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials [see Clinical Studies (14.1) in full Prescribing Information].

Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2) in full Prescribing Information].

Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in full Prescribing Information].

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood.

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

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

Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Twenty-five percent of patients with MCL and 26% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation.

Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in full Prescribing Information].

Second Primary Malignancies: Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%).

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].

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

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

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

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

Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.

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

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) System Organ Class Gastrointestinal disorders

Infections and infestations

Preferred Term Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis

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

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

34 14 14 14 13

0 3 7 5 1

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

Preferred Term

General disorders and administrative site conditions

Fatigue Peripheral edema Pyrexia Asthenia Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

All Grades (%)

Grade 3 or 4 (%)

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

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

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades Grade 3 or 4 (%) (%) 57 17 47 29 41 9

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

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

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

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

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

Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia.

Approximately five percent of patients receiving IMBRUVICA in Study 1 and 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea.

Adverse events leading to dose reduction occurred in approximately 6% of patients.

Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1 System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions

Skin and subcutaneous tissue disorders Respiratory, thoracic and mediastinal disorders Musculoskeletal and connective tissue disorders Nervous system disorders

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

Metabolism and nutrition disorders Neoplasms benign, malignant, Second malignancies* unspecified Injury, poisoning and Laceration procedural complications Psychiatric disorders Anxiety Insomnia Vascular disorders Hypertension *One patient death due to histiocytic sarcoma.

All Grades (%) 63 23 21 21 19 15 13

Grade 3 or 4 (%) 4 2 2 0 2 0 0

48 21 17 10 10 31 25 23 13 13 54 27 17 19 15 10 27 23 19 21 19 10 17

2 6 6 8 0 4 2 0 4 0 2 0 0 0 0 0 6 0 2 0 2 0 2

10*

0

10

2

10 10 17

0 0 8

IMBRUVICA® (ibrutinib) capsules

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

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1 Percent of Patients (N=48) All Grades Grade 3 or 4 (%) (%) 71 10 54 27 44 0

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements per IWCLL criteria and adverse reactions Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2.

Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2

System Organ Class ADR Term Gastrointestinal disorders Diarrhea Nausea Stomatitis* Constipation Vomiting General disorders and administration site conditions Fatigue Pyrexia Infections and infestations Upper respiratory tract infection Pneumonia* Sinusitis* Urinary tract infection Skin and subcutaneous tissue disorders Rash* Petechiae Bruising* Musculoskeletal and connective tissue disorders Musculoskeletal Pain* Arthralgia Nervous system disorders Headache Dizziness Injury, poisoning and procedural complications Contusion Eye disorders Vision blurred

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%)

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%)

48 26 17 15 14

4 2 1 0 0

18 18 6 9 6

2 0 1 0 1

28 24

2 2

30 15

2 1

16 15 11 10

1 10 1 4

11 13 6 5

2 9 0 1

24 14 12

3 0 0

13 1 1

0 0 0

28 17

2 1

18 7

1 0

14 11

1 0

6 5

0 0

11

0

3

0

10

0

3

0

Subjects with multiple events for a given ADR term are counted once only for each ADR term.

The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2

Neutrophils Decreased Platelets Decreased Hemoglobin Decreased

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%) 51 23 52 5 36 0

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%) 57 26 45 10 21 0

* Based on laboratory measurements per IWCLL criteria DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg).

Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information].

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

CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively.

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

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

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

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

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

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

Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65 versus 51% of younger patients) [see Clinical Studies (14.2) in full Prescribing Information].

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

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

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

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

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

• Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions].

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

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

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

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

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

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

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

Active ingredient made in China.

Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA® is a registered trademark owned by Pharmacyclics, Inc. © Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 PRC-00526 07/14

4th Conference

Oncology Pipeline Bustling, But Value Concerns Lead to Increased Payer...

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States in 2013 compared with 43% in 2008. The global oncology business in Europe declined from 27% to 24% over this same time, which Mr Long attributes to a lower likelihood to approve new cancer drugs, because government bodies there rely more on comparative effectiveness research and real-world evidence.

The Oncology Pipeline The IMS data document that the share of targeted therapies in oncology has quadrupled in the past 10 years, from 11% in 2003 to 46% in 2013.

“Oncology is the biggest area for development,” Mr Long said. Of the 6234 drugs in the pipeline, approximately 33% of them are cancer therapies, and more drugs are currently being developed for cancer than for other clinical categories.

“The majority of the new molecular entities approved for cancer over the past decade has been nonbiologics,” he said. We are going to see more nonbiologics coming to market in the

at a glance ➤ Of the 6234 drugs in the pipeline, approximately 33% are cancer therapies ➤ The focus on value increases payers’ scrutiny of drug costs ➤ Innovation in cancer drug development focuses on targeted therapies ➤ The majority of the new molecular entities approved for cancer over the past decade has been nonbiologics ➤ The impact of biosimilars in oncology will increasingly grow, expected to generate $12 billion by 2020 globally

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future. Although many pharmaceutical companies are seeking approval for their drugs using the breakthrough

“

However, the rest of oncology, “radiology oncologists, pediatric oncologists, gynecological oncologists, sur-

The ironic thing is that most of these drugs are developed here, and they’re more expensive here than they are in other places.

It’s because the other places use a lot of different techniques to contain or evaluate these drugs.

”

—Doug Long

therapy designation, the FDA has granted approval to only 26% of them, and an additional 18% of drugs are awaiting a decision. Of these drugs, 34% are in oncology.

Drugs for lung cancer are “far and away” the largest oncology category in phase 2 clinical trials. There are limited alternatives and high unmet needs for agents to treat bladder cancer, ovarian cancer, and melanoma, although the latter category has gotten more crowded with immune therapies recently.

Focus on Value Increases Cost Concerns Changes in the structure of the US healthcare delivery are having an impact on cancer treatment site of care, reimbursement, and patient out-ofpocket costs. Physician practices are becoming larger. Care covered by the 340B Drug Pricing Program has expanded its presence in oncology, resulting in a shift in patient care from physician offices to hospital outpatient facilities.

“The number of oncologists in the US through 2012, particularly medical oncologists, continues to rise.”

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gical oncologists, those numbers are relatively flat,” according to Mr Long, and this will affect value.

The higher infrastructure costs and overhead for the delivery of care incurred by hospitals means that their reimbursement levels for the admin-

Payers have intensified the scrutiny of the value of cancer medications versus their incremental benefits, largely because the average cost for a branded cancer drug is now approximately $10,000 monthly. The additional value of targeted treatments for individual patients is difficult to judge, because of a high variability in patient response, frequent changes in protocol, and variability in patient care.

Newly launched treatments are typically associated with 2 to 6 months of incremental overall survival. In the European Union, the trend is toward lower list prices at the time of launch compared with US list pricing, and European markets have other discount mechanisms.

“The ironic thing is that most of these drugs are developed here, and they’re more expensive here than they are in other places,” Mr Long said.

“It’s because the other places use a lot of different techniques to contain or evaluate these drugs.”

Payers have intensified the scrutiny of the value of cancer medications versus their incremental benefits. The additional value of targeted treatments for individual patients is difficult to judge, because of a high variability in patient response and in patient care. istration of drugs are higher than the levels for physician offices.

For infused or injected targeted therapies, reimbursed costs for hospitals are at least double those for physician offices and have brought sharply higher costs to payers over the past 2 years. These higher costs are associated with greater out-of-pocket costs for patients. The higher copays decrease therapeutic adherence, driving up the total cost of care, he said.

Biosimilars The impact of biosimilars and “nonoriginal” biologics is growing, as patent protection is expiring. In developed countries, however, the potential role of biosimilars will be limited by the expected introduction of patent-protected innovative drugs that will displace older, off-patent drugs.

By 2020, biosimilars are expected to generate $6 billion to $12 billion in oncology sales globally. n

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4th Conference

Using IBM Watson Electronic System to Guide Patient Management in Oncology

By Wayne Kuznar

Los Angeles, CA—IBM Watson computer is changing the face of oncology practice through its massive parallel computing system, utilizing natural language processing and cognitive machine computing. Unlike HAL 9000 from the movie 2001: A Space Odyssey, the IBM Watson system does not interpret the results but rather builds on information it receives from previous operations and offers possible solutions to new queries, said Mark G. Kris, MD, William and Joy Ruane Chair, Thoracic Oncology, Memorial Sloan Kettering Cancer Center, New York, at the Fourth Annual Conference of the Association for Value-Based Cancer Care. Dr Kris, lead physician of the Memorial Sloan Kettering Cancer Center–IBM Watson collaboration, discussed how the use of this system is transforming cancer care.

Exponentially growing data (ie, big data) that are increasing in specificity and complexity must be interpreted by oncologists, including medical rec­ords, test results, and information from medical publications. Dr Kris provided an example of next-generation sequencing, or integrated mutation profiling of actionable cancer targets, in which probes for 341 genes are examined.

“We do it in all the cancers with a good target; KRAS in colorectal, BRAF in melanoma, etc,” he said. “It’s very important not just to look for a mutation or an amplification, but to look for all those things.”

IBM Watson provides cognitive computing to build possible solutions from previous applications. “It learns, not like a human learns, but approaching that,” said Dr Kris. “In the course of performing operations and giving answers and solutions, that information informs the operating system the next time that same question is asked or a similar question is asked.”

In addition, IBM Watson uses natural language processing and cues from information provided to obtain possible solutions.

Memorial Sloan Kettering Cancer Center standards and “clinical wisdom” are integrated with up-to-date medical evidence to inform the care of the individual patient. For providers and patients, IBM Watson would be used to facilitate and accelerate

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research, test new treatments, and measure outcomes.

“We are today trying to aid physicians and patients in making the best

“”

We are today trying to aid physicians and patients in making the best choices at the first treatment selection for metastatic solid tumors.

—Mark G. Kris, MD

choices at the first treatment selection for metastatic solid tumors,” said Dr Kris.

Watson Guiding Treatment Decisions He presented a Watson Oncology demonstration that analyzes the data to which it has access and prioritizes it when presented to the physician. The system suggests test options based on the information that is available, such as the type and extent of disease evaluation and any pretreatment assessments. In the case of a nonsmoking female Asian patient, the information presented at the top of the web page showed that cancer was found after a biopsy of an adrenal gland. The case information deprioritized the importance of a magnetic resonance imaging (MRI) scan that the patient had after a knee injury 3 years ago.

If a molecular pathology report were available, an MRI scan of the brain would be recommended. “It knows what it needs to make medical decisions, so it looks for those things that are most critical to its making a decision and it puts it on top,” Dr Kris said.

An evidence button would pro-

Figure Treatment Options to Consider

vide access to the medical evidence that supports the decision to perform a particular test (ie, a molecular test) based on the literature, expert panels, guidelines, and medical literature.

Treatment options with evidence and confidence levels of these therapies are provided. Patient preferences are considered (ie, the patient’s lifestyles and desires in the treatment of the illness). Clinical trials relevant to the specific patient are also provided (Figure).

In the example provided, the patient had EGFR-mutation stage IV lung cancer. Guidelines from the National Comprehensive Cancer Network recommend a regimen containing erlotinib (Tarceva), but this therapy is at the bottom of the list according to the Watson demonstration. In this patient, an exon 20 insertion is not a sensitizing mutation. Therefore, the best treatment plan would be a standard 3-drug therapy that includes cisplatin (Platinol), pemetrexed (Alimta), and bevacizumab (Avastin).

IBM Watson evaluated all the available information against current

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therapy. “I think it’s tough enough to know the EGFR mutation has mandated therapy, but which EGFR mutations?” asked Dr Kris. “Taking this further, there are 10 or so exon 20 insertions. There is 1 of them that probably is still sensitized. You need to know which 1 of the 8 of these rare mutations is the right one.”

“

There are 10 or so exon 20 insertions.

There is 1 of them that probably is still sensitized.

You need to know which 1 of the 8 of these rare mutations is the right one.

”

—Mark G. Kris, MD

As he explained, “we try to train this computer as we train doctors, experientially.” n

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4th Conference

Big Data and CancerLinQ Can Help to Optimize Patient Outcomes in Oncology

By Wayne Kuznar

Los Angeles, CA—CancerLinQ is focused on improving quality of cancer care and enhancing outcomes by providing patients and providers real-time access to big data in a rapid electronic system, said George W. Sledge, Jr, MD, Chief, Division of Oncology, Stanford University Medical Center, CA. Dr Sledge discussed how CancerLinQ can improve patient care at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

of Medicine (IOM). The goal of the IOM report was “to facilitate progress toward a learning health system—in which science, informatics, incentives, and culture are aligned for continuous improvement and innovation, with best practices seamlessly embedded in the delivery process and new knowledge captured as an integral by-product of the delivery experience.”

According to Dr Sledge, “the primary purpose of CancerLinQ is to

“

The primary purpose of CancerLinQ is to improve the quality of care to enhance outcomes.

This…should allow patients to, in a very real way, be able to monitor which clinical trials would be best for them. It will allow us to improve safety monitoring…and real-time side effect management.

”

—George W. Sledge, Jr, MD

Improving Quality CancerLinQ began as the American Society of Clinical Oncology (ASCO)’s response to the 2012 publication of the “Roundtable on Value & ScienceDriven Health Care” from the Institute

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improve the quality of care to enhance outcomes. This hopefully will manifest itself at several different levels, first for patients.” CancerLinQ, he noted, “should allow patients to, in a very real way, be able to monitor which

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clinical trials would be best for them.

It will allow us to improve safety monitoring,” as well as “real-time side effect management” and improved patient reporting outcomes.

CancerLinQ “works off of ASCO’s long experience with quality initiatives through the Quality Oncology Practice Initiative [QOPI],” Dr Sledge said. “It leverages our long-stand­ ing experience in terms of guideline development.”

This tool will also allow oncologists to fill in the knowledge gaps because 97% of patients are never enrolled into a clinical trial.

Clinical Decision Support “The ability to scan for real-time second opinions is something that I think physicians as a group will love. Even the smartest doctor is not aware of all the data, and even the smartest doctor will pull aside his colleagues for a curbside consult on a regular basis,” he noted. “Being able to do this across the broad system of oncology healthcare will be very important.”

“Clinical decision support will have a primary place in CancerLinQ,” Dr Sledge said. Clinical decision support will be “based on ASCO guidelines, observational clinical decision, and research support, and, hopefully, reach a point where we can disrupt the pernicious preauthorization approaches

at a glance ➤ CancerLinQ used “big data” to improve the quality of oncology care and enhance outcomes ➤ Clinical decision support is a key goal that will help patients and providers ➤ This system will allow patients to be able to monitor which clinical trials would be best for them ➤ It will allow oncologists to monitor and manage side effects in real time ➤ Eventually, the goal is to expand the use of CancerLinQ to pharmaceutical companies, payers, and insurers

that swallow up so much of physicians’ and nurses’ time,” he said.

The ability to acquire data from electronic health records (EHRs) from multiple practices, “batch” the data, and automate the processing across numerous competing EHR systems was very important, said Dr Sledge.

Accessing Big Data in Clinical Practice “Physicians will be able to access research literature and guidelines in real time at the point of care and will be able to do quality reporting and benchmarking.”

Researchers and public health pro­ fessionals will benefit from CancerLinQ by being able to mine big data, Dr Sledge said. “Being able to aggregate data across very large healthcare systems will be crucially important as we move forward in personalized therapy,” he said.

Aggregation will improve hypothesis generation and will provide correlation analysis and trend analysis over time. These data will enhance patient recruitment into trials, identify early adverse effects, and will show early signals of effectiveness in the off-label use of drugs. The data will inevitably feed back into the clinic to allow improved patient care.

Over time, he said, the goal is to expand the use of CancerLinQ to pharmaceutical companies, payers, and insurers. n

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QOPI Measures Identify Areas for Quality Improvement in Oncology Practice

By Wayne Kuznar

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Benchmark Measures QOPI was developed by ASCO to give clinicians a role in defining, measuring, and improving the quality of care. QOPI measures are on­ cologist-developed, evidence-based,

least 1 of 10 possible rounds of data collection, and QOPI shows that most practices “have maxed out on treatment process measures,” noted Dr Blayney. For example, adherence to breast cancer process measures has

“

In oncology, we’re fortunate enough to have a rich evidence base upon which to make guidelines. We can measure adherence to guidelines, and then we can target interventions to improve adherence.

”

—Douglas W. Blayney, MD

guideline-based, and consensus-based, and are continually reviewed and updated by experts. They are grouped into several domains, including: • Core measures—care documentation, chemotherapy administration, pain management, smoking cessation, and psychosocial support • Disease-specific module • Domain-specific module—endof-life care, symptom/toxicity management.

Since the spring of 2014, more than 25,000 patient charts have been voluntarily submitted to QOPI for analysis. From 2006 to 2010, 308 unique practice groups participated in at

been approximately 95% over the past 5 years.

The rates of mutation testing in breast cancer, colorectal cancer, and NSCLC, as well as the appropriate use of anti-EGFR monoclonal antibodies have been improving, but gaps persist, Dr Blayney said.

QOPI data show a decline from 50% in 2006 to approximately 15% in 2010 in the use of chemotherapy in the last 2 weeks of life at the University of Michigan after a grand rounds presentation at the cancer center (Figure). The 15% rate is more in line with national aggregates, said Dr Blayney.

At Stanford University, using QOPI

Figure QOPI Process Improvement: Large Academic Medical Center University of Michigan Cancer Center QOPI measure: chemotherapy use within the last 2 weeks of life 60 Chemotherapy use, %

Los Angeles, CA—Value is the preeminent goal in cancer care, because it unites all of the interests of the stakeholders, including patients, said Douglas W. Blayney, MD, Medical Director, Stanford Cancer Institute, CA, at the Fourth Annual Conference of the Association for Value-Based Cancer Care. American Society of Clinical Oncology (ASCO)’s Quality Oncology Practice Initiative (QOPI) is providing oncology practices with the means to improve quality care through the use of quality measures toward the improvement of patient outcomes.

The 3 elements of quality are structure, process, and outcome. Structure is the site of delivery, which includes the information infrastructure. Uniform processes, such as those for ordering chemotherapy, are important to quality care, because they aid efficiency, said Dr Blayney. In addition to survival, appropriate symptom relief and palliation are important outcomes to patients.

Because testing the effect of a cancer intervention on the most meaningful outcome—survival—may take years, quality of cancer care should focus on the processes, Dr Blayney said. “In oncology, we’re fortunate enough to have a rich evidence base upon which to make guidelines. We can measure adherence to guidelines, and then we can target interventions to improve adherence,” he said, pointing to the many evidence-based guidelines issued by the National Comprehensive Cancer Network.

Poor quality processes can be defined by: • Too little care (underuse)—the failure to provide an effective service when it would have provided a favorable outcome • Too much care (overuse)—the provision of care when its risk of harm exceeds the potential benefit • The delivery of wrong care (misuse).

US Oncology measured the cumulative costs of care for non–small-cell lung cancer (NSCLC) by pathway status and found that over 12 months, “on-pathway” care costs slightly more than 50% of care that is “offpathway.” “It looks like a measure of overuse,” said Dr Blayney, “because the survival was exactly the same whether a patient was treated on or off pathway.”

Cancer center grand round presentation

50 40

20 10 0 Spring 06 Fall 06 Spring 07 Fall 07

Fall 08

Source: Blayney DW, et al. J Clin Oncol. 2009;27:3802-3807.

Fall 09 Spring 10 U of Michigan National Aggregate

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measures identified a deficiency in obtaining patient consent for chemotherapy.

The Michigan Oncology Quality Consortium is a quality collaborative funded by Blue Cross Blue Shield of Michigan, with the goal of improving the care of patients with cancer in Michigan by using data gathered as part of QOPI. The consortium practices are small; most practices see less than 500 new patients annually and have fewer than 4 oncologists. Despite the small size of most participating practices, small practice groups could collaborate to measure adherence to the processes.

A compilation of the results over 5 QOPI data collection rounds found that, in general, adherence to the cancer treatment process for breast cancer, colorectal cancer, and NSCLC is generally good, but adherence to other care processes, such as symptom and toxicity management and

“

The secret sauce here is that Blue Cross Blue Shield helped fund some of the infrastructure to do data extraction and also to hold quarterly meetings with these doctors.

”

—Douglas W. Blayney, MD

end-of-life care, is not as good and did not change with measure sharing.

Much unwanted variation in measured adherence to many processes of care was discovered. Because it measures processes, participation in the Michigan consortium does not necessarily improve outcome, but compliance with supportive care was improved when practices were asked to use the Edmonton Symptom Assessment Scale during the patient encounter. “This shows what can be done in a statewide collaborative,” Dr Blayney said.

“The secret sauce here is that Blue Cross Blue Shield helped fund some of the infrastructure to do data extraction and also to hold quarterly meetings with these doctors in the state,” he concluded. n

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Industry Perspective

End Points in Oncology Clinical Trials: Revisiting Overall Survival

By Ryan Saadi, MD, MPH Global Head, Market Access & Health Policy, Oncology, Janssen Pharmaceuticals, Johnson & Johnson

W

hen a promising investigational cancer drug enters a development area of great medical need, there is high pressure on the manufacturer from patients and from physicians to quickly secure patient access to this drug. This pressure can affect the trial design, regulatory requirements, and the trial results that are obtained before the drug is launched. For example, the drug may be approved based on data from phase 2 clinical trials that may have a single arm or a limited sample size or duration. These concessions are made as a result of the substantial unmet need for an effective therapy.

In clinical trials targeting a high unmet medical need, overall survival (OS) data may be immature, as a result of a long natural history of the disease or the limited follow-up period by the time the drug is being launched. In addition, patient crossover may confound the OS data. That is, for ethical reasons, when a patient’s disease progresses in the control arm of a phase 3 clinical trial, that patient should be switched to the best available therapy. However, in many cases when alternative therapies are limited, the options for best available therapies may include the experimental drug. This is due to the consequences of delaying treatment with

an effective therapy—even an experimental therapy—in situations where the patient has a limited life expectancy with the use of currently available therapies. In such cases, many patients in the control arm ultimately receive the investigational drug, but only after failure of another therapy and, therefore, with a lag time relative to the population in the active-treatment arm.

Although OS remains an important end point that is relevant to patients, clinicians, and payers, there will continue to be situations where clinical need demands a drug with imperfect OS data.

These instances require a collaborative approach among stakeholders.

This situation leads to a dilemma for drug makers, who have an ethical responsibility to provide access to investigational drugs. But exposure to the experimental drug in the control

arm reduces the possibility of showing an OS benefit in the active-treatment arm, because patients in the control arm also gain the benefit of the investigational drug. Moreover, even when a clinical trial is designed to prohibit crossover to the investigational therapy, the study may be halted early as a result of positive efficacy results. This, in turn, reduces the amount of data available to demonstrate a significant OS benefit.

Such barriers to demonstrating OS benefit within phase 3 clinical trials can have important implications for the clinical acceptance and for reimbursement of a new and effective therapy. The reimbursement of novel, potentially life-saving therapies is particularly challenging, because historically, an improvement in OS has been considered the clearest demonstration of clinical value. Improved OS indeed reflects the absolute goal of extending patient life and lends itself to health economic calculations of cost per lifeyear gained or cost per quality-adjusted life-year gained, without the need for the uncertainties of modeling based on surrogate end points. However, in cases where demonstration of an OS benefit may not be possible, or is underestimated, at the time of launch, the new drug may face reimbursement restrictions. Such restrictions have im-

portant implications for physicians and for patients, who may be unable to access the promising and potentially life-extending new drug.

Currently, methods for addressing limited OS data are gaining acceptance with payers. For example, in some cases, surrogate end points, such as response rate or progression-free survival, can be validated as predictors of OS. Similarly, when patients in the control group are crossed over to the investigational drug, statistical methods can be used to demonstrate an OS benefit by correcting for the efficacy of the experimental drug in the control arm.

In general, drug makers face a challenge in bridging the gap between the urgency for a new drug in a high-need area and the time required to collect data that can satisfy regulators and payers. Consequently, although OS remains an important end point that is relevant to patients, clinicians, and payers, there will continue to be situations where clinical need demands a drug with imperfect OS data. These instances require a collaborative approach among stakeholders, where drug makers collect the best possible data to demonstrate value, and payers acknowledge the limitations that may be necessary in terms of trial design (including end points). n

FDA Approved Idelalisib for 3 Types of Hematologic Cancers

phocytic leukemia,” said Dr Pazdur.

“Zydelig’s approval to treat CLL reflects the promise of the breakthrough therapy designation program and represents the FDA’s commitment to working cooperatively with companies to expedite a drug’s development, review and approval.”

On the same day, the FDA granted idelalisib an accelerated approval for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL), as well as relapsed small lymphocytic lymphoma (SLL). Idelalisib is intended to be used in patients who have received at least 2 previous systemic therapies.

Idelalisib’s safety and effectiveness for relapsed CLL were established in

FDA Drug Approvals Belinostat Approved for Peripheral T-Cell Lymphoma...

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diverse group of rare diseases in which lymph nodes become cancerous. PTCL represents approximately 10% to 15% of NHL cases in North America.

Belinostat works by preventing the development of T-cells from becoming cancerous. According to the FDA, “This is the third drug that has been approved since 2009 for the treatment of peripheral T-cell lymphoma,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

“Today’s approval expands the number of treatment options available to

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patients with serious and life-threatening diseases.”

The safety and effectiveness of bel­ inostat were evaluated in a clinical trial involving 129 patients with relapsed or refractory PTCL. All patients received belinostat until disease progression or until their side effects became unacceptable. In all, 25.8% of the patients showed complete or partial response after treatment with belinostat.

The most common side effects seen with belinostat were nausea, fatigue, fever, anemia, and vomiting.

Belinostat also received orphan drug designation by the FDA, because it is intended for the treatment of patients with PTCL, which is a rare disease.

(July 3, 2014)

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The FDA approved idelalisib (Zydelig; Gilead Sciences) for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) to be used in combination with rituximab (Rituxan). Idelalisib is recommended for use in this patient population in those for whom rituximab alone would be considered inappropriate therapy because of potential comorbidities. The drug received a breakthrough therapy designation for CLL earlier this year.

“In less than a year, we have seen considerable progress in the availability of treatments for chronic lym-

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Melanoma

Association between Indoor Tanning and Melanoma Confirmed in New Meta-Analysis

By Rosemary Frei, MSc

Toronto, Ontario—Going to more than 10 indoor tanning sessions over a person’s lifetime is associated with a 34% increased risk of developing melanoma, according to a new meta-analysis presented at the 2014 Canadian Dermatology Association annual meeting.

“Clinicians should continue to educate patients on the harms of indoor tanning and encourage its cessation,” said lead investigator Sophia Colan­ tonio, MD, MPH, of the Division of Dermatology, Department of Medicine, University of Ottowa, Ontario, Canada, in an e-mail to Value-Based Cancer Care.

These results confirm previous studies showing an increased rate of skin cancer among people who use tanning beds, and add new information as well. The other parameters of the study showed: • A 23% increased risk for melanoma among North Americans who had ever used indoor tanning compared with those who had never used it • People who first used indoor tanning before age 25 years had a 35% risk of developing melanoma compared with an 11% increased risk for those who started indoor tanning later in life.

“We feel this is an important area of research, and further high-quality studies such as prospective cohort studies will yield more valid results that clinicians can use to counsel their

“

Clinicians should continue to educate patients on the harms of indoor tanning and encourage its cessation.

”

—Sophia Colantonio, MD, MPH

patients about the risks of indoor tanning and promoting tanning bed avoidance,” Dr Colantonio said.

Study Details

The meta-analysis of the literature on indoor tanning included 37 cohort studies, case-control, or cross-sectional studies that were published in any language in peer-reviewed journals up to August 14, 2013. The team of re-

searchers focused the meta-analysis on the 31 studies that had risk estimates—13 provided crude odds ratios and the other 18 had adjusted odds ratios. Overall, the 31 studies included 14,956 cases of melanoma and 233,106 controls.

The results showed a significantly increased risk of melanoma associated with people who had ≥10 tanning sessions, lived in North America, and started indoor tanning before age 25 years.

Furthermore, a 61% increased melanoma risk was associated with using tanning beds for more than 1 year compared with having never used tanning beds, and a 37% increased risk among those who used tanning beds for less than 1 year compared with never-users.

The researchers also found that newer tanning bed bulb technology, which emits larger doses of long-wave ultraviolet A, increases the risk of melanoma: there was a 22% increased risk of melanoma among people who had ever used indoor tanning versus people who had never used indoor tanning after the year 2000, and only a 12% increased risk with ever use versus no use before 2000.

However, the investigators noted that the quality of the studies ranged from poor to mediocre, and several of the subgroup analyses involved heterogeneous studies.

“This meta-analysis has highlighted the poor to mediocre quality of evidence available on this topic, mainly because the majority of studies used a case-control design, which is prone to several biases,” the investigators noted in their article, which was simultaneously published in the Journal of the American Academy of Dermatology (Colantonio S, et al. 2014;70:847-857). “Future research should consider prospective study designs in large population cohorts,” they added. n

dication for ibrutinib (Imbruvica; Pharmacyclics) for the treatment of patients with CLL who have a deletion in chromosome 17 (17p deletion), which results in poor response to standard CLL therapies. Earlier in the year, the FDA approved ibrutinib for all patients with CLL, after having designated it as a breakthrough therapy.

With this new indication, the FDA also approved new labeling for the drug to reflect that the clinical benefit of ibrutinib for the treatment of CLL has been verified based on new clinical trial results. These results confirmed the PFS and overall survival (OS) benefits associated with ibrutinib.

The expanded indication for patients with 17p deletion is based on results from a clinical trial of 391 previously treated patients with CLL; of these, 127 patients had CLL with 17p

deletion. Patients were randomized to ibrutinib or to ofatumumab until disease progression or until side effects became intolerable.

The trial was stopped early after a preplanned interim analysis showed that patients receiving ibrutinib had a 78% PFS improvement and a 57% OS benefit. Among the 127 patients with CLL plus 17p deletion, those receiving ibrutinib had a 75% improvement in PFS. The most common side effects associated with ibrutinib were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and fever.

This new indication was approved under the FDA’s accelerated approval and was reviewed under the agency’s priority review program. (July 28, 2014) n

at a glance ➤ More than 10 indoor tanning sessions is associated with a 34% increased risk of developing melanoma ➤ North Americans who have ever used indoor tanning are at a 23% increased risk for melanoma ➤ Starting indoor tanning before age 25 years increases the risk ➤ Newer tanning bed bulb technology, which emits larger doses of long-wave ultraviolet A, increases the risk of melanoma ➤ Clinicians should inform patients on the serious risks associated with indoor tanning

FDA Drug approvals FDA Approved Idelalisib for 3 Types of... Continued from page 44

a clinical trial of 220 patients with this condition who were randomized to receive idelalisib plus rituximab or placebo plus rituximab. The trial was stopped after the first prespecified interim analysis point, which showed that the active combination resulted in a progression-free survival (PFS) of 10.7 months compared with approximately 5.5 months with rituximab plus placebo. Results from a second interim analysis continued to show a statistically significant improvement for the active combination.

The safety and effectiveness of idelalisib in the treatment of FL and relapsed SLL were established in a clinical trial with 123 patients with indolent non-Hodgkin lymphomas. All patients received idelalisib and were evaluated for objective response rate

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(ORR). Results showed a 54% ORR in patients with relapsed FL and a 58% ORR for patients with SLL. Idelalisib carries a Boxed Warning regarding the risk of fatal and serious toxicities, including liver toxicity, colitis, pneumonitis, and intestinal perforation. The drug was also approved with a REMS (Risk Evaluation and Mitigation Strategy) program.

Common side effects with idela­ lisib include diarrhea, fever, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash. Common laboratory abnormalities include neutropenia, hypertriglyceridemia, hyperglycemia, and elevated levels of liver enzymes. (July 23, 2014)

Ibrutinib Receives Expanded Indication for Patients with CLL and 17p Deletion

The FDA issued an expanded in-

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Lung Cancer

Necitumumab Extends Survival of Patients with Squamous Lung Cancer

By Wayne Kuznar

the past 2 decades compared with nonsquamous NSCLC, noted Dr Thatcher.

The main reason is the lack of relevant oncogenic drivers to inform treatment decisions. Necitumumab was chosen as an add-on to standard gemcitabine plus cisplatin because EGFR expression is detectable in most advanced squamous NSCLC tumors.

The open-label multicenter study randomized 1093 patients with stage IV squamous NSCLC to gemcitabine 1250 mg/m2 on days 1 and 8 and intravenous cisplatin 75 mg/m2 on day 1 plus necitumumab 800 mg on days 1 and 8, or to gemcitabine plus cisplatin alone, administered every 21 days for up to 6 cycles.

Patients assigned to gemcitabine plus cisplatin and necitumumab who had no disease progression continued to receive necitumumab alone until disease progression or intolerable toxicity. Overall, 51% of the patients randomized to necitumumab plus chemotherapy continued to receive necitumumab monotherapy for a median

Chicago, IL— Necitumumab, a human immunoglobulin G1 anti-EGFR monoclonal antibody, added to standard chemotherapy significantly improved survival compared with chemotherapy alone as first-line treatment of patients with stage IV non–small-cell lung cancer (NSCLC) of squamous histology.

The median overall survival (OS) was extended by 1.6 months in patients randomized to the arm receiving necitumumab plus gemcitabine and cisplatin in the phase 3 clinical trial, said Nick Thatcher, MD, PhD, Professor in Medical Oncology, University of Manchester, Christie Hospital NHS Foundation Trust, United Kingdom, at the 2014 American Society of Clinical Oncology meeting.

Although the results were criticized because of the less-than-2-month improvement in survival, Dr Thatcher remarked, “It’s the first time that we’ve seen benefit in this group of patients over the last 20 or 25 years.”

Progress in the treatment of squamous NSCLC has been minimal over

of 4 additional cycles.

The primary end point, median OS, was 11.5 months in the arm receiving necitumumab plus chemotherapy versus 9.9 months in the arm receiving chemotherapy alone (P = .012). The 1-year survival rate was 47.7% and the 2-year survival rate was 19.9% in the necitumumab plus chemotherapy compared with 42.8% and 16.5%, respectively, in the chemotherapy-alone arms.

“

It’s the first time that we’ve seen benefit in this group of patients over the last 20 or 25 years.

”

—Nick Thatcher, MD, PhD

The median progression-free survival (PFS) was extended from 5.5 months in the chemotherapy arm to 5.7 months in the necitumumab plus chemotherapy arm (P = .02).

The need for systemic therapy after the study was similar in the 2 treatment groups: 47.3% in the necitumu­

mab plus chemotherapy arm versus 44.7% in the chemotherapy-alone arm.

A preplanned exploratory analysis of the EGFR H-score, a potential predictive biomarker, using a prespecified cut point of 200, showed no association between it and the OS or PFS by cut-point interaction.

Adverse event rates leading to the study discontinuation were 31.2% in the necitumumab plus chemotherapy arm and 24.6% in the chemotherapy-alone arm; adverse event rates leading to death were 12.3% and 10.5%, respectively. Grade ≥3 adverse events that occurred significantly more often in the necitumumab arm were hypomagnesemia (9.3% vs 1.1%, respectively), skin rash (7.1% vs 0.4%, respectively), and venous thromboembolic events (5% vs 2.6%, respectively).

Although statistically significant, the improvement in OS did not meet ASCO’s threshold for a clinically meaningful difference of 2.5 months to 3 months in squamous NSCLC, noted Julie R. Brahmer, MD, Associate Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore. n

Ramucirumab Improves Survival in Patients with Lung Cancer

By Dana Butler

46

“

Photo by © ASCO/Scott Morgan 2014

Chicago, IL—When added to chemotherapy (ie, docetaxel), the new monoclonal antibody ramucirumab improved overall survival (OS) compared with chemotherapy alone in patients with stage IV non–small-cell lung cancer (NSCLC), according to phase 3 trial results presented at the 2014 American Society of Clinical Oncology meeting.

The results were presented by Maurice Pérol, MD, of the Département de Cancérologie Médicale, Centre LéonBérard, Lyon, France.

“This is the first treatment to have shown a significant survival advantage over chemotherapy alone in second-line therapy of NSCLC, and the first treatment in approximately a decade to improve outcomes in the second-line setting,” said Dr Pérol.

Ramucirumab was recently approved by the FDA for the treatment of patients with advanced gastric cancer; it targets vascular EGFR2, which blocks the formation of new blood in the tumor.

“This study met the primary end point of OS, reducing the risk of death by 14% and prolonging median sur-

This is the first treatment to have shown a significant survival advantage over chemotherapy alone in second-line therapy of NSCLC, and the first treatment in approximately a decade to improve outcomes in the second-line setting.

”

—Maurice Pérol, MD

vival by 1.4 months,” said Dr Pérol.

Furthermore, the combination of ramucirumab plus chemotherapy reduced the risk of disease progression by 24%.

“Ramucirumab represents a potential new option for treatment in the second-line setting,” Dr Pérol suggested.

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If approved by the FDA for NSCLC, ramucirumab would be the first antiangiogenic drug approved for the second-line treatment of patients with this type of cancer.

Survival improvement was seen in patients with squamous and with nonsquamous histology; the median OS benefit was significant but modest.

Dr Pérol said that the drug could be useful in patients lacking a specific mutation, such as EGFR or ALK, that would make them candidates for targeted therapy.

Study Details The double-blind, placebo-controlled, phase 3 REVEL clinical trial included 1253 patients with stage IV NSCLC (26% of whom had squamous histology) whose disease progressed with standard platinum-based therapy. Patients were randomized to ramucirumab plus docetaxel or to docetaxel plus placebo.

The active combination significantly improved response rate, progression-free survival (PFS), and OS compared with docetaxel alone. The

median PFS times were 4.5 months with ramucirumab versus 3 months without (P <.001), and the median OS times were 10.5 months versus 9.1 months (P = .023), respectively.

The safety profile was similar to other angiogenesis inhibitors. No increase in pulmonary hemorrhage was reported with the combination.

Commenting on the study, Gregory A. Masters, MD, Director, Medical Oncology Fellowship, Helen F. Graham Cancer Center, Newark, DE, said, “This combination shows good activity in the difficult-to-treat second-line setting of NSCLC.” Dr Masters noted that ramucirumab may be a small step along the pathway that will ultimately constitute improvement. “Progress is slow and step-wise, and we build one step at a time. The cumulative progress is what we find encouraging….A study like REVEL may not change the way we treat NSCLC, but it can influence our design of further studies,” he said. He added that the key to assessing the value of a drug is to “balance benefit with cost, and figure out how best to treat patients.” n

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A 4-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

™

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

Value-BasedCare

™

November 2013 u 8th IN A SERIES

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

Topics include: • Effective Treatment of Newly

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

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

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

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

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

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

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

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

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

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

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

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

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

AVBCC100-8.indd 1

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

An official publication of

11/15/13 9:58 AM

VIEW THE SERIES ONLINE AT:

www.ValueBasedCancer.com/myeloma VBCMM_AVBCC127_Ksize13114

Drug Update

Zykadia (Ceritinib) Approved for the Treatment of Patients with Crizotinib-Resistant ALK-Positive Non–Small-Cell Lung Cancer

By Lisa A. Raedler, PhD, RPh, Medical Writer

L

ung cancer is one of the most frequently diagnosed cancers, as well as the leading cause of cancer-related mortality in the United States.1 According to the American Cancer Society, more than 159,000 Americans will die from lung cancer in 2014, representing approximately 27% of all cancer deaths.1 Non–smallcell lung cancer (NSCLC), the most common form of lung cancer, accounts for 85% to 90% of all cases.2 NSCLC comprises a number of histologies, including adenocarcinoma, squamous-cell carcinoma, nonsquamous carcinoma, large-cell carcinoma, sarcomatoid carcinoma, and adenosquamous carcinoma.2 A recent analysis of claims data from an oncology registry associated with a large US commercial health plan has demonstrated the substantial cost burden associated with NSCLC.3 This study, which was published in 2013, assessed the total cost of treatment for more than 300 patients with advanced NSCLC who were continually enrolled in the plan from diagnosis until death.3 The average total healthcare costs ranged from approximately $19,000 to $167,000 for first-line NSCLC management, and from approximately $35,000 to $135,000 for second-line management.3 In this analysis, systemic therapy represented 20% to 55% of first-line total costs, and 22% to 68% of second-line total costs.3 Traditionally, patients with metastatic NSCLC have been managed with combinations of cytotoxic agents.

Although the use of platinum-based doublets has improved the median overall survival for patients with advanced NSCLC from 4 to 5 months to 8 to 10 months (in treatment-naïve patients), these chemotherapy combinations are limited by significant toxicities, including myelosuppression, nausea and vomiting, and severe fatigue.4-6 As knowledge of tumor-cell biology in lung cancer evolves, small molecules that target specific genetic mutations offer the opportunity to manage patients with NSCLC using a personalized approach.6 In NSCLC, multiple driver oncogenes have been identiCopyright © 2014 American Health & Drug Benefits. All rights reserved.

48

fied, including EGFR, ALK, and KRAS.6 Among North American patients with advanced NSCLC, approximately 10% express mutations in EGFR,7 approximately 23% express mutations in KRAS,8 and up to 13% express activating mutations or translocations of ALK.9 Identifying EGFR and ALK mutations can help to decide whether a given patient with NSCLC can benefit from today’s targeted therapies, including erlotinib and afatinib (EGFR inhibitors) or crizotinib (an ALK inhibitor).

Granted an accelerated approval by the US Food and Drug Administration (FDA) in 2011, crizotinib was the first treatment available for patients with metastatic NSCLC whose tumors are ALK-positive.10 An open-label, activecontrolled, multinational, randomized clinical trial demonstrated prolonged progression-free survival with crizotinib compared with chemotherapy in ALK-positive, metastatic NSCLC. Vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue were the most common adverse reactions observed among recipients of crizotinib in this trial.10 To overcome the documented resistance to crizotinib, researchers continue to investigate medications that target ALK mutations.6 Novel kinase inhibitors currently being investigated in clinical trials for patients with ALK mutation NSCLC include alectinib, ganetespib, and AP26113.6,11 Ceritinib: New Treatment Option for ALK-Positive NSCLC On April 29, 2014, the FDA approved ceritinib (Zykadia; Novartis Pharmaceuticals), a kinase inhibitor, for the treatment of patients with metastatic ALK-positive NSCLC who are intolerant of, or whose disease progressed during therapy with, crizotinib.12 This approval was granted under the FDA’s accelerated process based on unpublished clinical trial data demonstrating significant tumor response rate and duration of response.12 Improvements in survival or disease-related symptoms have not been demonstrated.13 The approval of ceritinib was based on the results of a multicenter, singlearm, open-label clinical trial that en-

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Table 1 Response Rate and Duration of Response with Crizotinib in Patients with ALK-Positive NSCLC Investigator assessment BIRC assessment Efficacy end point (N = 163) (N = 163) 54.6 (95% CI, 47-62)

43.6 (95% CI, 36-52)

Complete response, %

1.2

2.5

Partial response, %

53.4

41.1

7.4 (95% CI, 5.4-10.1)

7.1 (95% CI, 5.6-not estimable)

Overall response rate, %

Duration of response, median, months

BIRC indicates Blinded Independent Review Committee; CI, confidence interval.

Source: Zykadia (ceritinib) capsules prescribing information; April 2014. rolled 163 patients with ALK-positive metastatic NSCLC that had progressed with crizotinib or who were intolerant of that drug.12,13 Ceritinib was administered at a dose of 750 mg once daily.12,13 “Zykadia represents an important treatment option for ALK-positive NSCLC patients who relapse after starting initial therapy with crizotinib,” noted lead investigator Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.14 “This approval will affect the way we manage and monitor patients with this type of lung cancer, as we will now be able to offer them the opportunity for continued treatment response with a new ALK inhibitor.”14

“

Zykadia represents an important treatment option for ALK-positive NSCLC patients who relapse after starting initial therapy with crizotinib.

”

—Alice T. Shaw, MD, PhD

Mechanism of Action In vitro and in vivo assays demonstrate that ceritinib, a kinase inhibitor, hinders the proliferation of ALK-dependent cancer cells by blocking the autophosphorylation of ALK, as well as ALK-mediated phosphorylation of STAT3, a downstream signaling protein. Ceritinib also targets insulin-like growth factor 1 receptor, insulin re­ ceptor, and ROS1.13

Dosing and Administration Ceritinib should be administered at a dose of 750 mg orally once daily until disease progression or until unacceptable toxicity. It should be taken on an empty stomach, but not within 2 hours of a meal. If a dose of ceritinib is missed, it should be administered only if the next dose is not due within 12 hours.13 Single-Arm Phase 2 Trial The multicenter, single-arm, openlabel trial of ceritinib enrolled 163 patients with the ALK-mutation NSCLC whose disease progressed while receiving crizotinib or those who were intolerant of crizotinib.13 Objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.0 was the primary end point of this study. This parameter was evaluated by the investigators and by a central Blinded Independent Review Committee.13

Patient Population

In the phase 2 ceritinib trial, most patients with ALK-positive NSCLC were female (54%), Caucasian (66%), aged <65 years (87%), and never or former smokers (97%).13 The majority (87%) had an Eastern Cooperative Oncology Group performance status of 0 or 1.13 Overall, 91% of patients had progressed with previous treatment of crizotinib, 84% had received ≥2 previous therapies, and 93% had adenocarcinoma histology.13 Common sites of extrathoracic metastases included the brain (60%), liver (42%), and bone (42%).13 Retrospective verification of ALK positivity was performed by review of local test results for 99% of patients.13 Continued on page 49

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Drug Update

Zykadia (Ceritinib) Approved for the Treatment of...

Efficacy

The phase 2 study demonstrated that ceritinib is active in patients with ALK-positive NSCLC, with an ORR of 54.6% by investigator assessment and a median duration of response of 7.4 months. All participants received ceritinib at an initial dose of 750 mg daily.

The median duration of exposure to ceritinib was 6 months.13 The findings of the Blinded Independent Review Committee were similar to those of the investigators. Table 1 lists the findings on ORR and duration of response from this study.13 Safety and Adverse Events The safety of ceritinib was established based on data from 255 patients with ALK-positive disease in the phase 2 study—246 patients with NSCLC and 9 patients with other cancer types.13 A total of 59% of the patients receiving ceritinib required dose reductions as a result of adverse reactions.13 The adverse reactions that led to dose reductions or interruptions were reported in ≥10% of patients and included increased alanine aminotransferase (ALT; 29%), nausea (20%), increased aspartate aminotransferase (AST; 16%), diarrhea (16%), and vomiting (16%).13 Serious adverse drug reactions that were reported in ≥2% of patients receiving ceritinib included convulsion, pneumonia, interstitial lung disease/ pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea.13 Of the patients receiving ceritinib, 5% had fatal adverse reactions, including pneumonia, respiratory failure, interstitial lung disease/pneumonitis, pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary tuberculosis, cardiac tamponade, and 1 case of sepsis.13 Overall, 10% of patients receiving ceritinib discontinued therapy as a result of adverse reactions.13 Pneumonia, interstitial lung disease/pneumonitis, and decreased appetite were the most common adverse drug reactions that led to discontinuation in ≥1% of patients.13 Of note, ceritinib should be discontinued in patients who do not tolerate 300 mg daily dosing.13 Table 2 lists the common adverse reactions and Table 3 lists the laboratory abnormalities reported in patients treated with ceritinib.13 Additional adverse reactions occurring in ≥2% of the patients receiving ceritinib include neuropathy (17%), manifested as paresthesia, muscular weakness, gait disturbance, peripher-

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al neuropathy, hypoesthesia, peripheral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, or polyneuropathy; vision disorder (9%), including vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, or reduced visual acuity; prolonged QT interval (4%); and bradycardia (3%).13 Warnings and Precautions Severe/persistent gastrointestinal toxicity. Of the 255 patients receiving ceritinib in the phase 2 study, 96% had diarrhea, nausea, vomiting, or abdominal pain; severe cases were reported in 14% of the patients. Dose modification was required in 38% of patients as a result of diarrhea, nausea, vomiting, or abdominal pain. Patients should be managed using standards of care, as needed. Based on the severity of the adverse drug reaction, ceritinib should be withheld and then resumed with a 150-mg dose reduction.13 Hepatotoxicity. Of the 255 patients in the phase 2 study, 27% had elevations in ALT that were greater than 5 times the upper limit of normal. Permanent discontinuation resulting from elevated transaminases and jaundice was required in 1 (0.4%) patient. Patients should undergo laboratory tests, including ALT, AST, and total bili­ rubin, once monthly and as clinically indicated. More frequent testing is warranted in patients who develop transaminase elevations. Ceritinib should be withheld, dose reduced, or should be permanently discontinued based on the severity of the hepatotoxicity reaction.13 Interstitial lung disease/pneumonitis. Severe, life-threatening, or fatal interstitial lung disease/pneumonitis has occurred in patients receiving ceritinib. Pneumonitis was reported in 4% of the 255 patients in the phase 2 study. In all, 3% of patients had grade 3 or 4 disease, and 1 patient died.

Ceritinib was discontinued in 1% of patients because of interstitial lung disease/pneumonitis. If symptoms indicative of interstitial lung disease/ pneumonitis are observed, exclude other potential causes. If interstitial lung disease/pneumonitis is deemed to be treatment-related, discontinue ceritinib therapy permanently.13 QT interval prolongation. In the phase 2 study and across the development program of ceritinib, 3% of patients had corrected QT (QTc) interval increase from a baseline of >60 msec.13 Across the development program of ceritinib, 1 patient using doses ranging

Continued from page 48

Table 2 Adverse Reactions Reported with Ceritinib in >10% of Patients for

All Grades or ≥2% for Grades 3/4 Ceritinib (N = 255) Adverse reaction All grades, % Grade 3/4, % Gastrointestinal events Diarrhea

86

6

Nausea

80

4

Vomiting

60

4

Abdominal pain/discomfort, epigastric discomfort

54

2

Constipation

29

0

Esophageal disorder: dyspepsia, gastroesophageal reflux disease, dysphagia

16

1

Fatigue/asthenia

52

5

Decreased appetite

34

1

Rash, maculopapular rash, acneiform dermatitis

16

0

Other events

Source: Zykadia (ceritinib) capsules prescribing information; April 2014.

Table 3 Key Laboratory Abnormalities in >10% (All Grades) of Patients

Receiving Ceritinib Ceritinib (N = 255) Laboratory abnormality All grades, % Grade 3/4, % Hemoglobin decreased

84

5

Alanine transaminase increased

80

27

Aspartate transaminase increased

75

13

Creatinine increased

58

2

Glucose increased

49

13

Phosphate decreased

36

7

Lipase increased

28

10

Bilirubin (total) increased

15

1

Source: Zykadia (ceritinib) capsules prescribing information; April 2014.

from 50 mg to 750 mg had a QTc of >500 msec.13 Ceritinib should be avoided in patients with congenital long QT syndrome. Patients with congestive heart failure, bradyarrhythmias, or electrolyte abnormalities, and those taking medications known to prolong the QTc interval should undergo periodic electrocardiograms (ECGs) and electrolyte monitoring.13 Ceritinib should be withheld in patients who develop a QTc interval of >500 msec on at least 2 separate ECGs. Ceritinib can be resumed with a 150mg dose reduction if the QTc interval is <481 msec or on recovery to baseline if the QTc interval is ≥481 msec.13 Ceritinib should be permanently discontinued in patients who develop QTc interval prolongation in combination with torsades de pointes, polymorphic

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ventricular tachycardia, or signs or symptoms of serious arrhythmia.13 Hyperglycemia. Grade 3 or 4 hyperglycemia based on laboratory values occurred in 13% of patients in the phase 2 study of ceritinib. The risk for grade 3 or 4 hyperglycemia in patients with diabetes or glucose intolerance was increased 6-fold. There was a 2-fold increase in the risk for grade 3 or 4 hyperglycemia in patients taking corticosteroids. Serum glucose levels should be monitored, and antihyperglycemic medications should be used as indicated. Ceritinib should be withheld until hyperglycemia is controlled and then resumed with a 150-mg dose reduction. If adequate hyperglycemic control cannot be achieved, ceritinib should be discontinued.13 Bradycardia. Sinus bradycardia was observed as a new finding in 1% of

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Drug Update

Zykadia (Ceritinib) Approved for the Treatment of... patients and was reported as an adverse drug reaction in 3% of patients in the phase 2 study of ceritinib.13 Ceritinib should be avoided in patients taking other agents known to cause bradycardia (eg, beta-blockers, nondihydropyridine calcium channel blockers, clonidine, and digoxin) if possible.

Heart rate and blood pressure should be monitored regularly.13 If symptomatic bradycardia is not life-threatening, ceritinib should be withheld until recovery or until the heart rate is ≥60 beats per minute (bpm). Concomitant medication use should be evaluated, and ceritinib dose should be adjusted.

If bradycardia is associated with a medication known to cause bradycardia or hypotension, ceritinib can be withheld until recovery or to a heart rate of ≥60 bpm. If the concomitant medication can be adjusted or discontinued, ceritinib can be restarted at a 150-mg dose reduction on recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm, with frequent monitoring. Ceritinib should be discontinued if life-threatening bradycardia is observed and no concomitant medication use is identified.13 Embryofetal toxicity. Based on its mechanism of action, ceritinib may cause fetal harm when administered to a pregnant woman.

Specific Populations Pregnancy. Ceritinib is in Pregnancy

Category D. Women of reproductive potential should be made aware of the potential hazard to a fetus, as well as the need to use effective contraception during treatment with ceritinib and for at least 2 weeks after the completion of therapy.13 Nursing mothers. Whether ceritinib or its metabolites are excreted in human milk is not known. Nursing mothers who take ceritinib should discontinue breastfeeding.13 Pediatric use. The safety and effectiveness of ceritinib have not been established in pediatric patients.13 Geriatric use. Clinical studies of ceritinib did not include sufficient numbers of patients aged ≥65 years to assess its effect on older patients. Of the 255 patients in the phase 2 study, 40 (16%) were aged ≥65 years.13 Hepatic impairment. Because ceritinib is eliminated primarily in the liver, patients with hepatic impairment may have increased exposure. Based on a pharmacokinetic analysis, dose adjustment is not recommended for patients with mild hepatic impairment. A recommended dose has not been determined for patients with moderate-to-severe hepatic impairment.13 Conclusion NSCLC remains the main cause of death from cancer in the United States for men and women. The disease is still diagnosed mainly at advanced

stages; therefore, prognosis is poor, and long-term survival is rare. Ceritinib, the second oral kinase inhibitor approved for the initial treatment of ALK-positive metastatic NSCLC, has demonstrated efficacy with manageable side effects. Ceritinib joins crizotinib as the second FDA-approved agent for this subset of patients with NSCLC, offering an effective alternative to cytotoxic therapy.

Ceritinib may confer clinical value in other cancers in which ALK mutations are present. In addition to further exploration in NSCLC, clinical studies are evaluating ceritinib in pediatric malignancies and other tumors characterized by genetic abnormalities of ALK.15 n

Continued from page 49

1. American Cancer Society. What are the key statistics about lung cancer? Revised April 30, 2014. www.cancer.org/cancer/lungcancer-non-smallcell/ detailedguide/non-small-cell-lung-cancer-key-statis tics. Accessed May 15, 2014.

2. American Cancer Society. What is non-small cell lung cancer? Revised April 30, 2014. www.cancer.org/ cancer/lungcancer-non-smallcell/detailedguide/nonsmall-cell-lung-cancer-what-is-non-small-cell-lungcancer. Accessed May 15, 2014.

3. Henk HJ, Ray S. Treatment patterns and healthcare costs among patients with advanced non-small-cell lung cancer. Lung Cancer Manag. 2013;2:189-197.

4. Azzoli CG, Giaccone G, Temin S. American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer. J Oncol Pract. 2010;6:39-43.

5. American Cancer Society. Chemotherapy for nonsmall cell lung cancer. Revised April 30, 2014. www.

cancer.org/cancer/lungcancer-non-smallcell/detailed guide/non-small-cell-lung-cancer-treating-chemother apy. Accessed May 15, 2014.

6. Villaflor VM, Salgia R. Targeted agents in non-small cell lung cancer therapy: What is there on the horizon?

J Carcinog. 2013;12:7.

7. Hirsh V, Melosky B, Goss G, et al. A personalized approach to treatment: use of EGFR tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer in Canada. Curr Oncol. 2012;19:78-90. Erratum in: Curr Oncol. 2012;19:e228.

8. Massarelli E, Varella-Garcia M, Tang X, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non–small-cell lung cancer. Clin Cancer Res. 2007;13:2890-2896.

9. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non–small-cell lung cancer who harbor EML4-ALK. J Clin Oncol.

2009;27:4247-4253.

10. US Food and Drug Administration. Drugs: crizotinib. www.fda.gov/drugs/informationondrugs/ap proveddrugs/ucm376058.htm. Accessed May 17, 2014.

11. Iwama E, Okamoto I, Harada T, et al. Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer. Onco Targets Ther. 2014;7:375-385.

12. US Food and Drug Administration. FDA approves Zykadia for late-stage lung cancer: breakthrough therapy drug approved four months ahead of review completion goal date. Press release. April 29, 2014. www. fda.gov/newsevents/newsroom/pressannounce ments/ucm395299.htm. Accessed July 24, 2014.

13. Zykadia (ceritinib) capsules [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2014.

14. Novartis. Novartis gains FDA approval for Zykadia(TM), first therapy for patients with ALK+ NSCLC previously treated with the ALK inhibitor crizotinib. April 29, 2014. www.novartis.com/ newsroom/media-releases/en/2014/1776962.shtml.

Accessed May 17, 2014.

15. ClinicalTrials.gov. LDK378. Search results. http:// clinicaltrials.gov/ct2/results?term=LDK378&Search= Search. Accessed May 17, 2014.

prove quality and reduce costs over the 3-year study.

The study, which was conducted between October 2009 and December 2012, covered 810 patients with breast, lung, or colon cancer, and examined the difference in cost before and after the payment change. The researchers reported that the predicted FFS total cost for the episode cohort was $98,121,388, but the actual cost of medical care per episode for patients in this study was $64,760,116, representing a 34% reduction in medical costs for a savings of $33,361,272.

The predicted cost of chemotherapy medications was $7,519,504, but the actual cost was $20,979,417. The researcher noted that the tested

model still produced a 34% overall cost-savings.

The episode payment model showed significant savings for cancer care, without any measurable effects on quality outcomes or toxicity, concluded the researchers. They said that this study challenges the assumption that any reduction of resources results in worse outcomes for cancer. In addition, this model allowed each medical group to seek the solutions that worked best for its environment. Although this pilot should be replicated to answer questions about generalization, the researchers point out that this study validates a key concept that the cost of care for future generations can be reduced, without sacrificing quality. n

References

In the Literature New Payment Model Saves Money, Maintains Outcomes...

Continued from page 28

physician payment model that rewards physicians for focusing on best treatment practices and health outcomes rather than the widely used fee-for-service (FFS) model resulted in cost-savings, without affecting the quality of care among patients with 3 types of cancer. The findings were published early online in the Journal of Oncology Practice (Newcomer LN, et al. 2014 Jul 8.

Epub ahead of print). An accompanying commentary is discussed in this issue on page 29.

In a pilot study that began in Octo-

50

ber 2009, 5 medical oncology groups collaborated with UnitedHealthcare to use an episode-based payment model, which reimbursed physicians based on the expected cost of a standard treatment regimen for the specific condition, as predetermined by the physician. The oncologists were paid the same fee regardless of the drugs that were administered to the patient.

Patient visits were reimbursed using the FFS contract rates, and chemotherapy medications were reimbursed based on the average sales price. The oncology groups collaborated with UnitedHealthcare to develop more than 60 measures of quality and cost to compare the performance across groups and to determine how to im-

Value-Based Cancer Care

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august 2014

Vol. 5

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Now enrolling: MURANO study Investigating the Selective BCL-2 Inhibitor GDC-0199/ABT-199 in Chronic Lymphocytic Leukemia GDC-0199/ABT-199 is an investigational agent that has not been approved by regulatory agencies.

A Phase III Study of GDC-0199/ABT-199 Plus Rituximab Compared With Bendamustine Plus Rituximab in Patients With Relapsed or Resistant Chronic Lymphocytic Leukemia (CLL)

GDC-0199/ABT-199 + rituximab

Phase III Relapsed or resistant CLL (N=370)

GDC-0199/ABT-199 continued for 2 years or until disease progression

Bendamustine + rituximab Randomize Primary Endpoint

Secondary Endpoints

• Investigator-assessed progression-free survival, defined as time from randomization until disease progression or death from any cause

• Overall response rate • Incidence of adverse events

Key Inclusion Criteria

Key Exclusion Criteria

• Adult patients ≥18 years of age • Diagnosis of CLL per diagnostic criteria and relapsed or refractory CLL per the iwCLL guidelines • Previously treated with 1-3 lines of therapy (eg, completed ≥2 treatment cycles per therapy), including ≥1 standard chemotherapy-containing regimen • Previously treated with bendamustine, only if duration of response was ≥24 months • ECOG performance status of 0-1 • Adequate bone marrow function • Adequate renal and hepatic function

• Transformation of CLL to aggressive non-Hodgkin lymphoma or CNS involvement by CLL • Undergone an allogenic stem-cell transplant • A history of significant renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease • Hepatitis B, hepatitis C, or known HIV-positive • Receiving warfarin treatment • Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study drug • Received any anticancer or investigational therapy within 14 days prior to the first dose of study drug or has not recovered from previous therapy • Received CYP3A4 inhibitors (such as fluconazole, ketoconazole and clarithromycin) or inducers (such as rifampin, carbamezapine, phenytoin, St John’s Wort) within 7 days prior to the first dose of GDC-0199/ABT-199 • Prior GDC-0199/ABT-199 treatment

To learn more about this study, please visit www.ClinicalTrials.gov (NCT02005471, GO28667) or call the Trial Information Support Line at 1-888-662-6728.

GDC-0199/ABT-199 is being codeveloped by AbbVie and Genentech, a member of the Roche Group.

© 2014 Genentech USA, Inc. All rights reserved. BIO0002506000 Printed in USA.

Reference: ClinicalTrials.gov, as of 5/2014.

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