Evidence-Based Oncology

Bridging the gap between payer and provider perspectives

Volume 19 Special Issue 3 Evidence-Based Oncology

Payer Trends Disease Overview Also in this issue... Five Trends Emerge in Payer Chemoprevention SP93 Bundled Payment: Management of Oncology in Prostate Cancer: Practice Savior or Killer? Market Dynamics Change How Plans Manage Oral and SP98 Appl ying Accountable Identifying Patients Care to Oncology: Office-Administered Agents at Greatest Risk Developing an Oncology Susan Weber May Provide ACO f there’s a “reset” button for oncology drug management, SP102 Sear ching for Clinical payers are ready to press it. For years, management of Greatest Value and Economic Value in Ithese agents has been the exception, not the rule. Al- Marj P. Zimmerman, MS, BS Pharm; Pancreatic Cancer though payers have restricted the use of these drugs, they and Stanton R. Mehr have rarely denied coverage or required heavy cost sharing SP106 The Future of Melanoma by patients. But that is poised to change as market dynamics shift and oncology becomes more of a management priority rostate cancer is a common Treatment for health plans. cancer in men that, once it pro- SP113 V alue-Based Contracting According to research from Health Strategies Group’s Pgresses to the later stages, has Susan Weber Managed Care Complete service, oral oncolytics and office- serious morbidity and mortality con- for Pharmaceuticals: administered oncology agents are now among payers’ top sequences as well as burdensome fi- Getting Ready for Prime 5 management priorities. The reasons for this refocusing nancial issues for patients, the health- Time? (continued on page SP120) care system, and society. Prostate cancer, second only to skin cancer, is responsible for about 10% of the deaths attributed to all of the cancers.1 As a 2012 Cancer Center Business Summit Coverage result, several strategies have been developed to reduce the morbidity, Performance Metrics in Oncology mortality, and costs associated with prostate cancer, inclusing the iden- Thomas R. Barr, MBA tification of patients at risk, chemoprevention regimens that prevent the development of the disease in those n 2011, the Medicare Electronic Health Record (EHR) Incentive Program began at risk, and the early diagnosis of pa- paying physicians and hospitals for the measurement and reporting of perfor- tients with confirmed disease. Imance metrics through the utilization of certified electronic medical record software. This epic program began in earnest the irrevocable shift in the provision By the Numbers of healthcare from an individual craft-based art to a structured, evidence-based According to the American Cancer system. The EHR Incentive program has 3 specific phases that progressively Society, prostate cancer will be diag- Darius Lakdawalla, PhD, build from data capture and reporting, through nosed in about 240,000 men in 2013, discusses the payer/provider clinical process refinement, to the final goal and it will be listed as the cause of relationship in oncology 1 of achieving measurably improved healthcare death in 30,000. African Americans management outcomes.1 Currently, we are in the first phase have a higher incidence of prostate of this transition, and in oncology, trends are cancer than Caucasians and are also emerging about what metrics are important more likely to die from the disease. to 3 important groups—patients, payers, and Race, age, and family history are risk providers. Each seeks improvements to qual- factors. Around 2.5 million men cur- ity and lower, or at least stable, costs for cancer rently are prostate cancer patients.2 care. The broad utilization of electronic medi- The majority of cases (approxi- cal record technology has, for the first time in mately 60%) are diagnosed in men 65 history, enabled systematic measures of care years and older, and 97% of cases are delivery on a broad scale. diagnosed in men at least 50 years of Dennis Scanlon, PhD, addresses While management of clinical care using age. The average age at diagnosis is the importance of payer/provider 1 relationships modern information technology is important Thomas R. Barr, MBA approximately 67 years. Known ge- to providers and payers of oncology care, it is netic factors are linked to the disease Scan for additional content. in about 5% to 10% of patients.2 (continued on page SP122) The disease usually has no symp- Partner of toms and if diagnosed in the early stages, defined as being in the local Center For Value Based Medicine® (continued on page SP127) In advanced prostate cancer TREAT FIRST LINE WITH PROVENGE TO

PROVENGEPROVENGE

Resting Activate T cell

T-cell PROVENGE- activation activated T cells Amplify

Activated T cell attacks prostate cancer

Attack

ProstateProstate cancer cancer cell cell EXTEND SURVIVAL

> Extends median survival beyond 2 years1 2 years st First and only FDA-approved immunotherapy for advanced 1and only prostate cancer st First-line treatment for men with asymptomatic or minimally 1line symptomatic metastatic CRPC (NCCN Category 1 recommendation) 2

INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache. For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent page. www.PROVENGE.com

Trim size: 10.75” x 13.75” Live area: 10.25” x 13.25” Colors 4c full bleed Am. Journal Managed Care EBO Ad PROVENGE® (sipuleucel-T) The safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE Suspension for Intravenous Infusion Rx Only group who underwent at least 1 leukapheresis procedure in four randomized, controlled BRIEF SUMMARY — See full Prescribing Information for complete product information clinical trials. The control was non-activated autologous peripheral blood mononuclear cells. INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular The most common adverse events, reported in patients in the PROVENGE group at a rate immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic ≥15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Severe (Grade metastatic castrate resistant (hormone refractory) prostate cancer. 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. DOSAGE AND ADMINISTRATION Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group • For Autologous Use Only. compared with 3.6% of patients in the control group. • The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals. Serious adverse eevents wer reported in 24.0% of patients in the PROVENGE group and 25.1% • Premedicate patients with oral acetaminophen and an antihistamine such as of patients in the control group. Serious adverse events in the PROVENGE group included acute diphenhydramine. infusion reactions (see Warnings and Precautions), cerebrovascular events, and single case • Before infusion, confirm that the patient’s identity matches the patient identifiers on the reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare. infusion bag. PROVENGE was discontinued in 1.5% of patients in Study 1 (PROVENGE group n=341; • Do Not Initiate Infusion of Expired Product. Control group n=171) due to adverse events. Some patients who required central venous • Infuse PROVENGE intravenously over a period of approximately 60 minutes. catheters for treatment with PROVENGE developed infections, including sepsis. A small Do Not Use a Cell Filter. number of these patients discontinued treatment as a result. Monitoring for infectious • Interrupt or slow infusion as necessary for acute infusion reactions, depending on the sequelae in patients with central venous catheters is recommended. severity of the reaction. Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior (See Dosage and Administration [2] of full Prescribing Information.) to the infusion. Adverse events that were reported ≤1 day following a leukapheresis procedure CONTRAINDICATIONS: None. in ≥5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%). WARNINGS AND PRECAUTIONS Table 1 provides the frequency and severity of adverse events reported in ≥5% of patients • PROVENGE is intended solely for autologous use. in the PROVENGE group of randomized, controlled trials of men with prostate cancer. The • Acute infusion reactions (reported within 1 day of infusion) included, but were not population included 485 patients with metastatic castrate resistant prostate cancer and 116 limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), patients with non-metastatic androgen dependent prostate cancer who were scheduled to nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was 71.2% of patients in the PROVENGE group developed an acute infusion reaction. age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian. In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients vomiting. The incidence of severe events was greater following the second infusion (2.1% Randomized to PROVENGE vs 0.8% following the first infusion), and decreased to 1.3% following the third infusion. PROVENGE (N = 601) Control* (N = 303) Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions. No Grade 4 or 5 acute infusion reactions were All Grades Grade 3-5 All Grades Grade 3-5 reported in patients in the PROVENGE group. n (%) n (%) n (%) n (%) Closely monitor patients with cardiac or pulmonary conditions. In the event of an Any Adverse Event 591 (98.3) 186 (30.9) 291 (96.0) 97 (32.0) acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be Chills 319 (53.1) 13 (2.2) 33 (10.9) 0 (0.0) administered as needed. Fatigue 247 (41.1) 6 (1.0) 105 (34.7) 4 (1.3) • Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely Fever 188 (31.3) 6 (1.0) 29 (9.6) 3 (1.0) tested for transmissible infectious diseases. Therefore, patient leukapheresis material Back pain 178 (29.6) 18 (3.0) 87 (28.7) 9 (3.0) and PROVENGE may carry the risk of transmitting infectious diseases to health care Nausea 129 (21.5) 3 (0.5) 45 (14.9) 0 (0.0) professionals handling the product. Universal precautions should be followed. Joint ache 118 (19.6) 11 (1.8) 62 (20.5) 5 (1.7) • Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either Headache 109 (18.1) 4 (0.7) 20 (6.6) 0 (0.0) chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given Citrate toxicity 89 (14.8) 0 (0.0) 43 (14.2) 0 (0.0) concurrently with the leukapheresis procedure or PROVENGE has not been studied. Paresthesia 85 (14.1) 1 (0.2) 43 (14.2) 0 (0.0) PROVENGE is designed to stimulate the immune system, and concurrent use of Vomiting 80 (13.3) 2 (0.3) 23 (7.6) 0 (0.0) immunosuppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to Anemia 75 (12.5) 11 (1.8) 34 (11.2) 7 (2.3) reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE. Constipation 74 (12.3) 1 (0.2) 40 (13.2) 3 (1.0) • Product Safety Testing. PROVENGE is released for infusion based on the microbial and Pain 74 (12.3) 7 (1.2) 20 (6.6) 3 (1.0) sterility results from several tests: microbial contamination determination by Gram stain, Paresthesia oral 74 (12.3) 0 (0.0) 43 (14.2) 0 (0.0) endotoxin content, and in-process sterility with a 2-day incubation to determine absence Pain in extremity 73 (12.1) 5 (0.8) 40 (13.2) 1 (0.3) of microbial growth. The final (7-day incubation) sterility test results are not available at Dizziness 71 (11.8) 2 (0.3) 34 (11.2) 0 (0.0) the time of infusion. If the sterility results become positive for microbial contamination Muscle ache 71 (11.8) 3 (0.5) 17 (5.6) 0 (0.0) after PROVENGE has been approved for infusion, Dendreon will notify the treating Asthenia 65 (10.8) 6 (1.0) 20 (6.6) 2 (0.7) physician. Dendreon will attempt to identify the microorganism, perform antibiotic Diarrhea 60 (10.0) 1 (0.2) 34 (11.2) 3 (1.0) sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in Influenza-like illness 58 (9.7) 0 (0.0) 11 (3.6) 0 (0.0) order to determine the source of contamination. Musculoskeletal pain 54 (9.0) 3 (0.5) 31 (10.2) 3 (1.0) (See Warnings and Precautions [5] of full Prescribing Information.) Dyspnea 52 (8.7) 11 (1.8) 14 (4.6) 3 (1.0) Edema peripheral 50 (8.3) 1 (0.2) 31 (10.2) 1 (0.3) ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates Hot flush 49 (8.2) 2 (0.3) 29 (9.6) 1 (0.3) observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials Hematuria 46 (7.7) 6 (1.0) 18 (5.9) 3 (1.0) of another drug and may not reflect the rates observed in practice. Muscle spasms 46 (7.7) 2 (0.3) 17 (5.6) 0 (0.0)

(Table 1 continued on next page.)

5832_AJMC_EBO_Single_Ad_BS_L1.indd 1 7/16/12 5:43 PM Trim size: 10.75” x 13.75” Live area: 10.25” x 13.25” Colors Black Am. Journal Managed Care EBO Ad Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE

PROVENGE (N = 601) Control* (N = 303)

All Grades Grade 3-5 All Grades Grade 3-5 n (%) n (%) n (%) n (%)

Hypertension 45 (7.5) 3 (0.5) 14 (4.6) 0 (0.0) Anorexia 39 (6.5) 1 (0.2) 33 (10.9) 3 (1.0) Bone pain 38 (6.3) 4 (0.7) 22 (7.3) 3 (1.0) Upper respiratory 38 (6.3) 0 (0.0) 18 (5.9) 0 (0.0) tract infection Insomnia 37 (6.2) 0 (0.0) 22 (7.3) 1 (0.3) Musculoskeletal chest 36 (6.0) 2 (0.3) 23 (7.6) 2 (0.7) pain Cough 35 (5.8) 0 (0.0) 17 (5.6) 0 (0.0) Neck pain 34 (5.7) 3 (0.5) 14 (4.6) 2 (0.7) Weight decreased 34 (5.7) 2 (0.3) 24 (7.9) 1 (0.3) Urinary tract infection 33 (5.5) 1 (0.2) 18 (5.9) 2 (0.7) Rash 31 (5.2) 0 (0.0) 10 (3.3) 0 (0.0) Sweating 30 (5.0) 1 (0.2) 3 (1.0) 0 (0.0) Tremor 30 (5.0) 0 (0.0) 9 (3.0) 0 (0.0)

*Control was non-activated autologous peripheral blood mononuclear cells.

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group. (See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

References: 1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 2. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. V.3.2012. National Comprehensive Cancer Network Web site. www.nccn.org. Accessed April 26, 2012.

5832_AJMC_EBO_Single_Ad_BS_L1.indd 2 7/16/12 5:43 PM Trim size: 5.125” x 13.75” Live area: 4.625” x 13.25” Colors Black From the Publisher SP91 Editorial Board Michael E. Chernew, PhD s the healthcare landscape continues to evolve, so too do the efforts to move toward payment systems that Department of Health Care Policy place an emphasis on quality of care and cost sharing. But such shifts require an excessive amount of data Harvard Medical School Boston, MA analysis; pilot studies; and organizations that are willing to think outside of the box to drive healthcare re- Aform components forward. Jessica DeMartino, PhD In this issue of the Evidence-Based Oncology, Susan Weber of Health Strategies Group in Redwood City, California Manager, Health Policy Programs The National Comprehensive Cancer Network discusses some of the new trends in the payer management of oncology. In particular, Weber writes about how oral Fort Washington, PA oncolytics and office-administered oncology agents Jonas de Souza, MD are becoming increasingly important to payers’ man- Instructor of Medicine agement priorities, thanks in large part to new market University of Chicago Medical Center Chicago, IL factors and payer capabilities. One potential outcome While our healthcare system in for this shift will be the evolution of new benefit de- Jeffrey D. Dunn, PharmD, MBA signs to allow for high cost-sharing requirements as general is undergoing extensive Formulary and Contract Manager SelectHealth they apply to newly approved oral oncolytics. “Half of changes, the oncology field in Salt Lake City, UT [existing] plans already require members to pay ad- Bruce A. Feinberg, DO ditional fees for office-administered drugs, and more particular is poised to undergo Vice President and Chief Medical Officer plans will follow suit,” writes Weber. Cardinal Health Specialty Solutions a complete transformation Dublin, OH Also in this issue, Stanton R. Mehr provides an outlook of value-based contracting, a strategy that in terms of how care is both A. Mark Fendrick, MD has been gaining momentum in the oncology space. Professor of Medicine and Health Management and Policy “Comparative-effectiveness research and results re- delivered and reimbursed. Schools of Medicine & Health porting has compelled health plans and insurers to University of Michigan Ann Arbor, MI sharpen their focus on incorporating this information into coverage decision making,” says Mehr. But as is John L. Fox, MD, MS often the case in healthcare, payer adoption of new strategies will vary. Many health plans are currently more Associate Vice President Medical Affairs concerned with efforts to improve patient and physician support, rather than incorporating penalties and cover- Priority Health age denials. Grand Rapids, MI While our healthcare system in general is undergoing extensive changes, the oncology field in particular is Dana Goldman, PhD poised to undergo a complete transformation in terms of how care is both delivered and reimbursed. The goal for Director Leonard D. Schaeffer Center for Evidence-Based Oncology is to ensure that the latest strategies and data are delivered to you by professionals who are Health Policy and Economics experiencing and studying these changed firsthand. Such large decisions and shifts in strategy cannot be achieved University of Southern California Los Angeles, CA without being well informed on the latest pilot studies and innovations. We look forward to serving you as the evolution continues. Thank you for reading. Dawn G. Holcombe, MBA, FACMPE, ACHE President, DGH Consulting Executive Director, Connecticut Thank you for reading. Oncology Association South Windsor, CT

John Hornberger, MD, MS Cedar Associates, LLC Menlo Park, CA

Ira M. Klein, MD, MBA, FACP Chief of Staff Office of the Chief Medical Officer National Accounts Clinical Sales & Strategy Aetna Hartford, CT Brian Haug Publisher Darius Lakdawalla, PhD Associate Professor Sol Price School of Public Policy University of Southern California Los Angeles, CA

Kathleen G. Lokay President and CEO D3 Oncology Solutions Pittsburgh, PA

Joshua J. Ofman, MD, MSHA Editorial Mission SVP, Global Value and Access Amgen, Inc Thousand Oaks, CA To present policy makers, payers, and providers Eberechukwu Onukwugha, PhD Research Assistant Professor with the clinical, pharmacoeconomic, and regulatory Pharmaceutical Health Services Research University of Maryland School of Pharmacy Baltimore, MD information they need to improve efficiency and Debra Patt, MD, MPH Texas Oncology Cancer Center Austin, TX outcomes in cancer care. Andrew L. Pecora, MD Chief Innovations Officer Vice President of Cancer Services Opinions expressed by authors, contributors, and advertisers are their own and not necessarily those of Clinical Care Targeted Communications, LLC, d/b/a Managed Care & Healthcare Communica- John Theurer Cancer Center tions, LLC, the editorial staff, or any member of the editorial advisory board. Clinical Care Targeted Communications, LLC, d/b/a Managed Care & Healthcare Communications, LLC, is not responsible Hackensack, NJ for accuracy of dosages given in articles printed herein. The appearance of advertisements in this journal is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality, or safety. Clinical Care Targeted Communications, LLC, d/b/a Managed Care & Healthcare Communications disclaims responsibility for any injury to persons or property resulting from any ideas or products referred to in the articles or advertisements. Mark Zitter, MBA Founder and CEO The content contained in this publication is for general information purposes only. The reader is encouraged to confirm the information presented with other sources.Evidence-Based Oncology The Zitter Group makes no representations or warranties of any kind about the completeness, accuracy, timeliness, reliability, or suitability of any of the information, including content or advertisements, contained San Francisco, CA in this publication and expressly disclaims liability for any errors and omissions that may be presented in this publication. Evidence-Based Oncology reserves the right to alter or correct any error or omission in the information it provides in this publication, without any obligations. Evidence-Based Oncology further disclaims any and all liability for any direct, indirect, consequential, special, exemplary, or other damages arising from the use or misuse of any material or information presented in this publication. The views expressed in this publication are those of the authors and do not necessarily reflect the opinion or policy ofEvidence-Based Oncology.

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 SP92 In This Issue...

Publishing Staff Brian Haug SP93 practice management SP113 Value-Based Contracting Publisher Bundled Payment: V alue-Based Contracting for Janet Swaim Practice Savior or Killer? Pharmaceuticals: Getting Ready Managing Editor Kurt Ullman Sean Johnson for Prime Time? Digital Writer/Editor As payment reform models continue to Stanton R. Mehr Nicole Yanovsky evolve, practitioners must determine which Efforts to improve comparative- Associate Editor strategy makes the most sense for their effectiveness research and results reporting practice. Although the idea behind bundled have caught the attention of health plans Katie Sullivan payments may be worth considering, there and insurers. So much so that new data is Assistant Editor are some concerns that this system could being incorporated into coverage decision David Allikas causes disruptions in oncology practices. making. Quality Assurance Editor

Andrew Colon SP98 Payment Reform Gene Conselyea SP120 Payer Trends Phil Lindner Appl ying Accountable Care National Accounts Managers to Oncology: Developing an F ive Trends Emerge in Payer Management of Oncology Jennifer Rittmann Oncology ACO Design Director Stanton R. Mehr Mark et Dynamics Change How Plans Jeff D. Prescott, PharmD, RPh The cost-saving potential of specialty or Manage Oral and Office-Administered Vice President, Clinical and Scientific Affairs disease-specific ACOs can be huge...but it Agents is unclear whether these specialty services Susan Weber are more efficiently provided through their Corporate own ACO or as ancillary to the burgeoning Mike Hennessy primary care ACO marketplace. Chairman/Chief Executive Officer SP122 2012 Cancer Center Business Summit Coverage Tighe Blazier SP100c On ology Medical Home P erformance Metrics in Chief Operating Officer Measuring Quality Cancer Care Oncology Neil Glasser, CPA/CFE Robert Gamble Thomas R. Barr, MBA Chief Financial Officer

The presence of specific, essential clinical Brian Haug information as structured data in the President, Intellisphere, LLC SP102 Disease Overview clinical database is necessary for oncology Judy V. Lum, MPA care management. Sear ching for Clinical and Executive Vice President Economic Value in Pancreatic Executive Director of Education SP127 Disease Overview Cancer T eresa Fallon-Yandoli Marj P. Zimmerman, MS, BS Pharm; Chemopr evention in Prostate Executive Assistant and Stanton R. Mehr Cancer: Identifying Patients Jeff Brown at Greatest Risk May Provide Vice President Executive Creative Director Greatest Value SP106 Melanoma Pipeline Marj P. Zimmerman, MS, BS Pharm; The Future of Melanoma and Stanton R. Mehr Treatment Mic hael M. Mohundro, PharmD; and Alexis Horace, PharmD

Office Center at Princeton Meadows, Bldg. 300 Plainsboro, NJ 08536 • (609) 716-7777

Copyright © 2013 by Managed Care & Healthcare Communications, LLC The American Journal of Managed Care ISSN 1088-0224 (print) & ISSN 1936-2692 (online) is published monthly by Managed Care & Healthcare Communications, LLC, 666 Plainsboro Rd, Bldg. 300, Plainsboro, NJ 08536. Copyright© 2013 by Managed Care & Healthcare Communications, LLC. All rights reserved. As provided by US copyright law, no part of this publication may be reproduced, displayed, or transmitted in any form or by any means, electronic or mechanical, without the prior written permission of the publisher. For subscription inquiries or change of address, please call 888-826-3066. For permission to photocopy or reuse material from this journal, please contact the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923; Tel: 978-750-8400; Web: www.copyright.com. Reprints of articles are available in minimum quantities of 250 copies. To order custom reprints, please contact Brian Haug,The American Journal of Managed Care, bhaug@ ajmc.com; Tel: 609-716-7777. The American Journal of Managed Care is a registered trademark of Managed Care & Healthcare Communications, LLC. www.ajmc.com • Printed on acid-free paper.

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 Practice Management SP93

Bundled Payment: Practice Savior or Killer?

Kurt Ullman

he new “in” term among those Episode of care a better fit? at their processes and find ways to looking to lower the cost of The model that may be the best pay- streamline them. Physicians, according “I think eventually Thealthcare is “bundled payment” ment fit for oncologists is episode of to both experts, should look to imple- (BP). Although there is still disagree- care (EOC). As currently evolving, this menting established clinical guidelines fee-for-service for ment about what it means, the bun- transfers a specific part of the risk to as a first step. But they will also need dling of payments revolves around on- the oncologists, but one that is easier to update information-gathering abili- both Medicare and cologists being paid a set fee for man- to manage. ties through use of electronic medical aging their patients’ care. Gould’s group is participating in an record (EMR) programs tracking both private insurers “Five or 10 years ago, the oncology early pilot in cooperation with United what they are doing well and where spend was not high on the payer’s Healthcare. The participants defined they need to improve. is going down. priority list,” said 19 categories for lung, Matthew Farber, MA, breast, and colon can- What practices should consider Instead they will director of provider cers. Compare current treatment modalities economics and pub- “They have taken with guidelines from the National Com- pay for better, more lic policy, at the As- our margins for che- prehensive Cancer Network (NCCN) sociation of Commu- motherapy medica- or other professional sources. Getting efficient, and less nity Cancer Centers in tions, added extra a physician to buy in is important, as Rockville, Maryland. money for hospitaliza- just 1 opting out of the predetermined duplicative care.” “As the number of tions, and that is what treatment regimens could harm the patients goes up, the we get when a patient program for all. This also highlights the —Matthew Farber, MA, number of those who is registered as an EOC need for ways to monitor compliance. Director of provider economics survive increases and fee,” said Gould. “We Full commitment to EMR technology and public policy the general demo- are still paid a fee-for- is another important part of this puz- The Association of Community Cancer Centers graphic shifts, the cost service when we see zle. Both BP and EOC require practices Rockville, Maryland of cancer care goes up. the patients in our of- to have the ability to monitor, docu- In addition, the recent fices and to administer ment, and report treatment regimens. run of new (and ex- the medications. The These systems help analyze costs, an tomorrow is gone,” with an immediate pensive) drug approv- Matthew Farber, MA drugs are reimbursed important part of the process when ne- need to get the office in order. als has caused payer’s at Average Sales Price.” gotiating your fee and managing your On the other hand, Mr Farber thinks focus to turn toward The insurance com- costs. there is still time for practices to watch oncology.” pany knows what its medicine costs Practice business management may the early adopters work out the kinks. will be and the most it has to spend for play as big a role in profitability as the Both agree that keeping track of the Concerns about BP in cancer physician services should its enrollees medical management side. For exam- various models as they mature is im- treatment need hospital treatment. It hopes to ple, the efficiency and accuracy of your portant so that you are “leaning” the True bundled payments would give the save money by giving oncologists in- coding and billing staff will impact on right way when approached. They also oncologists a single amount of money centives to treat patients in the office your cash flow. concur that things like per patient to cover all costs from ini- (where they get paid) and not in the “The investment in establishing EMRs and tial visit through to discharge from care hospital. Hospital in-patient costs are a strong management familiarizing physi- or to hospice. There are concerns that still paid by the insurance company. team is not cheap, but cians with guidelines a BP system would not work in cancer The oncologists are only assuming the will pay dividends and should begin immedi- treatment, and could cause disruptions risk for their in-hospital services. keep practices strong ately. EBO in practices. and independent,” One reason is that cancers are a very Shifts in how practices make money said Gould. “Over the Author Affiliation: From individualized and diverse group of How practices make their money is last few years all of KVU Communication, diseases. To say that a payer will offer shifting, and getting the bulk of in- the fat has been re- Inc, Carmel, IN. a set amount of money for 2 lines of come from drug charges is past. Other moved from the sys- Funding Source: None. treatment will have to address who is responses by oncologists such as pay tem. If you don’t have Author Disclosure: Mr responsible should a third be needed. for administering medications and in- a lean, mean practice Ullman reports no re- There is enough variability in oncology creasing in-office diagnostic radiology that is collecting every lationship or financial that true BP is likely to be problematic. have come under greater scrutiny. penny due you on the interest with any entity “Oncologists do not take care of large “This gradual reduction in payment first try, the chances that would pose a con- populations of patients where you can is a long-term trend that practices have the practice will fold flict of interest with the mitigate the risk of outliers who utilize to recognize to stay afloat,” said Farber. increase.” Bruce J. Gould, MD subject matter of this a lot of costs, time, and energy,” noted “I think eventually fee-for-service for article. Bruce J. Gould, MD, medical director of both Medicare and private insurers is How long to get Authorship Information: Northwest Georgia Oncology Centers going down. Instead they will pay for ready? Drafting of the manuscript; critical re- in Marietta, Georgia. “Any payment better, more efficient, and less duplica- There is some disagreement on how vision of the manuscript for important system has to reflect this so that one tive care.” long practices have to get themselves intellectual content; and administrative, or two expensive patients don’t break Because of this, it is important for ready for whichever system wins out. technical, or logistic support; and super- a practice.” practices to take a long and close look Gould thinks the “ability to worry about vision.

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 NEW INDICATION: ZYTIGA® (abiraterone acetate) is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

ADRENALS INTRODUCING More than 20,000 patients with mCRPC have received ZYTIGA® (post-chemotherapy with docetaxel) to date.†1 MECHANISM OF ACTION ZYTIGA® is a CYP17 (17␣-hydroxylase/C17, 20-lyase) inhibitor that inhibits androgen production at 3 sources: the testes, adrenal glands, and the prostate tumor tissue itself.

NEW EFFICACY DATA —In a recent Phase 3 clinical trial in patients with mCRPC who had progressed on ADT and had not received chemotherapy.*

Efficacy was also demonstrated in a Phase 3 trial of patients who had received prior chemotherapy PROSTATE TUMOR TISSUE containing docetaxel.*

TESTES

ZytigaOne™ is your single source for personalized access services for you and your patients: Visit www.zytigaone.com or call 1-855-998-4421. ADT = androgen-deprivation therapy. IMPORTANT SAFETY INFORMATION Contraindications —ZYTIGA® is not indicated for use in women. with mineralocorticoid excess seen in patients treated with Adverse Reactions—The most common adverse reactions *Study Designs: ZYTIGA®, in combination with prednisone, was evaluated in ZYTIGA® can cause fetal harm (Pregnancy Category X) when ZYTIGA®. Perform appropriate tests, if indicated, to confi rm AI. (≥ 10%) are fatigue, joint swelling or discomfort, edema, hot fl ush, 2 Phase 3, randomized, double-blind, placebo-controlled, multicenter trials in patients with mCRPC. Study 1 enrolled patients who received prior administered to a pregnant woman and is contraindicated in Increased dosages of corticosteroids may be used before, during, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract chemotherapy containing docetaxel (N = 1,195), whereas Study 2 enrolled women who are or may become pregnant. and after stressful situations. infection, and contusion. patients who had not received prior chemotherapy (N = 1,088). In both studies, Hypertension, Hypokalemia, and Fluid Retention Due to Hepatotoxicity —Monitor liver function and modify, withhold, The most common laboratory abnormalities (> 20%) are patients were using a luteinizing hormone-releasing hormone agonist or were Mineralocorticoid Excess—Use with caution in patients with or discontinue ZYTIGA® dosing as recommended (see Prescribing anemia, elevated alkaline phosphatase, hypertriglyceridemia, previously treated with orchiectomy. In the active treatment arms, patients a history of cardiovascular disease or with medical conditions received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice Information for more information). Measure serum transaminases lymphopenia, hypercholesterolemia, hyperglycemia, elevated daily. In the control arms, patients received placebo orally once daily + that might be compromised by increases in blood pressure, [alanine aminotransferase (ALT) and aspartate aminotransferase AST, hypophosphatemia, elevated ALT, and hypokalemia. prednisone 5 mg orally twice daily. In Study 1, the primary efficacy endpoint hypokalemia, or fl uid retention. ZYTIGA® may cause hypertension, (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, Drug Interactions—ZYTIGA® is an inhibitor of the hepatic was overall survival. In Study 2, the coprimary efficacy endpoints were overall hypokalemia, and fl uid retention as a consequence of increased every two weeks for the fi rst three months of treatment, and drug-metabolizing enzyme CYP2D6. Avoid co-administration survival and radiographic progression-free survival. mineralocorticoid levels resulting from CYP17 inhibition. Safety monthly thereafter. Promptly measure serum total bilirubin, AST, with CYP2D6 substrates that have a narrow therapeutic index. † Estimate based on sales and use data from May 2011 to November 2012. has not been established in patients with LVEF < 50% or New and ALT if clinical symptoms or signs suggestive of hepatotoxicity If an alternative cannot be used, exercise caution and consider Reference: 1. Data on file. Janssen Biotech, Inc. York Heart Association (NYHA) Class III or IV heart failure (in a dose reduction of the CYP2D6 substrate. In vitro, ZYTIGA® study 1) or NYHA Class II to IV heart failure (in study 2) because develop. Elevations of AST, ALT, or bilirubin from the patient’s www.zytigahcp.com these patients were excluded from these randomized clinical baseline should prompt more frequent monitoring. If at any time inhibits CYP2C8. There are no clinical data on its use with drugs trials. Control hypertension and correct hypokalemia before and AST or ALT rise above fi ve times the upper limit of normal (ULN) or that are substrates of CYP2C8. Patients should be monitored Please see adjacent pages for brief summary during treatment. Monitor blood pressure, serum potassium, and the bilirubin rises above three times the ULN, interrupt ZYTIGA® closely for signs of toxicity related to the CYP2C8 substrate if of full Prescribing Information. symptoms of fl uid retention at least monthly. treatment and closely monitor liver function. used concomitantly with abiraterone acetate. Adrenocortical Insuffi ciency (AI)—AI was reported in patients Increased ZYTIGA® Exposures With Food—ZYTIGA® must be Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. The eff ects receiving ZYTIGA® in combination with prednisone, after an taken on an empty stomach. No food should be eaten for at least of strong CYP3A4 inhibitors or inducers on the pharmacokinetics interruption of daily steroids and/or with concurrent infection two hours before the dose of ZYTIGA® is taken and for at least of abiraterone have not been evaluated, in vivo. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution or stress. Use caution and monitor for symptoms and signs of one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and during treatment with ZYTIGA®. AI if prednisone is stopped or withdrawn, if prednisone dose is AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, Janssen Biotech, Inc. reduced, or if the patient experiences unusual stress. Symptoms respectively, when a single dose of abiraterone acetate was Use in Specifi c Populations—Do not use ZYTIGA® in patients © Janssen Biotech, Inc. 2012

and signs of AI may be masked by adverse reactions associated administered with a meal compared to a fasted state. with baseline severe hepatic impairment (Child-Pugh Class C). K08Z121176 12/12 08Z12264B

Y12903ALT_M07DR_ZYT_King_v1.indd 1-2 1/4/13 8:33 PM NEW INDICATION: ZYTIGA® (abiraterone acetate) is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

NEW EFFICACY DATA —In a recent Phase 3 clinical trial in patients with mCRPC who had progressed on ADT and had not received chemotherapy.*

Efficacy was also demonstrated in a Phase 3 trial of patients who had received prior chemotherapy PROSTATE TUMOR TISSUE containing docetaxel.*

TESTES

Y12903ALT_M07DR_ZYT_King_v1.indd 1-2 1/4/13 8:33 PM ZYTIGA® (abiraterone acetate) Tablets ZYTIGA® (abiraterone acetate) Tablets ZYTIGA® (abiraterone acetate) Tablets ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. o o o o o o Table 1: Adverse Reactions due to ZYTIGA in Study 1 Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) 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 INDICATIONS AND USAGE in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high (59oF to 86°F) [see USP controlled room temperature]. ZYTIGA with Placebo with alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with Prednisone (N=791) Prednisone (N=394) Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant metastatic castration-resistant prostate cancer. 1 or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Table 4: Laboratory Abnormalities in > 15% of Patients in the ZYTIGA Arm of Study 2 Adverse reaction % %%% Populations]. CONTRAINDICATIONS Abiraterone (N = 542) Placebo (N = 540) Musculoskeletal and connective tissue disorders Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 PATIENT COUNSELING INFORMATION Joint swelling/discomfort2 29.5 4.2 23.4 4.1 Laboratory Abnormality See FDA-approved patient labeling (Patient Information) use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during 3 % % % % pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to Muscle discomfort 26.2 3.0 23.1 2.3 • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt General disorders Hematology the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. or stop either of these medications without consulting their physician. Edema4 26.7 1.9 18.3 0.8 Lymphopenia 38.2 8.7 31.7 7.4 WARNINGS AND PRECAUTIONS Vascular disorders Chemistry • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hyper- Hot flush 19.0 0.3 16.8 0.3 Hyperglycemia1 56.6 6.5 50.9 5.2 Hypertension 8.5 1.3 6.9 0.3 tension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from High ALT 41.9 6.1 29.1 0.7 • Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for CYP17 inhibition . In the two randomized clinical Gastrointestinal disorders at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is [see Clinical Pharmacology (12.1) in full Prescribing Information] High AST 37.3 3.1 28.7 1.1 trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 Diarrhea 17.6 0.6 13.5 1.3 taken. They should be informed that the tablets should be swallowed whole with water without crushing or Hypernatremia 32.8 0.4 25.0 0.2 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Dyspepsia 6.1 0 3.3 0 chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may Infections and infestations Hypokalemia 17.2 2.8 10.2 1.7 result in adverse reactions. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a Urinary tract infection 11.5 2.1 7.1 0.5 1Based on non-fasting blood draws • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose Upper respiratory tract infection 5.4 0 2.5 0 their physician’s instructions. underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid Respiratory, thoracic and mediastinal disorders Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with Cough 10.6 0 7.6 0 commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left Renal and urinary disorders 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform ventricular ejection fraction < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study Urinary frequency 7.2 0.3 5.1 0.3 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment their physician. 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded Nocturia 6.2 0 4.1 0 discon tinuations and one death due to cardiac failure in the placebo group. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients Injury, poisoning and procedural complications hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a 5 In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct Fractures 5.9 1.4 2.3 0 and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) complete list of adverse drug reactions in PATIENT INFORMATION. hypokalemia before and during treatment with ZYTIGA. Cardiac disorders deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Arrhythmia6 7.2 1.1 4.6 1.0 • Patients should be advised that their liver function will be monitored using blood tests. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the Chest pain or chest discomfort7 3.8 0.5 2.8 0 of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in ZYTIGA arms. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or Cardiac failure8 2.3 1.9 1.0 0.3 women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with DRUG INTERACTIONS 1 be informed that it is not known whether abiraterone or its metabolites are present in semen and they should concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, Adverse events graded according to CTCAE version 3.0 Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness use a condom if having sex with a pregnant woman. The patient should use a condom and another effective particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and method of birth control if he is having sex with a woman of child-bearing potential. These measures are stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate required during and for one week after treatment with ZYTIGA. mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests Musculoskeletal stiffness 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates 4 to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise 5 Includes all fractures with the exception of pathological fracture caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology before, during and after stressful situations [see Warnings and Precautions]. 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, (12.3) in full Prescribing Information]. Manufactured by: Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Patheon Inc. reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Bradyarrhythmia In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates Mississauga, Canada Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if Manufactured for: beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). used concomitantly with abiraterone acetate. Janssen Biotech, Inc. 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Horsham, PA 19044 of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, © Janssen Biotech, Inc. 2012 two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Revised: December 2012 hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical start of treatment, every week for the first month, every two weeks for the following two months of treatment Table 2: Laboratory Abnormalities of Interest in Study 1 Pharmacology (12.3) in full Prescribing Information]. 2000005445 and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs Abiraterone (N=791) Placebo (N=394) suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should USE IN SPECIFIC POPULATIONS K08Z121174A prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises All Grades Grade 3-4 All Grades Grade 3-4 Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered Laboratory Abnormality (%) (%) (%) (%) above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate Hypertriglyceridemia 62.5 0.4 53.0 0 and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the High AST 30.6 2.1 36.3 1.5 is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to Hypokalemia 28.3 5.3 19.8 1.0 acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. Hypophosphatemia 23.8 7.2 15.7 5.8 the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or High ALT 11.1 1.4 10.4 0.8 the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the bilirubin greater than or equal to 10X ULN is unknown. High Total Bilirubin 6.6 0.1 4.6 0 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. Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed Study 2: Metastatic CRPC Prior to Chemotherapy In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days taken. Abiraterone C and AUC (exposure) were increased up to 17- and 10-fold higher, respectively, when a Patients were ineligible if AST and/or ALT ≥ 2.5X ULN and patients were excluded if they had liver metastases. max 0-∞ 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥ 2% absolute increase in number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 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. ADVERSE REACTIONS ZYTIGA with Placebo with The following are discussed in more detail in other sections of the labeling: Prednisone (N=542) Prednisone (N=540) 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 • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue Precautions]. Adverse reaction % %%% the drug taking into account the importance of the drug to the mother. • Adrenocortical Insufficiency [see Warnings and Precautions]. General disorders Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. • Hepatotoxicity [see Warnings and Precautions]. Fatigue 39.1 2.2 34.3 1.7 2 Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and • Increased ZYTIGA Exposures with Food [see Warnings and Precautions]. Edema 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction Musculoskeletal and connective tissue disorders these elderly patients and younger patients. Other reported clinical experience has not identified differences in rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be drug and may not reflect the rates observed in clinical practice. Groin pain 6.6 0.4 4.1 0.7 ruled out. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration- Gastrointestinal disorders Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously Constipation 23.1 0.4 19.1 0.6 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 treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in Diarrhea 21.6 0.9 17.8 0.9 dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice Dyspepsia 11.1 0.0 5.0 0.2 hepatic impairment, respectively compared to subjects with normal hepatic function. daily was given to control patients. Vascular disorders Hot flush 22.3 0.2 18.1 0.0 No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred Hypertension 21.6 3.9 13.1 3.0 moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot Respiratory, thoracic and mediastinal disorders daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. Cough 17.3 0.0 13.5 0.2 hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred Dyspnea 11.8 2.4 9.6 0.9 Pharmacology (12.3) in full Prescribing Information]. more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, Psychiatric disorders The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypo phosphatemia, Insomnia 13.5 0.2 11.3 0.0 should not receive ZYTIGA. elevated ALT and hypokalemia. Injury, poisoning and procedural complications For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may Contusion 13.3 0.0 9.1 0.0 Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Falls 5.9 0.0 3.3 0.0 Clinical Pharmacology (12.3) in full Prescribing Information]. received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥ 2.5X ULN in the absence of Infections and infestations liver metastases. Patients with liver metastases were excluded if AST and/or ALT > 5X ULN. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable Upper respiratory tract infection 12.7 0.0 8.0 0.0 between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in Nasopharyngitis 10.7 0.0 8.1 0.0 on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for frequency compared to placebo or were events of special interest. The median duration of treatment with Renal and urinary disorders patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full ZYTIGA was 8 months. Hematuria 10.3 1.3 5.6 0.6 Prescribing Information]. Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 OVERDOSAGE There have been no reports of overdose of ZYTIGA during clinical studies. 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness including monitoring for arrhythmias and cardiac failure and assess liver function.

Y12903ALT_M07DR_ZYT_King_v1.indd 3-4 1/4/13 8:33 PM ZYTIGA® (abiraterone acetate) Tablets ZYTIGA® (abiraterone acetate) Tablets ZYTIGA® (abiraterone acetate) Tablets ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. o o o o o o Table 1: Adverse Reactions due to ZYTIGA in Study 1 Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) 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 INDICATIONS AND USAGE in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high (59oF to 86°F) [see USP controlled room temperature]. ZYTIGA with Placebo with alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with Prednisone (N=791) Prednisone (N=394) Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant metastatic castration-resistant prostate cancer. 1 or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Table 4: Laboratory Abnormalities in > 15% of Patients in the ZYTIGA Arm of Study 2 Adverse reaction % %%% Populations]. CONTRAINDICATIONS Abiraterone (N = 542) Placebo (N = 540) Musculoskeletal and connective tissue disorders Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 PATIENT COUNSELING INFORMATION Joint swelling/discomfort2 29.5 4.2 23.4 4.1 Laboratory Abnormality See FDA-approved patient labeling (Patient Information) use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during 3 % % % % pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to Muscle discomfort 26.2 3.0 23.1 2.3 • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt General disorders Hematology the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. or stop either of these medications without consulting their physician. Edema4 26.7 1.9 18.3 0.8 Lymphopenia 38.2 8.7 31.7 7.4 WARNINGS AND PRECAUTIONS Vascular disorders Chemistry • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hyper- Hot flush 19.0 0.3 16.8 0.3 Hyperglycemia1 56.6 6.5 50.9 5.2 Hypertension 8.5 1.3 6.9 0.3 tension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from High ALT 41.9 6.1 29.1 0.7 • Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for CYP17 inhibition . In the two randomized clinical Gastrointestinal disorders at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is [see Clinical Pharmacology (12.1) in full Prescribing Information] High AST 37.3 3.1 28.7 1.1 trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 Diarrhea 17.6 0.6 13.5 1.3 taken. They should be informed that the tablets should be swallowed whole with water without crushing or Hypernatremia 32.8 0.4 25.0 0.2 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Dyspepsia 6.1 0 3.3 0 chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may Infections and infestations Hypokalemia 17.2 2.8 10.2 1.7 result in adverse reactions. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a Urinary tract infection 11.5 2.1 7.1 0.5 1Based on non-fasting blood draws • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose Upper respiratory tract infection 5.4 0 2.5 0 their physician’s instructions. underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid Respiratory, thoracic and mediastinal disorders Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with Cough 10.6 0 7.6 0 commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left Renal and urinary disorders 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform ventricular ejection fraction < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study Urinary frequency 7.2 0.3 5.1 0.3 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment their physician. 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded Nocturia 6.2 0 4.1 0 discon tinuations and one death due to cardiac failure in the placebo group. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients Injury, poisoning and procedural complications hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a 5 In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct Fractures 5.9 1.4 2.3 0 and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) complete list of adverse drug reactions in PATIENT INFORMATION. hypokalemia before and during treatment with ZYTIGA. Cardiac disorders deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Arrhythmia6 7.2 1.1 4.6 1.0 • Patients should be advised that their liver function will be monitored using blood tests. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the Chest pain or chest discomfort7 3.8 0.5 2.8 0 of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in ZYTIGA arms. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or Cardiac failure8 2.3 1.9 1.0 0.3 women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with DRUG INTERACTIONS 1 be informed that it is not known whether abiraterone or its metabolites are present in semen and they should concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, Adverse events graded according to CTCAE version 3.0 Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness use a condom if having sex with a pregnant woman. The patient should use a condom and another effective particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and method of birth control if he is having sex with a woman of child-bearing potential. These measures are stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate required during and for one week after treatment with ZYTIGA. mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests Musculoskeletal stiffness 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates 4 to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise 5 Includes all fractures with the exception of pathological fracture caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology before, during and after stressful situations [see Warnings and Precautions]. 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, (12.3) in full Prescribing Information]. Manufactured by: Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Patheon Inc. reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Bradyarrhythmia In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates Mississauga, Canada Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if Manufactured for: beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). used concomitantly with abiraterone acetate. Janssen Biotech, Inc. 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Horsham, PA 19044 of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, © Janssen Biotech, Inc. 2012 two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Revised: December 2012 hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical start of treatment, every week for the first month, every two weeks for the following two months of treatment Table 2: Laboratory Abnormalities of Interest in Study 1 Pharmacology (12.3) in full Prescribing Information]. 2000005445 and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs Abiraterone (N=791) Placebo (N=394) suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should USE IN SPECIFIC POPULATIONS K08Z121174A prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises All Grades Grade 3-4 All Grades Grade 3-4 Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered Laboratory Abnormality (%) (%) (%) (%) above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate Hypertriglyceridemia 62.5 0.4 53.0 0 and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the High AST 30.6 2.1 36.3 1.5 is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to Hypokalemia 28.3 5.3 19.8 1.0 acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. Hypophosphatemia 23.8 7.2 15.7 5.8 the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or High ALT 11.1 1.4 10.4 0.8 the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the bilirubin greater than or equal to 10X ULN is unknown. High Total Bilirubin 6.6 0.1 4.6 0 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. Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed Study 2: Metastatic CRPC Prior to Chemotherapy In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days taken. Abiraterone C and AUC (exposure) were increased up to 17- and 10-fold higher, respectively, when a Patients were ineligible if AST and/or ALT ≥ 2.5X ULN and patients were excluded if they had liver metastases. max 0-∞ 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥ 2% absolute increase in number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 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. ADVERSE REACTIONS ZYTIGA with Placebo with The following are discussed in more detail in other sections of the labeling: Prednisone (N=542) Prednisone (N=540) 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 • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue Precautions]. Adverse reaction % %%% the drug taking into account the importance of the drug to the mother. • Adrenocortical Insufficiency [see Warnings and Precautions]. General disorders Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. • Hepatotoxicity [see Warnings and Precautions]. Fatigue 39.1 2.2 34.3 1.7 2 Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and • Increased ZYTIGA Exposures with Food [see Warnings and Precautions]. Edema 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction Musculoskeletal and connective tissue disorders these elderly patients and younger patients. Other reported clinical experience has not identified differences in rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be drug and may not reflect the rates observed in clinical practice. Groin pain 6.6 0.4 4.1 0.7 ruled out. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration- Gastrointestinal disorders Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously Constipation 23.1 0.4 19.1 0.6 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 treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in Diarrhea 21.6 0.9 17.8 0.9 dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice Dyspepsia 11.1 0.0 5.0 0.2 hepatic impairment, respectively compared to subjects with normal hepatic function. daily was given to control patients. Vascular disorders Hot flush 22.3 0.2 18.1 0.0 No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred Hypertension 21.6 3.9 13.1 3.0 moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot Respiratory, thoracic and mediastinal disorders daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. Cough 17.3 0.0 13.5 0.2 hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred Dyspnea 11.8 2.4 9.6 0.9 Pharmacology (12.3) in full Prescribing Information]. more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, Psychiatric disorders The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypo phosphatemia, Insomnia 13.5 0.2 11.3 0.0 should not receive ZYTIGA. elevated ALT and hypokalemia. Injury, poisoning and procedural complications For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may Contusion 13.3 0.0 9.1 0.0 Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Falls 5.9 0.0 3.3 0.0 Clinical Pharmacology (12.3) in full Prescribing Information]. received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥ 2.5X ULN in the absence of Infections and infestations liver metastases. Patients with liver metastases were excluded if AST and/or ALT > 5X ULN. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable Upper respiratory tract infection 12.7 0.0 8.0 0.0 between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in Nasopharyngitis 10.7 0.0 8.1 0.0 on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for frequency compared to placebo or were events of special interest. The median duration of treatment with Renal and urinary disorders patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full ZYTIGA was 8 months. Hematuria 10.3 1.3 5.6 0.6 Prescribing Information]. Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 OVERDOSAGE There have been no reports of overdose of ZYTIGA during clinical studies. 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness including monitoring for arrhythmias and cardiac failure and assess liver function.

Y12903ALT_M07DR_ZYT_King_v1.indd 3-4 1/4/13 8:33 PM SP98 Payment Reform Applying Accountable Care to Oncology: Developing an Oncology ACO

Stanton R. Mehr

he accountable care organization savings be a primary goal? Perhaps the (ACO) has been the buzzword on principal mission of an oncology ACO Scan for additional content. the tip of everyone’s tongue. With would be to better standardize care T Ira Klein, MD, discusses quality measures in January’s announcement by the Centers pathways, use integrated care, and im- for Medicare & Medicaid Services of an prove counseling of patients in how to oncology (http://goo.gl/RQ5Rp) additional 106 ACOs, the number join- manage the course of disease.3 ing the Medicare Shared Savings Pro- If this is the case, oncology ACOs fo- gram is now 259, serving 4 million bene- cused on the shared-savings model will ficiaries.1 An estimate by the consultant likely come up short. In fact, the choice organization Leavitt Partners pegs the of whether to treat actively or simply vanced Medical Specialties, which pro- overall and improve outcomes.3 In the number of active ACOs at 428, operating monitor a cancer’s progress (ie, watch- vides oncology services in Miami, to press release announcing the agree- in 49 states.1 ful waiting in prostate cancer) may be form an oncology ACO. Next, in Decem- ment, Dr Alan F. List, president and CEO The principal ideas underlying the money saving to the ACO, but may seem ber 2012, Florida Blue unveiled an on- of Moffitt, said, “This partnership with ACO concept are (1) coordination of care to others as a sign that the organization cology ACO with Moffitt Cancer Center Florida Blue focuses on the value we through integrated services (or virtually is willfully withholding care in order in Tampa.5 This collaboration will focus provide our patients, and that becomes integrated services) and (2) financial to save money.3 This on common cancers a positive for everyone. I anticipate that incentives for clinicians and hospitals challenge ensures that and will “identify and we will learn a lot from this new ven- to efficiently manage patients, saving the decision making select quality met- ture and that it will help us to continue money in the process, and in the Ac- and clinical pathways rics for the program.” to improve cancer care.” countable Care Act’s Medicare Shared must be dictated by Slated to start this Aetna has been involved with oncol- Savings initiative,2 sharing those sav- the clinicians, not the year, Florida Blue and ogy ACO model formation for the past ings with the provider-partners in the organization. Moffitt hope to im- few years. The health plan doesn’t view ACO. The majority of ACOs have focused Of course, the ques- prove patient care by it simply as a new way to pay physi- on primary care. Policy makers agree tion of developing an sharing clinical and cians. Aetna views it as necessary to that the ACO concept is most easily ap- oncology-based ACO administrative claims try to move clinical pathways front and plied to primary care, which may have should not imply that data. It seems that this center in the oncologists’ offices. Ira the highest payoff in terms of cost sav- present ACOs do not venture will seek to Klein, MD, chief of staff to Aetna’s chief ings through disease prevention and provide oncology ser- incorporate a value- medical officer, and the head of its on- early diagnosis and management. vices through their based reimbursement cology strategy, told Evidence-Based On- A few specialty models of ACOs are networks. A survey system. Additionally, cology, “Cancer care is among the top 3 being piloted, but these are more de- conducted in 2011 this agreement will highest medical cost categories in the pendent on secondary prevention of found that health Ira Klein, MD emphasize patient United States. Oncology also is an area disease episodes or complications. For plans and health sys- engagement in their of clinical care that is characterized by example, DaVita (www.davita.com), tems forming ACOs care and provide ser- high variability in costs and treatment based in Denver, focuses on patients were indeed including oncology provid- vices for family members who care for choices across the country. Given this with kidney disease and owns more ers in their plans.4 According to health the patients, in an effort to reduce costs large medical cost footprint and signifi- than 1900 outpatient dialysis centers.3 plan and health system executives who Its Accountable Kidney Care Collab- were forming ACOs, 65% indicated that Figure. Oncology Positioning Within ACO Responder Organizationsa orative seeks to use the ACO model for oncology services were closely aligned patients with end-stage renal disease. or already employed by the organization Not aligned/competitive (5%) The cost-saving potential of specialty (Figure). Another 30% had loose affilia- or disease-specific ACOs can be huge, tions with oncology providers. Overall, because of the existing costs associated the executives responding to the survey with treating these patients, but it is un- questioned whether a cancer-related clear whether these specialty services ACO model would be the way forward. are more efficiently provided through They indicated that because of the com- Loosely their own ACO or as ancillary to the bur- plex issues associated with oncology aligned/mixed geoning primary care ACO marketplace. care (and other specialty-treated dis- affliations eases, for that matter), most were more (30%) Considerations in an Oncology focused on learning how the ACO will Closely ACO Model perform in clinical areas that have more aligned/employed The various common cancer types and predictable costs, like primary care. (65%) multitude of therapies used to treat them may complicate the mission of an Two Health Plans Take the Lead ACO. For patients with advanced kidney Despite these challenges, Florida Blue dysfunction, a specialty ACO may ex- (Blue Cross and Blue Shield of Florida) pect savings to be derived from lower recently dove headlong into the oncol- hospitalization costs through improved ogy ACO arena. First, in May 2012, the aData from 2011 patient care. Considering the cost of insurer announced an agreement with ACO indicates accountable care organization Source: Adapted from Barkley R. Where does oncology fit in the scheme of accountable care? J Oncol Pract. treating many neoplasms, should cost Baptist Health South Florida and Ad- 2012;8:71-74.

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 Payment Reform SP99

ity improvement back to the physicians this episode-of-care payment can be Table. Greater Efficiency: Preliminary Results of Aetna’s Oncology and offices at the practice level.” Klein renewed every 4 months during the ACO Compared With Those Not in the ACO noted that from earlier pilots, they real- course of the disease. This provides the ized that oncologists appreciated these continuity of payment needed for on- tools as learning guides. “Process im- cologists to continue overseeing the pa- Emergency Department Visits  40% provement reduces error while teaching tient’s care (regardless of whether drug Hospital Admissions  16% about habits, both good and bad.” therapy is utilized). Hospital Days  36% And what of Aetna’s long-term goals? This move is echoed by the efforts of “While we focus on tools used within others, such as those by Andrew Pecora, Total Costsa  12% practices for many reasons (workflow, MD, president of the New Jersey–based ACO indicates accountable care organization. precertification relief, error reduction), Regional Cancer Care Associates, which aLung, breast, and colon cancers only. we will be looking to connect the in- was featured in the last issue of Evi- office environment with the care deliv- dence-Based Oncology.8 From the stand- cant potential for clinical improvement, physicians do for patients in the office ery ecosystem outside the oncology of- point of building ACOs, it looks like a we believed and showed that apply- as well as what they do to keep them fice in the future,” replied Klein. “Oncol- move in the right direction. EBO ing evidence-based guidelines—path- out of the need for care.” ogists can be ideal ‘medical neighbors’ ways—to cancer care can help address What, if any, early lessons have plans in medical home–type integrated de- Funding Source: None. the variability and get to equal or better learned about developing the relation- livery systems. In an ACO, it’s all about Author Disclosure: Mr Mehr reports receiving health outcomes and lower costs.” ships necessary for an oncology ACO? working together. This can be parlayed payment for involvement in the prepara- He noted that widespread adoption According to Klein at Aetna, “Physicians into bundles of care, as well.” tion of this article. of a pathways-based model requires are a key component to the success of Additional pilot programs in oncology Authorship Information: Concept and design; changes in the approach to care, deci- pathways implementation, and aligned ACOs are being sponsored by Blue plans drafting of the manuscript; critical revision support, and payment. “Supporting incentives are a must. Having a trusted in California, Maryland, Michigan, New sion of the manuscript for important in- oncologists through these changes is relationship with oncologists is critical Jersey, Tennessee, and South Carolina.4 tellectual content. critical,” said Klein, “and new contrac- as well, because they are providing the tual relationships must drive positive Tackling Oncology Care Payments References change for their practices and their pa- The cost-saving One of the daunting challenges when 1. Accountable care organizations have more tients.” considering shared savings methods than doubled since 2011 (press release). Leavitt Aetna teamed with US Oncology Net- potential of for oncologists, as well as many other Partners, February 20, 2013. http://news work’s Texas Affiliate, announcing the specialties, is the use of fee-for-service .leavittpartners.com/newsrelease-cid-1-id-48 results of a shared savings model at the specialty or disease- reimbursement, along with the “buy- .html. Accessed February 22, 2013. American Society of Clinical Oncology and-bill” system for purchasing oncol- 2. Medicare Program; Medicare Shared Savings symposium in late 2012.6 According to specific ACOs can ogy medications, both sources of reve- Program: Accountable Care Organizations. Aetna, members in the program had nue for the oncology practice. Medicare CMS-1345-P. Federal Register, Vol. 76, Issue 67. at least the same clinical outcomes as be huge...but it is and commercial plans have moved to November 2, 2011. members not under the shared savings average manufacturer price–based bill- 3. Stagg Elliott V. Disease-specific ACOs make program, but emergency department unclear whether ing for drugs, which have limited buy- their debut. American Medical News, January 28, and hospital visits dropped significant- and-bill practices in recent years, but 2013. www.ama-assn.org/amednews/2013/01 ly, as did hospital admissions and hos- these specialty these issues need to be tackled before /28/bisb0128.htm. Accessed January 31, 2013. pital days (Table). This resulted in 12% oncology ACOs can be developed in the 4. Barkley R. Where does oncology fit in the lower costs overall for lung, breast, and services are more mainstream. scheme of accountable care? J Oncol Pract. colorectal cancers alone. UnitedHealthcare, though not start- 2012;8:71-74. “The concept for a shared savings efficiently provided ing an oncology ACO per se, has a pilot 5. Florida Blue and Moffitt Cancer Center Create model came from the understanding program (more of a patient-centered Cancer-Specific Accountable Care Arrangement that oncology care is clinically com- through their own medical home model) which may help (press release). Florida Blue, December 20, plex in almost every case,” commented set benchmarks as to how oncology 2012. www3.bcbsfl.com/wps/portal/bcbsfl/ Klein. “A comprehensive oncology man- ACO or as ancillary providers can be paid in such an orga- newsroom?WCM_GLOBAL_CONTEXT=. Accessed agement strategy starts with patients nization. In this pilot, providers are paid January 31, 2013. and the goal of adding value to their to the burgeoning on an episode-of-care basis. This pilot 6. Aetna, the US Oncology Network provide cancer therapies. But unless incentives involves 5 oncology practice sites.7 The more evidence that clinically proven, integrated are aligned, there’s no traction for the primary care ACO episodes of care were defined by the cancer care enhances quality and controls costs: physicians and support staff to un- practices themselves for 19 cancer sub- positive outcomes from new study presented at dertake the difficult work of practice marketplace. categories. This payment for cancer care ASCO Quality Care Symposium. Aetna, Decem- change at the office level. We feel that is fixed, and drugs are reimbursed only ber 6, 2012. http://newshub.aetna.com/press- to gain increased value, you have to flip care. Without their input, no program at the manufacturer’s cost, discourag- release/products-and-services/aetna-us-oncol- the coin to the other side and negotiate can really be effective.” ing buy-and-bill practices. Patient visits ogy-network-provide-more-evidence-clinically- shared risk. He also pointed out that “Physicians are billed separately, and UnitedHealth- prove. Accessed January 12, 2013. “We replaced the traditional buy-and- also have an important role in helping care also pays oncology practices a case 7. Blum K. Episodic payment put to the test. Clini- bill model with a system that is reward- the insurer gather and analyze data, management fee, which may promote cal Oncology News, December 2010. www ing in more appropriate ways, including which can help in developing addition- better coordination of care.7 .clinicaloncology.com/ViewArticle.aspx?d=Policy payment redesign and use of a medical al program goals going forward. We re- In this move away from fee-for-ser- +and+Management&d_id=151&i=December+ home model approach to patient care. quire some mechanism of data capture vice payments, which would be un- 2010&i_id=685&a_id=16263. Accessed January We offer greater payment as an incen- and strongly encourage interactive elec- workable in an ACO or shared savings 15, 2013. tive for adherence to pathways, espe- tronic clinical decision support tools. environment, the up-front episode- 8. Focusing on clinical and economic outcomes— cially with regard to prescribing generic This gives us an unbiased activity re- of-care fee covers the usual treatment not guidelines: is it time for a new direction in drug products when appropriate. The porting, which we can then use to feed period for a patient with breast, lung, oncology care? Am J Manag Care. 2013(1 Spec payment structure also focuses on what the ‘plan, do, check, act’ cycle of qual- or colon cancer. If the cancer recurs, No.):SP43.

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 SP100 Oncology Medical Home Measuring Quality Cancer Care Robert Gamble

wo of my favorite activities are run- cross-section and balanced approach erly, the door is left open for miracles,

ning and salt-water fishing. Both to defining key determinants to patient but the patient and family are able to Scan for additional content. T are very precise and numbers-ori- care, resource utilization, survivorship, make informed decisions regarding their ented activities. Running is about time, and end-of-life care may prove challeng- care. Electronic medical record vendors Robert Gamble pace, distance, calorie burn rates, and ing, but its time is past due. For example, will need to enhance their data capture talks about the heart rate zones, among other factors. as an outdoor enthusiast my hope is that fields from a simple “Advanced directive challenges pay- When talking with runners it does not I will be called home while running, fish- on file – Y or N” to a more detailed and ers and providers take long for the conversation to come ing, or simply walking on a trail. For a comprehensive approach to this ques- face in oncology around to the essential questions: “What cancer patient the hope is that they may tion if we are to raise the bar in care and management (http://goo.gl/uJtv7) is your PR (personal record) for a half (or leave this earth among family or friends compassion. There should be similar full) marathon?” or “What is your aver- and surrounded by a known and friendly guidelines for the specifics of care plans financial incentives to curb unnecessary age weekly miles?” Both of these ques- environment—peacefully and quietly. Dy- and cancer survivorship plans. ED visits or hospitalizations. This is why tions reflect standard benchmarks of the ing at home would seem to be the choice Another milestone by the COA Oncol- the COA OMH Steering Committee has level of accomplishment in the sport. for all, if we had a choice. And there is no ogy Medical Home Steering Committee endorsed this measure. Perhaps we need Fishing, or as we say in the South, “fish- better indicator of the quality of life, at was the endorsement that all cancer to revise this notion of “precertification” in’,” has its own set of standards. Before end of life, than the place of death. How- care providers should calculate their own and insert the patient’s medical home we graduate to the point ever, it seems that the 5-year survival rates for breast, colon, and provider as the “mother may I” author- of hoping the fish do not national death registry lung cancers. This is completely logical ity before these services are rendered. bother us, we are watch- does not record a “place” and is a measurement whose time has This procedural change would allow the ful of length, weight, creel of death. The standard come. As a former manager of a cancer patient’s main care team to intervene limit, and also making death certificate includes center, I often wondered what I would say with, hopefully, a more efficient solution sure the catch falls with- the following choices for when asked for our own 5-year survival and it would also assist in nurturing the in season. Measurement place of death: “Hospital rate for stage 3 breast cancer. It would relationship between the patient and his is serious business, to inpatient, ER/Outpatient seem to be a logical and reasonable ques- medical home physician. Only then will the point that the fish- or DOA; Nursing home, tion but one that currently has no an- we be able to measure and benchmark ing industry has its own Residence or Other (Spec- swer—at least not for an individual can- the utilization of these valuable resour- “Golden Rule”—an official ify).” It would seem that cer center. “Survival” rates, when they are ces and reward those care teams that use calibrated tool to measure it would be beneficial to the only measure, are not necessarily a them appropriately. the length of a fish. Woe to include these data in the good indication of quality, particularly if a the person who is caught national death registry patient is being kept alive through artifi- Applying Our Own “Golden Rule” with a fish under or over and to recognize same as cial means and against the wishes of the Other industries seem to have a head the size requirements. a quality and value indi- patient or family. But, when combined start on defining quality statements. The fisherman strives to Robert Gmable cator for all of healthcare, with other standards and educational re- Healthcare, and particularly cancer care, have the best answer to not just cancer care. This quirements, this information can be very seems to be the last industry to define, the routine question, “Did you catch any- seems to be an easy fix. helpful to the patient and their families measure, benchmark, and promote qual- thing?” If that is answered in the affirma- And somewhat related is the entire in planning and in the celebration of sig- ity, value, and positive outcomes. Perhaps tive the next question will hopefully be discussion surrounding end-of-life care nificant milestones. it is because we have been busy taking answered with a boast: “Any size?” discussions. The patient and their family care of others that we have not been able Both of these activities have finite and need open and honest dialogue regard- Overutilization of Hospital Services to focus on such a mammoth undertak- very specific criteria of what is consid- ing their current status, their wishes, and One of the more elusive measures but one ing. Now may be the time to apply our ered “good” or “excellent.” Why is it we how their wishes are to be carried out. that has great significance in the value own “Golden Rule” to measuring quality struggle with the similar concepts in This goes beyond the simple question of department is the use, or overuse, of hos- and value in cancer care. After all, and as healthcare and particularly cancer care? asking a patient if they are ready to meet pital services. Some patients and health- I am sometimes reminded, there is more It is interesting that healthcare accoun- their maker. One of several programs care providers are quick to utilize these to life than running and fishing. ted for 15.2% of GDP in 2008.1 Fishing that attempt to remedy this issue is the expensive inpatient, outpatient, or emer- (even when included in the category of “5 Wishes” program.3 This program asks gency department (ED) resources over a Funding Source: None. agriculture, hunting, forestry, and fish- 5 probing questions regarding assign- less expensive setting such as the exam Author Disclosure: The author reports no rela- ing) is only 1.1% of GDP.2 The running in- ing decision makers, medical treatment or procedure room of their medical home. tionship or financial interest with any entity dustry is not even high enough to score preferences, preferred comfort levels, Governmental and commercial payers all that would pose a conflict of interest with a 1/100 of a percent. If healthcare con- preferences on interactions with others, agree that the overuse of these resources the subject matter of this article. sumes so much of our world, why is it and last wishes. This program provides represents a significant expense and an Authorship Information: Concept and design; then that we focus so little attention on specific guidance on how to conduct opportunity to realize savings in time analysis and interpretation of data; draft- the specifics of quality or value or out- these conversations. Dr John Sprandio and dollars to the payer and patient. The ing of the manuscript; administrative, tech- comes in healthcare? (Pennsylvania) and Dr John Fox (Michi- challenge with curbing this misuse of nical, or logistic support; and supervision. gan) have indicated that when these resources is that the person who should Defining Quality, Value, and Outcome discussions occur, and at the right time, know of these encounters, the patient’s References Measures patients have made decisions to dis- medical home physician, does not always 1. Healthcare in the United States. http:// The lack of attention in systematically continue aggressive cancer treatment. know when they occur. The hospital staff en.wikipedia.org/wiki/Health_care_in_the_Unit- measuring quality and value in cancer The end result is more comfortable end- will be the first to know, the patient’s ed_States. Accessed January 3, 2013. care became particularly obvious when of-life care. Although some patients (or payer may be the second to know, but 2. OECD. StatExtracts. http://stats.oecd.org/In- working with the Oncology Medical family members) may resist these dis- the person who should know first, the dex.aspx?DatasetCode=SNA_TABLE1. Accessed Home (OMH) Steering Committee on its cussions, they should be required for any patient’s physician, may never know if or January 3, 2013. objective of defining 16 quality, value, and healthcare team charged with managing when this event occurs. Some commer- 3. Aging with Dignity website. www.agingwithdigni- outcomes measures for cancer care. This any terminal disease. When done prop- cial insurance companies are providing ty.org/five-wishes.php. Accessed January 3, 2013.

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 A One-Stop App for Managed Care Professionals

Now Available!

All our monthly content in one place! Download the AJMC iPad edition for full access to our content, such as: • Print issue • eAppendices • Web exclusives • Audio summaries

www.ajmc.com

AJMC_ipadAd_0213_EBO.indd 1 2/7/13 3:06 PM SP102 Disease Overview Searching for Clinical and Economic Value in Pancreatic Cancer

Marj P. Zimmerman, MS, BS Pharm; and Stanton R. Mehr

ancreatic cancer is an extremely of Patrick Swayze (who had exocrine aggressive tumor type that con- pancreatic cancer) and Steve Jobs (who Table. Probability (%) of Developing Pancreatic Cancer Over Selected Ptinues to carry a dismal progno- had endocrine pancreatic cancer).3 In Age Interval by Gender (2007-2009) sis. Research regarding the cause of the fact, the dire prognosis for patients with cancer has continued, but important pancreatic cancer has driven people Age (y) Men Women breakthroughs have been slow in com- like Jobs to seek unorthodox treatment 0 to 39 0.01 (1 in 9746) 0.01 (1 in 7479) ing. Additionally, pancreatic tumors and unproven therapies. demonstrate a resistance to chemo- Patients with pancreatic neuroendo- 40 to 49 0.05 (1 in 2063) 0.04 (1 in 2475) therapy, which has contributed to cli- crine tumors have a somewhat better 50 to 59 0.18 (1 in 563) 0.12 (1 in 843) nicians’ frustration in obtaining remis- median overall survival than those with 60 to 69 0.41 (1 in 241) 0.30 (1 in 335) sion, or even a firm foothold in manag- ductal adenocarcinomas. Unfortunate- ing it. This may also be related to the ly, the incidence of these tumors ap- 70 to 79 0.65 (1 in 155) 0.56 (1 in 179) relatively late stage of the tumor at the pears to be increasing.4 Lifetime risk 1.48 (1 in 67) 1.45 (1 in 69) time of diagnosis. Therefore, early diag- The cause(s) of pancreatic cancer Source: Reprinted with permission from American Cancer Society. Cancer Facts & Figures 2013. Atlanta: nosis and the future discovery of an ef- are unknown. Family history is a posi- American Cancer Society; 2013.1 fective screening method could change tive risk factor and is identified in 5% the clinical picture and alter the search to 10% of those diagnosed; the risk tients to the physician’s office include: that germline mutations in BRCA1 and for value in managing this deadly can- increases as the number of family nausea, vomiting, abdominal discom- BRCA2 predispose women to pancreatic cer. members diagnosed with the disease fort, abdominal pain that is localized to cancer, doubling their risk for develop- increases. Smoking is also a risk fac- the tumor area, anorexia, weight loss, ing it. The 5-year survival for these indi- Mortality Increasing Unlike for Other tor, with a 2.5% to 3.6% increase in risk generalized weakness, and fatigue. The viduals was no greater than 5%.7 Cancers compared with non-smokers. As the majority of the tumors develop in the Epidermal growth factor receptor Death rates for most cancers have tren- number of life-years of smoking in- head of the pancreas, which leads to (EGFR) overexpression has been iden- ded downward over the past 10 years; creases, so does the risk for pancreatic obstructive cholestasis, rather than the tified in 40% to 65% of pancreatic tu- however, this has not been the case for cancer.5 Other potential risk factors tail of the pancreas. Overall, most tumors. This overexpression leads to tu- pancreatic cancer. The incidence rate include age; obesity; alcohol use; con- mors are found when only about 15% to mors being resistant to chemotherapy has increased by 0.9% per year in Cau- 20% of patients are still candidates for and an even poorer prognosis.8 Since casian men and women and African surgery.1,5 pancreatic tumors vary so much be- American men, while remaining stable As would be expected, costs for tween patients, a highly individualized in all others.1 The Table illustrates the Pancreatic cancer is treating patients who undergo surgery approach to treating the disease will likelihood of developing pancreatic are greater than costs for patients who probably be needed to improve patient cancer over one’s lifetime.1 The major- not one of the top 5 have nonresectable tumors (either lo- outcomes.9 ity of patients (74%) diagnosed will die coregional or metastatic). A Surveil- Currently, only 1 biomarker is ap- within 1 year of diagnosis, whereas only cancers in men or lance, Epidemiology, and End Results proved by the US Food and Drug Admin- 6% will survive for 5 years—this is the (SEER) Medicare database study that istration for pancreatic cancer, serum lowest relative survival of any cancer women in terms of included patients diagnosed between Ca-19-9 (carbohydrate antigen 19-9, tracked by the American Cancer Soci- 2000 and 2007 found the mean total also known as cancer antigen-GI and ety and the National Cancer Institute. incidence, yet it is costs for those 3 patient groups to be CA-GI).10 This marker is useful for iden- Patients’ average life expectancy after $134,000 (surgical candidates), $65,300 tifying the tumor location, stage, and diagnosis of metastatic disease is only the fourth leading (patients with locoregional tumors), resectability.11 However, not all pancre- 5 to 7 months.2 It is not one of the top and $49,000 (patients with metastat- atic tumors produce Ca-19-9; therefore, 5 cancers in men or women in terms cause of cancer ic disease), with an average cost of it is not sensitive or specific enough to of incidence, yet it is the fourth leading $61,700. The largest portion of the costs be used as a screening test.1,12 However, cause of cancer death among men and death among men was related to hospitalizations and the test does have value for evaluating women. More than 45,000 Americans cancer-related procedures (Figure).6 Un- effectiveness of treatment and early de- will be diagnosed with pancreatic can- and women. doubtedly, improved treatment strate- tection of recurrent disease.5 cer in 2013, and over 38,000 will die this gies may increase the cost of treating Other frequently used tests include year.1 patients with pancreatic cancer by in- endoscopic ultrasound, helical compu- The incidence of pancreatic cancer sumption of red and processed meat, creasing their lifespans. ted tomography, magnetic resonance increases with age, with the median age and fructose sweeteners; chronic pan- imaging, and endoscopic retrograde at diagnosis being 71 years. More men creatitis; diabetes; chronic infections Genetics and Biomarkers cholangiopancreatolography. To con- than women are diagnosed with the (eg, hepatitis B virus, hepatitis C virus, Pancreatic cancer is genetically hetero- firm the diagnosis, fine-needle aspira- disease.1 and Helicobacter pylori); some surgeries geneous. One study analyzing 24 tumors tion biopsy is standard procedure.1,13 Pancreatic cancer typically refers to a (eg, partial gastrectomy, cholecystec- found 63 genetic abnormalities in each ductal adenocarcinoma (exocrine pan- tomy); cystic fibrosis; and periodontal tumor that were believed to be likely Staging of Pancreatic Cancer creatic cancer). A less common type disease.1 relevant for the disease. It has been de- Staging of the disease guides the type is a neuroendocrine tumor (endocrine Pancreatic cancer is usually not determined that there are always at least of treatment that will be the most effec- pancreatic cancer). The public profile tected or diagnosed in the early stages 1 or more genetic defects involving 4 tive. The 4 stages associated with pan- of pancreatic cancer has been raised in of the disease, as there are no specific genes in patients with pancreatic can- creatic cancer are differentiated by the recent years with the chronicled cases symptoms. Symptoms that bring pa- cer.5 Recent research has determined location of the tumor and whether it

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 Disease Overview SP103

has spread to lymph nodes and distant with leucovorin, or capecitabine.14 an improved median overall survival compared with gemcitabine alone. organs. Stage I indicates that the tumor Since surgery for pancreatic can- (11.1 vs 6.8 mo, respectively; P <.0001). Using a willingness to pay of $50,000 is restricted to the pancreas, and stage cer can involve several organs in the Median progression-free survival was per QALY as the threshold for cost- IV describes cancer that has spread to a digestive system in addition to an al- also longer in the combination thera- effectiveness, the probability of cost- distant organ, such as the liver or lungs. ready diseased organ, several potential py group (6.4 vs 3.3 mo, respectively; effectiveness was 78% for gemcitabine Patients with stage III or IV tumors are morbidities should be considered. Up P <.001).22 Targeted EGFR therapy us- monotherapy and 21% for SBRT, while generally not candidates for surgical to 80% of patients undergoing surgical ing erlotinib plus gemcitabine led to a at a willingness-to-pay threshold of resection, and this comprises about procedures for pancreatic cancer will marginally longer overall survival than $200,000 per QALY, the probability of 80% of patients.13,14 The lethality of this require oral pancreatic enzyme replace- gemcitabine alone (6.2 vs 5.9 mo, re- cost-effectiveness for SBRT was 73%.26 cancer in late stages cannot be overem- ment therapy (PERT). The dose of lipase spectively; P = .038).23 Another type of cost strategy evalu- phasized; survival is somewhat greater required usually ranges from 160,000 to ation was undertaken that determined when diagnosed at an earlier stage. 400,000 units daily. A proton pump in- Cost Considerations the budget impact of adding erlotinib When a patient has surgery after being hibitor may be added to improve the ef- Since pancreatic cancer is such a devas- to gemcitabine therapy in patients with diagnosed with stage I or stage II can- ficacy of the PERT, if there is adequate tating disease, strategies for screening nonresectable pancreatic cancer. The cer, the 5-year survival is 20% to 25%, gastric acid secretion.17 Since at least a individuals at high risk would be ben- budget impact was $0.02 per member whereas a patient diagnosed with stage portion of the pancreas is removed dur- eficial. Two cost-effectiveness studies of per month; this small amount was pri- IV cancer has a 5-year survival that is ing surgery, the body’s ability to produce screening high-risk individuals led re- marily the result of the low incidence below 1%.1,15 insulin is compromised. As a result, up searchers to conclude that early cancer of pancreatic cancer among the hypo- to 50% of patients develop diabetes and can be detected by screening; however, thetical managed care organization of Treatment Options require insulin therapy postsurgery.18 until new biomarkers with high speci- 500,000 members. It would be difficult Surgery is the only treatment option Other complications observed after ficity and sensitivity become available, to deny patients the additional drug that can cure early-stage disease. How- surgery include gastroparesis, dump- this strategy may not be cost-effective.24 being added to a gemcitabine regimen ever, a small percentage of patients ing syndrome, and vitamin and mineral Owing to the poor outcomes of patients even with limited survival benefits.27 present with stage I pancreatic cancer, deficiencies.19 with pancreatic cancer, the evaluation Both the National Cancer Institute because of the difficulty in diagnosing For the majority of patients whose of cost-effective treatment strategies (NCI) and pharmaceutical companies it. Surgical procedures most commonly tumor is not resectable, the therapeu- remains challenging. Alas, the survival are investigating new modalities for performed include cephalic pancre- tic options are chemoradiation and/or of these patients is consistently short, treating pancreatic cancer. The NCI atoduodenectomy (also known as the chemotherapy. Gemcitabine has been and expressing incremental cost-effec- has increased its budget for this dis- Whipple procedure), distal pancreatec- the mainstay of therapy since the late tiveness ratios (ICERs) in terms of years ease by more than 50% since 2000. Yet, tomy, and total pancreatectomy. Pre- 1990s, when the drug was shown to in- yields inadequate comparisons. For this the complexity and variability of each dictors of improved survival include crease median survival to 5.7 months reason, ICERs for pancreatic cancer in- tumor continues to challenge clinical younger age and early-disease stage.5,16 compared with 4.4 months for those terventions are often expressed in qual- treatment. As we learn more about the After surgery, adjuvant chemotherapy taking 5-FU (P = .0025), but the 1-year ity-adjusted life-months (QALMs), not genetic makeup of pancreatic cancer, it either alone or in combination with survival was worth noting (18% versus life-years. will undoubtedly lead to new therapies, radiation therapy has been shown to 2%, respectively).20 Capecitabine is a A recent review examined 6 treat- new combination therapy regimens, improve survival. Neoadjuvant therapy, pro-drug of 5-FU, and it has also dem- ment strategies: no treatment, ra- and biomarkers that will aid in the both chemoradiation or chemotherapy onstrated benefit in treating patients diotherapy only, chemotherapy only, detection and monitoring of therapy. in combination or alone, are also op- with pancreatic cancer.21 A combination chemotherapy plus radiotherapy, sur- These advances will hopefully trans- tions, especially when the patient has therapy regimen, FOLFIRINOX (oxalipla- gery alone, and surgery plus adjuvant late into better patient outcomes and locally advanced or borderline rescect- tin, irinotecan, fluorouracil, and leucov- therapy. The groups having surgery economically sound treatment strate- able disease. In patients undergoing orin), was compared with gemcitabine plus adjuvant therapy, chemotherapy gies. EBO surgery, the chemotherapy regimens in patients with stage IV metastatic dis- alone, and no treatment were the only initiated after the surgery usually in- ease that involved up to 6 distal sites. groups that were considered cost- Funding Source: None. clude gemcitabine, 5-fluorouracil (5-FU) The combination therapy group showed effective. An ICER of $7663 per QALM Author Disclosures: Mr Mehr reports receiv- was seen in the surgery plus adjuvant ing payment for involvement in the prepa- Figure. Breakdown of Mean Direct Medical Costs for All 3 Patient therapy group compared with the no- ration of this article. Ms Zimmerman re- treatment group, which was primarily ports no relationship or financial interest Groups related to an increase in survival. Of with any entity that would pose a conflict note was that the ICER was most fa- of interest with the subject matter of this vorable in high-performing healthcare article. centers versus low-performing centers Authorship Information: Concept and design ($5991/QALM vs $9144/QALM, respec- (SRM); acquisition of data (MPZ, SRM); Other healthcare Procedures (22%) tively). This indicates that decreasing analysis and interpretation of data (MPZ, services (24%)a costs will be related to improved thera- SRM); drafting of the manuscript (MPZ, pies and utilizing high-performing care SRM); critical revision of the manuscript centers for providing the treatments.25 for important intellectual content (MPZ, Chemo/ Another study examined the cost-ef- SRM); and supervision (SRM). Hospice (7%) radiotherapy (13%) fectiveness of gemcitabine monotherapy, gemcitabine plus conventional ra- References diotherapy, gemcitabine plus intensity- 1. American Cancer Society. Cancer Facts & modulated radiotherapy (IMRT), and Figures 2013. Atlanta: American Cancer Society; Inpatient (33%) gemcitabine with stereotactic body ra- 2013. diotherapy (SBRT). The SBRT group had 2. Pancreatic Cancer Facts 0212. Pancreatic better results both clinically and eco- Cancer Action Network. www.pancan.org/sec- nomically than each of conventional tion_get_involved/advocate/downloads/Pan- radiotherapy and SBRT groups, respec- creatic%20Cancer%20Facts%20June%202012.pdf. aOther healthcare services includes outpatient care and physician services. tively, but only produced an increase Accessed February 5, 2013. *Figures are accurate to within 1% of 0.20 quality-adjusted life-years (QA- 3. Begley S. Jobs’s unorthodox treatment. The Source: Adapted with permission from O’Neill CB, Atoria CL, O’Reilly EM, et al. Costs and trends in pancreatic cancer treatment. Cancer. 2012;118(20):5132-5139.6 LYs), at an incremental cost of $13,700 Daily Beast. October 2011. www.thedailybeast

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 SP104 Disease Overview

PRESENT

.com/articles/2011/10/05/steve-jobs-dies-his- 10. Fong ZV, Winter JM. Biomarkers in pancreatic 1382. creatic cancer. N Engl J Med. 2011;364(19):1817- unorthodox-treatment-for-neuroendocrine-cancer. cancer: diagnostic, prognostic, and predictive. 17. Dominguez-Munoz, JE. Pancreatic enzyme 1825. Hear the leaders in html. Accessed February 5, 2013. Cancer J. 2012;18(6):530-538. replacement therapy: exocrine pancreatic 23. Moore MJ, Goldstein D, Hamm J, et al. 4. Halfdanarson TR, Rabe KG, Rubin J, et al. 11. Molina V, Visa L, Conill, et al. Ca 19-9 in insufficiency after gastrointestinal surgery. HPB Erlotinib plus gemcitabine compared with diabetes discuss the Pancreatic neuroendocrine tumors (PNETS): pancreatic cancer: retrospective evaluation of pa- (Oxford). 2009:11(suppl 3):3-6. gemcitabine alone in patients with advanced incidence, prognosis and recent trend toward tients with suspicion of pancreatic cancer. Tumour 18. Tran TCK, van Lanschot JJB, Bruno MJ, et al. pancreatic cancer: a phase III trial of the National issues and concerns improved survival. Ann Oncol. 2008;19(10):1727- Biol. 2012;33(3):799-807. Functional changes after pancreatoduodenec- Cancer Institute of Canada Clinical Trials Group. J facing payers and 1733. 12. CA 19-9. Lab test online. http://labtestson- tomy: diagnosis and treatment. Pancreatology. Clin Oncol. 2007;25(15):1960-1966. 5. Hidalgo, M. Pancreatic cancer. N Engl J Med. line.org/understanding/analytes/ca19-9/tab/ 2009;9(6):729-737. 24. Stoita A, Penman ID, Williams, DB. Review of providers, including: 2010;362(17):1605-1607. test. Accessed February 5, 2013. 19. Decher N, Berry A. Post-whipple: a practical screening for pancreatic cancer in high-risk indi- 6. O’Neill CB, Atoria CL, O’Reilly EM, et al. Costs 13. What you need to know about cancer of the approach to nutrition management. Practical Gas- viduals. World J Gastroenterol. 2011;17(19):2365- and trends in pancreatic cancer treatment. Can- pancreas. National Cancer Institute. July 2010. troenterology. www.medicine.virginia.edu/clini- 2371. • Individualized Treatment and cer. 2012;118(20):5132-5139. www.cancer.gov/cancertopics/wyntk/pancreas/ cal/departments/medicine/divisions/digestive- 25. Abbott DE, Merkow RP, Cantor SB, et al. June 20, 2013 7. Iqbal J, Ragone A, Lubinski J, et al. The inci- page1/AllPages. Accessed February 4, 2013. health/nutrition-support-team/nutrition-articles/ Cost-effectiveness of treatment strategies for University of Chicago Improving Outcomes: A Provider dence of pancreatic cancer in BRCA1 and BRCA2 14. NCCN Clinical practice guidelines in oncol- Decher_Berry_Aug_12.pdf. Published August pancreatic head adenocarcinoma and potential Chicago, IL mutation carriers. Br J Cancer. 2012;107 ogy: pancreatic adenocarcinoma. V.2.2012. 2012. Accessed February 13, 2013. opportunities for improvement. Ann Surg Oncol. Panel Discussion (12):2005-2009. National Comprehensive Cancer Network. www. 20. Burris HA III, Moore MJ, Andersen J, et al. 2012;19(12):3659-3667. 8. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib nccn.org/professionals/physician_gls/pdf/pan- Improvements in survival and clinical benefit with . Murphy JD, Chang DT, Abrelson J, et al. Cost- 26 Panelists plus gemcitabine compared with gemcitabine creatic.pdf. Accessed February 4, 2013. gemcitabine as first-line therapy for patients with effectiveness of modern radiotherapy techniques Dana Goldman, PhD William H. Herman, MD, MPH • The Impact of Patient Behavior on alone in patients with advanced pancreatic 15. Billmoria KY, Bentrem DJ, Ko CY, et al. Valida- advanced pancreas cancer: a randomized trial. J in locally advanced pancreatic cancer. Cancer. Director Director cancer: a phase III trial of the National Cancer tion of the 6th edition EJCC pancreatic cancer Clin Oncol. 1997;15(6):2403-2413. 2012;118(4):1119-1129. Leonard D. Schaeffer Center for Michigan Diabetes Research and Quality of Care and Outcomes Institute of Canada Clinical Trials Group. J Clin staging system. Cancer. 2007;110(4):738-744. 21. Warsame R, Grothey A. Treatment options for 27. Danese MD, Reyes C, Northridge K, et al. Health Policy and Economics Training Center Oncol. 2007;25(15):1960-1966. 16. Shaib Y, Davila J, Naumann C, et al. The advanced pancreatic cancer. Expert Rev Antican- Budget impact model of adding erlotinib to a regi- University of Southern California University of Michigan 9. Michl P, Gress TM. Current concepts and impact of curative intent surgery on the survival cer Ther. 2012;12(10):1327-1336. men of gemcitabine for the treatment of locally • Meeting the Clinical and Social novel targets in advanced pancreatic cancer. Gut. of pancreatic cancer patients: a U.S. population- 22. Conroy T, Desseigne F, Ychou M, et al. FOL- advance, nonresectable or metastatic pancreatic Anne Peters, MD, CDE Rebecca W. Killion, MA 2013;62(2):317-326. based study. Am J Gastroenterol. 2007;102:1377- FIRINOX versus gemcitabine for metastatic pan- cancer. Clin Ther. 2008;30(4):775-784. Director Director Needs of Patients With Diabetes: Clinical Diabetes Program Professional Development University of Southern California McKenna Long & Aldridge Payer Perspectives

Payer Perspective Amitabh Chandra, PhD Albert Tzeel, MD, MHSA, FACPE Director of Health Policy Research National Medical Director Interview With Irwin W. Tischler, MD Harvard University HumanaOne & KMG

Anupam Jena, MD, PhD Wade M. Aubry, MD Associate Clinical Professor EBO: Why is pancreatic cancer such a difficult problem today? Do we will continue to increase as newer chemotherapy agents become available, espe- Assistant Professor of Department of Medicine have sufficient information on its risk factors to be of use in prevention? cially the targeted agents that are being used to treat many other malignancies. Health Care Policy Harvard Medical School Philip R. Lee Institute for Health Dr Tischler: Pancreatic cancer is the fourth-most common cause of cancer- Policy Studies related deaths in the United States. There is little doubt that there are risk factors EBO: Do you think that other treatment-associated costs will become Michael E. Chernew, PhD University of California, associated with pancreatic cancer. These include cigarette smoking, heavy alco- major contributors to this scenario in the future (eg, pancreatic enzyme Register Professor of Health Care Policy San Francisco Now hol intake, exposure to certain occupation-related chemicals, and obesity. Chronic replacement or biomarker testing)? Harvard Medical School pancreatitis has also been identified as a risk factor. A recent study demonstrated Dr Tischler: Biomarker, molecular profiling, and gene array studies are currently Jan Berger, MD, MJ for the a 7-fold increase of pancreatic cancer for patients with a history of pancreatitis, in progress, and I believe this is the future—not only for pancreatic cancer, but for Peter Huckfeldt, PhD President & CEO and clinical studies are evaluating pancreatic cancer’s relationship with other risk managing other malignancies as well. The results of these studies may enable us Professor Health Intelligence Partners Best Price! factors. Truly familial pancreatic cancer is uncommon. However, there may be a to take a novel and personalized approach to treat specific molecular targets that Pardee RAND Graduate School Date Purchased Price genetic predisposition in up to 10% of patients with pancreatic cancer. There is can be identified, and that will be predictive of chemotherapy sensitivity to treat Tomas Philipson, PhD also an increase of pancreatic cancer in families who have the BRCA2 gene muta- pancreatic and other malignancies. Darius Lakdawalla, PhD Daniel Levin Chair in Public Policy April 1 through April 30 $200 tion. Director of Research Irving B. Harris Graduate School of EBO: In terms of pancreatic cancer (or perhaps all cancers), what, if any, Leonard D. Schaeffer Center for Public Policy Studies May 1 through May 31 $300 EBO: What do you see as the best value for our efforts to prevent, treat, clinical guidelines do you encourage oncologists to follow? Health Policy and Economics The University of Chicago

or manage pancreatic cancer today? Dr Tischler: Cigna encourages doctors who are treating our customers to follow University of Southern California After May 31 $400 Dr Tischler: I believe our best efforts lie in educating our customers about their evidence-based guidelines published by the NCCN and ASCO (American Society of Deneen Vojta, MD risk factors and how those risks can be reduced by changing lifestyle behaviors. Clinical Oncology). Cigna uses these guidelines to develop our coverage policies for Senior Vice President pancreatic cancer and other malignancies. Business Initiatives and Clinical Affairs EBO: Pancreatic cancer is usually detected or diagnosed in the latter UnitedHealth Group www.ajmc.com/meetings/diabetes Chief Clinical Officer stages of the disease. What can health plans do to help improve this EBO: Because of the limited success with current treatments of patients situation or is this more of an issue requiring better provider education? with pancreatic cancer, are you perhaps more lenient in your approval Diabetes Prevention and Control Alliance Dr Tischler: It is unclear whether screening high-risk individuals is beneficial. of investigational treatments? Studies are ongoing in an effort to answer this question. Dr Tischler: Cigna covers experimental treatments for pancreatic cancer if the treatment is being done in conjunction with a listed clinical trial. EBO: With regard to the direct costs of treating the disease, surgical procedures and hospital stays are responsible for the lion’s share (22% EBO: Where do you expect the next big leap in pancreatic cancer man- and 33%, respectively). Chemotherapy and radiotherapy account for agement? only 13% combined. Do you expect that the chemotherapy costs will Dr Tischler: I believe the next big leap, not only for pancreatic cancer but for all increase as more effective treatments are introduced? malignancies in general, will occur once we further unravel genetic and tumor- Dr Tischler: The overwhelming share of costs do relate to surgical procedures, specific markers. Hopefully, this will enable oncologists to deliver personalized, including the cost of inpatient hospital stays. Mortality in the United States for effective therapy for all cancers. pancreatic cancer has not changed much over the past 20 years, despite the intro- duction of more chemotherapy drug combination treatments. Overall, costs likely Dr Tischler is national medical director for oncology at Cigna in Philadelphia, PA.

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3

Mar_TabAd_032613.indd 1 3/26/13 2:37 PM PRESENT Hear the leaders in diabetes discuss the issues and concerns facing payers and providers, including:

June 20, 2013 • Individualized Treatment and University of Chicago Improving Outcomes: A Provider Chicago, IL Panel Discussion

Panelists Dana Goldman, PhD William H. Herman, MD, MPH • The Impact of Patient Behavior on Director Director Leonard D. Schaeffer Center for Michigan Diabetes Research and Quality of Care and Outcomes Health Policy and Economics Training Center University of Southern California University of Michigan • Meeting the Clinical and Social Anne Peters, MD, CDE Rebecca W. Killion, MA Director Director Needs of Patients With Diabetes: Clinical Diabetes Program Professional Development University of Southern California McKenna Long & Aldridge Payer Perspectives

Amitabh Chandra, PhD Albert Tzeel, MD, MHSA, FACPE Director of Health Policy Research National Medical Director Harvard University HumanaOne & KMG

Anupam Jena, MD, PhD Wade M. Aubry, MD Assistant Professor of Associate Clinical Professor Health Care Policy Department of Medicine Harvard Medical School Philip R. Lee Institute for Health Policy Studies Michael E. Chernew, PhD University of California, Register Professor of Health Care Policy San Francisco Now Harvard Medical School Jan Berger, MD, MJ for the Peter Huckfeldt, PhD President & CEO Professor Health Intelligence Partners Best Price! Pardee RAND Graduate School Date Purchased Price Tomas Philipson, PhD Darius Lakdawalla, PhD Daniel Levin Chair in Public Policy April 1 through April 30 $200 Director of Research Irving B. Harris Graduate School of Leonard D. Schaeffer Center for Public Policy Studies May 1 through May 31 $300 Health Policy and Economics The University of Chicago

University of Southern California After May 31 $400 Deneen Vojta, MD Senior Vice President Business Initiatives and Clinical Affairs UnitedHealth Group www.ajmc.com/meetings/diabetes Chief Clinical Officer Diabetes Prevention and Control Alliance

Mar_TabAd_032613.indd 1 3/26/13 2:37 PM SP106 Melanoma Pipeline The Future of Melanoma Treatment

Michael M. Mohundro, PharmD; and Alexis Horace, PharmD

ccording to the National Cancer a poor prognostic indicator.7 While the Institute’s Surveillance Epide- exact role in melanoma treatment has Amiology and End Results data, yet to be fully defined, the efficacy of melanoma of the skin was estimated to nab-paclitaxel has been comparable to be the cause of death in almost 10,000 standard dacarbazine treatment and people in 2012.1 Unfortunately, mela- single-agent paclitaxel as well as oth- noma incidence has been on the rise er combination therapies.7 In a recent in the United States since 1981, with phase II trial in combination with car- annual increases of almost 3%; how- boplatin in patients with unresectable ever in white women under the age of stage IV melanoma, the nab-paclitaxel/ 44 years, the increase has been double carboplatin combination had a slight that, at 6.1%. The upward trend in this advantage in survival rate over ipilu- population may be due to the increased mimab.6 However, the survival benefit popularity of tanning bed use.2 was limited to the chemotherapy-naïve Currently there are 5 types of treat- subgroup.6 Several more phase II trials ments available to patients diagnosed evaluating nab-paclitaxel in combina- with melanoma. The treatment types tion with either bevacizumab or other are surgery, chemotherapy, radiation, agents have been completed and re- biologic therapy, and targeted therapy.3 sults are pending.6,8 Results of a phase Melanoma is classified as a chemo- III open-label, multicenter trial inves- therapy-resistant tumor; however, a tigating nab-paclitaxel versus dacar- response rate of 10% to 15% has been bazine in treatment-naïve metastatic tients.14 Response rates for dacarbazine patients with stage IV cutaneous mela- noted with certain single agents. Dat- malignant melanoma demonstrated were 11.6% and 13.2% for dacarbazine/ noma.18 Another randomized phase II ing back to 1972, the gold standard for better median progression-free sur- velimogene aliplasmid. When compar- study is looking at the effectiveness treatment of metastatic melanoma vival (PFS) and interim overall survival ing dacarbazine with dacarbazine/veli- of the vaccine in combination with IL- has been dacarbazine.4 Drugs current- (OS) with nab-paclitaxel (PFS: 4.8 vs 2.5 mogene aliplasmid, survival durations 12 followed by daclizumab in patients ly approved by the US Food and Drug months [hazard ratio (HR): 0.792, 95.1% were 9.24 months versus 10.75 months, with metastatic melanoma.19 Administration (FDA) for treatment of confidence interval (CI): 0.631-0.992, respectively. Time to progression was melanoma include aldesleukin, dacar- P = .044], OS: 12.8 vs 10.7 months [HR: 1.6 versus 1.9 months for dacarbazine bazine, ipilimumab, and vemurafenib.5 0.831, 99.9% CI: 0.578-1.196, P = .094]).9 and the combination. The authors con- This article will explore pharmacologic cluded that velimogene aliplasmid did agents currently being investigated for Plasmid/Lipid Complex not increase clinical improvements Melanoma is the treatment of melanoma. Containing MHC I beyond the standard of care. However, Velimogene aliplasmid velimogene aliplasmid is currently be- classified as a Microtubule Inhibitor Velimogene aliplasmid is a new form ing compared with dacarbazine alone nab-paclitaxel of immunotherapy for the treatment of in an ongoing phase III clinical trial in- chemotherapy- Solvent-based taxanes have limited metastatic melanoma. MHC class I and vestigating the safety/tolerability and utility due to limited efficacy and high II expression is important for detection OS rates of the 2 therapies.15 resistant tumor; rate of toxicity. In addition to adverse and lysis of foreign antigens by the im- effects from the taxane, patients often mune system. Oftentimes, tumor cells Vaccines however, a response experience reactions to the solvent. Al- go undetected by class I-restricted MAGE-A3 ASCI (astuprotimut-r) bumin-bound paclitaxel is a 130-nano- T cells by downregulating these pro- Since therapeutic vaccination with rate of 10% to 15% meter albumin-bound (nab) particle cesses.10-12 Velimogene aliplasmid con- dendritic cells (DCs) for melanoma was formulation of paclitaxel which does sists of a DNA plasmid, which hosts first proposed in the 1990s, knowledge has been noted not require the use of a solvent. Utiliza- the genetic code for MHC class I pro- has grown with regard to their devel- tion of nab-paclitaxel over traditional teins, HLA-B7, and B2-microglobulin, opment and efficacy.16 With the boost with certain single paclitaxel has the advantage of being which improve expression of the HLA- from the recent FDA approval of sipu- able to deliver a higher dose while de- B7 gene.12 By encoding these 3 genes leucel-T in castrate-resistant prostate agents. creasing the incidence of serious grade together, it provides several immune- cancer, DC-based vaccinations remain 3 or 4 side effects.6 Further, the nab- stimulating features that increase the a focused area of interest in solid tu- Paclitaxel formulation does not have potential for tumor cell lysis. Several mors including melanoma.16 While the same “allergic” potential as the sol- phase I studies have been conducted progress has been made in the under- Oncolytic Herpes Simplex VirusType vent-based formulation.6,7 Of particular in small groups and demonstrated im- standing of DC-based vaccines, further 1(HSV-1) Granulocyte-Macrophage Colo- note, the albumin-binding protein Se- proved T-cell infiltration into tumor study is needed in the hopes of realiz- ny-Stimulating Factor (GM-CSF) creted Protein, Acidic and Rich in Cyste- lesion, improved HLA-B7 surface ex- ing the dramatic results seen in animal An oncolytic HSV-1 vaccine using GM- ine (SPARC) may play an important role pression, and promoted regression.12,13 models.16,17 Several studies are current- CSF to modulate antitumor immunity in the effectiveness of nab-paclitaxel An unpublished phase III trial in 2001 ly recruiting participants to evaluate is being explored.20,21 In addition to this in melanoma. It is often overexpressed compared velimogene aliplasmid com- vaccine therapy, including an open- cytokine-modified, cell-based vaccine in a large number of malignancies, in- bined with dacarbazine with dacarba- label, non-randomized phase I/II study activating the cytotoxic effects of mac- cluding melanoma, and is considered zine alone in chemotherapy-naïve pa- investigating the effect of MAGE-3 in rophages to human melanoma cells,

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 SP107 Evidence-Based Oncology Melanoma Pipeline

Company/ License/ PDUFA Date Updated Sponsor Product Mechanism of Action Indication(s) Stage(s) Partner(s) Date 11/26/12 Celgene nab-paclitaxel Microtubule HER-2(+) BC; inflammatory Phase III N/A N/A (Abraxane) inhibitor BC (IV); mucinous BC (II); tubular BC (II/III) 01/11/13 Vical Velimogene Plasmid/lipid complex Metastatic melanoma (III/ Phase III N/A N/A aliplasmid containing MHC-I IV) (Allovectin-7) 02/28/13 GlaxoSmith Astuprotimut-R MAGE-A3 Metastatic/progressive/ Phase I/II N/A N/A Kline vaccine unresectable melanoma 06/01/12 BioVex talimogene Oncolytic HSV-1 Melanoma Phase III Amgen N/A Limited laherparepvec vaccine (OncoVEXGM-CSF) 02/21/13 Novartis Nilotinib TKI ALL; CML; melanoma Phase II N/A N/A (AMN-107) 10/01/12 AB Science Masitinib TKI GI stromal tumors; Phase III N/A N/A (AB1010) metastatic melanoma; MM; MS; RA 03/04/13 Genentech; GDC-0973; MEK inhibitor Malignant melanoma Phase III Roche Group N/A Exelixis XL518 01/08/13 Array MEK 162 MEK inhibitor Metastatic/unresectable Phase III Novartis N/A Biopharma (ARRY-438162) cutaneous melanoma 02/28/13 GlaxoSmith Trametinib MEK inhibitor Melanoma Phase III N/A N/A Kline (GSK1120212) 07/27/12 Pfizer Ticilimumab; IgG2 monoclonal Advanced melanoma (IIIc/ Phase II N/A N/A Tremelimumab antibody IV) (Phase III no (CP-675,206) longer available) 02/28/13 GlaxoSmith Dabrafenib Selective BRAF Melanoma Phase III N/A N/A Kline (GSK2118436) inhibitor 02/22/13 Bristol-Myers Anti-PD-L1 Anti-PD-L1 CML; melanoma (III/IV); Phase I N/A N/A Squibb (BMS-936559; monoclonal antibody MM; (N)HL MDX-1195) 02/01/13 Bristol-Myers Nivolumab Anti-PD-L1 Metastatic melanoma; RCC; Phase III N/A N/A Squibb (BMS-936558; monoclonal antibody Squamous NSCLC MDX-1106) 01/04/23 Genta Oblimersen Bcl-2 antisense Advanced melanoma; AML Phase III N/A N/A Incorporated sodium oligodeoxynucleotide (Genasense; GS3139) ALL indicates acute lymphoblastic leukemia; AML, acute myelogenous leukemia; BC, breast cancer; CML, chronic myelogenous leukemia; GI, gastrointestinal; MM, multiple myeloma; MS, multiple sclerosis; (N)HL, (non)- Hodgkin’s lymphoma; NSCLC, non-small cell lung cancer; PD, programmed death; RA, rheumatoid arthritis; RCC, renal cell carcinoma.

GM-CSF is a mediator for the matura- effects noted. A current phase III study tion and mobility of DCs, and increases is examining the efficacy and safety of While it has been demonstrated in the production of matrix metalloelastase, the oncolytic HSV1/GM-CSF vaccine ultimately leading to the suppression compared with GM-CSF. The purpose is early stages of melanoma that the immune of pulmonary metastases.20 Treatment to investigate the overall survival (OS) involves directly injecting the vaccine rate.23 Another phase III clinical trial is system mounts a strong response, tumors into the tumor, which avoids host im- currently enrolling patients to investi- munity from destroying the virus.21 A gate the safety of the vaccine over 12 ultimately develop mechanisms to evade small phase II clinical trial examined months.24 16 the use of GM-CSF as adjuvant therapy detection and destruction. in stage III and IV malignant melano- Tyrosine Kinase Inhibitors ma.22 The authors concluded that sur- Nilotinib well established as a therapeutic target c-KIT.26 Additionally, phase II trials have vival was significantly better for the Nilotinib is an orally bioavailable, small in cancer, there is limited research in demonstrated overall response rates overall patient population in the GM- molecule tyrosine kinase inhibitor the area of melanoma.26 In preclinical of 16% to as high as 30.2% with ima- CSF group (P = .001; P = .04 for stage (TKI) that targets abl-kinases, c-KIT, trials, evidence has shown that mela- tinib. Common reactions to treatment III; P = .001 stage IV). Median survival and PDGFR. Currently, it is FDA ap- noma cell lines containing KIT muta- have included alopecia, skin rash, and increased approximately 25 months in proved for patients with chronic my- tions had a favorable response to treat- treatment groups with minimal side eloid leukemia.25,26 While KIT has been ment with imatinib, which also targets (continued on page SP110)

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 Patient Assistance NOW Oncology Mapped! ®

Our Patient Assistance Now Oncology (PANO) Web site makes it easy with all-in-one convenience providing simplicity, efficiency, and better access for you, your patients, and your oncology practice managers (OPMs).

Convenience and patient Let’s Get Started! access are one click away: The Patient Assistance NOW Oncology (PANO) Web 1. Click on the Provider site offers quick and easy navigation to information Portal section on the about the broad array of reimbursement and home page. support programs available to your patients. 2. Register your practice and click “submit.” 3. Receive validation phone call from PANO.

What Can the Provider Portal Do for Me? • Enroll a new patient or check the status of a current patient • Organize patient reports tailored to meet your needs • See a listing of all your patients as soon as you enter the portal • Get immediate alerts that highlight important tasks and events to expedite patient treatment • Download forms • Click on a patient’s name to instantly display that patient’s information • Attach a document to a patient’s electronic file (as easy as adding an attachment to an e-mail) For Patient Care • Manage your individual user profile and easily change your A link to our central hub of patient access resources, where contact information you will find tools for insurance verification, assistance with identifying alternate sources of coverage/funding that may assist with patient costs, assistance for low-income and uninsured patients, and more. Patient Assistance NOW Oncology www.OncologyAccessNow.com

What’s New in Healthcare Reform? Patient Access SOS A Program Just for OPMs Patient Assistance NOW Oncology Hotline: Links to information about the ever-changing landscape Find pertinent information to help support A link to an OPM program that provides 1-800-282-7630 of healthcare reform, guideline requirements, Medicare, your patients, including details on quality education and tools and drug purchasing options. measures, e-prescriptions, and Medicare • Managed care trends Administrative Contractor (MAC) and Recovery Audit Contractor (RAC) tools. • Overcoming challenges and barriers that impact patient access • Link to e-slide library

Brought to you by the publisher of Helping to make access to therapies easier

PANO_Mapped!_Ad-K_1.0.indd 1-2 2/2/12 12:23 PM Patient Assistance NOW Oncology Mapped! ®

Brought to you by the publisher of Helping to make access to therapies easier

PANO_Mapped!_Ad-K_1.0.indd 1-2 2/2/12 12:23 PM SP110 Melanoma Pipeline

(continued from SP107)

headache. Multiple studies are ongoing untreated BRAF V600 mutations and metinib in patients with BRAF-mutated only demonstrating modest results, it in melanoma to determine the value unresectable, locally advanced meta- cutaneous melanoma.46 Patients were was the first drug treatment for mela- of treatment in melanoma, specifically static melanoma to evaluate the safety assigned to 2 cohorts: those previously noma to show a significant increase with KIT mutations.26 A phase II study and efficacy of vemurafenib compared treated with vemurafenib or dabrafenib in OS.16,49 Another anti-CTLA-4 mAb evaluating nilotinib in patients with with vemurafenib combined with GDC- (cohort A) or those previously treated under development is tremelimumab, melanoma from sun-damaged skin 0973.36 with chemotherapy/or immunothera- which also blocks CTLA-4 signaling who did not respond to or could not py, but no BRAF treatment (cohort B). and thus extends T-cell activation and tolerate treatment with another TKI MEK162 No cohort A patients had a confirmed stimulates T-cell proliferation.16 By re- is ongoing. Four other phase II stud- MEK162 is another powerful inhibitor clinical response; however, 20% expe- storing T-cell mediated immunity, it in- ies investigating nilotinib in patients of MEK1 and MEK2. This novel agent rienced tumor reduction at the time creases the patient’s ability to fight the with melanoma are currently open to is also being studied for inhibition of of study cutoff. Out of cohort B, there tumor.16 While early clinical trials with accrual.27 NRAS mutations. Research has shown tremelimumab suggested favorable re- that NRAS mutations are associated sults, a subsequent randomized phase with a poor OS as well as the develop- III trial was ended early after failing to Masitinib ment of CNS metastases.37 Preclinical show superiority to a standard of care Masitinib, an orally bioavailable TKI, is trials using in vitro and in vivo studies Many tumors, chemotherapy regimen.50 Additionally, being investigated for use in both hu- have shown MEK162 inhibited growth there were serious autoimmune reac- man and veterinary medicine simulta- of NRAS, Val600GLU BRAF-mutated including tions including colitis, rash, and en- neously.28 This small molecule inhibitor melanoma.32,38 Recently, MEK162 was melanoma, have docrinopathy.16 Future analysis looks of KIT, PDGFR (α + β), and Lyn has been investigated in an open label, phase II to study these agents in the adjuvant conditionally approved by the FDA for clinical trial. No patients had a com- setting as well as in combination with use in dogs with cutaneous mast cell plete response to therapy with MEK162. been shown to other agents targeting BRAF and c-KIT tumors.29,30 Although no clinical data However, 20% of the NRAS-mutated mutations.16 are available regarding human use of melanoma group and 20% of the BRAF- selectively express masitinib for melanoma treatment, mutated melanoma group had a par- PD-L1, making it an BRAF Inhibitor preclinical data suggest patients carry- tial response. The most common side Dabrafenib ing a c-KIT juxtamembrane (JM) muta- effects included acneform dermatitis, excellent therapeutic Dabrafenib is a reversible, selective in- tion will respond.28 One phase III study rash, diarrhea, and increased creatine hibitor of BRAF Val600GLu. Very similar comparing masitinib with dacarbazine phosphokinase. Another phase II trial target. to vemurafenib in its mechanism of in patients with melanoma with a mu- is in progress, which is assessing the action and pharmacodynamics, it dif- tation in the JM domain of C-Kit is cur- safety and efficacy of MEK162 in ma- fers in the length of its half-life (5.2 rently recruiting patients.31 lignant, cutaneous melanoma that has hours vs 50 hours).51 A phase II study NRAS and BRAFV600 mutations.39 Fu- was 1 complete response (2%) and 13 used dabrafenib in patients with Val- MEK Inhibitors ture studies include a phase Ib/II study partial responses (23%), which result- 600Glu or Val600Lys BRAF-mutation GDC-0973 assessing the use of LEE011 in com- ed in a relative risk of 25% (95% CI, melanoma that had metastasized.52 Pa- Mutations in proto-oncogene B-Raf bination with MEK162 and phase III 14.1%-37.8%). Currently there are seve- tients were placed into one of 2 groups, (BRAF) are common in 40% to 60% of study investigating efficacy of MEK162 ral phase II and III clinical trials ac- those who had not received any local melanomas and the MAP/ERK kinase versus dacarbazine for metastatic mel- tively recruiting patients to further treatments (cohort A) and those who (MEK) pathway is a part of the mutation anoma. Both studies have yet to recruit research trametinib in treating mela- had progressive brain metastases after cascade.32 GDC-0973 is a new and high- participants.40,41 noma.47 previous local treatments (cohort B). ly selective, small molecule MEK inhib- Patients with the Val600Glu mutation itor being studied for its antineoplastic Trametinib IgG2 Monoclonal Antibody in cohort A had a 39.2% response rate activity. Mutations in the MEK cascade Trametinib is another small-molecule, Tremelimumab (n = 74; 95% CI 28.0-51.2) and patients contribute to increased cell prolifera- selective inhibitor of MEK1 and MEK2 While it has been demonstrated in in cohort B had a 30.8% response rate tion, invasion, metastasis, angiogen- that can be taken orally.42 Trametinib the early stages of melanoma that (n = 65, 95% CI, 19.9-43.4); 95% CI, 19.9- esis, and inhibition of apoptosis.33 Ma- has been shown to decrease cell pro- the immune system mounts a strong 43.4). For those with the Val600Lys mu- lignant melanomas commonly have liferation and induce apoptosis.43 In response, tumors ultimately develop tation, response rates were 6.7% (n = 15; single amino acid mutations (BRAF vitro evidence suggests trametinib in mechanisms to evade detection and 95% CI 0.2-31.9) and 22.2% (n = 18; 95% V600E) in a single loop of the kinase.33 combination with a BRAF inhibitor in- destruction.16 Immunosuppressive CI 6.4-47.6) in cohorts A and B. Grade 3 GDC-0973 binds to MEK1 and inhibits creased rate of tumor-infiltrating lym- adaptations include induction of im- adverse events occurred in 22% of the ERK2 phosphorylation, ultimately de- phocytes in selected biopsy material. mune tolerance as well as resistance to total patient population. The authors creasing tumor growth.34 Preclinical However, responses to the treatment cell death by activated effector arms of concluded that dabrafenib is active in trials have shown that this novel agent varied and the authors were unable to the immune system.16,48 Under normal treating metastatic brain melanoma in combination with vemurafenib and definitively distinguish the role of MEK physiologic conditions, the immune and has an acceptable safety profile. GDC-0941, a PI3K inhibitor, is effec- in the results.44 A phase III clinical trial system has checkpoints and feedback Dabrafenib was further investigated in tive in decreasing growth in those tu- assessing survival benefit in patients mechanisms that establish tolerance to a phase III study which randomized pa- mors harboring a BRAF mutation.33,34 with BRAF-mutated melanoma re- self-antigens and prevent autoimmu- tients with previously untreated stage An open-label, dose escalation, phase ceived either trametinib or chemother- nity.16 Cytotoxic T-Lymphocyte Antigen IV or unresectable stage III BRAF-mu- I clinical trial is currently recruiting apy (dacarbazine or paclitaxel). Median 4 (CTLA-4) is one of the molecules that tated melanoma to receive dabrafenib patients with BRAF V600E malignant duration of PFS was 4.8 months in the assists in maintaining immune ho- or dacarbazine.53 Median PFS was 5.1 melanoma to evaluate the safety, toler- trametinib group compared with 1.5 meostasis by downregulating T-cell ac- versus 2.7 months for dabrafenib com- ability, and pharmacokinetics of GDC- months in the chemotherapy groups tivation. In 2011, the FDA approved ipil- pared with dacarbazine (HR 0.30; 95% 0973.35 Concurrently, a phase III clini- (n = 322; P <.001).45 An open-label, imumab, the first monoclonal antibody CI 0.18-0.51; P <.001). Patients in the cal trial is also recruiting patients with 2-stage phase II study examined tra- (mAb) directed against CTLA-4. While dabrafenib group had increased overall

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 Melanoma Pipeline SP111

survival (HR 0.16, 95% CI 0.25-1.48). The BMS-936559 albumin-bound paclitaxel in patients these soaring costs of treatment and most common adverse events listed for BMS-936559, formerly MDX-1105, is a with stage III or IV melanoma.63 A to- the burden on the healthcare system, dabrafenib included fever, fatigue, ar- human monoclonal antibody specific tal of 14 grade 3 and 4 adverse effects ethical questions frequently enter the thralgia, and headache. Due to side ef- to PD-L1 (Anti-PD-L1 mAb) that inhibits (fatigue, allergic reaction, neutrope- conversation. While certainly sharing fects, dose reductions occurred in 28% the binding of PD-L1 to both PD-1 and nia, thrombocytopenia, neuropathy, the decision making and costs with the of patients. Currently, dabrafenib is be- CD80.57 Results from a phase I clinical and hyponatremia) were recorded, but patient as well as educating the health ing studied in a phase II clinical trial to trial in patients with advanced cancer eventually resolved. The authors also providers helps, properly characteriz- further assess its safety and efficacy.54 including metastatic melanoma indi- reported complete response in 2 pa- ing the patient’s tumor is equally im- Simultaneously, a phase II clinical tri- cated that treatment with BMS-936559 tients, and partial responses in 11 pa- portant. There is a big difference be- al conducted in patients with BRAF- yielded a 6% to 17% objective response tients. A phase III, randomized, open- tween blindly using a drug with little mutated metastatic melanoma of the rate and that the effect on disease sta- label, multicenter study comparing or no evidence that it will work and brain is examining the overall intracra- bilization was prolonged at greater disease progression of patients treated knowing that the tumor has the right nial response rate over approximately than or equal to 24 weeks.57 Early evi- with dexamethasone with or without markers for success. All things consid- 15 years.55 Other studies are also un- dence suggests that the adverse effect oblimersen demonstrated no signifi- ered equal, the standard of care should derway evaluating dabrafenib in mela- profile is more favorable than seen with cant difference in response to TTP or likely be the first approach. noma.56 anti-CTLA-4 treatments.48,57 Grade 3 or objective response rate.64 Oblimersen 4 events occurred in 9% of the study is currently being tested in a phase I Funding Source: None. Anti–Programmed Death 1 Agents population and were consistent with trial combining it with nab-paclitaxel Author Disclosures: None. Programmed death 1 (PD-1) protein a mild autoimmune profile.48,57 Curi- and temozolomide in patients with ad- Authorship Information: Concept and design and its ligand, PD-L1, play a critical ously, there are currently no follow- vanced melanoma.65 (MM); acquisition of data (MM, AH); analy- role in melanoma’s ability to escape up studies recruiting nor ongoing on sis and interpretation of data (MM, AH); the natural immune response.48,57 In the clinical trials website. There was a Conclusion drafting of the manuscript (MM, AH); crit- preclinical models, blockade of the phase I anti-PD-L1 biomarker study for The management and treatment of ical revision of the manuscript for impor- interactions between PD-1 and PD-L1 advanced melanoma listed, but it has patients with metastatic melanoma is tant intellectual content (MM); statistical improved immunologic response and a status of withdrawn with no reason quickly evolving. Despite the limited analysis; provision of study materials or enhanced in vitro antitumor activity.57 given.58 and poor therapeutic options to date, patients; and obtaining funding. According to Zitvogel and Kroemer, a wide array of therapies are under the interaction between PD-1 and PD- Nivolumab development. Research has advanced References On the other hand, nivolumab, which the understanding of the disease pro- 1. SEER Stat Fact Sheets: Melanoma of the is an Anti-PD-1 mAb, has a wide array cesses and we are gaining a better un- Skin. http://seer.cancer.gov/statfacts/html/ of studies either planned or ongoing.59 derstanding of resistance mechanisms. melan.html. Accessed February 17, 2013. While it is unclear why the focus has Previously viewed as 1 disease, mela- 2. Little EG, Eide MJ. Update on the current been shifted away from BMS-936559, noma is now recognized as a hetero- state of melanoma incidence. Dermatol Clin. Despite the it was observed in initial trials that geneous mixture of cancer subtypes. 2012;30(3): 355-361. the objective response rate was higher Likewise, the traditional “one size fits 3. Melanoma treatment. http://www.cancer limited and with nivolumab.48 all” model of treatment is no longer ac- .gov/cancertopics/pdq/treatment/melanoma/ cepted as the most effective approach. Patient/page4#Keypoint17. Accessed February poor therapeutic Bcl-2 Inhibitor Hydroxyurea, high-dose IL-2, and da- 17, 2013. Oblimersen Sodium carbazine were the only drugs FDA ap- 4. s Yang AS, Chapman PB. The history and options to date, Oblimersen sodium is a new medi- proved for treating metastatic mela- future of chemotherapy for melanoma. Hematol cation that downregulates the Bcl-2 noma in 2011. As of today, ipilimumab Oncol Clin North Am. 2009;23(3):583-597. a wide array of protein and increases apoptosis of and vemurafinib are FDA approved and 5. Drugs for melanoma. http://www.cancer. chemotherapy-treated human cancer there are numerous other agents in the gov/cancertopics/druginfo/melanoma. Ac- therapies are under xenografts.60-62 Bcl-2 is an antiapop- pipeline. Further investigation is need- cessed February 17, 2013. totic protein that stops the release of ed because these newer agents have 6. Kottschade LA, Suman VJ, Amatruda T 3rd, development. cytochrome C, which is vital for trig- had only a limited benefit, with over- et al. A phase II trial of nab-paclitaxel (ABI-007) gering apoptosis of cancer cells.60 all survival still very low. Combining and carboplatin in patients with unresectable Oblimersen consists of an 18-based newer agents with established older stage IV melanoma: a North Central Cancer phosphothiate antisense oglionucleo- therapies may have value in treating Treatment Group Study, N057E(1). Cancer. tide, which binds to Bcl-2 mRNA and this complex disease state, but combi- 2011;117(8):1704-1710. L1 inhibits T lymphocyte proliferation, mediates its cleavage.60 A phase I study nations of the newer medications may 7. Hersh EM, O’Day SJ, Ribas A, at al. A phase cytotoxicity, and cytokine release, in- comparing oblimersen/dacarbazine yield the synergy that is desperately 2 clinical trial of nab-paclitaxel in previously duces apoptosis of tumor-specific T with dacarbazine alone demonstrated needed to overcome the flat rate of treated and chemotherapy-naive patients with cells, and promotes the differentiation that patients in the oblimersen treat- survival. Along with some of the new metastatic melanoma. Cancer. 2010;116(1):155- of CD4+ T cells into Foxp3-regulatory T ment arm had improved survival (P = breast cancer therapies, ipilumumab 163. cells as well as the resistance of tumor .007) and increases in PFS (P <.001) over has put the cost-to-benefit argument 8. ClinicalTrials.gov website. http://www. cells to CTL attack.57 Unlike CTLA-4 li- a minimum of 24 months. There were directly in the national spotlight. Mar- clinicaltrials.gov/ct2/results?term=nab-paclitax gands, many tumors, including melano increases in infections or bleed- ginal gains in outcomes with increased el+melanoma&Search=Search. Accessed March noma, have been shown to selectively ing events despite increases in neu- toxicities does not make a good argu- 2, 2013. express PD-L1, making it an excellent tropenia and thrombocytopenia with ment to payers. This is further aggra- 9. Hersh E, Del Vecchio M, Brown M, et al. therapeutic target.57 Overexpression of oblimersen. The purpose of another vated in melanoma due to the rela- Phase 3, randomized, open-label multicenter PD-L1 can suppress cytokine produc- phase I trial in 2011 was to determine tively low number of cases annually trial of nab-paclitaxel (nab-P) vs dacarbazine tion and cytolytic activity of tumor-in- the safety and dose of oblimersen in and the cost of research and develop- (DTIC) in previously untreated patients with met- filtrating CD4+ and CD8+ T cells.57 combination with temozolomide and ment: basic supply and demand. With astatic malignant melanoma (MMM) [abstract].

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 SP112 Melanoma Pipeline

Pigment Cell Melanoma Res. 25;836-903. cessed March 1, 2013. 40. ClinicalTrials.gov website. http://www trials.gov/ct2/show/NCT01153763?term=D 10. Natali PG, Nicotra MR, Bigotti A, et al. 26. Cho JH, Kim KM, Kwon M, Kim JH, Lee J. .clinicaltrials.gov/ct2/show/NCT01781572?ter abrafenib&cond=%22Melanoma%22&rank=9. Selective changes in expression of HLA class Nilotinib in patients with metastatic melanoma m=MEK162&cond=%22Melanoma%22&rank=2. Accessed February 22, 2013. I polymorphic determinants in human solid harboring KIT gene aberration. Invest New Accessed March 4, 2013. 55. ClinicalTrials.gov website. http://clinical- tumors. Proc Natl Acad Sci. 1989;86(17):6719- Drugs. 2012;30(5):2008-2014. 41. ClinicalTrials.gov website. http://www trials.gov/ct2/show/NCT01266967?term=D 6723. 27. ClinicalTrials.gov website. http://clinicaltri- .clinicaltrials.gov/ct2/show/NCT01763164?ter abrafenib&cond=%22Melanoma%22&rank=7. 11. Van Duinen SG, Ruiter DJ, Broecker EB, et al. als.gov/ct2/results?term=nilotinib+melanoma& m=MEK162&cond=%22Melanoma%22&rank=1. Accessed February, 2013. Level of HLA antigens in locoregional metasta- Search=Search. Accessed February 25, 2013. Accessed March 4, 2013. 56. ClinicalTrials.gov website. http://clinicaltri- ses and clinical course of the disease in patients 28. Masitinib scientific data for veterinary medi- 42. Jang S, Atkins MB. Which drug, and when, als.gov/ct2/results?term=Dabrafenib&cond=%2 with melanoma. Cancer Res. 1988;48(4):1019- cine. http://www.kinavet.com/file/Kinavet%20 for patients with BRAF-mutant melanoma? 2Melanoma%22. Accessed February 22, 2013. 1025. Scientific%20Data%20for%20Veterinary%20 Lancet Oncol. 2013;14(2):e60-e69. 57. Topalian SL, Hodi FS, Brahmer JR, et al. 12. Stopeck AT, Jones A, Evan M, et al. Phase Medicine%20-%20July2011.pdf. Accessed March 43. Gilmartin AG, Bleam MR, Groy A, et al. Safety, activity, and immune correlates of II study of direct intralaesional gene transfer of 2, 2013. GSK1120212 (JTP-74057) is an inhibitor of MEK anti-PD-1 antibody in cancer. N Engl J Med. Allovectin-7, an HLA-B7/B2-Microglobulin DNA- 29. Kim EJ, Zalupski MM. Systemic therapy activity and activation with favorable phar- 2012;366(26):2443-2454. Liposome Complex, in patients with metastatic for advanced gastrointestinal stromal tumors: macokinetic properties for sustained in vivo 58. ClinicalTrials.gov website. http://www melanoma. Clin Cancer Res. 2001;7(8):2285- beyond imatinib. J Surg Oncol. 2011;104(8):901- pathway inhibition. Clin Cancer Res. 2011;17(5): .clinicaltrials.gov/ct2/results?term=BMS- 2291. 906. 989-1000. 936559+melanoma&Search=Search. Accessed 13. Stopeck AT, Hersh EM, Akporiaye ET, et 30. Kinavet-CA1 package insert. http://www.ki- 44. Frederick DT, Adriano P, Cogdill AP, et al. March 4, 2013. al. Phase I study of the direct gene transfer of navet.com/file/Kinavet%20CA1%20package%20 BRAF inhibition is associated with enhanced 59. ClinicalTrials.gov website. http://www. allogenic histocompatability antigen, HLA-B7, in insert%20draft.pdf. Accessed March 1, 2013. melanoma antigen expression and a more favor- clinicaltrials.gov/ct2/results?term=nivolumab patients with metastatic melanoma. J Clin Oncol. 31. ClinicalTrials.gov.http://www.clinicaltrials able tumor microenvironment in patients with +melanoma&Search=Search. Accessed March 1997;15:341-349. .gov/ct2/show/NCT01280565?term=masitinib metastatic melanoma [published online January 4, 2013. 14. Bedikian AY, Vecchio M. Alovectin-7 therapy +melanoma&rank=1. Accessed March 4, 2013. 10, 2013]. Clin Cancer Res. 60. Bedikian AY, Millward M, Pehamberger H. in metastatic melanoma. Expert Opin Biol Ther. 32. Ascierto PA, Schadendorf D, Berking C, 45. Flaherty KT, Robert C, Hersey P, et al. Im- Bcl-2 antisense (oblimersen sodium) plus dacar- 2008;8(6):839-844. et al. MEK162 for patients with advanced proved survival with MEK inhibition in BRAF-mu- bazine in patients with advanced melanoma: the 15. ClinicalTrials.gov website. http://clinicaltri- melanoma harbouring NRAS or VAL600 BRAF tated melanoma. N Engl J Med. 2013;367(2):107- oblimersen melanoma study group. J Clin Oncol. als.gov/show/NCT00395070. Accessed Febru- mutations: a non-randomized, open label phase 114 . 2006;24(29):4738-4745. ary 25, 2013. 2 study [published online February 13, 2013]. 46. Kim KB, Kefford R, Pavlick AC, et al. Phase II 61. Jansen B, Schalagbauer-Wald H, Brown BD, 16. Kirkwood JM, Butterfield LH, Tarhini AA, et Lancet. study of the MEK1/MEK2 inhibitor trametinib in et al. Bcl-2 antisense therapy chemosensitizes al. Immunotherapy of cancer in 2012. CA Cancer 33. Hoeflich KP, Merchang M, Orr K, et al. In- patients with metastatic BRAF-mutant cutane- human melanoma in SCID mice. Nat Med. 1998; J Clin. 2012;62(5):309-335. termittent administration of MEK inhibitor GDC- ous melanoma previously treated with or without 4(2):232-234. 17. Oshita C, Takikawa M, Kume A, et al. 0973 plus PI3K inhibitor GDC-0941 triggers a BRAF inhibitor. J Clin Oncol. 2013;31(4):482- 62. Klasa RJ, Gillum AM, Klem RE, et al. Oblim- Dendritic cell-based vaccination in metastatic robust apoptosis and tumor growth inhibition. 489. ersen Bcl-2 antisense: facilitating apoptosis in melanoma patients: phase II clinical trial. Oncol Cancer Res. 2011;72:210-219. 47. ClinicalTrials.gov website. http://clinicaltri- anticancer treatment. Antisense Nucleic Acid Rep. 2012;28(4):1131-1138. 34. Baudy AR, Dogan T, Flores-Mercado JE, et als.gov/ct2/results?term=Trametinib&cond=%2 Drug Dev. 2002;12(3):193-213. 18. ClinicalTrials.gov website. http://clinicaltri- al. FDG-PET is a good biomarker of both early 2Melanoma%22. Accessed February 22, 2013. 63. Ott PA, Chang J, Madden K, et al. Oblim- als.gov/ct2/show/NCT00074230?term=mag response and acquired resistance in BRAF V600 48. Zitvogel L, Kroemer G. Targeting PD-1/ ersen in combination with temozolomide and e+melanoma&rank=17. Accessed February 25, mutant melanomas treated with vemurafenib PD-L1 interactions for cancer immunotherapy. albumin-bound paclitaxel in patients with 2013. and MEK inhibitor GDC-0973. EJNMMMI Re- Oncoimmunology. 2012;1(8):1223-1225. advanced melanoma: a phase I trial. Cancer 19. ClinicalTrials.gov website. http://clinicaltri- search. 2012;2:22. 49. Brahmer JR, Tykodi SS, Chow LQ, et al. Chemother Pharmacol. 2013;71(1):183-191. als.gov/ct2/show/NCT01437605?term=mag 35. ClinicalTrials.gov website. http://www Safety and activity of anti-PD-L1 antibody in 64. Chanan-Khan AA, Niesvizky R, Hohl RJ, et e+melanoma&rank=8. Accessed February 25, .clinicaltrials.gov/ct2/show/NCT01271803 patients with advanced cancer. N Engl J Med. al. Phase III randomised study of dexametha- 2013. ?term=GDC-0973&cond=%22Melanoma%22&ra 2012;366(26):2455-2465. sone with or without oblimersen sodium for 20. Chang EY, Chen CH, Hongxiu Jr, et al. nk=2. Accessed February 25, 2013. 50. Ribas A, Hauschild A, Kefford R, et al. Phase patients with advanced multiple myeloma. Leuk Antigen-specific cancer immunotherapy using 36. ClinicalTrials.gov website. http://www III, open-label, randomized, comparative study of Lymphoma. 2009;50(4):559-565. a GM-CSF secreting allogenic tumor cell-based .clinicaltrials.gov/ct2/show/NCT01689519 tremelimumab (CP-675,206) and chemotherapy 65. ClinicalTrials.gov website. http://www vaccine. Int J Cancer. 2000;86:725-730. ?term=GDC-0973&cond=%22Melanoma%22&ra (temozolomide [TMZ] or dacarbazine [DTIC]) in .clinicaltrials.gov/ct2/show/NCT00409383?t 21. Schmidt C. Amgen spikes interest in live nk=1. Accessed February 25, 2013. patients with advanced melanoma. J Clin Oncol. erm=oblimersen&cond=%22Melanoma%22&ra virus vaccines for hard-to-treat cancers. Nat 37. Jakob JA, Bassett RL Jr, Ng CS, et al. NRAS 26:2008 (May 20 suppl; abstr LBA9011). nk=3). Accessed March 3, 2013. Biotechnol. 2011;29(4):295-296. mutation status is an independent prognos- 51. Falchook GS, Long GV, Kurzrock R, et 22. Spitler LE, Grossbard ML, Ernstoff MS, tic factor in metastatic melanoma. Cancer. al. Dabrafenib in patients with melanoma, et al. Adjuvant therapy of stage III and IV 2012;118 untreated brain metastases, and other solid malignant melanoma using granulocyte-mac- (16):4014-4023. tumors: a phase 1 dose escalation trial. Lancet. rophase colony-stimulating factor. J Clin Oncol. 38. Winski S, Anderson D, Bouhana K, et al. 2012;379(9829):1893-1901. 2000;18(8):1614-1621. MEK162 (ARRY-162), a novel MEK ½ inhibitor, 52. Long GV, Trefzer U, Davies MA, et al. Dab- 23. ClinicalTrials.gov website. http://clinicaltri- inhibits tumor growth regardless of KRas/Raf rafenib in patients with Val600Glu or Val600Lys als.gov/ct2/show/NCT00769704?term=oncov pathway mutations. Proceedings of the 22nd BRAF-mutant melanoma metastatic to the brain ex&rank=3. Accessed February 23, 2013. EORTC-NCI-AACR symposium on Molecular Tar- (BREAK-MB): a multicentre, open-label, phase 2 24. ClinicalTrials.gov website. http://clinicaltri- gets and Cancer Therapeutics; Berlin, Germany; trial. Lancet Oncol. 2012;13(11):1087-1095. als.gov/ct2/show/NCT01368276?term=oncove Nov 16-19, 2010. 53. Hauschild A, Grab J, Demidov L, et al. Dab- x&rank=4. Accessed February 23, 2013. 39. ClinicalTrials.gov website. http://www rafenib in BRAF-mutated metastatic melanoma: 25. Tasigna website.https://www.us.tasigna .clinicaltrials.gov/ct2/show/NCT01320085?te a multicentre, open-label, phase 3 randomized .com/health-care-professional/index.jsp?site rm=MEK162&cond=%22Melanoma%22&rank=3. control trial. Lancet. 2012;380(9839):358-365. =PC002491&source=01030&irmasrc=NA. Ac- Accessed March 4, 2013. 54. ClinicalTrials.gov website. http://clinical-

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 Value-Based Contracting SP113 Value-Based Contracting for Pharmaceuticals: Getting Ready for Prime Time?

Stanton R. Mehr

he full-court press toward com- Today’s price-volume agreements or Specialty Pharmaceuticals Shine a want to be seen as ‘being too close’ to parative-effectiveness research patient-access initiatives (where pa- Light on the Issue such a negative industry—especially Tand results reporting has com- tients would be given access to a drug at The costs associated with specialty when it is a business proposition.” pelled health plans and insurers to reduced cost to try to prove value to pay- pharmaceuticals continue to concern Clor continued, “This potential to help sharpen their focus on incorporating ers, in the hope of landing preferred for- payers and represent a difficult chal- patients, improve care, and lower costs this information into coverage decision mulary positioning) are a form of “val- lenge for the years ahead. Specialty is partially lost owing to the ‘politics’ of making. Managed care executives have ue-based contracting,”2 pharmaceuticals today the current state of affairs within the long complained that too few evidence- but if outcomes are account for 80% of the pharmaceutical industry. Too many big based data of this type are available to what the payers are af- total drug spend in the pharmaceutical companies have been improve coverage decisions. If the evi- ter, these contracts are medical benefit, and 8 of caught behaving badly and brought into dence were available and payers were low on the evolution- the top 10 drug catego- the public eye. How then can a health ready to incorporate it, widespread de- ary scale. “Outcomes- ries in 2014 are forecast plan expect to partner with them? So velopment of value-based formularies based contracting” rep- to be specialty drugs.5 In politics and public sentiment trump might result. resents the next evo- the future, specialty uti- good medicine in this case.” Any pharmaceutical manufacturer lution, encompassing lization is expected to whose small-molecule drug is the third risk-based agreements grow rapidly, owing to Myeloma Drug Pioneers the Concept or fourth product of a category to reach with performance new drug introductions In 2007, the prototype value-based or the market faces its own value-based guarantees or payment and rising numbers of performance-based contract for a drug quandary: How can it prove the value scales for attaining not patients with chronic was introduced in the United Kingdom proposition of its agent in the face of utilization or market diseases for which spe- by Johnson & Johnson.6 The National In- heavy competition? Drug rebates and share benchmarks, but cialty drugs may be institute for Clinical Excellence (NICE) had discounts can provide access to a plan’s clinical status improve- dicated. Robert Kritzler, deemed its product Velcade provided membership, but this does not truly ment or prevention of Robert Kritzler, MD MD, deputy chief medi- too little value for the cost to recom- address the economic value of a drug. adverse events. This cal officer, Johns Hop- mend coverage by the National Health The question is even more difficult (and is truly value-based kins HealthCare, Glen Service. The company, worried about scrutinized) in the case of expensive bi- contracting. It boils down to the fol- Burnie, Maryland, believes that “with being locked out of the British market, ologic medications. A survey published lowing: if the drug doesn’t provide the the rising cost of specialty pharmaceu- offered a radical contract: The use of in 2012 demonstrated that managed outcome that is expected, the manufac- ticals, especially those with variable the drug must achieve a 50% reduction care executives are not satisfied with turer would be at risk in some way—re- outcomes based on patient selection, in serum paraprotein (M-protein) lev- the current approach of contracting and imbursement would be discounted or there will need to be a different way of els by the fourth cycle of therapy or the discounts to obtaining formulary ac- possibly even free, or the manufacturer contracting.” manufacturer would reimburse the Na- cess.1 Only 4% indicated that they were would bear the cost of complications Payers are not yet convinced of the tional Health Service the full cost of the “very satisfied” with this form of con- suffered by the patient. It may make it value proposition behind these prod- drug. Technically, this compensation tracting. more palatable for payers to cover an ucts. They are actively was most commonly One innovation that has yet to be- expensive agent, and gain credibility for seeking reassurances made in the form of ad- come mainstream involves manufac- the maker of a specialty drug. that an agent that may ditional free Velcade.2 turers offering to back their product’s If the pharmaceutical companies will cost $10,000 for each The decision makers at performance by taking some of the need to eventually move away from month of therapy is NICE took them up on risk. This does not necessarily mean a volume-based sales, it would be rea- money well spent. This their offer. “money-back guarantee,” but it certain- sonable to expect “the industry to shift is partly behind the The first value-based ly could. This is in stark contrast to the into a world in which outcomes-based push for companion pharmaceutical con- present situation, where the manufac- contracting will be the standard reim- diagnostics, to help de- tracts in the United turer’s “risk” has been defined by the bursement methodology,” according termine those patients States were seen in 2009. difficulty in successfully navigating the to one pharmaceutical executive.1 Yet, who may optimally One well-publicized drug development process from pre- this concept has not spread to date. Pay benefit from the use of contract was between clinical studies through US Food and for performance has been utilized for specific specialty drugs. Cigna and Merck for the Drug Administration (FDA) approval, provider reimbursement for a decade.3 It is also responsible diabetes products sita- and subsequently, the risk in market- Why not apply this concept to pharma- for the interest in per- gliptin and sitagliptin/ ing the drug successfully to payers. This ceuticals? Assuming one does not run formance guarantees Gerald Clor, MBA metformin. Merck pro- risk must not be minimized—according afoul of federal anti-kickback statutes, and other ways to link vided discounts if Cigna to past reports from the Tufts Center for and the remuneration, discounts, or a drug’s costs to its ac- members with type 2 the Study of Drug Development (www. incremental reimbursement resulting tual outcome in the patient. diabetes mellitus lowered their blood csdd.tufts.edu), the cost to develop bio- from an outcomes-based contract that “The pharmaceutical and biotech in- sugar levels, and also provided for addi- technology drugs was approximately can be coordinated under an accepted dustries have done a bad job of clearly tional discounts if people who were pre- $1.2 billion in 2006. In addition, the safe harbor,4 then one can explore some stating the value equation and life- scribed Merck’s drugs took their medi- pharmaceutical industry spends hun- of the outcomes-based pharmaceutical saving value of their products,” assert- cations according to their physicians’ dreds of millions of dollars on market- contracting options being discussed to- ed Gerald Clor, MBA, of Clor Training & instructions. In return, Cigna placed the ing efforts to increase awareness and day. Consulting, LLC, Bethlehem Township, agents on a low copayment tier, in the focus on their products’ benefits. Pennsylvania. “Health plans do not hopes of optimizing adherence to the

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 SP114 Value-Based Contracting

Table. Perception of Value Biopharmaceutical Biopharmaceutical Generic Health insurance company services provider pharmaceutical company company Government payer Regulatory agency Degree of improved efficacy over 49% 28% 34% 27% 19% 26% existing products Total patient outcomes 55% 58% 27% 32% 26% 23% Whether it addresses an unmet 36% 31% 34% 21% 29% 24% medical need Potential number of patients who 14% 14% 56% 31% 29% 19% could use the drug Costs compared with competing 29% 36% 32% 26% 23% 25% products Improved longevity of patient 17% 11% 17% 29% 492% 25% Improved quality of life of patient 26% 28% 34% 58% 52% 70% Source: Economist Intelligence Unit survey, September 2011 Responses to the question, “In the next 3 years, which, if any, of these attributes will become significantly more important in your assessment of the value of a new drug?” Adapted with permission from Kielstra P. Reinvent- ing biopharma: strategies for an evolving marketplace—the value challenge. The Economist Intelligence Unit. April 25, 2012. http://www.slideshare.net/Management-Thinking/the-value-challenge-reinventing-biopharma- strategies-for-an-evolving-marketplace. Accessed February 19, 2013. medication.6 According to a Cigna press additional societal benefits gained with er the total cost of care,” Clor wondered, sponse as a clinical or patient-related release, “The results demonstrated im- the new medicine. This value-based “how do I measure my (pharmaceutical) outcome, but consider the next stage of proved blood sugar levels of more than pricing system will supplant the exist- impact on that cost parameter? This discussion: Would the terms of the out- 5% for those continuously enrolled in ing system used by the National Health complication adds too many variables comes-based oncology contract change the program, regardless of which dia- Service when evaluating all new medi- and components that the contract (or for patients diagnosed at a different betes drug they were taking. There was cations.9 the drug company) cannot control.” stage of cancer? For example, should also a 4.5% increase in blood sugar lab Australia, Germany, and Italy have all These challenges are difficult to over- the successful outcomes of a drug giv- testing during the period.”7 undertaken several initiatives aimed at come from a pharmaceutical manu- en in patients with stage III tumors be Also in 2009, Health Alliance Plan increasing the number of outcomes- facturer’s perspective. From the health judged differently from the outcomes contracted with Procter & Gamble and based pharmaceutical contracts.1 The plan perspective, the complexity of of a drug given in patients with stage sanofi-aventis on the osteoporosis drug Australian drug pricing authority has these arrangements is no less an is- I or II disease? These permutations Actonel (risedronate). In this deal, the at least 90 contracts of this type on the sue. Dr Kritzler of Johns Hopkins Health can boggle the mind. In addition, how manufacturers agreed to reimburse books. There is no lacking for motiva- Care explained, “Many plans, including might a contract define objective result Health Alliance Plan for the costs of tion among payers worldwide. It is only our own, have considered some sort of reporting? treating nonspinal, osteoporosis-rela- a matter of time before US payers are value-based contracting based on final With these questions in mind, it ted fractures in eligible postmenopausal greater players in this area. outcome. Areas that many of us have should not be surprising to see initial women who were using the product, up considered are in the oncology, neurol- outcomes- or value-based contracting to a predefined amount, which greatly Hurdles to Overcome in Outcomes- ogy, and the autoimmune space,” he efforts focused on other diseases. Al- limited their financial risk. This gamble Based Pharmaceutical Contracting commented, “but plans are having a though oncology is an area that may worked well, as the effectiveness of If 1 word characterizes the nature of rough time implementing this, as the optimally benefit from this approach— the osteoporosis drugs in general were outcomes-based contracting for phar- details are extraordinarily complex.” many primary drug treatments qualify heavily questioned at this time, and maceutical drugs, it is “complexity.” Ger- Not only are the details to implemen- as specialty pharmaceuticals—it may the arrangement ensured health plan ald Clor believes that multidrug therapy, tation complex, but the administration not be practical for many cancers. members had access to risedronate. promoted by many clinical guidelines, of these types of contracts can be bar- Still, Johnson & Johnson success- Nine months after starting the program, muddies the waters quite a bit. “It be- riers to payers. Assume that they would fully implemented and administered the manufacturers found that they had comes very difficult to measure the need a tracking mechanism for particu- its Velcade contract with NICE, so there paid far less (79% less) than the pre- impact of clinical improvement when lar patients’ clinical status over time. In is some experience to build upon. In defined limit established in the con- there is more than 1 single aspect to some cases, they would save less money this example, M-protein may not be a tract. In addition, the data gained cor- that improvement,” he said. “Few com- from the outcomes-based contract than good outcomes indicator of survival.2 roborated Procter & Gamble’s original panies will want to enter into a risk- it would cost to launch and manage the Furthermore, up to 15% of all patients clinical trial data for risedronate’s effi- shared contract if the measure of suc- patient tracking system needed to ana- do not have measureable M-protein cacy in preventing nonspinal fractures.8 cess goes past the drug monotherapy.” lyze the intervention’s effects. levels.2 Furthermore, it may have delayed the Just coming to agreement on which However, Dr Kritzler believes that A value-based approach might help plan’s generic substitution for risedro- outcomes measures are actually of once the ball begins rolling, it will be advance an approach that emphasizes nate, as well as kept it in preferred posi- importance is a notable obstacle. For hard to stop. “As soon as a few of these biomarker testing before treatment, to tion relative to the newer branded prod- example, according to one survey, pay- arrangements gain traction, it is likely help identify who would be most likely uct Boniva (ibandronate). ers focus on measures of longevity and that this type of contracting will take to benefit. Additionally, such contract- In general, non-US payers are inter- quality of life, but pharmaceutical man- off,” he said. ing could be an incentive for manufac- ested in seeking alternative methods of ufacturers are focused on specific units turers to engage in greater efforts to payment for pharmaceuticals. Although of clinical efficacy or the “cost-benefit Oncology-Specific Questions educate providers as to who might be NICE is currently utilizing cost-effec- implications of a new drug for overall The idea of outcomes-based contract- the most appropriate subpopulations tiveness thresholds in making coverage treatment.” Furthermore, healthcare ing for oncology products adds a new of patients for these expensive agents. recommendations, it is seeking to re- providers and patients may point to level of complexity to an already chal- vamp its decision making as it applies to other preferred outcomes measures.9 lenging issue. How to measure out- The Pace of Change Is Slow any new drug by 2014, and include other Adding to this measure of complexity comes becomes not only a question The industry has just begun to con- factors as well, such as unmet need, the is the desire to move toward new pay- about the value of overall survival sider what payers mean when they say burden of illness, degree of innovation ment methods. “If a ‘bundled’ or ‘global’ versus progression-free survival or they want more value for the money associated with a new medicine, and payment is used, and the goal is to low- complete response versus clinical re- they spend. A survey by a unit of The

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 Value-Based Contracting SP115

Economist found that the biopharma- and pharmaceutical manufacturers References patients do. New York Times, April 23, 2009. ceutical industry is a harsh critic of hold numerous discussions and hold 1. Unleashing value: the changing payment http://www.nytimes.com/2009/04/23/ the progress made to date (Figure).10 them early in the contracting process landscape for US pharmaceutical manufactur- business/23cigna.html?_r=0. Accessed February The survey report specifies that “More “to determine what is of value to each ers. PriceWaterhouseCoopers Health Research 2, 2013. than one-half of respondents overall stakeholder.”1 This may be augmented Institute. http://www.pwc.com/us/en/health- 7. Cigna and Merck help customers better man- (55%) say that the sector is adjusting by developing formal, well-defined, industries/publications/pharma-reimbursement- age diabetes (press release). Cigna, October 28, well to increasing demands for proof consensus-driven value metrics, and by value.jhtml. Published May 2012. Accessed 2010. http://newsroom.cigna.com/article_dis- of value, but only 36% from traditional obtaining a consensus on a “common February 1, 2013. play.cfm?article_id=126. Accessed February 14, biopharmaceutical companies agree.”10 set of principles, policies, and techni- 2. Adamski J, Godman B, Ofierska-Sujkowska G, 2012. Furthermore, just over half (56%) be- cal methods for the data collection et al. Risk sharing arrangements for pharmaceuti- 8. Issue brief: value-based pricing for pharma- lieve that “The industry will introduce program.” Without this extremely high cals: potential considerations and recommenda- ceuticals: implications of the shift from volume to products with demonstrably more val- level of agreement on what constitutes tions for European payers. BMC Health Serv Res. value. Deloitte Center for Health Solutions; 2012. ue than existing offerings in the next an outcome of value to both payer and 2010;10:153-169. http://deloitte.wsj.com/cfo/files/2012/09/ 3 years. Worse still, only 39% believe manufacturer, the vast effort to develop 3. 2011 annual report. Integrated Healthcare ValueBasedPricingPharma.pdf. Accessed Febru- that the industry is more than just outcomes-based pharmaceutical con- Association, Oakland, California. www.iha.org/ ary 1, 2013. somewhat effective at creating such tracts (for any disease category) will be pdfs_documents/resource_library/IHA_Annu- 9. Faden RR, Chalkidou K. Determining the value products.” Not insignificantly, the sur- destined to fail. alReport_2011_Final.pdf. Accessed January 25, of medications—the evolving British experience. N vey respondents didn’t believe that the 2013. Engl J Med. 2011;364:1289-1291. industry does a good job of proving val- Funding Source: None. 4. Lutes ME, Gottlieb DG. Managing regulatory 10. Kielstra P. Reinventing biopharma: strategies ue, even when their products may be Author Disclosure: Mr Mehr reports receiving risk in value-based contracting. Presented at for an evolving marketplace—the value challenge. of real value. Only 25% of payers and payment for involvement in the prepara- Value-Based Contracting and Risk-Sharing The Economist Intelligence Unit. April 25, 2012. government policy makers interviewed tion of this article. Agreements, Sponsored by CBI. Philadelphia, PA: http://www.slideshare.net/Management-Think- expressed a level of confidence about Authorship Information: Concept and design; January 30-31, 2013. ing/the-value-challenge-reinventing-biopharma- claims of value made by the industry.10 drafting of the manuscript; critical revi- 5. 2011 care insights: changing rules changing strategies-for-an-evolving-marketplace. Accessed Based on PriceWaterhouseCoopers’ sion of the manuscript for important in- roles. Scottsdale, AZ: CVS Caremark; 2012. February 19, 2013. analysis, it is imperative that payers tellectual content. 6. Pollack A. Drug deals tie prices to how well Payer Perspective Outcomes-Based Contracting for Pharmaceuticals: A Health Plan Perspective Jeffery D. Dunn, PharmD, MBA

Outcomes-based contracting for pharma- if patients were compliant with the drug therapy. However, there was a cap on the ceuticals has been discussed for years as exposure to the manufacturer—a maximum payment was set at a percentage of plan an incentive to offer preferred formulary spend on the drug. This was substantially less than the total cost of any 1 fracture. For positioning for certain drugs and to lower the diabetes and statin examples, the manufacturers offered a few extra percentage costs. Drug categories and their associ- rebate points if a plan’s population met certain A1C or lipid goals. Often this results ated outcomes have included diabetes in a few thousand dollars in incremental rebates, which needs to be weighed against agents and reductions in hemoglobin the effort required to code and measure the input data (not even considering the re- A1C; bisphosphonates and decreased quests to stratify risk, which can’t be accomplished through claims databases). There fracture rates; statins and cholesterol is also the issue of how a plan addresses, and invests in, the education or incentives lowering; and even guarantees against necessary to change both prescriber and member behavior to improve the respective dose escalation in specialty categories lab values or outcome measures. These measures and activities would often have to like rheumatoid arthritis and psoriasis. be above and beyond what is occurring for quality measurements such as HEDIS or However, true outcomes-based con- Medicare Star ratings. tracting is elusive. Many healthcare plans Despite the poor history of these types of contracts, they will continue to be ex- are incapable of capturing, measuring, plored, owing to the shift toward specialty drug management. It will be more feasible and reporting the data elements neces- to implement outcome-based contracts in these categories, because the sample size sary to comply with the contract terms. is much smaller and can be more easily measured at a member level, and the cost of Even integrated plans lack the information the drugs is significantly higher, making the return to the managed care plan poten- technology to adequately marry medical tially much higher. claims with pharmacy data. Furthermore, In conclusion, most plans cannot comply with outcomes-based contracts. This is most contracts would require plans to manage down to the individual member level not for lack of desire but rather operational or philosophical shortcomings. However, rather than use high-level aggregate data that are typically required for rebates. we need to figure out a way for all stakeholders to share risk as we move toward more It is also often difficult to identify and agree on what outcomes will be measured. It niche specialty drugs, new models of healthcare delivery, and payment reform. Phar- can be done with objective measures such as low-density lipoprotein and hemoglo- maceutical companies should have an active role in backing up the efficacy, or lack bin A1C levels, but when exploring more intriguing disease states, such as multiple thereof, of expensive medications that currently are paid for by plans and members. sclerosis, rheumatoid arthritis, and oncology, the outcomes are often subjective. For The government, FDA, or other body may play a role in requiring manufacturers to example, a plan cannot be expected to define what is progression-free survival in a provide a value proposition for all medications similar to that played by the National patient with metastatic prostate cancer or what is a clinically significant relapse in Institute for Clinical Effectiveness in the United Kingdom. All stakeholders (plan, pro- multiple sclerosis. vider, member, manufacturer, and government) must have a role in delivering value in Plans also often find the investment in maintaining and complying with the con- medications and delivering cost-effective healthcare. tracts not worth the return warranted by the effort expended, partly because the pharmaceutical manufacturers have never gone truly at risk. Using a previously mentioned Dr Dunn is formulary and contract manager for SelectHealth in Salt Lake City, UT. example, a bisphosphonate contract was touted as paying for the cost of a fracture

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 For the treatment of patients with multiple myeloma who have received at least 2 prior Kyprolis™ (carfi lzomib) for Injection is engineered for selective inhibition1 therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of last therapy. Approval is based on response rate. • Single-agent KYPROLIS phase 2 study results2,* Clinical benefi t, such as improvement in survival or symptoms, has not been verifi ed. - Overall response rate (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Median duration of response of 7.8 months (95% CI: 5.6, 9.2) • Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event THE POWER OF - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each) ADVERSE REACTIONS SECOND-GENERATION The safety of KYPROLIS was evaluated in clinical trials of 526 patients with relapsed and/or refractory multiple myeloma. PROTEASOME INHIBITION • Serious adverse reactions were reported in 45% of patients. The most common were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), TAKES FLIGHT thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%)

*Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma and whose disease had a ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria. References: 1. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383-6391. 2. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

Important Safety Information imaging and/or other tests as indicated. Withhold KYPROLIS Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet ADVERSE REACTIONS for pulmonary hypertension until resolved or returned to baseline nadirs occurring around Day 8 of each 28-day cycle and recovery to Serious adverse reactions were reported in 45% of patients. The most CONTRAINDICATIONS and consider whether to restart KYPROLIS based on a baseline by the start of the next 28-day cycle. In patients with multiple common serious adverse reactions were pneumonia (10%), acute renal benefi t/risk assessment. myeloma, 36% of patients experienced thrombocytopenia, including None. failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration reactions leading to discontinuation of KYPROLIS occurred in 15% of Pulmonary Complications: Dyspnea was reported in 35% of resulted in a dose reduction in 1% of patients and discontinuation of WARNINGS AND PRECAUTIONS patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; patients and included congestive heart failure (2%), cardiac arrest, treatment with KYPROLIS in < 1% of patients. Monitor platelet counts dyspnea, increased blood creatinine, and acute renal failure (1% each). The safety of KYPROLIS was evaluated in clinical studies of no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and frequently during treatment with KYPROLIS. Reduce or interrupt dose as 526 patients with relapsed and/or refractory multiple myeloma. manage dyspnea immediately; interrupt KYPROLIS until symptoms clinically indicated. The most common adverse reactions (incidence ≥ 30%) were have resolved or returned to baseline. fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, dyspnea (35%), diarrhea (33%), and pyrexia (30%). Death due to cardiac arrest has occurred within a day of KYPROLIS Infusion Reactions: Infusion reactions were characterized by a including fatal cases, have been reported (< 1%). KYPROLIS can administration. New onset or worsening of pre-existing congestive spectrum of systemic symptoms including fever, chills, arthralgia, cause elevations of serum transaminases and bilirubin. Withhold USE IN SPECIFIC POPULATIONS heart failure with decreased left ventricular function or myocardial myalgia, facial fl ushing, facial edema, vomiting, weakness, shortness KYPROLIS in patients experiencing Grade 3 or greater elevations ischemia have occurred following administration of KYPROLIS. of breath, hypotension, syncope, chest tightness, or angina. These Since dialysis clearance of KYPROLIS concentrations has not been of transaminases, bilirubin, or other liver enzyme abnormalities until Cardiac failure events (e.g., cardiac failure congestive, pulmonary reactions can occur immediately following infusion or up to 24 hours studied, the drug should be administered after the dialysis procedure. resolved or returned to baseline. After resolution, consider if restarting edema, ejection fraction decreased) were reported in 7% of patients. after administration of KYPROLIS. Administer dexamethasone prior KYPROLIS is appropriate. Monitor liver enzymes frequently. Monitor for cardiac complications and manage promptly. Withhold to KYPROLIS to reduce the incidence and severity of reactions. Please see Brief Summary of the full Inform patients of the risk and symptoms, and to contact physician KYPROLIS for Grade 3 or 4 cardiac events until recovery and Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when Prescribing Information on adjacent pages. if symptoms of an infusion reaction occur. consider whether to restart KYPROLIS based on a benefi t/risk administered to a pregnant woman based on its mechanism of action assessment. Patients with New York Heart Association Class III and Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred and fi ndings in animals. There are no adequate and well-controlled IV heart failure, myocardial infarction in the preceding 6 months, following KYPROLIS administration in < 1% of patients. Patients with studies in pregnant women using KYPROLIS. Carfi lzomib caused and conduction abnormalities uncontrolled by medications may be multiple myeloma and a high tumor burden should be considered to embryo-fetal toxicity in pregnant rabbits at doses that were lower at greater risk for cardiac complications. be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that than in patients receiving the recommended dose. Females of Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) patients are well hydrated. Monitor for evidence of TLS during reproductive potential should be advised to avoid becoming pregnant was reported in 2% of patients treated with KYPROLIS and was treatment, and manage promptly. Interrupt KYPROLIS until TLS while being treated with KYPROLIS. Grade 3 or greater in less than 1% of patients. Evaluate with cardiac is resolved. ©2012 Onyx Pharmaceuticals, Inc., South San Francisco, CA 0512-CARF-243 September 2012 Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued) reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold Description of Selected Adverse Drug Reactions. Renal Events: The most common renal Renal Toxicity • Withhold until renal function has recovered to Grade 1 reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other Descriptionadverse reactions of Selected were increaseAdverse in Drugblood Reactions.creatinine (24%) Renal and Events: renal failure The most(9%), whichcommon were renal mostly • Serum creatinine equal to or or to baseline and monitor renal function. KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restartingadverse Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly greater than 2 × baseline • If attributable to KYPROLIS, restart at the next scheduled liver KYPROLISabnormalities is appropriate. until resolved Monitor or returned liver enzymes to baseline. frequently After [seeresolution, Dosage consider and Administration if restarting andGrade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal 2 KYPROLISAdverse is Reactionsappropriate.]. Embryo-fetal Monitor liver Toxicity. enzymes KYPROLIS frequently can [see cause Dosage fetal harmand Administrationwhen administered and to aGrade 4 failure events were occurred1% each. in In 1%. one Discontinuations patient, death occurreddue to increased with concurrent blood creatinine sepsis and and worsening acute renal renal [see Adverse Reactions] treatment at a reduced dose (from 27 mg/m to KYPROLIS™ (carfilzomib) for Injection 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). Adversepregnant Reactions woman]. Embryo-fetalbased on its mechanism Toxicity. KYPROLISof action and can findings cause fetal in animals. harm when There administered are no adequate to a andfailure function were [see1% each.Dosage In andone Administration patient, death]. occurredPeripheral with Neuropathy: concurrent Peripheralsepsis and neuropathy worsening (including renal Brief Summary of Prescribing Information. Please see the KYPROLIS package insert • If not attributable to KYPROLIS, restart at the dose used pregnantwell‑ controlledwoman based studies on inits pregnantmechanism women of action using and KYPROLIS. findings Carfilzomib in animals. Therecaused are embryo no adequate‑fetal toxicity and infunction all events [see Dosageof peripheral and Administration sensory neuropathy]. Peripheral and peripheralNeuropathy: motor Peripheral neuropathy) neuropathy occurred (including in 14% of for full prescribing information. prior to the event. well‑pregnantcontrolled rabbits studies at indoses pregnant that were women lower using than KYPROLIS. in patients Carfilzomib receiving the caused recommended embryo‑fetal dose. toxicity Females in ofall eventspatients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple pregnantreproductive rabbits atpotential doses thatshould were be loweradvised than to avoidin patients becoming receiving pregnant the recommended while being treated dose. withFemales KYPROLIS. of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% • If tolerated, the reduced dose may be escalated to the If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see myeloma who have received at least two prior therapies including bortezomib and an previous dose at the discretion of the physician. reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% If thispatient drug shouldis used be during apprised pregnancy, of the potential or if the hazard patient to becomesthe fetus [seepregnant Use inwhile Specific taking Populations this drug,]. the and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% immunomodulatory agent and have demonstrated disease progression on or within 60 days of Peripheral Neuropathy • Withhold until resolved or returned to baseline. completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full patientADVERSE should be REACTIONS: apprised of the The potential following hazard adverse to reactionsthe fetus are[see discussed Use in Specific in greater Populations detail in other]. sectionsDosage of patients. and Administration Consider antiviral]. Herpes prophylaxis Virus Infection: for patients Herpes who zosterhave a reactivation history of herpes was reported zoster infection. in 2% • Grade 3 or 4 • Restart at the dose used prior to the event or reduced ADVERSEof the labeling: REACTIONS: The following adverse reactions are discussed in greater detail in other sections of patients.DRUG INTERACTIONS:Consider antiviral Carfilzomibprophylaxis for is patientsprimarily who metabolized have a history via peptidase of herpes and zoster epoxide infection. hydrolase PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 2 2 [see Adverse Reactions] dose (from 27 mg/m to 20 mg/m , OR from 20 mg/m of the labeling:• Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] DRUGactivities, INTERACTIONS: and as a result, Carfilzomib the pharmacokinetic is primarily metabolized profile of viacarfilzomib peptidase is and unlikely epoxide to behydrolase affected by DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously to 15 mg/m2), at the discretion of the physician. over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see • Pulmonary Hypertension [see Warnings and Precautions] Warnings and Precautions] activities,concomitant and as administration a result, the ofpharmacokinetic cytochrome P450 profile inhibitors of carfilzomib and inducers. is unlikelyCarfilzomib to be is affected not expected by • If tolerated, the reduced dose may be escalated to the 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment • Pulmonary Hypertension [see • Pulmonary Complications [see WarningsWarnings and Precautionsand Precautions] ] concomitantto influence administration exposure of of other cytochrome drugs [see P450Clinical inhibitors Pharmacology and inducers. section Carfilzomib of full PI]. is not expected previous dose at the discretion of the physician. cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the • Pulmonary Complications [see • Infusion Reactions [see WarningsWarnings and and Precautions Precautions] ] to influenceUSE IN exposureSPECIFIC of otherPOPULATIONS: drugs [seeClinical Pregnancy. Pharmacology Pregnancy section Category of full PI]. D [see Warnings and dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent Other • Withhold until resolved or returned to baseline. • Infusion Reactions [see • Tumor Lysis Syndrome [see WarningsWarnings and Precautions and Precautions] ] USEPrecautions IN SPECIFIC]. Females of reproductive potential should be advised to avoid becoming pregnant while POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see • Grade 3 or 4 non-hematological • Consider restarting at the next scheduled treatment • Tumor Lysis Syndrome [see • Thrombocytopenia [see Warnings and Precautions]] Precautionsbeing treated]. Females of reproductive potential should be advised to avoid becoming pregnant while with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS ]. The dose is calculated using the patient’s actual body surface area at toxicities with one dose level reduction (from 27 mg/m2 to • Thrombocytopenia [see• Hepatic Toxicity and Hepatic Failure [see Warnings and PrecautionsWarnings] and Precautions] beingcan treated cause with fetal KYPROLIS. harm when Based administered on its mechanism to a pregnant of action woman. and findings Carfilzomib in animals, caused KYPROLISembryo‑fetal Dosage and Administration 2 2 2 baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a 20 mg/m , OR from 20 mg/m to 15 mg/m ). • Hepatic Toxicity and Hepatic Failure [see The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical Warnings and Precautions] can toxicitycause fetalin pregnant harm when rabbits administered at doses that to awere pregnant lower woman.than in patientsCarfilzomib receiving caused the embryorecommended‑fetal body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than • If tolerated, the reduced dose may be escalated to the The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea,toxicity dose. in Ifpregnant KYPROLIS rabbits is used at dosesduring thatpregnancy, were lower or if thanthe patientin patients becomes receiving pregnant the recommended while taking this or equal to 20%. previous dose at the discretion of the physician. trialsdiarrhea, of patients and with pyrexia. multiple Clinical myeloma Trials were Safety fatigue, Experience. anemia, nausea, Because thrombocytopenia, clinical trials are dyspnea, conducted dose. drug, If KYPROLIS the patient is should used duringbe apprised pregnancy, of the potentialor if the hazardpatient tobecomes the fetus. pregnant Carfilzomib while was taking administered this a diarrhea,under andwidely pyrexia. varying Clinical conditions, Trials adverse Safety reaction Experience. rates observed Because in theclinical clinical trials trials are of conducteda drug cannot drug, intravenously the patient shouldto pregnant be apprised rats and of rabbitsthe potential during hazard the period to the of fetus.organogenesis Carfilzomib at doseswas administered of 0.5, 1, and Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. underbe widely directly varying compared conditions, with rates adverse in the reaction clinical rates trials observed of another in the drug, clinical and trialsmay ofnot a reflectdrug cannot the rates intravenously 2 mg/kg/day to pregnant in rats andrats 0.2,and rabbits0.4, and during 0.8 mg/kg/daythe period ofin organogenesisrabbits. Carfilzomib at doses was of 0.5,not teratogenic1, and Cycle 1 Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg be directlyobserved compared in medical with practice. rates in A thetotal clinical of 526 trialspatients of anotherwith relapsed drug, and/orand may refractory not reflect multiple the myeloma rates 2 mg/kg/dayat any dose in ratstested. and In 0.2, rabbits, 0.4, thereand 0.8was mg/kg/day an increase in inrabbits. pre‑implantation Carfilzomib loss was at not≥ 0.4 teratogenic mg/kg/day carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity observedreceived in medicalKYPROLIS practice. as monotherapy A total of 526 or with patients pre‑ dosewith relapseddexamethasone. and/or refractory Patients multiplereceived myeloma a median ofat anyand dose an increase tested. Inin rabbits,early resorptions there was andan increasepost‑implantation in pre‑implantation loss and a loss decrease at ≥ 0.4 in fetalmg/kg/day weight at Week 1 Week 2 Week 3 Week 4 delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other Day Days Day Day Days Day Day Days Days receivedfour treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all KYPROLIS as monotherapy or with pre‑dose dexamethasone. Patients received a median of and thean increase maternally in toxicearly doseresorptions of 0.8 mg/kg/day. and post‑implantation The doses lossof 0.4 and and a decrease 0.8 mg/kg/day in fetal inweight rabbits at are Day medicinal products. The intravenous administration line should be flushed with normal saline or 5% 2 1 2 3–7 8 9 10–14 15 16 17–21 22–28 four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not the approximatelymaternally toxic 20% dose and of 40%, 0.8 mg/kg/day. respectively, Theof the doses recommended of 0.4 and dose 0.8 in mg/kg/day humans of in 27 rabbits mg/m are based Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not 2 KYPROLIS 20 20 No 20 20 No 20 20 No No causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest,approximately on body surface 20% and area. 40%, Nursing respectively, Mothers. of the It isrecommended not known whether dose in KYPROLIShumans of is 27 excreted mg/m basedin human 2 be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution (20 mg/m ): Dosing Dosing Dosing Dosing attributedcardiac to disorder),disease progression end‑organ werefailure cardiac in 4 patients in 5 patients (multi (acute‑organ coronary failure, syndrome,hepatic failure, cardiac renal arrest, failure), on bodymilk. surfaceSince many area. drugs Nursing are excreted Mothers. in humanIt is not milk known and whether because KYPROLIS of the potential is excreted for serious in human adverse a and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and reactions in nursing infants from KYPROLIS, a decision should be made whether to discontinue nursing Cycles 2 and Beyond cardiac disorder), end‑organ failure in 4 patients (multi‑organ failure, hepatic failure, renal failure), milk. Since many drugs are excreted in human milk and because of the potential for serious adverse preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the infectionintracranial in 4 patientshemorrhage (sepsis, in 1 patientpneumonia, each, respiratoryand 1 patient tract found bacterial dead ofinfection), unknown dyspnea causes. andSerious reactions or to discontinuein nursing infants the drug, from taking KYPROLIS, into account a decision the should importance be made of thewhether drug toto discontinuethe mother. nursing Pediatric Week 1 Week 2 Week 3 Week 4 date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The intracranialadverse hemorrhagereactions were in 1reported patient in each, 45% andpatients. 1 patient The mostfound common dead of serious unknown adverse causes. reactions Serious were or toUse. discontinue The safety the anddrug, effectiveness taking into account of KYPROLIS the importance in pediatric of thepatients drug tohave the notmother. been Pediatric established. Day Day Days Day Day Days Day Day Days Days reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete adversepneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions were reported in 45% patients. The most common serious adverse reactions were Use.Geriatric The safety Use. and In studieseffectiveness of KYPROLIS of KYPROLIS there were in nopediatric clinically patients significant have differences not been observedestablished. in safety 1 2 3–7 8 9 10–14 15 16 17–21 22–28 preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestiveGeriatric and efficacy Use. In betweenstudies ofpatients KYPROLIS less therethan were65 years no clinically of age and significant patients differences65 years of observedage and inolder. safetyRenal KYPROLIS 27 27 No 27 27 No 27 27 No No from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mL reactionsheart leadingfailure (2%),to discontinuation cardiac arrest, of KYPROLISdyspnea, increasedoccurred in blood 15% creatinine,of patients and includedacute renal congestive failure (1% and Impairment.efficacy between The patientspharmacokinetics less than 65 years and safety of age of KYPROLISand patients were 65 years evaluated of age in and a Phaseolder.Renal 2 trial in 2 Dosing Dosing Dosing Dosing (27 mg/m ): Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize hearteach). failure Adverse (2%), cardiacreactions arrest, occurring dyspnea, at a rateincreased of 10% blood or greater creatinine, are presented and acute in renalTable failure4. (1% Impairment.patients with The normal pharmacokinetics renal function and and safety those of KYPROLISwith mild, moderate,were evaluated and severein a Phase renal 2 impairment trial in a If previous cycle dosage is tolerated. foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution each).Table Adverse 4: Incidence reactions occurringof Adverse at aReactions rate of 10% Occurring or greater in are ≥ 10% presented of Multiple in Table Myeloma 4. patientsand patientswith normal on chronic renal functiondialysis. andOn average,those with patients mild, weremoderate, treated and for severe 5.5 cycles renal using impairment KYPROLIS of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow 2 2 2 Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor TablePatients 4: Incidence Treated of with Adverse KYPROLIS Reactions Occurring in ≥ 10% of Multiple Myeloma and dosespatients of on15 chronicmg/m dialysis.on Cycle On 1, average,20 mg/m patients on Cycle were 2, treatedand 27 for mg/m 5.5 cycles on Cycles 3 and beyond. using KYPROLIS solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, 2 2 2 lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate Patients Treated with KYPROLIS dosesThe of pharmacokinetics 15 mg/m on Cycle and 1,safety 20 mg/mof KYPROLIS on Cycle were 2, notand influenced 27 mg/m on Cycles 3 and beyond. by the degree of baseline renal KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, Patients (N = 526) impairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrations fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in [n (%)] The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline renal Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted Patients (N = 526) impairment,has not includingbeen studied, the patientsthe drug on should dialysis. be Since administered dialysis clearanceafter the ofdialysis KYPROLIS procedure concentrations [see Clinical product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and All [n (%)]Grade 3 Grade 4 Pharmacology section of full PI]. Hepatic Impairment. The safety, efficacy and pharmacokinetics Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS a has not been studied, the drug should be administered after the dialysis procedure [see Clinical administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag. Event AllGrades Grade 3Events Grade 4Events Pharmacologyof KYPROLIS section have notof fullbeen PI]. evaluated Hepatic in Impairment. patients with Thebaseline safety, hepatic efficacy impairment. and pharmacokinetics Patients with the a patients during this period for fluid overload [seeWarnings and Precautions]. Dexamethasone 6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted Fatigue Event Grades292 (55.5) Events38 (7.2) Events2 (0.4) of KYPROLISfollowing laboratory values were excluded from the KYPROLIS clinical trials: have not been evaluated in patients with baseline hepatic impairment. ALT/AST ≥ 3 × upper Patients with the Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS under various temperature and container conditions are shown in Table 3. FatigueAnemia 292246 (55.5) (46.8)38 (7.2) 111 (21.1) 2 (0.4)7 (1.3) following laboratory values were excluded from the KYPROLIS clinical trials:limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology sectionALT/AST ≥ 3 × upper of full PI]. Cardiac KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to Table 3: Stability of Reconstituted KYPROLIS AnemiaNausea 246236 (44.9) (46.8) 111 (21.1) 7 (1.3) 7 (1.3)0 limitImpairment. of normal (ULN) Patients and bilirubin with New ≥ 2York × ULNHeart [see Association Clinical Pharmacology Class III and IV section heart failure of full werePI]. Cardiac not eligible 27 mg/m2 to reduce the incidence and severity of infusion reactions [see ]. for the clinicalPatients trials. with Safety New in York this Heartpopulation Association has not Class been III evaluated. and IV heart failure were not eligible Warnings and Precautions Stabilitya per Container NauseaThrombocytopenia 236 (44.9)191 (36.3) 7 (1.3) 69 (13.1) 54 (10.3)0 Impairment. for theOVERDOSAGE: clinical trials. SafetyThere isin nothis known population specific has notantidote been forevaluated. KYPROLIS overdosage. In the event of an Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or Storage Conditions of Reconstituted b reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended ThrombocytopeniaDyspnea 191 (36.3)182 (34.6) 69 (13.1)25 (4.8) 54 (10.3) 1 (0.2) OVERDOSAGE:overdosage, monitorThere is the no patientknown andspecific provide antidote appropriate for KYPROLIS supportive overdosage. care. In the event of an KYPROLIS IV Bag b actions and dose modifications are presented in Table 2. Vial Syringe (D5Wb) DyspneaDiarrhea 182 (34.6)172 (32.7) 25 (4.8)4 (0.8) 1 (0.2) 1 (0.2) overdosage,NONCLINICAL monitor TOXICOLOGY:the patient and Carcinogenesis,provide appropriate Mutagenesis, supportive care. and Impairment of Fertility. Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment DiarrheaPyrexia 172 (32.7)160 (30.4)4 (0.8) 7 (1.3) 1 (0.2)2 (0.4) NONCLINICALCarcinogenicity TOXICOLOGY: studies have Carcinogenesis,not been conducted Mutagenesis, with carfilzomib. and Carfilzomib Impairment was ofclastogenic Fertility. in the Refrigerated (2°C to 8°C; 36°F to 46°F) 24 hours 24 hours 24 hours PyrexiaUpper respiratory tract infection 160149 (28.3) (30.4) 7 (1.3) 17 (3.2) 2 (0.4)0 Carcinogenicityin vitro chromosomal studies have aberration not been test conducted in peripheral with blood carfilzomib. lymphocytes. Carfilzomib Carfilzomib was clastogenic was not mutagenicin the Hematologic Toxicity Recommended Action in thechromosomal in vitro bacterial aberration reverse test mutation in peripheral (Ames) blood test lymphocytes. and was not Carfilzomib clastogenic wasin the not in mutagenicvivo mouse a UpperHeadache respiratory tract infection 149 (28.3)145 (27.6) 17 (3.2)7 (1.3) 0 0 in vitro • Grade 3 or 4 Neutropenia • Withhold dose. Room Temperature (15°C to 30°C; 59°F to 86°F) 4 hours 4 hours 4 hours in thebone in vitromarrow bacterial micronucleus reverse mutationassay. Fertility (Ames) studies test and with was carfilzomib not clastogenic have in not the in been vivo mouse conducted. No HeadacheCough 145137 (27.6) (26.0) 7 (1.3)1 (0.2) 0 0 • Grade 4 Thrombocytopenia • If fully recovered before next scheduled dose, continue aTotal time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP. boneeffects marrow on micronucleusreproductive assay.tissues Fertility were noted studies during with carfilzomib 28‑day repeat have ‑dose not rat and been monkey conducted. toxicity No at same dose level. CoughBlood creatinine increased 137 (26.0)127 (24.1) 1 (0.2)13 (2.5) 01 (0.2) studies or in 6‑month rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/ [see Warnings and Precautions] WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial effects on reproductive tissues were noted during 28‑day repeat‑dose rat and monkey toxicity • If recovered to Grade 2 neutropenia or Grade 3 BloodLymphopenia creatinine increased 127126 (24.1) (24.0)13 (2.5) 84 (16.0)1 (0.2) 11 (2.1) studiesor Pharmacology. or in 6‑month rat Monkeys and 9‑ monthadministered monkey a chronicsingle bolus toxicity intravenous studies. doseAnimal of carfilzomibToxicology at 3 and/mg/kg Ischemia. Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on body surface area) thrombocytopenia, reduce dose by one dose level onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function or LymphopeniaEdema peripheral 126126 (24.0) (24.0) 84 (16.0)3 (0.6) 11 (2.1)0 or Pharmacology. Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg 2 2 2 experienced hypotension, increased heart rate, and increased serum2 levels of troponin‑T. The repeated (from 27 mg/m to 20 mg/m , OR from 20 mg/m to myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., EdemaVomiting peripheral 126117 (24.0) (22.2)3 (0.6) 5 (1.0) 0 0 (approximately 1.3 times recommended dose in humans of 27 mg/m based on body surface area) 15 mg/m2). experiencedbolus intravenous hypotension, administration increased heart of carfilzomibrate, and increased at ≥ 2 serummg/kg/dose levels inof troponin‑T.rats and The2 mg/kg/doserepeated in cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of VomitingConstipation 117110 (22.2) (20.9) 5 (1.0) 1 (0.2) 0 0 • If tolerated, the reduced dose may be escalated to the bolusmonkeys intravenous using administration dosing schedules of carfilzomib similar to thoseat ≥ 2used mg/kg/dose clinically in resulted rats and in mortalities2 mg/kg/dose that inwere patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or ConstipationNeutropenia 110109 (20.9) (20.7) 1 (0.2) 50 (9.5)0 4 (0.8) due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid previous dose at the discretion of the physician. 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk monkeys using dosing schedules similar to those used clinically resulted in mortalities that were NeutropeniaBack pain 109106 (20.7) (20.2) 50 (9.5) 15 (2.9) 4 (0.8)0 due accumulation,to toxicities occurring cardiac inhemorrhage/degeneration), the cardiovascular (cardiac gastrointestinal failure, cardiac (necrosis/hemorrhage), fibrosis, pericardial fluid renal Non-Hematologic Toxicity Recommended Action assessment [see Dosage and Administration]. Patients with New York Heart Association Class III and (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities BackInsomnia pain 106 (20.2)94 (17.9) 15 (2.9)0 0 0 accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal Cardiac Toxicity • Withhold until resolved or returned to baseline. (glomerulonephropathy,systems. The dose of tubular2 mg/kg/dose necrosis, in rats dysfunction), is approximately and pulmonary half the recommended (hemorrhage/inflammation) dose in humans uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater InsomniaChills 94 (17.9)84 (16.0)0 1 (0.2) 0 0 2 Grade 3 or 4, new onset or worsening of: • After resolution, consider if restarting KYPROLIS at systems.of 27 The mg/m dose based of 2 mg/kg/dose on body surface in rats area. is approximately The dose of 2half mg/kg/dose the recommended in monkeys dose is inapproximately humans 2 risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) • congestive heart failure; a reduced dose is appropriate (from 27 mg/m to ChillsArthralgia 84 (16.0)83 (15.8) 1 (0.2) 7 (1.3) 0 0 of 27equivalent mg/m2 based to the onrecommended body surface dose area. in Thehumans dose based of 2 mg/kg/dose on body surface in monkeys area. is approximately 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of ArthralgiaMuscle spasms 83 (15.8)76 (14.4) 7 (1.3) 2 (0.4) 0 0 PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with • decreased left ventricular patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for equivalent to the recommended dose in humans based on body surface area. • If tolerated, the reduced dose may be escalated to the MuscleHypertension spasms 76 (14.4)75 (14.3) 2 (0.4)15 (2.9)0 2 (0.4) KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: function; pulmonary hypertension until resolved or returned to baseline and consider whether to restart PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with • or myocardial ischemia previous dose at the discretion of the physician. HypertensionAsthenia 75 (14.3)73 (13.9)15 (2.9) 12 (2.3) 2 (0.4)1 (0.2) KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms:fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS KYPROLIS based on a benefit/risk assessment [seeDosage and Administration]. Pulmonary may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or [see Warnings and Precautions] Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea AstheniaHypokalemia 73 (13.9)72 (13.7) 12 (2.3)14 (2.7) 1 (0.2)3 (0.6) fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS mayoperate cause fatigue,machinery dizziness, if they experience fainting, and/or any of drop these in symptoms. blood pressure. Advise Advise patients patients that they not may to driveexperience or Pulmonary Hypertension • Withhold until resolved or returned to baseline. occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage HypokalemiaHypomagnesemia 72 (13.7)71 (13.5) 14 (2.7)2 (0.4) 3 (0.6)0 shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see operate machinery if they experience any of these symptoms. Advise patients that they may experience [see Warnings and Precautions] • Restart at the dose used prior to the event or reduced HypomagnesemiaLeukopenia 71 (13.5)71 (13.5) 2 (0.4)27 (5.1)0 1 (0.2) shortnessa day of dosing.breath (dyspnea)Advise patients during to treatment contact theirwith physiciansKYPROLIS. ifThis they most experience commonly shortness occurs ofwithin breath. dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were LeukopeniaPain in extremity 71 (13.5)70 (13.3)27 (5.1) 7 (1.3) 1 (0.2)0 a dayCounsel of dosing. patients Advise to avoidpatients dehydration, to contact sincetheir physicianspatients receiving if they experienceKYPROLIS therapyshortness may of experiencebreath. to 15 mg/m2), at the discretion of the physician. characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial PainPneumonia in extremity 70 (13.3)67 (12.7) 7 (1.3) 52 (9.9) 03 (0.6)b Counselvomiting patients and/or to avoiddiarrhea. dehydration, Instruct patientssince patients to seek receiving medical KYPROLIS advice if therapythey experience may experience symptoms • If tolerated, the reduced dose may be escalated to the flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, of dizziness, lightheadedness, or fainting spells. Counsel females of reproductive potential to use or angina. These reactions can occur immediately following or up to 24 hours after administration of PneumoniaAspartate aminotransferase increased 67 (12.7)66 (12.5) 52 (9.9) 15 (2.9)3 (0.6) 1 (0.2)b vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms previous dose at the discretion of the physician. of dizziness,effective contraceptivelightheadedness, measures or fainting to prevent spells. pregnancy Counsel femalesduring treatment of reproductive with KYPROLIS. potential Adviseto use the KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of Dizziness 66 (12.5) 5 (1.0) 1 (0.2) Pulmonary Complications • Withhold until resolved or returned to baseline. Aspartate aminotransferase increased 66 (12.5) 15 (2.9) 1 (0.2) effectivepatient contraceptive that if she becomes measures pregnant to prevent during pregnancy treatment, during to contact treatment her withphysician KYPROLIS. immediately. Advise theAdvise reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact • Grade 3 or 4 • Consider restarting at the next scheduled treatment DizzinessHypoesthesia 66 (12.5)64 (12.2) 5 (1.0)3 (0.6) 1 (0.2)0 patientpatients that ifnot she to becomestake KYPROLIS pregnant treatment during while treatment, pregnant to contact or breastfeeding. her physician If a patientimmediately. wishes Advise to restart 2 physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. Tumor Lysis [see Warnings and Precautions] with one dose level reduction (from 27 mg/m to HypoesthesiaAnorexia 64 (12.2)63 (12.0) 3 (0.6)1 (0.2) 0 0 patientsbreastfeeding not to take after KYPROLIS treatment, treatment advise while her to pregnant discuss orthe breastfeeding. appropriate timing If a patient with her wishes physician. to restart Advise 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients to discuss with their physician any medication they are currently taking prior to starting patients. Patients with multiple myeloma and a high tumor burden should be considered to be at AnorexiaPain 63 (12.0)63 (12.0)1 (0.2) 12 (2.3) 0 0 breastfeeding after treatment, advise her to discuss the appropriate timing with her physician. Advise • If tolerated, the reduced dose may be escalated to the patientstreatment to discuss with KYPROLIS, with their orphysician prior to startingany medication any new medication(s)they are currently during taking treatment prior with to startingKYPROLIS. greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage PainHyperglycemia 63 (12.0)62 (11.8) 12 (2.3)16 (3.0)0 3 (0.6) previous dose at the discretion of the physician. treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS. and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt HyperglycemiaChest wall pain 62 (11.8)60 (11.4) 16 (3.0)3 (0.6) 3 (0.6)0 Hepatic Toxicity • Withhold until resolved or returned to baseline. KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia. KYPROLIS ChestHypercalcemia wall pain 60 (11.4)58 (11.0) 3 (0.6)13 (2.5) 08 (1.5) • Grade 3 or 4 elevation of • After resolution, consider if restarting KYPROLIS is causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and Hypophosphatemia 55 (10.5) 24 (4.6) 3 (0.6) transaminases, bilirubin or other appropriate; may be reinitiated at a reduced dose (from recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of Hypercalcemia 58 (11.0) 13 (2.5) 8 (1.5) liver abnormalities 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following HypophosphatemiaHyponatremia 55 (10.5)54 (10.3) 24 (4.6) 31 (5.9)3 (0.6) 3 (0.6) Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand A venue, with frequent monitoring of liver function. a [see Warnings and Precautions)] KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of HyponatremiaNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.54 (10.3) 31 (5.9) 3 (0.6) ManufacturedSouth San Francisco, CA 94080 for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, b • If tolerated, the reduced dose may be escalated to the treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.One event was Grade 5 severity. South San Francisco, CA 94080 U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 previous dose at the discretion of the physician. with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration]. bOne event was Grade 5 severity. U.S.©2012 Patent Onyx Numbers Pharmaceuticals,: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 Inc. 1012-CARF-409 September 2012 (continued) Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012 Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued) reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold Description of Selected Adverse Drug Reactions. Renal Events: The most common renal Renal Toxicity • Withhold until renal function has recovered to Grade 1 reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other Descriptionadverse reactions of Selected were increaseAdverse in Drugblood Reactions.creatinine (24%) Renal and Events: renal failure The most(9%), whichcommon were renal mostly • Serum creatinine equal to or or to baseline and monitor renal function. KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restartingadverse Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly greater than 2 × baseline • If attributable to KYPROLIS, restart at the next scheduled liver KYPROLISabnormalities is appropriate. until resolved Monitor or returned liver enzymes to baseline. frequently After [seeresolution, Dosage consider and Administration if restarting andGrade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal 2 KYPROLISAdverse is Reactionsappropriate.]. Embryo-fetal Monitor liver Toxicity. enzymes KYPROLIS frequently can [see cause Dosage fetal harmand Administrationwhen administered and to aGrade 4 failure events were occurred1% each. in In 1%. one Discontinuations patient, death occurreddue to increased with concurrent blood creatinine sepsis and and worsening acute renal renal [see Adverse Reactions] treatment at a reduced dose (from 27 mg/m to KYPROLIS™ (carfilzomib) for Injection 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). Adversepregnant Reactions woman]. Embryo-fetalbased on its mechanism Toxicity. KYPROLISof action and can findings cause fetal in animals. harm when There administered are no adequate to a andfailure function were [see1% each.Dosage In andone Administration patient, death]. occurredPeripheral with Neuropathy: concurrent Peripheralsepsis and neuropathy worsening (including renal Brief Summary of Prescribing Information. Please see the KYPROLIS package insert • If not attributable to KYPROLIS, restart at the dose used pregnantwell‑ controlledwoman based studies on inits pregnantmechanism women of action using and KYPROLIS. findings Carfilzomib in animals. Therecaused are embryo no adequate‑fetal toxicity and infunction all events [see Dosageof peripheral and Administration sensory neuropathy]. Peripheral and peripheralNeuropathy: motor Peripheral neuropathy) neuropathy occurred (including in 14% of for full prescribing information. prior to the event. well‑pregnantcontrolled rabbits studies at indoses pregnant that were women lower using than KYPROLIS. in patients Carfilzomib receiving the caused recommended embryo‑fetal dose. toxicity Females in ofall eventspatients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple pregnantreproductive rabbits atpotential doses thatshould were be loweradvised than to avoidin patients becoming receiving pregnant the recommended while being treated dose. withFemales KYPROLIS. of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% • If tolerated, the reduced dose may be escalated to the If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see myeloma who have received at least two prior therapies including bortezomib and an previous dose at the discretion of the physician. reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% If thispatient drug shouldis used be during apprised pregnancy, of the potential or if the hazard patient to becomesthe fetus [seepregnant Use inwhile Specific taking Populations this drug,]. the and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% immunomodulatory agent and have demonstrated disease progression on or within 60 days of Peripheral Neuropathy • Withhold until resolved or returned to baseline. completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full patientADVERSE should be REACTIONS: apprised of the The potential following hazard adverse to reactionsthe fetus are[see discussed Use in Specific in greater Populations detail in other]. sectionsDosage of patients. and Administration Consider antiviral]. Herpes prophylaxis Virus Infection: for patients Herpes who zosterhave a reactivation history of herpes was reported zoster infection. in 2% • Grade 3 or 4 • Restart at the dose used prior to the event or reduced ADVERSEof the labeling: REACTIONS: The following adverse reactions are discussed in greater detail in other sections of patients.DRUG INTERACTIONS:Consider antiviral Carfilzomibprophylaxis for is patientsprimarily who metabolized have a history via peptidase of herpes and zoster epoxide infection. hydrolase PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 2 2 [see Adverse Reactions] dose (from 27 mg/m to 20 mg/m , OR from 20 mg/m of the labeling:• Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] DRUGactivities, INTERACTIONS: and as a result, Carfilzomib the pharmacokinetic is primarily metabolized profile of viacarfilzomib peptidase is and unlikely epoxide to behydrolase affected by DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously to 15 mg/m2), at the discretion of the physician. over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see • Pulmonary Hypertension [see Warnings and Precautions] Warnings and Precautions] activities,concomitant and as administration a result, the ofpharmacokinetic cytochrome P450 profile inhibitors of carfilzomib and inducers. is unlikelyCarfilzomib to be is affected not expected by • If tolerated, the reduced dose may be escalated to the 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment • Pulmonary Hypertension [see • Pulmonary Complications [see WarningsWarnings and Precautionsand Precautions] ] concomitantto influence administration exposure of of other cytochrome drugs [see P450Clinical inhibitors Pharmacology and inducers. section Carfilzomib of full PI]. is not expected previous dose at the discretion of the physician. cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the • Pulmonary Complications [see • Infusion Reactions [see WarningsWarnings and and Precautions Precautions] ] to influenceUSE IN exposureSPECIFIC of otherPOPULATIONS: drugs [seeClinical Pregnancy. Pharmacology Pregnancy section Category of full PI]. D [see Warnings and dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent Other • Withhold until resolved or returned to baseline. • Infusion Reactions [see • Tumor Lysis Syndrome [see WarningsWarnings and Precautions and Precautions] ] USEPrecautions IN SPECIFIC]. Females of reproductive potential should be advised to avoid becoming pregnant while POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see • Grade 3 or 4 non-hematological • Consider restarting at the next scheduled treatment • Tumor Lysis Syndrome [see • Thrombocytopenia [see Warnings and Precautions]] Precautionsbeing treated]. Females of reproductive potential should be advised to avoid becoming pregnant while with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS ]. The dose is calculated using the patient’s actual body surface area at toxicities with one dose level reduction (from 27 mg/m2 to • Thrombocytopenia [see• Hepatic Toxicity and Hepatic Failure [see Warnings and PrecautionsWarnings] and Precautions] beingcan treated cause with fetal KYPROLIS. harm when Based administered on its mechanism to a pregnant of action woman. and findings Carfilzomib in animals, caused KYPROLISembryo‑fetal Dosage and Administration 2 2 2 baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a 20 mg/m , OR from 20 mg/m to 15 mg/m ). • Hepatic Toxicity and Hepatic Failure [see The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical Warnings and Precautions] can toxicitycause fetalin pregnant harm when rabbits administered at doses that to awere pregnant lower woman.than in patientsCarfilzomib receiving caused the embryorecommended‑fetal body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than • If tolerated, the reduced dose may be escalated to the The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea,toxicity dose. in Ifpregnant KYPROLIS rabbits is used at dosesduring thatpregnancy, were lower or if thanthe patientin patients becomes receiving pregnant the recommended while taking this or equal to 20%. previous dose at the discretion of the physician. trialsdiarrhea, of patients and with pyrexia. multiple Clinical myeloma Trials were Safety fatigue, Experience. anemia, nausea, Because thrombocytopenia, clinical trials are dyspnea, conducted dose. drug, If KYPROLIS the patient is should used duringbe apprised pregnancy, of the potentialor if the hazardpatient tobecomes the fetus. pregnant Carfilzomib while was taking administered this a diarrhea,under andwidely pyrexia. varying Clinical conditions, Trials adverse Safety reaction Experience. rates observed Because in theclinical clinical trials trials are of conducteda drug cannot drug, intravenously the patient shouldto pregnant be apprised rats and of rabbitsthe potential during hazard the period to the of fetus.organogenesis Carfilzomib at doseswas administered of 0.5, 1, and Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. underbe widely directly varying compared conditions, with rates adverse in the reaction clinical rates trials observed of another in the drug, clinical and trialsmay ofnot a reflectdrug cannot the rates intravenously 2 mg/kg/day to pregnant in rats andrats 0.2,and rabbits0.4, and during 0.8 mg/kg/daythe period ofin organogenesisrabbits. Carfilzomib at doses was of 0.5,not teratogenic1, and Cycle 1 Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg be directlyobserved compared in medical with practice. rates in A thetotal clinical of 526 trialspatients of anotherwith relapsed drug, and/orand may refractory not reflect multiple the myeloma rates 2 mg/kg/dayat any dose in ratstested. and In 0.2, rabbits, 0.4, thereand 0.8was mg/kg/day an increase in inrabbits. pre‑implantation Carfilzomib loss was at not≥ 0.4 teratogenic mg/kg/day carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity observedreceived in medicalKYPROLIS practice. as monotherapy A total of 526 or with patients pre‑ dosewith relapseddexamethasone. and/or refractory Patients multiplereceived myeloma a median ofat anyand dose an increase tested. Inin rabbits,early resorptions there was andan increasepost‑implantation in pre‑implantation loss and a loss decrease at ≥ 0.4 in fetalmg/kg/day weight at Week 1 Week 2 Week 3 Week 4 delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other Day Days Day Day Days Day Day Days Days receivedfour treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all KYPROLIS as monotherapy or with pre‑dose dexamethasone. Patients received a median of and thean increase maternally in toxicearly doseresorptions of 0.8 mg/kg/day. and post‑implantation The doses lossof 0.4 and and a decrease 0.8 mg/kg/day in fetal inweight rabbits at are Day medicinal products. The intravenous administration line should be flushed with normal saline or 5% 2 1 2 3–7 8 9 10–14 15 16 17–21 22–28 four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not the approximatelymaternally toxic 20% dose and of 40%, 0.8 mg/kg/day. respectively, Theof the doses recommended of 0.4 and dose 0.8 in mg/kg/day humans of in 27 rabbits mg/m are based Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not 2 KYPROLIS 20 20 No 20 20 No 20 20 No No causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest,approximately on body surface 20% and area. 40%, Nursing respectively, Mothers. of the It isrecommended not known whether dose in KYPROLIShumans of is 27 excreted mg/m basedin human 2 be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution (20 mg/m ): Dosing Dosing Dosing Dosing attributedcardiac to disorder),disease progression end‑organ werefailure cardiac in 4 patients in 5 patients (multi (acute‑organ coronary failure, syndrome,hepatic failure, cardiac renal arrest, failure), on bodymilk. surfaceSince many area. drugs Nursing are excreted Mothers. in humanIt is not milk known and whether because KYPROLIS of the potential is excreted for serious in human adverse a and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and reactions in nursing infants from KYPROLIS, a decision should be made whether to discontinue nursing Cycles 2 and Beyond cardiac disorder), end‑organ failure in 4 patients (multi‑organ failure, hepatic failure, renal failure), milk. Since many drugs are excreted in human milk and because of the potential for serious adverse preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the infectionintracranial in 4 patientshemorrhage (sepsis, in 1 patientpneumonia, each, respiratoryand 1 patient tract found bacterial dead ofinfection), unknown dyspnea causes. andSerious reactions or to discontinuein nursing infants the drug, from taking KYPROLIS, into account a decision the should importance be made of thewhether drug toto discontinuethe mother. nursing Pediatric Week 1 Week 2 Week 3 Week 4 date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The intracranialadverse hemorrhagereactions were in 1reported patient in each, 45% andpatients. 1 patient The mostfound common dead of serious unknown adverse causes. reactions Serious were or toUse. discontinue The safety the anddrug, effectiveness taking into account of KYPROLIS the importance in pediatric of thepatients drug tohave the notmother. been Pediatric established. Day Day Days Day Day Days Day Day Days Days reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete adversepneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions were reported in 45% patients. The most common serious adverse reactions were Use.Geriatric The safety Use. and In studieseffectiveness of KYPROLIS of KYPROLIS there were in nopediatric clinically patients significant have differences not been observedestablished. in safety 1 2 3–7 8 9 10–14 15 16 17–21 22–28 preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestiveGeriatric and efficacy Use. In betweenstudies ofpatients KYPROLIS less therethan were65 years no clinically of age and significant patients differences65 years of observedage and inolder. safetyRenal KYPROLIS 27 27 No 27 27 No 27 27 No No from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mL reactionsheart leadingfailure (2%),to discontinuation cardiac arrest, of KYPROLISdyspnea, increasedoccurred in blood 15% creatinine,of patients and includedacute renal congestive failure (1% and Impairment.efficacy between The patientspharmacokinetics less than 65 years and safety of age of KYPROLISand patients were 65 years evaluated of age in and a Phaseolder.Renal 2 trial in 2 Dosing Dosing Dosing Dosing (27 mg/m ): Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize hearteach). failure Adverse (2%), cardiacreactions arrest, occurring dyspnea, at a rateincreased of 10% blood or greater creatinine, are presented and acute in renalTable failure4. (1% Impairment.patients with The normal pharmacokinetics renal function and and safety those of KYPROLISwith mild, moderate,were evaluated and severein a Phase renal 2 impairment trial in a If previous cycle dosage is tolerated. foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution each).Table Adverse 4: Incidence reactions occurringof Adverse at aReactions rate of 10% Occurring or greater in are ≥ 10% presented of Multiple in Table Myeloma 4. patientsand patientswith normal on chronic renal functiondialysis. andOn average,those with patients mild, weremoderate, treated and for severe 5.5 cycles renal using impairment KYPROLIS of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow 2 2 2 Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor TablePatients 4: Incidence Treated of with Adverse KYPROLIS Reactions Occurring in ≥ 10% of Multiple Myeloma and dosespatients of on15 chronicmg/m dialysis.on Cycle On 1, average,20 mg/m patients on Cycle were 2, treatedand 27 for mg/m 5.5 cycles on Cycles 3 and beyond. using KYPROLIS solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, 2 2 2 lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate Patients Treated with KYPROLIS dosesThe of pharmacokinetics 15 mg/m on Cycle and 1,safety 20 mg/mof KYPROLIS on Cycle were 2, notand influenced 27 mg/m on Cycles 3 and beyond. by the degree of baseline renal KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, Patients (N = 526) impairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrations fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in [n (%)] The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline renal Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted Patients (N = 526) impairment,has not includingbeen studied, the patientsthe drug on should dialysis. be Since administered dialysis clearanceafter the ofdialysis KYPROLIS procedure concentrations [see Clinical product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and All [n (%)]Grade 3 Grade 4 Pharmacology section of full PI]. Hepatic Impairment. The safety, efficacy and pharmacokinetics Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS a has not been studied, the drug should be administered after the dialysis procedure [see Clinical administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag. Event AllGrades Grade 3Events Grade 4Events Pharmacologyof KYPROLIS section have notof fullbeen PI]. evaluated Hepatic in Impairment. patients with Thebaseline safety, hepatic efficacy impairment. and pharmacokinetics Patients with the a patients during this period for fluid overload [seeWarnings and Precautions]. Dexamethasone 6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted Fatigue Event Grades292 (55.5) Events38 (7.2) Events2 (0.4) of KYPROLISfollowing laboratory values were excluded from the KYPROLIS clinical trials: have not been evaluated in patients with baseline hepatic impairment. ALT/AST ≥ 3 × upper Patients with the Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS under various temperature and container conditions are shown in Table 3. FatigueAnemia 292246 (55.5) (46.8)38 (7.2) 111 (21.1) 2 (0.4)7 (1.3) following laboratory values were excluded from the KYPROLIS clinical trials:limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology sectionALT/AST ≥ 3 × upper of full PI]. Cardiac KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to Table 3: Stability of Reconstituted KYPROLIS AnemiaNausea 246236 (44.9) (46.8) 111 (21.1) 7 (1.3) 7 (1.3)0 limitImpairment. of normal (ULN) Patients and bilirubin with New ≥ 2York × ULNHeart [see Association Clinical Pharmacology Class III and IV section heart failure of full werePI]. Cardiac not eligible 27 mg/m2 to reduce the incidence and severity of infusion reactions [see ]. for the clinicalPatients trials. with Safety New in York this Heartpopulation Association has not Class been III evaluated. and IV heart failure were not eligible Warnings and Precautions Stabilitya per Container NauseaThrombocytopenia 236 (44.9)191 (36.3) 7 (1.3) 69 (13.1) 54 (10.3)0 Impairment. for theOVERDOSAGE: clinical trials. SafetyThere isin nothis known population specific has notantidote been forevaluated. KYPROLIS overdosage. In the event of an Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or Storage Conditions of Reconstituted b reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended ThrombocytopeniaDyspnea 191 (36.3)182 (34.6) 69 (13.1)25 (4.8) 54 (10.3) 1 (0.2) OVERDOSAGE:overdosage, monitorThere is the no patientknown andspecific provide antidote appropriate for KYPROLIS supportive overdosage. care. In the event of an KYPROLIS IV Bag b actions and dose modifications are presented in Table 2. Vial Syringe (D5Wb) DyspneaDiarrhea 182 (34.6)172 (32.7) 25 (4.8)4 (0.8) 1 (0.2) 1 (0.2) overdosage,NONCLINICAL monitor TOXICOLOGY:the patient and Carcinogenesis,provide appropriate Mutagenesis, supportive care. and Impairment of Fertility. Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment DiarrheaPyrexia 172 (32.7)160 (30.4)4 (0.8) 7 (1.3) 1 (0.2)2 (0.4) NONCLINICALCarcinogenicity TOXICOLOGY: studies have Carcinogenesis,not been conducted Mutagenesis, with carfilzomib. and Carfilzomib Impairment was ofclastogenic Fertility. in the Refrigerated (2°C to 8°C; 36°F to 46°F) 24 hours 24 hours 24 hours PyrexiaUpper respiratory tract infection 160149 (28.3) (30.4) 7 (1.3) 17 (3.2) 2 (0.4)0 Carcinogenicityin vitro chromosomal studies have aberration not been test conducted in peripheral with blood carfilzomib. lymphocytes. Carfilzomib Carfilzomib was clastogenic was not mutagenicin the Hematologic Toxicity Recommended Action in thechromosomal in vitro bacterial aberration reverse test mutation in peripheral (Ames) blood test lymphocytes. and was not Carfilzomib clastogenic wasin the not in mutagenicvivo mouse a UpperHeadache respiratory tract infection 149 (28.3)145 (27.6) 17 (3.2)7 (1.3) 0 0 in vitro • Grade 3 or 4 Neutropenia • Withhold dose. Room Temperature (15°C to 30°C; 59°F to 86°F) 4 hours 4 hours 4 hours in thebone in vitromarrow bacterial micronucleus reverse mutationassay. Fertility (Ames) studies test and with was carfilzomib not clastogenic have in not the in been vivo mouse conducted. No HeadacheCough 145137 (26.0) (27.6) 7 (1.3)1 (0.2) 0 0 • Grade 4 Thrombocytopenia • If fully recovered before next scheduled dose, continue aTotal time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP. boneeffects marrow on micronucleusreproductive assay.tissues Fertility were noted studies during with carfilzomib 28‑day repeat have ‑dose not rat and been monkey conducted. toxicity No at same dose level. CoughBlood creatinine increased 137 (26.0)127 (24.1) 1 (0.2)13 (2.5) 01 (0.2) studies or in 6‑month rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/ [see Warnings and Precautions] WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial effects on reproductive tissues were noted during 28‑day repeat‑dose rat and monkey toxicity • If recovered to Grade 2 neutropenia or Grade 3 BloodLymphopenia creatinine increased 127126 (24.1) (24.0)13 (2.5) 84 (16.0)1 (0.2) 11 (2.1) studiesor Pharmacology. or in 6‑month rat Monkeys and 9‑ monthadministered monkey a chronicsingle bolus toxicity intravenous studies. doseAnimal of carfilzomibToxicology at 3 and/mg/kg Ischemia. Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on body surface area) thrombocytopenia, reduce dose by one dose level onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function or LymphopeniaEdema peripheral 126126 (24.0) (24.0) 84 (16.0)3 (0.6) 11 (2.1)0 or Pharmacology. Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg 2 2 2 experienced hypotension, increased heart rate, and increased serum2 levels of troponin‑T. The repeated (from 27 mg/m to 20 mg/m , OR from 20 mg/m to myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., EdemaVomiting peripheral 126117 (24.0) (22.2)3 (0.6) 5 (1.0) 0 0 (approximately 1.3 times recommended dose in humans of 27 mg/m based on body surface area) 15 mg/m2). experiencedbolus intravenous hypotension, administration increased heart of carfilzomibrate, and increased at ≥ 2 serummg/kg/dose levels inof troponin‑T.rats and The2 mg/kg/doserepeated in cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of VomitingConstipation 117110 (22.2) (20.9) 5 (1.0) 1 (0.2) 0 0 • If tolerated, the reduced dose may be escalated to the bolusmonkeys intravenous using administration dosing schedules of carfilzomib similar to thoseat ≥ 2used mg/kg/dose clinically in resulted rats and in mortalities2 mg/kg/dose that inwere patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or ConstipationNeutropenia 110109 (20.9) (20.7) 1 (0.2) 50 (9.5)0 4 (0.8) due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid previous dose at the discretion of the physician. 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk monkeys using dosing schedules similar to those used clinically resulted in mortalities that were NeutropeniaBack pain 109106 (20.7) (20.2) 50 (9.5) 15 (2.9) 4 (0.8)0 due accumulation,to toxicities occurring cardiac inhemorrhage/degeneration), the cardiovascular (cardiac gastrointestinal failure, cardiac (necrosis/hemorrhage), fibrosis, pericardial fluid renal Non-Hematologic Toxicity Recommended Action assessment [see Dosage and Administration]. Patients with New York Heart Association Class III and (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities BackInsomnia pain 106 (20.2)94 (17.9) 15 (2.9)0 0 0 accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal Cardiac Toxicity • Withhold until resolved or returned to baseline. (glomerulonephropathy,systems. The dose of tubular2 mg/kg/dose necrosis, in rats dysfunction), is approximately and pulmonary half the recommended (hemorrhage/inflammation) dose in humans uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater InsomniaChills 94 (17.9)84 (16.0)0 1 (0.2) 0 0 2 Grade 3 or 4, new onset or worsening of: • After resolution, consider if restarting KYPROLIS at systems.of 27 The mg/m dose based of 2 mg/kg/dose on body surface in rats area. is approximately The dose of 2half mg/kg/dose the recommended in monkeys dose is inapproximately humans 2 risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) • congestive heart failure; a reduced dose is appropriate (from 27 mg/m to ChillsArthralgia 84 (16.0)83 (15.8) 1 (0.2) 7 (1.3) 0 0 of 27equivalent mg/m2 based to the onrecommended body surface dose area. in Thehumans dose based of 2 mg/kg/dose on body surface in monkeys area. is approximately 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of ArthralgiaMuscle spasms 83 (15.8)76 (14.4) 7 (1.3) 2 (0.4) 0 0 PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with • decreased left ventricular patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for equivalent to the recommended dose in humans based on body surface area. • If tolerated, the reduced dose may be escalated to the MuscleHypertension spasms 76 (14.4)75 (14.3) 2 (0.4)15 (2.9)0 2 (0.4) KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: function; pulmonary hypertension until resolved or returned to baseline and consider whether to restart PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with • or myocardial ischemia previous dose at the discretion of the physician. HypertensionAsthenia 75 (14.3)73 (13.9)15 (2.9) 12 (2.3) 2 (0.4)1 (0.2) KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms:fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS KYPROLIS based on a benefit/risk assessment [seeDosage and Administration]. Pulmonary may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or [see Warnings and Precautions] Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea AstheniaHypokalemia 73 (13.9)72 (13.7) 12 (2.3)14 (2.7) 1 (0.2)3 (0.6) fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS mayoperate cause fatigue,machinery dizziness, if they experience fainting, and/or any of drop these in symptoms. blood pressure. Advise Advise patients patients that they not may to driveexperience or Pulmonary Hypertension • Withhold until resolved or returned to baseline. occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage HypokalemiaHypomagnesemia 72 (13.7)71 (13.5) 14 (2.7)2 (0.4) 3 (0.6)0 shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see operate machinery if they experience any of these symptoms. Advise patients that they may experience [see Warnings and Precautions] • Restart at the dose used prior to the event or reduced HypomagnesemiaLeukopenia 71 (13.5)71 (13.5) 2 (0.4)27 (5.1)0 1 (0.2) shortnessa day of dosing.breath (dyspnea)Advise patients during to treatment contact theirwith physiciansKYPROLIS. ifThis they most experience commonly shortness occurs ofwithin breath. dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were LeukopeniaPain in extremity 71 (13.5)70 (13.3)27 (5.1) 7 (1.3) 1 (0.2)0 a dayCounsel of dosing. patients Advise to avoidpatients dehydration, to contact sincetheir physicianspatients receiving if they experienceKYPROLIS therapyshortness may of experiencebreath. to 15 mg/m2), at the discretion of the physician. characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial PainPneumonia in extremity 70 (13.3)67 (12.7) 7 (1.3) 52 (9.9) 03 (0.6)b Counselvomiting patients and/or to avoiddiarrhea. dehydration, Instruct patientssince patients to seek receiving medical KYPROLIS advice if therapythey experience may experience symptoms • If tolerated, the reduced dose may be escalated to the flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, of dizziness, lightheadedness, or fainting spells. Counsel females of reproductive potential to use or angina. These reactions can occur immediately following or up to 24 hours after administration of PneumoniaAspartate aminotransferase increased 67 (12.7)66 (12.5) 52 (9.9) 15 (2.9)3 (0.6) 1 (0.2)b vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms previous dose at the discretion of the physician. of dizziness,effective contraceptivelightheadedness, measures or fainting to prevent spells. pregnancy Counsel femalesduring treatment of reproductive with KYPROLIS. potential Adviseto use the KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of Dizziness 66 (12.5) 5 (1.0) 1 (0.2) Pulmonary Complications • Withhold until resolved or returned to baseline. Aspartate aminotransferase increased 66 (12.5) 15 (2.9) 1 (0.2) effectivepatient contraceptive that if she becomes measures pregnant to prevent during pregnancy treatment, during to contact treatment her withphysician KYPROLIS. immediately. Advise theAdvise reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact • Grade 3 or 4 • Consider restarting at the next scheduled treatment DizzinessHypoesthesia 66 (12.5)64 (12.2) 5 (1.0)3 (0.6) 1 (0.2)0 patientpatients that ifnot she to becomestake KYPROLIS pregnant treatment during while treatment, pregnant to contact or breastfeeding. her physician If a patientimmediately. wishes Advise to restart 2 physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. Tumor Lysis [see Warnings and Precautions] with one dose level reduction (from 27 mg/m to HypoesthesiaAnorexia 64 (12.2)63 (12.0) 3 (0.6)1 (0.2) 0 0 patientsbreastfeeding not to take after KYPROLIS treatment, treatment advise while her to pregnant discuss orthe breastfeeding. appropriate timing If a patient with her wishes physician. to restart Advise 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients to discuss with their physician any medication they are currently taking prior to starting patients. Patients with multiple myeloma and a high tumor burden should be considered to be at AnorexiaPain 63 (12.0)63 (12.0)1 (0.2) 12 (2.3) 0 0 breastfeeding after treatment, advise her to discuss the appropriate timing with her physician. Advise • If tolerated, the reduced dose may be escalated to the patientstreatment to discuss with KYPROLIS, with their orphysician prior to startingany medication any new medication(s)they are currently during taking treatment prior with to startingKYPROLIS. greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage PainHyperglycemia 63 (12.0)62 (11.8) 12 (2.3)16 (3.0)0 3 (0.6) previous dose at the discretion of the physician. treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS. and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt HyperglycemiaChest wall pain 62 (11.8)60 (11.4) 16 (3.0)3 (0.6) 3 (0.6)0 Hepatic Toxicity • Withhold until resolved or returned to baseline. KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia. KYPROLIS ChestHypercalcemia wall pain 60 (11.4)58 (11.0) 3 (0.6)13 (2.5) 08 (1.5) • Grade 3 or 4 elevation of • After resolution, consider if restarting KYPROLIS is causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and Hypophosphatemia 55 (10.5) 24 (4.6) 3 (0.6) transaminases, bilirubin or other appropriate; may be reinitiated at a reduced dose (from recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of Hypercalcemia 58 (11.0) 13 (2.5) 8 (1.5) liver abnormalities 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following HypophosphatemiaHyponatremia 55 (10.5)54 (10.3) 24 (4.6) 31 (5.9)3 (0.6) 3 (0.6) Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand A venue, with frequent monitoring of liver function. a [see Warnings and Precautions)] KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of HyponatremiaNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.54 (10.3) 31 (5.9) 3 (0.6) ManufacturedSouth San Francisco, CA 94080 for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, b • If tolerated, the reduced dose may be escalated to the treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.One event was Grade 5 severity. South San Francisco, CA 94080 U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 previous dose at the discretion of the physician. with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration]. bOne event was Grade 5 severity. U.S.©2012 Patent Onyx Numbers Pharmaceuticals,: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 Inc. 1012-CARF-409 September 2012 (continued) Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012 SP120 Payer Trends

Trends in Payer Management (continued from cover) Emerging Plan Access Approaches in Oncology Figure 1. Emerging Plan Access Approaches in Oncology Trend #2: Management of Office- Market dynamics fuel significant changes in health plans’ approach Administered Agents Marketto oral dynamics and fueloffice-administered significant changes in healthoncology plans’ approachesagents. Office-administered agents will face to oral and office-administered oncology agents. more access barriers. In the past 18 months, many plans rolled out changes to their infrastructure to improve Trend #2 management of these drugs. One of Trend #1 Management Trend #3 Trend #4 Trend #5 the newest changes is claims adjudica- Rigorous of office- Site-of-care Oncologist Use of low- tion by National Drug Code (NDC) data. approval administered management engagement cost agents Widespread plan requirements to col- criteria agents lect NDC data in claims submissions by 2014 will improve plans’ ability to en- force use of low-cost agents. With the Increasing cost-containment Increased hospital End-of-life data specificity provided by NDC codes, Generic entrants pressures infusions concerns plans can set different reimbursement amounts for generic and branded op- Better technical Increased tions, reducing physicians’ incentive to Clinical pathways P4P expansion platforms therapeutic choice use high-priced choices. Oncologists should expect even greater communication with payers around alignment as more practices Brands face limited approved use implement electronic medical records (EMRs). Automatic payer precertification through EMRs will save time and reduce financial risks for practices. Plans will also benefit from greater P4P indicates pay for performance. alignment as oncologists are able to view pathways and PA criteria in “real include both market factors and new During this expansion, plans will rely requiring reauthorization for extended time.” This technology will provide payer capabilities. on compendia guidelines from the Na- use of a product. plans with more opportunities to build tional Comprehensive Cancer Network Despite these efforts, plans recog- tools that can help them manage of- External, Internal Factors and other organizations to guide path- nize that PAs have a limited role and fice-administered agents. The way health plans make decisions ways. If successful, these pilots will that pathways are a better long-term on oncology agents is changing in part help create the foundation for greater strategy to ensure appropriate use. As Trend #3: Site-of-Care Management because of their success containing control of access. Health Strategies plans roll out clinical pathways, they Moving forward, plans will take steps costs in other complex drug catego- Group expects that after rolling out the will likely remove PA requirements. to influence site of care and move ad- ries comprising both self-injected and additional pathways, plans will start To encourage provider adherence to ministration of office-administered office-administered biologics, such as narrowing pathway choice to specific the new pathways, plans will likely ask oncology agents away from hospitals. autoimmune and multiple sclerosis first-line agents beginning in 2015. oncologists for their input and provide Their goal will be to drive patients to agents. Plans also have better infor- While these strategies are suited for technology that helps integrate the the most cost-effective setting, which mation technology with expanded ca- the short term, they do not address pathways into their process. In addi- may be a specialty pharmacy manager. pabilities in data analysis, so they can payers’ goals over the long haul. Our tion, plans will likely provide financial However, plans are somewhat limited identify inappropriate use and refine research suggests that shifting man- incentives to oncologists to encourage in how they can drive the local mar- drug reimbursement. These improved agement priorities are likely to gener- adherence. ket dynamics that determine where capabilities—combined with the ex- ate 5 trends during the next 5 years panded choices afforded by new drug (Figure 1). Figure 2. Prior Authorization (PA) Goals for Oral Oncolytics in 2014 approvals and generic options, as well Plans will narrow PA approval criteria to restrict use of high-cost agents lacking as a robust pipeline—are driving plans’ Trend #1: Rigorous Approval Criteria substantial survival improvements. interest in using more management Plans say they will narrow prior autho- tactics. rization (PA) approval criteria to restrict Initial approval criteria will prospectively confirm dosing, duration. use of oncology agents, particularly More plans will require reauthorization for extended use. Likely Short-Term Steps high-cost agents lacking substantial Plans will remove PA requirements when pathways roll out. With their focus squarely on oncology survival improvements. As they com- agents, payers will take several man- monly do today, health plans will use Plan PA Goals for Oral Oncolytics in 2014 agement actions in the short term. For PAs to ensure alignment with label- (Percentage plans) instance, newly approved oral oncolyt- ing and compendia (Figure 2). In addi- ics will face high cost-sharing require- tion, 60% of plans expect to influence ments. Many plans will change their treatment order by requiring trials of benefit designs—by adding more tiers specific first- and second-line agents. or raising copay levels, for example— As new therapeutic choices emerge to increase cost sharing. Half of plans to treat certain tumor types, such as already require members to pay ad- metastatic breast cancer and prostate ditional fees for office-administered cancer, we expect more plans to adopt drugs, and more plans will follow suit. a similar “lines of therapy” strategy. In Payers will also roll out clinical path- addition, more plans will manage ther- ways that cover more tumor types and apy duration by not only prospectively more oncologists in their networks. confirming treatment plans but also FDA indicates US Food and Drug Administration.

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 Payer Trends SP121

before to implement P4P with oncolo- ing Sprycel (dasatinib) or Tasigna (nilo- Figure 3. Anticipated Plan Tactics to Reduce Hospital gists—building on their experience de- tinib) (Figure 4). These intended moves Administration in 2014 signing P4P for primary care providers, demonstrate payers’ increasing will- plans can refine their approaches for ingness to influence therapy order— Plans may take steps to influence site of care. the unique challenges of oncologists. fewer plans were interested in taking Site-of-care challenges vary by local market area. These challenges include the availabil- such actions as recently as 2010. ity of new generics as well as the wide Plans will also take steps to increase Some plans may pilot episodic payment models. variation in prescribing in oncology. use of generic alternatives for office- Plans will consider more fundamental network design changes. Plans have yet to develop an effective administered agents in the next few “We want to make sure that what we pay for is in the most cost-effective setting, whether it’s the physi- solution for managing the high costs years, primarily by embedding recom- cian’s office or a freestanding infusion center, but not the outpatient hospital.” – Regional Independent of care at the end of life (EOL). Given mendations in clinical pathways or PA Medical the sensitive nature of this topic, plans criteria. But encouraging use of these aren’t likely to deny therapy to patients lower-cost infused agents is a little Anticipated Plan Tactics to Reduce Hospital Administration in 2014 (Percentage plans) with advanced cancer. For their part, trickier for plans. Coding and current oncologists are often reluctant to have fee schedules need to be refined to EOL discussions with their patients. neutralize profit incentives associated One possible solution for plans would with brands and encourage generic be to utilize case managers and social use. workers to initiate advance care planning, although they would need to be More Access Barriers Down the Road careful not to overstep their bounds. Payer adoption of these emerging Another possibility is for plans to in- trends will vary greatly. In the short crease payments to oncologists for term, health plans will likely focus on improving patient and physician sup- P4P indicates pay for performance. port, rather than implementing penalties and coverage denials. Over time patients receive these agents. Of late, will likely lead this effort. Plans may payers will be more interested in ad- these dynamics include more hospitals also consider more fundamental net- Recognizing that vanced management strategies that buying up oncology practices, a trend work design changes, such as only of- require collaboration with providers to that has driven steady increases in fering “preferred” or “in-network” sta- oncologists are key ensure appropriate use. EBO hospital outpatient infusions in some tus to hospitals with reasonable infu- markets. In addition, diminishing prof- sion charges. partners in their Acknowledgments it margins on drugs have prompted All figures and statistics in this article some oncology groups to refer patients Trend #4: Oncologist Engagement efforts to provide are based on the 2012 findings of Health to hospital outpatient departments for Recognizing that oncologists are key Strategies Group’s Managed Care Complete infusions. Accountable care organiza- partners in their efforts to provide bet- better value and research series, which reports on 10 cat- tion growth may accelerate this trend. ter value and higher quality care, plans egories, including oral oncolytics and of- For now, the best tool for plans is to will introduce new financial incentives higher quality fice-administered oncology agents. Man- ratchet down hospital reimbursement, to influence provider decisions. These aged Care Complete provides future-ori- which 46% of plans will try in 2014 (Fig- will include oncologist-specific pay- care, plans will ented, strategic insights on the decisions ure 3). In addition, many plans will pilot for-performance (P4P) programs, which that all relevant managed care customers reimbursement models, including epi- will reward oncologists for cost-of-care introduce new and business lines make that affect brand sodic payments that encourage provid- reductions, quality improvements, in- access. Health Strategies Group offers ers to select low-cost administration creased generic prescribing, reduced financial incentives syndicated research and client-private locations. Integrated health plans with hospital infusions, and other goals. consulting, which focus on understand- strong relations with oncology groups Plans are in a better position than ever to influence provider ing the pharmaceutical and biotech industry’s key customers and influencers. decisions. Author Affiliation: From Health Strategies Figure 4. Anticipated Plan Actions to Optimize Generic Group, Redwood City, CA. Imatinib Use in 2014 Funding Source: None. Author Disclosure: The author reports no Plans will take steps to maximize oral generic use. holding counseling sessions and in- relationship or financial interest with any When the price is 50% less, most plans (up from 43% in 2011) will require clude a counseling metric in their P4P entity that would pose a conflict of inter- imatinib use prior to covering competitive brands Sprycel and Tasigna. programs, thereby paying oncologists est with the subject matter of this article. for discussing the options with their Authorship Information: Concept and design; Plans will promote expansion of generic trials by embedding recommendations patients. acquisition of data; analysis and interpre- in clinical pathways or PA criteria. tation of data; drafting of the manuscript;

a Trend #5: Use of Low-Cost Agents critical revision of the manuscript for AnticipatedAnticipated Plan PlanAnticipated Actions Actions to toPlan Optimize Optimize Actions GenericGeneric to Optimize Imatinib Generic UseUse inImatinibin 20142014a Use in 2014a (Percentage enrollment) As part of their long-term manage- important intellectual content; adminis- (Percentage enrollment)(Percentage enrollment) ment strategy, plans will take more ag- trative, technical, or logistic support; and gressive steps to maximize oral generic supervision. use. Multisource availability of Gleevec Author correspondence to: Susan Weber, Re- (imatinib), likely in 2014, will provide search Director, Health. Strategies Group, a significant cost-saving opportunity. 303 Twin Dolphin Dr, Ste 600, Redwood Almost two-thirds of plans intend to City, CA 94065. E-mail: sweber@health- reimburse Gleevec on a higher copay strategies.com. tier, and over one-third say they will require a trial of Gleevec prior to cover-

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 SP122 2012 Cancer Center Business Summit Coverage

Performance Metrics in Oncology (continued from cover)

basic elements are needed to enable Figure 1. Survey Data Showing Who Is Entering Information Into the EMRa such measurement. For every patient, we need to have structured data in the electronic medical record for stage, intent of therapy, toxicity, disease status, patient status, and line of therapy. When there is substantial data density for these 6 process measures, the foundation is in place to begin to measure clinical outcomes across large popula- Staging tions of patients and then, in real time, see what is working. Diagnosis code So how do we get from low density, as presently observed in oncology elec- Treatment regimens tronic medical record data, to high density on these process measures? Figure 1 shows data from an Oncology Metrics Dosing information survey performed in 2009 and reveals that physicians directly enter most of Adverse events these data as part of their clinical management activity. There is ample evidence that peer Physician Physician Nurse Medical Office staff Other review does alter physician behavior. Assistant/ Assistant Oncologists who received feedback Nurse Practitioner about the amount of chemotherapy that they were giving at the end of life aEMR indicates electronic medical record. Data from 87 oncology practices using an electronic medical record and surveyed in 2009. reduced from 50% of patients to 20% of patients in only 6 months.4 Structured critical to those of us who have a can- encourage patients to seek care where for the measure from data that are clinical data offer the opportunity to cer diagnosis in our family or in our fu- these quality indicators are available available at low cost and with low ad- show individuals how they compare ture—and that is just about everyone. and exemplary. ministrative burden. Today the fact is with named physicians in their own Providers must participate in the move that payment drives process measure- practice. Additionally, this lets the phy- to active measurement of clinical vari- Discussion ment and most systematic data are sician know that others see his score Three visions of performance metrics about billing, not about medical care. too (Figure 2). in oncology were presented at the Can- The EHR incentive program, coupled Deb Hood, vice president of the na- The presence of cer Center Business Summit held Oc- with many providers and payers seek- tional oncology service line of Catholic tober 11-12, 2013, in Fort Worth, Texas. ing a departure from fee for service, Health Initiatives (CHI), spoke about specific, essential The theme of the conference was tran- are factors driving oncology data fea- the experience of her institution in sitioning to value-based oncology and sibility toward important, scientifically beginning to establish what she called clinical information most of the program content, including sound measurements. value-based care metrics. While there the full program that is summarized in The presence of specific, essential are 5 dimensions to their hospital per- as structured this article, is available online.2 While clinical information as structured data spective, she emphasized improve- the 3 perspectives are different, there in the clinical database is necessary ment in quality and reduction of cost. data in the were consistent themes throughout. for oncology care management. These Although there are many quality met- All speakers endorsed the use of avail- data support pathway and guideline rics in oncology, CHI has decided to clinical database able data, keeping metrics simple, adherence, reduce treatment variabil- focus on data that are readily avail- delivering measurements to the care ity, take advantage of emerging com- able and easy to audit. The best data is necessary for providers who can affect the numera- panion treatment diagnostics, and pro- source for them is registry data, as they tor, and showing these providers how mote cost savings through the avoid- are extracted in real time, and encom- oncology care they compare with peers. The speakers ance of valueless care. In oncology, 6 pass more that 30,000 new cases each all understand that current payment management. methodology does not support process optimization, yet view that as a transi- Figure 2. Sample Process Metric Presented to Physicians ables or become obsolete. They must tional barrier that will not persist. also integrate reporting and measure- I presented the 3 criteria that are ment of important process measures generally accepted for choosing clinical into routine clinical management. Pay- performance measures.3 To be success- ers have a critical role in promoting ful, measures must be important, sci- this technology adoption. They are po- entifically sound, and feasible. Impor- sitioned to promote payment method- tance is measured by the relevance of ologies that support and reward clini- the measure to patients and providers cal measurement. Without such sup- and the promise that being measured port, innovative practices suffer eco- offers for improvement. To be scientifi- nomically as they push toward rational cally sound, there must be substantial, care. We all should expect basic quality explicit evidence with validity, reliabil- process measures that are indicative ity, and sufficient specificity to patient of good clinical management of can- factors to be clinically useful. Feasibil- cer care for our families and ourselves. ity requires an explicit definition of the Successful payers and providers will numerator and denominator needed

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 2012 Cancer Center Business Summit Coverage SP123

tation of data; drafting of the manuscript; Figure 3. Service Line Dashboard From Catholic Health Initiatives critical revision of the manuscript for important intellectual content; statistical analysis; provision of study materials or patients; and obtaining funding. Address correspondence to: Thomas R. Barr, MBA, 520 Hopkins St, Neptune Beach, FL 32266. E-mail: [email protected].

References 1. EHR incentive programs. Centers for Medi- care & Medicaid Services website. www.cms .gov/Regulations-and-Guidance/Legislation/ EHRIncentivePrograms/index.html. Accessed December 6, 2012. 2. Cancer Center Business Summit website. www.cancerbusinesssummit.com/program.htm. Accessed December 6, 2012. 3. Center for Health Policy Studies, Harvard School of Public Health, Center for Quality of Care Research and Education. Understanding and choosing clinical performance measures for quality improvement: development of typology: final report. Rockville, MD: Agency for Health- care Research and Quality; 1995. 4. Blayney DW, McNiff K, Hanauer D, et al. Implementation of quality practice initiative at a university comprehensive cancer center. J Clin Oncol. 2009;27(23):3802-3807. 5. Bloomberg highlights Vermont cancer pilot; PCD partners plays key HIT role. PCD Systems website. http://pcdsys.com/bloomberg-highlights-vermont-cancer-pilot/. Published August 24, 2012. Accessed December 6, 2012. 6. Decreasing complexity, improving care quality, and reducing cost in oncology. http:// pcdsys.com/care-quality-in-oncology/. PCD year. From these data, they have cre- tion are not standardized. This short- Author Disclosure: The author reports em- Systems website. Published July 5, 2012. Ac- ated “dashboards” for breast cancer, coming limits the ability of process ployment with Altos Solutions, which cessed December 6, 2012. exception reporting for chemotherapy measurement to provide compelling produces electronic health records. and radiation therapy, readmission information about problems addressed Authorship Information: Concept and design; tracking for all oncology patients, and and determine if improvements are re- acquisition of data; analysis and interpre- pharmaceutical expense tracking. To alized. To achieve process control and leverage these reports to create mea- improvement, it is necessary to define surable improvement in care, they are the process and train process opera- Figure 4. Hierarchy of Metrics and the Organizational Sponsors presenting comparative measures at tors, collect process performance data, the institutional level with color cod- and then audit process for compliance. Transitioning to Value-Based Oncology: Strategies to Survive ing to promote easy understanding. None of this functionality is present in and Thrive Green is compliant, yellow is nearly large-scale systems today and this is in range, and red is out of compliance a limiting reality to the application of Metrics/Quality & Process Change standard. A sample of such a report tested process management technol- card is shown in Figure 3. ogy that is used in the manufacturing Figure 2. Sample Process Metric Presented to Physicians Wes Chapman, president and CEO of environment. To no small degree, this Process Metrics: PCD Partners, provided an overview of fractioning of healthcare is part of the • Measure compliance CMS the application of ISO 9001 and Lean payment methodology. Fee for service • Almost all metrics are Six Sigma in 2 large-scale projects.5,6 provides incentives for more process process metrics Noting that outcome metrics are only steps and leads to variable endpoints, AHRQ, NQF viable in the context of a uniform pro- uncoordinated care, and undocument- Outcome Metrics: cess, and understanding that health- ed outcomes. When healthcare delivery • Only viable in context ASCO, ACS CoC, care provision is not at all a uniform and payment more closely resemble of uniform processes ACCC, ASTRO process, useful metrics are limited to typical manufacturing environments, process metrics (Figure 4). characterized by a drive to reduce pro- To adequately measure processes in cess steps and maximize value, then NCCN large systems, the integration of docu- the tools from that sector will become Other oncology organizations ments and data into a single system applicable. EBO is necessary. Chapman said that this novel functionality could be created in Author Affiliation: From Altos Solutions, ACCC indicates Association of Community Cancer Centers; ACS CoC, American College of Surgeons Com- mission on Cancer; AHRQ, Agency for Healthcare Research & Quality; ASCO, American Society of Clinical a cloud-based relational database but Neptune Beach, FL. Oncology; ASTRO, American Society for Radiation Oncology; CMS, Centers for Medicare & Medicaid noted that these 2 types of informa- Funding Source: None. Services; NCCN, National Comprehensive Cancer Center; NQF, National Quality Forum.

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 In treating multiple myeloma What is the value of VELCADE® (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost

If you DEfInE VALuE As An oVErALL surVIVAL ADVAntAgE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage At 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies If you DEfInE VALuE As DEfInED LEngth of thErApy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1 If you DEfInE VALuE As MEDICAtIon Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,540 per 3.5-mg vial as of January 2013 When determining the value of a prescription drug regimen, it may be worth considering medication cost, The median age of patients in the VISTA† trial was 71 years length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider (range: 48-91). when determining value for a given regimen

Indication and Important safety Information for VELCADE® (bortezomib)

▼ Cardiac toxicity: Worsening of and development of cardiac ▼ Embryo-fetal risk: Women should avoid becoming Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan InDICAtIon and prednisone compared with melphalan and prednisone in previously untreated multiple VELCADE (bortezomib) is indicated for the treatment of failure have occurred. Closely monitor patients with existing pregnant while being treated with VELCADE. Advise myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. patients with multiple myeloma. heart disease or risk factors for heart disease. pregnant women of potential embryo-fetal harm. J Clin Oncol. 2010;28(13):2259-2266. ▼ Pulmonary toxicity: Acute respiratory syndromes have ▼ Closely monitor patients receiving VELCADE in combination *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating ContrAInDICAtIons occurred. Monitor closely for new or worsening symptoms. with strong CYP3A4 inhibitors. Avoid concomitant use of the efficacy and safety of VELCADE administered intravenously in combination with MP vs VELCADE is contraindicated in patients with hypersensitivity ▼ Posterior reversible encephalopathy syndrome: Consider strong CYP3A4 inducers. MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (not including local reactions) to bortezomib, boron, or mannitol, MRI imaging for onset of visual or neurological symptoms; (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results including anaphylactic reactions. VELCADE is contraindicated for discontinue VELCADE if suspected. ADVErsE rEACtIons for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), Most commonly reported adverse reactions (incidence ≥20%) PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP intrathecal administration. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, were offered VELCADE in addition. Updated analysis was performed. and vomiting may require use of antiemetic and antidiarrheal in clinical studies include nausea, diarrhea, thrombocytopenia, WArnIngs, prECAutIons, AnD Drug IntErACtIons medications or fluid replacement. neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, ▼ Peripheral neuropathy: Manage with dose modification ▼ Thrombocytopenia or Neutropenia: Monitor complete blood leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, or discontinuation. Patients with preexisting severe counts regularly throughout treatment. and anorexia. neuropathy should be treated with VELCADE only after ▼ Tumor lysis syndrome: Closely monitor patients with Please see Brief Summary for VELCADE on the next page careful risk-benefit assessment. high tumor burden. of this advertisement. ▼ Use caution when treating patients Hypotension: ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment. taking antihypertensives, with a history of syncope, For Reimbursement Assistance, call 1-866-VELCADE or with dehydration. (835-2233), Option 2, or visit VELCADEHCP.com.

3790_milpro_fa2_hpay_ebo.indd 1 2/26/13 2:35 PM In treating multiple myeloma What is the value of VELCADE® (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost

Indication and Important safety Information for VELCADE® (bortezomib)

3790_milpro_fa2_hpay_ebo.indd 1 2/26/13 2:35 PM Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body Brief Summary surface area caused post-implantation loss and a decreased number of live fetuses. ADVERSE EVENT DATA: INDICATIONS: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated received at least 1 prior therapy. mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. CONTRAINDICATIONS: In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS intrathecal administration. (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness WARNINGS AND PRECAUTIONS: (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. A total of 26% of patients experienced a serious adverse reaction during the studies. The Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such peripheral neuropathies NEC, and herpes zoster (1% each). as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs myeloma, the safety profile of VELCADE administered intravenously in combination with intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous melphalan/prednisone is consistent with the known safety profiles of both VELCADE and and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the melphalan/prednisone. The most commonly reported adverse reactions in this study subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea peripheral neuropathy. (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%). following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 data were similar between the two treatment groups. The most commonly reported adverse peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia peripheral neuropathy has not been studied in mantle cell lymphoma. (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), These events are observed throughout therapy. Caution should be used when treating patients with vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious a history of syncope, patients receiving medications known to be associated with hypotension, adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous and patients who are dehydrated. Management of orthostatic/postural hypotension may include treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral and/or sympathomimetics. sensory neuropathy (3% each) in the intravenous treatment group. Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset DRUG INTERACTIONS: of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% with risk factors for, or existing, heart disease should be closely monitored. In the relapsed in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac Because the drug interaction study (n=6) was not designed to exert the maximum effect of failure and congestive cardiac failure; there were no reported reactions of acute pulmonary rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant prolongation in clinical studies; causality has not been established. use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal. exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS clinically relevant. early in the course of therapy. There have been reports of pulmonary hypertension associated with USE IN SPECIFIC POPULATIONS: VELCADE administration in the absence of left heart failure or significant pulmonary disease. In Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a drugs are excreted in human milk and because of the potential for serious adverse reactions in prompt, comprehensive, diagnostic evaluation is conducted. nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy discontinue the drug, taking into account the importance of the drug to the mother. Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and Geriatric Use: No overall differences in safety or effectiveness were observed between neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating individuals cannot be ruled out. VELCADE therapy in patients previously experiencing PRES is not known. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt should be administered after the dialysis procedure. For information concerning dosing of VELCADE for severe symptoms. melphalan in patients with renal impairment, see manufacturer’s prescribing information. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of moderate and severe hepatic impairment. Starting dose should be reduced in those patients. each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia VELCADE treatment may require close monitoring of their blood glucose levels and adjustment or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. of the dose of their antidiabetic medication. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) Please see full Prescribing Information for VELCADE at VELCADEHCP.com. was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple Other trademarks are property of their respective owners. concomitant medications and with serious underlying medical conditions. Other reported hepatic Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE Copyright © 2013, Millennium Pharmaceuticals, Inc. therapy to assess reversibility. There is limited re-challenge information in these patients. All rights reserved. Printed in USA V-12-0306 11/12

3790_milpro_fa2_hpay_ebo.indd 2 2/26/13 2:35 PM Disease Overview SP127

Chemoprevention in Prostate Cancer (continued from cover) or regional stages, it has an excellent it did not apply this recommendation to 5-year survival (nearly 100%) and sur- men who had already been diagnosed Table 1. Potential Chemoprevention Strategies vival after 15 years is also very high with or were being treated for pros- (93%).2 Ironically, since patients with tate cancer.6 This recommendation was Drugs Vitamins Other early-stage prostate cancer experience based on the potential harms of screen- Finasteride Vitamn E Selenium few or no symptoms, the cancer may ing, which included: Dutasteride Vitamin C Soy Proteins not be diagnosed until it has spread • High false-positive rate—approxi- to distant areas of the body, including mately 100 to 120 of every 1000 Aspirin Lycopene lymph nodes, bones, and other organs. men screened may receive an in- Statins The 5-year survival for patients with correct diagnosis based on the PSA Adapted from Millar LB. What is chemoprevention? OncoLink, March 2011. http://oncolink.org/resourc- metastatic disease is only 28%.2 test result, subjecting them to un- es/article.cfm?id=1049. Accessed February 17, 2013. Since the disease is usually diag- necessary biopsies, which could re- Abbey C, Al B. Prostate cancer chemoprevention: a current review. J Cancer Sci Ther. 2011;100:S3. nosed in older patients, men with sult in undesirable side effects and Davis J. Current state and future challenges of chemoprevention. Discov Med. 2012;13(72):385-390. slow-growing tumors are frequently unneeded worry or anxiety. monitored using a strategy termed • Ov erdiagnosis—most cancers of screening strategies that varied by the clinical practice guideline for the use “active surveillance,” monitoring the the prostate do not grow or cause starting and ending age for screening, of 5-α-reductase inhibitors (eg, finas- disease and delaying therapy until the symptoms. If the tumor does grow, screening intervals, and thresholds for teride and dutasteride) for the chemo- disease demonstrates signs of being it does so at a slow rate and usu- recommending a biopsy. Raising the prevention of prostate cancer (primary progressive.3 ally does not cause health prob- PSA threshold in men aged 50 to 74 prevention only). This guideline was As would be expected, costs associa- lems in the duration of the man’s years being screened yearly was found developed based on the results of 15 ted with the treatment of prostate life (based on the older age at diag- to reduce the risk of prostate cancer randomized clinical trials, of which 9 cancer are greatest (approximately nosis). The potential for overdiag- and the risk for overdiagnosis. In even included the prevalence of prostate $34,000) in the last year of life. In 2006, nosis exists, as current technology older men, the risk for prostate can- cancer studies over 1 to 7 years (clini- the total estimated cost for all prostate cannot differentiate slow-growing cer was similar to that observed in the cal trial data do not extend beyond 7 cancer care was $9.86 billion.4 Newer tumors from aggressive tumors (a men aged between 50 and 74 years, but years). Only 1 completed trial, the Pros- treatments, such as sipuleucel-T, cost- small minority of cases, but life- the risk for overdiagnosis was further tate Cancer Prevention Trial (PCPT), was ing more than $93,000 for a full course threatening when they do occur). reduced. Screening done every other randomized and was designed to show of therapy, will undoubtedly increase • Overtreatment—if more men are year in men at low risk reduced the in a reduction in period-prevalence of these estimates.5 diagnosed, it is likely that some risk for prostate cancer and overdiag- prostate cancer. This trial, using finas- proportion of them will undergo nosis; moreover, this strategy reduced teride as the intervention, had a very Screening for Prostate Cancer active treatment, with potentially the number of total tests by 59% and large study population of men who During the years from 2005 to 2009, the deleterious effects. false-positive tests by 50%.8 This study were being actively screened for pros- incidence of prostate cancer and num- The Task Force suggested that phy- suggests that screening may not be tate cancer. The clinical trial REDUCE ber of deaths attributed to it decreased sicians should not offer PSA testing needed in men older than 70 years, and (Reduction by Dutasteride of Prostate each year. Policy makers speculated that unless the patient raises the issue, thresholds for recommending biopsies Cancer Events), in which men with a screening with the prostate-specific an- and then the physician discusses with could be raised in older men. Overall, PSA >3 ng/mL were enrolled, was not tigen (PSA) blood test was responsible the patient the benefits and potential men with normal PSA levels at baseline yet completed at the time of review by for the decline.1 Interestingly, the US harms of PSA testing, as well as risks may need less frequent monitoring.9 the guideline development panel. Thus, Preventive Services Task Force (USPSTF) involved with the diagnostic testing the panel knew that additional infor- issued a statement on PSA screening in and treatment.7 The Chemoprevention Controversy mation would be forthcoming from the May 2012 that recommended against Recently, a computer model was Chemoprevention is the use of drugs, REDUCE trial, and that the PCPT trial PSA-based screening for prostate can- used to assess alternative PSA screen- vitamins, or other agents (Table 1) to try results would be further analyzed. Nei- cer in the general population. However, ing strategies. The model evaluated 35 to reduce the risk of, or delay the de- ther of these 2 trials was designed to velopment or recurrence of, cancer as assess the risk of death resulting from defined by the National Cancer Insti- prostate cancer. The primary objective tute.10 It is further classified as prima- of both of these clinical trials was to ry, secondary, and tertiary prevention. study the safety and efficacy of drugs Primary prevention refers to prevent- indicated for the treatment of benign ing the development of cancer, usually prostatic hyperplasia (BPH). in men who have an average or high The panel concluded that therapy risk for its occurrence. This includes with a 5-α-reductase inhibitor during men with a family history of cancer. a 7-year period would lead to a 25% Secondary prevention is aimed at in- relative risk reduction (but only a 1.4% dividuals with known precancerous le- absolute risk reduction) for a prostate sions. In this case, chemoprevention is cancer diagnosis. The panel noted an used to deter the progression of these increase in high-grade cancers, but lesions to the cancerous state. Tertiary they believed it was doubtful that this prevention is used in patients with could occur while there was also a de- diagnosed prostate cancer to prevent crease in low-grade tumors. However, new cancers or metastasis.11-14 The pre- since men are prescribed 5-α-reductase cancerous state is usually typified by inhibitors for BPH and male pattern the presence of intra-epithelial neopla- baldness, they recommended that this sia, which is identified most commonly potential finding should be discussed through biopsy or pathologic samples with these respective patients. Addi- taken at surgery.15 tionally, they knew that data from the In 2008, the American Society of Clin- REDUCE trial would support or dispute ical Oncology (ASCO) and the American the findings of the presence of in- Urological Association (AUA) issued a creased high-grade prostate cancer in

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 SP128 Disease Overview

Age alone (ie, men older than 50 aration of this article. Ms Zimmerman re- Table 2. Effects of Chemoprevention in 2 Major Clinical Trials years) does not appear to be the only ports no relationship or financial interest criterion for initiating chemopreven- with any entity that would pose a conflict PCPT Trial REDUCE Trial tion. Assuming that finasteride use re- of interest with the subject matter of this Relative Risk of Prostate Decreased 25% Decreased 23% sulted in a constant risk reduction for article. Cancer all tumor grades, the drug was found Authorship Information: Concept and design not cost-effective because of the costs (SRM); acquisition of data (MPZ, SRM); Absolute Risk of Prostate Decreased 6% Decreased 5% associated with side effects (urinary analysis and interpretation of data (MPZ, Cancer and bowel incontinence, impotence, SRM); drafting of the manuscript (MPZ, Absolute Risk of High- Increased 0.6% Increased 0.5% and erectile dysfunction).28 A Markov SRM); critical revision of the manuscript Grade Prostate Cancer model has been developed that shows for important intellectual content (MPZ, PCPT indicates Prostate Cancer Prevention Trial; REDUCE, Reducation by Dutasteride of Prostate Cancer high-risk men, defined as those having SRM); and supervision (SRM). Events. a positive family history and the presence of genetic markers for prostate References men receiving a 5-α-reductase inhibi- of 5-α-reductase inhibitors could sig- cancer, would benefit from chemopre- 1. American Cancer Society. Cancer Facts & tor. nificantly reduce the risk of prostate vention.29 Figures 2013. Atlanta: American Cancer Society; The suggestion from the panel was cancer.19 Even the USPSTF concluded 2013. that men with a PSA level below 3.0 that additional studies were needed to What Exactly Is the Focus 2. American Cancer Society. Prostate Cancer ng/mL who agreed to annual PSA determine the impact of 5α-reductase of the Debate? 2013. Atlanta: American Cancer Society; 2013. screening might benefit from inhibitors on the mortality of men with There is little question that PSA testing www.cancer.org/cancer/prostatecancer/ 5-α-reductase inhibitor therapy for a prostate cancer.20 Furthermore, a re- at present is a useful tool, but has been detailedguide/prostate-cancer-key-statistics. period of 7 years. Men should also be analysis of the data from the PCPT and an overused one, in our limited arse- Accessed January 29, 2013. made aware of the potential benefits REDUCE trials for mortality suggested nal to screen for prostate cancer. And 3. NCCN Clinical Practice Guidelines in Oncolo- and risks of such therapy by their phy- there may have been a small increase when it is used appropriately, there is gy: Prostate Cancer. www.nccn.org/profession- sicians.11 in deaths due to therapy, but that there little consensus (except in cases of ex- als/physician_gls/pdf/prostate.pdf. Accessed The results of the REDUCE trial were could have also been a modest de- treme readings) on how to interpret the January 29, 2013. similar to those seen in the PCPT tri- crease.21 results. Many even argue that the logic 4. Roehrborn CG, Black LK. The economic burden al (Table 2). There was a decrease in Coupled with the clinical analysis of in favor of screening is faulty, owing of prostate cancer. BJU Int. 2011;108(6):806-813. relative risk and absolute risk for de- the use of 5-α-reductase inhibitors for to the relatively slow growth of early- 5. Mulkhy N. Medicare already paying for veloping prostate cancer when using the chemoprevention of prostate can- stage prostate tumors. However, few Provenge for some patients: national cover- 5-α-reductase inhibitor therapy, but cer, several investigators examined the would not want to prevent late-stage age analysis still important. Medscape Medical there was in increase in the absolute cost-effectiveness and cost utility of us- prostate cancer and seek to improve its News, January 6, 2011. www.medscape.com/ risk for the development of high-grade ing these drugs specifically for chemo- poor 5-year survival. viewarticle/735366. Accessed January 30, prostate cancer. The original publica- prevention. A study in the mid-2000s Therefore, the real debate seems 2013. tion of the trial did not show an in- utilizing a Markov decision analysis not to address the value of preventing 6. Screening for prostate cancer. US Preventive creased risk for high-grade prostate model concluded that prescribing fin- prostate cancer but whether our tech- Services website. www.uspreventiveservices- cancer, but the FDA mandated a re- asteride in a lower-risk population ≥50 nologies for prevention (both screening taskforce.org/prostatecancerscreening.htm. analysis of the data using a modified years would not be cost-effective; how- and treatment) are efficient enough Published 2012. Accessed February 17, 2013. scoring scale which resulted in an in- ever, if it were used in men with a high to yield cost-effective outcomes. If 7. Talking with your patients about screening crease in high-grade prostate cancer.16 risk for prostate cancer (defined as at 5-α-reductase inhibitors are not suf- for prostate cancer. US Preventive Services In December 2010, the Oncolog- least 50 years of age with a probability ficiently effective in preventing the website. www.uspreventiveservicestaskforce. ic Drugs Advisory Committee voted of at least 30% for developing prostate development of prostate cancer, or if org/prostatecancerscreening/prostatecancer- against approving dutasteride and fin- cancer), the chemoprevention strat- the side effects of the medications are script.pdf. Published 2012. Accessed January asteride for the prevention of prostate egy could be cost-effective. If the life- such that the costs to treat (or in terms 29, 2013. cancer based on the findings of the time prevalence were to be increased, of reduced quality of life) result in in- 8. Gulati R, Gore JL, Etzioni R. Comparative REDUCE and PCPT trials. The FDA fol- the costs per life-year saved would adequate cost-effectiveness, are there effectiveness of alternative prostate-specific lowed the committee’s recommenda- be reduced; moreover, the cost of the specific patients where the drugs may antigen-based prostate cancer screening strate- tion in January 2011.17 Since the FDA did chemoprevention strategy would also be useful and are there more effective gies: model estimate of potential benefits and not approve the drugs for the preven- affect the costs.22 Another study utiliz- chemoprevention strategies available harms. Ann Intern Med. 2013;158(3):145-153. tion of prostate cancer, ASCO and AUA ing a Markov decision analysis model or on the horizon? 9. American College of Physicians. Summaries subsequently archived the 2008 clinical also concluded that finasteride would The debate about the use of for patients: screening smarter, not harder, for guideline on the use of 5-α reductase not be likely to be cost-effective for use 5-α-reductase inhibitors as chemopre- prostate cancer. Ann Intern Med. 2013;158(3): inhibitors for prostate cancer chemo- in the general population, but that it vention for prostate cancer continues, 1-30. http://annals.org/article.aspx?articleid prevention. However, the guideline is would be cost-effective to prescribe it as does the utilization of PSA testing to =1567366. Accessed February 18, 2013. available in the “Archived Guides” sec- in high-risk men (defined as ≥50 y and screen men for the disease. Based on 10. NCI dictionary of cancer terms. National tion of the AAU website.18 a ≥30% chance of developing prostate the sheer numbers of men who devel- Cancer Institute website. www.cancer.gov/ The AUA communicated that it be- cancer), especially if quality-of-life is- op prostate cancer and the cost burden dictionary?cdrid=45487. Accessed January 30, lieves some urologists and urologist- sues (erectile dysfunction, loss of li- of the disease, it seems that the need 2013. oncologists would continue to pre- bido, and incontinence) were consid- exists for both a useful screening tool 11. Kramer BS, Hagerty KL, Justman S, et al. Use scribe these medications for men at ered. The sensitivity analysis showed and a chemoprevention strategy. Ap- of 5-α-reductase inhibitors for prostate cancer potentially high risk for prostate cancer a cost-effectiveness ratio of <$50,000 propriate application of this strategy chemoprevention: American society of clinical and that these agents should be used per QALY with a 25% risk reduction in will be the key to success. Evolving oncology/American urological association with caution. It believed the decision the men at high risk.23 There appears and improved technology will be para- 2008 clinical practice guideline. J Clin Oncol. was controversial and still debatable.18 to be a level of agreement that utilizing mount in making this happen. EBO 2009;27(9)1502-1516. The Southwestern Oncology Group these medications in low-risk popula- 12. Abbey C, Al B. Prostate cancer chemopre- (SWOG) disagreed with the FDA’s deci- tions would not be cost-effective, but Funding Source: None. vention: a current review. J Cancer Sci Ther. sion, saying that it believed the PCPT that there is a cost benefit to their use Author Disclosures: Mr Mehr reports receiv- 2011;100:S3. reanalysis demonstrated that the use in high-risk men.24-27 ing payment for involvement in the prep- 13. Davis, J. Current state and future challenges

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 Disease Overview

of chemoprevention. Discov Med. 2012;13(72): prostatecancerinfolink.net/2012/12/03/ 22. Svatek RS, Lee JJ, Roehrborn CG, et al. men with an elevated prostate specific antigen. 385-390. aua-and-asco-to-archive-clinical-guidance-of- The cost of prostate cancer chemoprevention: Cancer Prev Res. 2011;4(2):277-283. 14. Millar LB. What is chemoprevention? Onco- use-of-5-aris-for-prostate-cancer-prevention/. a decision analysis model. Cancer Epidemiol 27. Kattan MW, Earnshaw SR, McDade CL, Link 2011. www.oncolinkorg/resources/article/ Published December 3, 2012. Accessed January Biomarkers Prev. 2006;15(8):1485-1489. Black LK, Andriole GL. Cost-effectiveness of cfm?id=1049. Accessed January 30, 2013. 30, 2013. 23. Svatek RS, Lee JJ, Roehrborn CB, et al. chemoprevention for prostate cancer with dutas- 15. Bostwick DG, Qian J. High-grade prostatic 19. SWOG Newsletter. FDA’s ODAC votes no, Cost-effectiveness of prostate cancer che- teride in a high-risk population based on results intraepithelial neoplasia. Mod Pathol. 2004;17: loudly, on finasteride for prostate cancer preven- moprevention: a quality of life-years analysis. from the REDUCE clinical trial. Appl Health Econ 360-379. tion. http://swog.org/visitors/newsletters/ Cancer. 2008;112(5):1058-1065. Health Policy. 2011;9(5):305-315. 16. Violette PD, Saad, F. Chemoprevention of 2010/12/index.asp?a=spotlight. Published 24. Earnshaw SR, McDade CL, Black LK, Bell 28. Stewart SB, Scales CD, Moul JW, Reed SD. prostate cancer: myths and realities. J Am Board December 2010. Accessed January 31, 2013. CF, Kattan MW. Cost effectiveness of 5-al- Does variation in either age at start of therapy Fam Med. 2012;25(1):111-119. 20. Moyer VA on behalf of the US Preventive pha reductase inhibitors for the prevention of or duration of therapy make chemoprevention 17. Chustecka Z. Dutasteride not approved for Services Task Force. Screening for prostate prostate cancer in multiple patient populations. with finasteride cost-effective? Prostate Cancer prostate cancer prevention. Medscape Medical cancer: United States Preventive Services Task Pharmacoeconomics. 2010;28(6):489-505. Prostatic Dis. 2012;15(4):380-385. News Oncology News, January 28, 2011. www Force recommendation statement. Ann Intern 25. Zeliadt SB, Ramsey SD. Cost-effectiveness 29. Reed SD, Scales CD, Stewart SB, et al. .medscape.com/viewarticle/736465. Accessed Med. 2012;157(2):120-134. of prostate cancer chemoprevention among Effects of family history and genetic polymor- January 30, 2013. 21. Pinsky PF, Black A, Grubb R, et al. Projecting high-risk men. Expert Rev Pharmacoecon Out- phism on the cost-effective of chemopreven- 18. The New Prostate Cancer Infolink. AUA and prostate cancer mortality in the PCPT and RE- comes Res. 2010;10(5):505-508. tion with finasteride for prostate cancer. J Urol. ASCO to “archive” clinical guidance of use of DUCE chemoprevention trials. Cancer. 2013;119 26. Svatek RS, Lotan Y. Cost utility of prostate 2011;185(3):841-847. 5-ARIs for prostate cancer prevention. http:// (3):593-601. cancer chemoprevention with dutasteride in

Payer Perspective Interview With Paul Handel, MD

The Need to Stress Primary Prevention Is a Huge EBO: There has been a bit of controversy surrounding the use of chemo- Opportunity in Prostate Cancer prevention (ie, finasteride, dutasteride, other agents) in prostate cancer. Does HCSC cover the use of these agents for primary prevention EBO: At this point in time, what are your person- (general population or those with BPH) and secondary prevention (high- al impressions of prostate-specific antigen (PSA) risk patients—those in whom interstitial neoplasia has been found)? screening overall? Dr Handel: Since HCSC does not have any UM requirements for finasteride or dutas- Dr Handel: I am a urologist. In the pre-PSA test era, teride, we would not know if these agents are being prescribed off-label for primary most cases of prostate cancer were detected in ad- or secondary prevention of BPH. As a result, these agents could be covered for che- vanced stages, which precluded curative management. moprevention. As you are aware, the NCI Prostate Cancer Prevention Trial showed a The benefits of the screening have been eclipsed but positive benefit of reducing the incidence of prostate cancer with the use of finas- not negated by the overly aggressive technological ap- teride for chemoprevention, but there also was a statistically significant increase in proach to testing. With appropriate age limitations, the percentage of high-grade prostate cancers. This risk, combined with the side ef- health status evaluation, and shared decision making, fect profile of these drugs, will continue to limit their use to only high-risk patients. the PSA testing remains a valuable screening test. I am not aware of any current testing modalities that would replace the PSA test in EBO: Do you believe the preventive benefit of these agents outweigh the combination with a digital rectal examination. side effects associated with the 5-α-reductase inhibitors (finasteride and dutasteride)? EBO: What are HCSC’s recommendations regarding prostate cancer Dr Handel: Yes, in the appropriate patients. Their side effects are relatively mild screening? and occur in perhaps 5% of the patients treated. Initiating therapy and then stop- Dr Handel: We leave it to the discretion of the treating physician and the patient. ping it based on side effects is not unreasonable. We don’t have internal guidelines in this area. Our own recommendations are re- flective of the American Urological Association, National Comprehensive Cancer EBO: How do you think prostate cancer chemoprevention will change by Network, and other guidelines. the year 2025? Dr Handel: Most likely in the use of novel antiandrogens or androgen-receptor EBO: How would you characterize current prostate cancer screening ef- blocking agents. forts today? Dr Handel: Current screening efforts have been confused by the US Preventive EBO: As a health plan executive, where do you see the greatest value in Services Task Force (USPSTF) recommendations. There is confusion about when prostate cancer today? to start and stop the screenings. Generally, the frequency of testing (yearly) has Dr Handel: Two areas emerge immediately: First, the primary prevention must be not been an issue. The larger question is what next steps should be followed after stressed! Again, these concentrate on animal fat restriction and increased physical a positive PSA test is revealed. The urologic community needs, and is working on, activity. guidelines for intervention. An additional consideration needs to be the medicole- Second, closer adherence to diagnostic and therapeutic guidelines would benefit gal implications, mandating full consent and possibly tort reform. patients. The major shortcomings of screening efforts today have been in the relatively indiscriminate testing based on age and physical condition. Additionally, many EBO: Where would you like to see more comparative effectiveness re- patients and doctors forgo a digital rectal exam, relying on the PSA test results search done in this area? alone for screening. Dr Handel: I believe the Holy Grail may be better identification of the cohort of In contrast, a huge overlooked opportunity relates to the preventive aspect. It is patients who will benefit from treatment. rare to see recommendations about physical activity and dietary changes to help reduce the potential for prostate cancer. Dr Handel is senior vice president and chief medical officer at Health Care Service Corpo- ration in Chicago, IL.

The American Journal of Managed Care • March/April 2013 • Volume 19, Special Issue 3 Safety= .5” Trim= 10.75” x 13.75” Bleed= 11” x 14”

This is the biologic medicine

That the patient counts on

That the nurse trusts

That the pharmacist has conﬁ dence in

That the doctor relies on

Because it was manufactured knowing the patient’s treatment depends on it.

Building conﬁ dence in the quality and supply of biologic medicines starts with a deeper understanding of how these medicines are made.

After all, there’s so much at stake.

That’s why manufacturing matters.

Learn more at buildingbiologics.com

665399_M03DR_AMGEN_Journal Ads_KingTabloid_8.indd 1 1/25/13 9:43 AM