OPM Feb 2015 | Vol 5 | No 1

february 2015

www.OncPracticeManagement.com

Title

Volume 5 • Number 1

Oncology Practice Management ™

FOR ONCOLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

Building the Oncology System of the Future

By Gail Thompson

P

ractice managers, physicians, and members of industry gathered recently at the Cancer Center Business Summit (CCBS) to consider the state of cancer care delivery and its future. A panel discussion among key thought leaders featured perspectives from the oncology community as well as national policy advisors.

Paul H. Keckley, PhD, Managing Director of the Navigant Center for Healthcare Research and Policy Analysis, joined Allen S. Lichter, MD, FASCO, Chief Executive Officer of the American Society of Clinical Oncology (ASCO); Lindsay Conway, MSEd, Practice Manager of the Oncology Roundtable at The Advisory Board Company; and Gary H. Lyman, MD, MPH, Codirector of the Fred Hutchison Institute for Cancer Outcomes Research, for the discussion.

In his presentation, Dr Keckley shared

Pharmacy Benefit Managers and the Influence on Cancer Care

By Dawn Holcombe, MBA, FACMPE, ACHE; President, DGH Consulting, South Windsor, CT; Editor-in-Chief, Oncology Practice Management

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was disturbed recently after reading a news report in which the head of a large pharmacy benefit manager (PBM) stated the company’s intentions to eventually start influencing the price of oncology drugs as well as

extend its management, oversight, and influence to cancer drugs administered in doctors’ offices and hospitals. Meetings have already begun with top oncologists, according to the company leader who was interviewed, and the Continued on page 18

Clinician and Survivor Shares Perspectives on Cancer Care An Interview with Lillie D. Shockney, RN, BS, MAS

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ncology Practice Management recently conducted the following interview with Lillie D. Shockney, RN, BS, MAS, Administrative Director, The Johns Hopkins Breast Center; Director, Cancer Survivorship Programs at the Sidney Kimmel Cancer

Center at Johns Hopkins; and Associate Professor, Johns Hopkins University School of Medicine and School of Nursing, Baltimore, MD. Ms Shockney is also a cancer survivor and the editor-in-chief of the Journal of Oncology Navigation & Survivorship.

Continued on page 8

Continued on page 14 From the publishers of

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INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM

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© 2015 Engage Healthcare Communications, LLC

Take a bite out of G-CSF acquisition costs Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

GRANIX® is an option in short-acting G-CSF therapy » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1 » The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)1 » Now offering a new presentation for self-administration

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

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

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

For more information, visit GRANIXhcp.com.

Reference: 1. GRANIX® (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40490 January 2015.

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

4 CONTRAINDICATIONS None.

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

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

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

5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colony-stimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

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

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Capillary Leak Syndrome [see Warnings and Precautions (5.5)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

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

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

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

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

Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia.

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

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

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

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes.

This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure.

GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

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

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

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

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

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

10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40503 December 2014 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

Table of Contents

PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Director, Client Services Zach Ceretelle zceretelle@the-lynx-group.com Editorial Directors Dalia Buffery dbuffery@the-lynx-group.com Anne Cooper acooper@the-lynx-group.com Associate Editor Lara J. Lorton Editorial Assistant Cara Guglielmon Senior Production Manager Lynn Hamilton

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President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistants Lora LaRocca Wayne Williams Director, Digital Media Anthony Romano Jr Digital Media Specialist Charles Easton IV Web Content Manager Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Mezzacappa Senior Project Managers Alyson Bruni Jini Gopalaswamy Project Manager Deanna Martinez Project Coordinator Mike Kodada IT Manager Kashif Javaid Administrative Services Team Leaders Rachael Baranoski Allison Ingram Administrative Assistant Amanda Hedman Office Coordinator Robert Sorensen Engage Healthcare Communications 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

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February 2015 • Volume 5 • Number 1

Oncology Practice Management ™

FOR ONCOLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

From The Editor Pharmacy Benefit Managers and the Influence on Cancer Care.............................................................................................1

By Dawn Holcombe, MBA, FACMPE, ACHE

Features Perspectives on Cancer Care Clinician and Survivor Shares Perspectives on Cancer Care.......................................................................................1 An Interview with Lillie D. Shockney, RN, BS, MAS

Cancer Center Business Summit Building the Oncology System of the Future....................................... 1

By Gail Thompson

The Future of Oncology Reimbursement...........................................15

By Gail Thompson

Regulatory Update FDA Issues Final Rule on Pregnancy and Lactation Labeling.........25

By Rosemary Frei, MSc

Personalized Medicine Payers Debate the Economics of Personalized Medicine in Oncology.............................................................................................26

By Wayne Kuznar

Continued on page 6

Mission Statement Oncology healthcare requires providers to focus attention on financial concerns and strategic decisions that affect the bottom line. To continue to provide the high-quality care that patients with cancer deserve, providers must master the ever-changing business of oncology. Oncology Practice Management offers process solutions for members of the cancer care team—medical, surgical, and radiation oncologists, as well as executives, administrators, and coders/billers—to assist them in reimbursement, staffing, electronic health records, REMS, and compliance with state and federal regulations.

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

Oncology Practice Management

I February 2015

New from Bayer HealthCare and Onyx Pharmaceuticals

Introducing

Up to $4,000 per month and up to $16,000 per year per patient for privately-insured patients

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A new level of financial support for privately-insured NEXAVAR patients Available through AND

A network of specialty pharmacy providers (SPPs)

For more information, please visit www.REACHPatientSupport.com or www.nexavar-us.com *Patients who are enrolled in any type of government insurance or reimbursement programs are not eligible. As a condition precedent of the co-payment support provided under this program, e.g., co-pay refunds, participating patients and pharmacies are obligated to inform insurance companies and third-party payors of any benefits they receive and the value of this program, and may not participate if this program is prohibited by or conflicts with their private insurance policy, as required by contract or otherwise. Void where prohibited by law, taxed, or restricted. Patients enrolled in Bayerâ&#x20AC;&#x2122;s Patient Assistance Program are not eligible. Bayer and Onyx may determine eligibility, monitor participation, equitably distribute product and modify or discontinue any aspect of the REACH program at any time, including but not limited to this commercial co-pay assistance program.

Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, PO Box 915, Whippany, NJ 07981 USA BAYER, the Bayer Cross, and NEXAVAR are registered trademarks of Bayer.

REACH is a service mark of Bayer HealthCare Pharmaceuticals Inc. Š2015 Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ PP-810-US-1632

249 E. Grand Avenue, South San Francisco, CA 94080 USA

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Printed in USA

Table of Contents

February 2015 • Volume 5 • Number 1

Oncology Practice Management™, ISSN 2164-4403 (print), is published 10 times a year by Engage Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2015 by Engage Healthcare Communications, LLC. All rights reserved. Oncology Practice Management™ is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or here­ after known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

The ideas and opinions expressed in Oncology Practice Management™ do not necessarily reflect those of the editorial board, the editors, or the publisher.

Publication of an advertisement or other product mentioned in Oncology Practice Management ™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

Oncology Practice Management ™

FOR ONCOLOGISTS, PRACTICE MANAGERS, FINANCIAL COUNSELORS, AND REIMBURSEMENT SPECIALISTS™

Continued from page 4

DEPARTMENTS Wealth Management How to Choose a 529 College Savings Plan.................................... 28

By W. Ben Utley, CFP®, and Lawrence B. Keller, CFP®, CLU®, ChFC®, RHU®, LUTCF

Clinical Trial Tracker New Clinical Trials Under Way............................................................. 31 FDA Update Recent Drug Approvals........................................................................ 33 Drug Update Nivolumab (Opdivo): Second PD-1 Inhibitor Receives FDA Approval for Unresectable or Metastatic Melanoma..................................................... 39

By Lisa A. Raedler, PhD, RPh

Drug Coding FDA-Approved Medications Used for the Treatment of Renal Cell Carcinoma...................................................................................... 48

Editorial Advisory Board Editor-in-Chief Dawn Holcombe, MBA, FACMPE, ACHE President DGH Consulting South Windsor, CT Carla Balch CEO, Altos Solutions a Division of Flatiron Health, Inc New York, NY Peggy Barton, RN Practice Manager Toledo, OH

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Risë Marie Cleland President Oplinc, Inc Portland, OR Patrick A. Grusenmeyer, ScD, FACHE President Christiana Care Health Initiatives Newark, DE Teri U. Guidi, MBA, FAAMA President and CEO Oncology Management Consulting Group Pipersville, PA

Oncology Practice Management

Mariana Lamb, MS Executive Director Medical Oncology Association of Southern California Upland, CA

Robert D. Orzechowski, MBA, SPHR Chief Operating Officer Lancaster Cancer Center Lancaster, PA

Bonnie J. Miller, RN, BSN, OCN, FAAMA Administrative Director Women’s Cancer Center Fox Chase Cancer Center Philadelphia, PA

Sheryl A. Riley, RN, OCN, CMCN Director of Clinical Services SAI Systems Shelton, CT

Karna W. Morrow, CPC, RCC, CCS-P, PCS Senior Consultant CSI Coding Strategies, Inc Powder Springs, GA

I February 2015

*The VELCADE Reimbursement Assistance Program does not file claims or appeal claims for callers, nor can it guarantee that you will be successful in obtaining reimbursement

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

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright Š 2010, Millennium Pharmaceuticals, Inc. All rights reserved.

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Perspectives on Cancer Care

Clinician and Survivor Shares...Continued from the cover Q: What do you think are the most pressing issues facing patients in your community who are seeking care?

Lillie Shockney (LS): In our particular community in East Baltimore, the majority of patients who are coming to us are part of an underserved population. They experience a fear of coming to the institution for screening. They have heard of other people coming to the emergency room with pain and subsequently dying. They assume that something happened to them while they were at the hospital and don’t really understand that a delay in diagnosis or having neglected cancer is something that not only will result in death but is something that can be prevented. They also may be very worried about the cost of care. If they don’t have insurance or are underinsured, that also can be a barrier that keeps them from coming to see us.

They also have other things that take priority. I had a patient last year who was diagnosed with metastatic breast cancer. We treated her a few years before for locally advanced disease, and she said to me, “I can’t afford to die. I have to be here to raise my son. As you know, I had a delayed diagnosis before because I was spending time trying to keep my husband out of jail. He is now in prison. I then tried to keep both my boys alive. My one boy died here on the streets of Baltimore as a gang member. He got into a gang war and died. I have one son left. I want to get him on the right path, and that’s going to take some time.”

As you can see, if they are dealing with life and death in very different ways, cancer is not on their radar screen.

Q: How do the nurses and physicians address the issues found within this patient population?

LS: They are faced with some

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tough issues. This patient may not consider her cancer diagnosis a priority, because instead she’s focused on how to get food on the table and, how to keep her son, who is part of a gang, alive. We need to factor those issues in. Because they aren’t going to consider this a priority, we need to make it a priority, and help them understand that by overcoming their cancer, by getting it appropriately treated, they may be in a better position to help their family.

“We often assume that all resources need to come from our cancer center, when the majority of them are out there in the form of patient advocacy organizations.”

–Lillie D. Shockney, RN, BS, MAS

We need to give them resources, as well. In some cases, it may be that we need to get a female patient into House of Ruth (intimate partner violence center) so that she is not going back home into a domestic violence setting. It also means that we need to make sure that patients do have food on the table, that they have access to psychosocial support, and that they can afford their prescriptions, which may mean utilizing resources to cover copayments and related expenses.

Q: What tips would you share with nurse or patient navigators to facilitate access to care for their patients?

LS: One of the best ways to facilitate access to care is to assess the re-

Oncology Practice Management

I February 2015

sources that are available within their own community. We often assume that all resources need to come from our cancer center, when the majority of them are out there in the form of patient advocacy organizations.

Whether it is transportation assistance or coverage for copays, resources do exist in the majority of community settings or state‑based settings.

Navigators simply need to ask.

Q: Some institutions may feel intimidated about starting a navigation program. What would you recommend to start the process?

LS: Some institutions feel vulnerable when they are in the process of determining how to develop a navigation program. There is not one particular program or process that fits every single institution; it should be tailored toward the patient population being served as well as the in­ stitution’s organizational structure.

One of the best ways in which an institution can initiate a program without feeling too intimidated is to visit other institutions that have already developed such programs and published regarding their success.

That’s a really good starting point.

Institutions and centers should assess from an operations management process how their patients currently flow through their program.

Do not assume anything; follow alongside a patient and see what really happens from the point of diagnosis, rather than what they have been told happens. That will provide a great deal of insight as to where the inefficiencies are, where things need to be reworked, where there are barriers to care that must be identified and resolved for their patient population, and where their nurse navigators and patient navigators can be of the best use. Cancer centers that are implementing a navigation program

Perspectives on Cancer Care

can also visit other centers for a site visit to see how they were successful in implementing such a program.

Q: Are there any barriers to care within Johns Hopkins’ patient community?

LS: There are many barriers faced by patients who receive care at Johns Hopkins. One is transportation. We may have a patient who says, “We have a car, but my husband uses it to go to work. I use the subway.” The subway may not be near their care center; we can provide resources to ensure they have transportation to get there.

Asking the right questions and how the questions are asked regarding the barriers very much influences whether a patient will honestly tell us what the barriers are. If I say to a patient, “You are not going to have any trouble covering your prescriptions, are you?,” that is kind of a mother–daughter type of conversation, which is inappropriate.

But if instead I say, “A lot of medications are expensive, and you weren’t planning to build into your budget a $50 bill each month to take this medication that’s really impor­ tant for preventing recurrence of your adjuvant cancer. Is this something I can help you with?” Now, that patient is going to feel far more comfortable in saying, “Yes, I don’t have those extra dollars, whatsoever.

If you could help me with that, I would greatly appreciate it.”

We also have issues such as ethnicity and racial barriers. We have large African American and Korean populations in downtown Baltimore.

Culturally and from an ethnicity perspective, there may be language barriers when we are trying to explain their treatments to them. They also have myths associated with cancer and its diagnosis. Some actually refer to their diagnosis as “cancer fate,” meaning that if you get it, then you are destined to die, so why bother being treated?

Q: You offer the unique perspective of being a patient with cancer, a cancer survivor, and a healthcare provider. Based on this experience, what insights can you give to fellow nurses and care managers to improve patient care?

LS: I have had either the good fortune or misfortune to experience cancer from several different venues.

derailment, not a dead end.”

The patient may say to me, “I’ve been married a year. My husband and I were hoping to start a family this coming year.” She’s 35 years old.

If I know, based on the stage and prognostic factors, that she probably is going to be looking at chemotherapy, then I want to make sure as her nurse navigator to get a referral for her into fertility preservation. I want to preserve that life goal. I do not want to steal it away.

Let’s say she is starting to be a concert pianist. I want to talk to the medical oncologist and say, “Let’s not rob her of her career goals. Let’s take a look at regimens that don’t involve drugs that will cause peripheral neuropathy. Otherwise, she won’t even be able to teach piano in her own home.” Preserving those life goals is really important.

Also, it is important to assess how we can prevent side effects rather than having to fix the consequences of those side effects posttreatment. We know from research that if you power walk for 30 minutes, 5 times a week, you could reduce your fatigue during radiation by 70%. Why wouldn’t we teach patients that upfront? That just makes absolutely no sense.

Also, setting them on a path of survivorship from that moment of diagnosis is really important: preserve those life goals, prevent side effects, and develop new goals they want to add when they finish their treatment. Help them create their new normal. Do not tell them they have to find a new normal or accept a new normal because they have all of these side effects that we fail to address proactively.

Lillie D. Shockney, RN, BS, MAS

One is as a patient. I’m a 23‑year breast cancer survivor, also a 21‑year breast cancer survivor, and an 8‑year uterine cancer survivor. I flipped to the other side of the side rail. I’ve also been in the field of oncology nursing and nurse navigation for a very long time, and serve formally as a clinician at Johns Hopkins.

One of the most important things I can share with nurses, nurse navigators, and care managers is that the patient is more than his or her pathology. We focus so much on the stage of the disease, the prognostic factors, and what the treatment is going to be. We need first to ask that patient, “Tell me what your life goals were before you heard that you were diagnosed with cancer.” Commonly, that patient will say, “It doesn’t matter. Just save my life.” I will say, “It does matter, and I want to know what they are, because we are hoping this will be a bump in the road, not a

Q: Based on your unique perspective, what advice would you give to oncologists?

LS: Because of my perspective with cancer and looking at it as a patient, a caregiver, and as an oncology nurse navigator and clinician, one of the Continued on page 27

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For patients with bone metastases from solid tumors

Prevent bone complications longer In a prespecified integrated analysis of 3 pivotal trials (N = 5,723),

8.2

XGEVA® was proven to delay the median time to first bone complication by

months longer vs zoledronic acid1

XGEVA® is a convenient 120 mg subcutaneous injection administered once every 4 weeks.2

Bone complications, or skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.2,3 Median Time to First Bone Complication1 27.7

months

XGEVA VA® 120 mg Q4W (n = 2,862) VA

Data from a prespecified integrated analysis of three international, phase 3, double-blind, double-dummy, active-controlled trials comparing XGEVA® with zoledronic acid for the prevention of bone complications in patients with bone metastases from solid tumors or multiple myeloma.1

19.5

months

zoledronic acid 4 mg Q4W (n = 2,861) 1 YEAR

HR* = 0.83 (95% CI: 0.76-0.90)

2 YEARS

P < 0.001†

IMPORTANT SAFETY INFORMATION Hypocalcemia • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®. XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels.

Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

• An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation.

Monitor calcium levels and calcium and vitamin D intake.

Hypersensitivity • XGEVA® is contraindicated in patients with known clinically significant hypersensitivity to XGEVA®, including anaphylaxis that has been reported with use of XGEVA®. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA® therapy permanently.

*Hazard ratio (HR) is defined as the increase or decrease in likelihood of an event of interest (in this case a bone complication) for one group relative to that in a comparator group.

P value for superiority.

†

Drug Products with Same Active Ingredient • Patients receiving XGEVA® should not take Prolia® (denosumab).

Osteonecrosis of the Jaw • Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure.

• Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®.

• Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture • Atypical femoral fracture has been reported with XGEVA®.

These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

• RANK Ligand (RANKL) is produced by bone cells in the skeleton and is a key mediator of bone resorption4 • RANKL production is increased at sites of bone metastases, and stimulates osteoclasts to destroy bone4 • XGEVA® acts precisely to bind RANKL and inhibits osteoclast formation, function, and survival2 • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®2

Learn more at XGEVA.com

• Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA® treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA® therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Embryo-Fetal Toxicity • XGEVA® can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA® is expected to result in adverse reproductive effects.

©2014 Amgen Inc. All rights reserved. 04/14 80218-R1-V1

• Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of XGEVA®. Apprise the patient of the potential hazard to a fetus if XGEVA® is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA®.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea.

The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

Please see brief summary of Prescribing Information on the following page.

REFERENCES: 1. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012;48:30823092. 2. XGEVA® (denosumab) prescribing information, Amgen. 3. Brodowicz T, O’Byrne K, Manegold C. Bone matters in lung cancer. Ann Oncol. 2012;23:22152222. 4. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664.

www.XGEVA.com

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Brief Summary: Consult package insert for complete Prescribing Information

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INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.

Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter.

Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way. Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry.

CONTRAINDICATIONS: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva.

Hypersensitivity. Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva.

WARNINGS AND PRECAUTIONS: Drug Products with Same Active Ingredient. Xgeva includes the same active ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not take Prolia.

Hypersensitivity. Clinically significant hypersensitivity including anaphylaxis has been reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva therapy permanently.

Hypocalcemia. Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation.

Monitor calcium levels and calcium and vitamin D intake.

Osteonecrosis of the Jaw. Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure (see Adverse Reactions).

Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should

receive care by a dentist or an oral surgeon. In these on-study was 13 months (range: 0.1 – 41). Of patients patients, extensive dental surgery to treat ONJ may who received Xgeva, 46% were female. Eighty-five exacerbate the condition. percent were White, 5% Hispanic/Latino, 6% Asian, and Atypical Subtrochanteric and Diaphyseal Femoral 3% Black. The median age was 63 years (range: 18 – 93).

Fracture. Atypical femoral fracture has been reported Seventy-five percent of patients who received Xgeva with Xgeva. These fractures can occur anywhere in the received concomitant chemotherapy. femoral shaft from just below the lesser trochanter to Table 1. Per-patient Incidence of Selecteda Adverse above the supracondylar flare and are transverse or short Reactions of Any Severity (Trials 1, 2, and 3) oblique in orientation without evidence of comminution.

Zoledronic Atypical femoral fractures most commonly occur with Xgeva Acid minimal or no trauma to the affected area. They may Body System n = 2841 n = 2836 % be bilateral and many patients report prodromal pain % in the affected area, usually presenting as dull, aching GASTROINTESTINAL thigh pain, weeks to months before a complete fracture 32 31 Nausea occurs. A number of reports note that patients were also 19 20 Diarrhea receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients GENERAL should be advised to report new or unusual thigh, hip, or Fatigue/ Asthenia 45 46 groin pain. Any patient who presents with thigh or groin IN VESTIGATIONS pain should be suspected of having an atypical fracture Hypocalcemiab 9 18 and should be evaluated to rule out an incomplete femur 20 32 Hypophosphatemiab fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and NEUROLOGICAL signs of fracture in the contralateral limb. Interruption Headache 13 14 of Xgeva therapy should be considered, pending a risk/ RESPIRATORY benefit assessment, on an individual basis.

18 21 Dyspnea EMBRYO-FETAL TOXICITY: Xgeva can cause fetal harm 15 15 Cough when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse a Adverse reactions reported in at least 10% of patients reproductive effects. In utero denosumab exposure in receiving Xgeva in Trials 1, 2, and 3, and meeting one cynomolgus monkeys resulted in increased fetal loss, of the following criteria: stillbirths, and postnatal mortality, along with evidence of • At least 1% greater incidence in Xgeva-treated absent peripheral lymph nodes, abnormal bone growth, patients, or and decreased neonatal growth (see Use in Specific • Between-group difference (either direction) of less than Populations). Advise females of reproductive potential 1% and more than 5% greater incidence in patients to use highly effective contraception during therapy, treated with zoledronic acid compared to placebo (US and for at least 5 months after with the last dose of Prescribing Information for zoledronic acid) Xgeva. Apprise the patient of the potential hazard to a b Laboratory-derived and below the central laboratory lower fetus if Xgeva is used during pregnancy or if the patient limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) becomes pregnant while patients are exposed to Xgeva. for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) Advise patients to contact their healthcare provider for phosphorus] if they become pregnant or a pregnancy is suspected Severe Mineral/Electrolyte Abnormalities during this time.

• Severe hypocalcemia (corrected serum calcium less ADVERSE REACTIONS: The following adverse reactions than 7 mg/dL or less than 1.75 mmol/L) occurred are discussed below and elsewhere in the labeling: in 3.1% of patients treated with Xgeva and 1.3% of • Hypocalcemia patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced • Osteonecrosis of the Jaw The most common adverse reactions in patients receiving 2 or more episodes of severe hypocalcemia and 16% Xgeva (per-patient incidence greater than or equal to 25%) experienced 3 or more episodes. were fatigue/asthenia, hypophosphatemia, and nausea • Severe hypophosphatemia (serum phosphorus less (see Table 1). The most common serious adverse reaction than 2 mg/dL or less than 0.6 mmol/L) occurred in in patients receiving Xgeva was dyspnea. The most 15.4% of patients treated with Xgeva and 7.4% of common adverse reactions resulting in discontinuation of patients treated with zoledronic acid.

Xgeva were osteonecrosis and hypocalcemia.

Osteonecrosis of the Jaw Clinical Trials Experience. Because clinical trials are In the primary treatment phases of Trials 1, 2, and 3, conducted under widely varying conditions, adverse ONJ was confirmed in 1.8% of patients in the Xgeva group reaction rates observed in the clinical trials of a drug (median exposure of 12.0 months; range 0.1 – 40.5) cannot be directly compared to rates in other clinical and 1.3% of patients in the zoledronic acid group. The trials and may not reflect the rates observed in practice. trials in patients with breast (Trial 1) or prostate (Trial The safety of Xgeva was evaluated in three randomized, 3) cancer included an Xgeva open label extension double-blind, double-dummy trials in which a total treatment phase where patients were offered Xgeva 120 of 2841 patients with bone metastasis from prostate mg once every 4 weeks (median overall exposure of 14.9 cancer, breast cancer, or other solid tumors, or lytic bony months; range 0.1 – 67.2). The patient-year adjusted lesions from multiple myeloma received at least one dose incidence of confirmed ONJ was 1.1% during the first of Xgeva. In Trials 1, 2, and 3, patients were randomized year of treatment and 4.1% thereafter. The median time to receive either 120 mg of Xgeva every 4 weeks as to ONJ was 20.6 months (range: 4 – 53). a subcutaneous injection or 4 mg (dose adjusted for Atypical Subtrochanteric and Diaphyseal Fracture reduced renal function) of zoledronic acid every 4 weeks Atypical femoral fracture has been reported with Xgeva. by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to Postmarketing Experience. Because postmarketing 2.9 mmol/L) and creatinine clearance 30 mL/min or reactions are reported voluntarily from a population greater. Patients who had received IV bisphosphonates of uncertain size, it is not always possible to reliably were excluded, as were patients with prior history of estimate their frequency or establish a causal relationship ONJ or osteomyelitis of the jaw, an active dental or jaw to drug exposure. condition requiring oral surgery, non-healed dental/ The following adverse reactions have been identified oral surgery, or any planned invasive dental procedure. during post approval use of Xgeva: During the study, serum chemistries including calcium • Hypocalcemia: Severe symptomatic hypocalcemia, and phosphorus were monitored every 4 weeks. Calcium including fatal cases. and vitamin D supplementation was recommended but • Hypersensitivity, including anaphylactic reactions. not required. The median duration of exposure to Xgeva • Musculoskeletal pain, including severe musculoskeletal was 12 months (range: 0.1 – 41) and median duration pain. Positive rechallenge has been reported.

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to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor.

Maternal mammary gland development was normal.

There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation.

Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/ RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated.

Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption.

Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab.

Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth.

Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older.

No overall differences in safety or efficacy were observed between these patients and younger patients.

Renal Impairment. Two clinical trials were conducted in patients without cancer and with varying degrees of renal function. In one study, patients (N=55) with varying degrees of renal function (ranging from normal through end-stage renal disease requiring dialysis) received a single 60 mg subcutaneous dose of denosumab. In a second study, patients (N=32) with severe renal dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis) were given two 120 mg subcutaneous doses of denosumab. In both studies, greater risk of developing hypocalcemia was observed with increasing renal impairment, and with inadequate/ no calcium supplementation. Hypocalcemia was mild to moderate in severity in 96% of patients. Monitor calcium levels and, calcium and vitamin D intake.

DOUS14CDNY4736_A_XGEVA_Asize_BS_V10_8pt_r10.indd 2

Females and Males of Reproductive Potential.

Contraception Females: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of Xgeva. Advise patients to contact their healthcare provider if they become pregnant, or a pregnancy is suspected, during treatment or within 5 months after the last dose of Xgeva. Males: The extent to which denosumab is present in seminal fluid is unknown. There is potential for fetal exposure to denosumab when a male treated with Xgeva has unprotected sexual intercourse with a pregnant partner. Advise males of this potential risk.

OVERDOSAGE: There is no experience with overdosage of Xgeva.

HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva.

PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of a hypersensitivity reaction, including rash, urticaria, pruritus, lip swelling, shortness of breath, hypotension and respiratory tract edema • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth • Persistent pain or slow healing of the mouth or jaw after dental surgery • Symptoms of atypical femoral fracture, including new or unusual thigh, hip, or groin pain • Pregnancy or nursing Advise patients of the need for: • Avoiding therapy with Xgeva if a serious allergic reaction occurred with prior Xgeva or Prolia therapy • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva • The use of highly effective contraception during and for at least 5 months after treatment with Xgeva for females of reproductive potential Advise patients that denosumab is also marketed as Prolia®. Patients should inform their healthcare provider if they are taking Prolia.

Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 ©2010-2014 Amgen Inc. All rights reserved.

Printed in USA.

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Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cellbased in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy.

USE IN SPECIFIC POPULATIONS: Pregnancy: Category D. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program.

Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva.

Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels).

Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned

Cancer Center Business Summit

Building the Oncology System... Continued from the cover that the pressure to reduce healthcare spending will not dissipate, even if reform is challenging, because costs and the growth of costs in healthcare continue to adversely affect the economy. There are examples of large systems (eg, investor-owned healthcare) that have fared fairly well since the passage of the Patient Protection and Affordable Care Act (ACA); these systems have not yet overtly addressed cancer care, but he expects that they will in the future.

The Patient-Centered Outcomes Research Institute, established through the ACA, has the potential to provide a substantial shift in the delivery of cancer care, Dr Keckley stated. The institute was charged with supporting comparative clinical effectiveness research that helps patients, caregivers, clinicians, employers, and insurers make informed health decisions. The open market is already responding with announcements of technical gadgets and a biometrics revolution of what we wear and how it interacts with us physicallyâ&#x20AC;&#x201D;representing a movement toward putting more health information directly in consumersâ&#x20AC;&#x2122; hands.

Dr Keckley summarized with his vision that it is conceivable to have just 80 to 100 integrated health systems across the United States within the next 10 years, paid on a capitated basis, with responsibility for early disease detection as well as longterm care. Such a scenario would inevitably change the dynamics of cancer care.

Dr Lichter presented the initiatives that ASCO has considered to build the delivery system of the future. Solutions include at least 3 simultaneous revolutions: cancer panomics, big data, and the cost structure and valuation of healthcare, with a possible fourth revolution related to patient engagement.

He emphasized a growing recognition of treatment value (compared with cost only) as the primary driver for innovation in clinical practice.

ASCO is actively engaged to move these revolutions forward, but it is not easy or fast to accomplish, he said. He also noted that in the future, the utility of treatment will be driven by real-time analysis of realworld data from active clinical care, rather than by clinical trials and research alone.

The pressure to reduce healthcare spending will not dissipate, even if reform is challenging, because costs and the growth of costs in healthcare continue to adversely affect the economy.

Ms Conway shared trends that the Oncology Roundtable has seen to be shaping community hospitals and cancer care. Patients will become more demanding and discerning healthcare consumers by 2018, she said, driven by new insurance plans, activist employers, new financial incentives, and growth in private health markets. Shrinking health insurance networks will exclude providers, and the providers who find themselves outside of or within key networks will have to find ways either to survive out of network or to conform to the greater cost sensitivities within them, respectively. Treatment decisions are likely to change as providers begin to stratify patients for management choices based on risk assessments.

In the northwest United States, the Fred Hutchison Institute for Cancer Outcomes Research, as a leading area cancer provider, has been involved in a regional collaborative network looking at cancer outcomes with 60 regional employer and plan stakeholders. Dr Lyman shared that from an initial list of more than 100 recommendations for factors to consider when studying cancer care outcomes, the network has narrowed those choices to a list of 6. These data will be tracked over the next year and benchmarked for adherence; he indicated that perhaps this approach could extend to other regions or nationwide. Currently, 2 specific interventions are moving forward: one involves capturing data before and after a patient-centered education campaign, and the other involves tracking the use of growth factors.

General consensus among participants was that major networks and growing systems of healthcare providers will transition treatment choices from individual physicianâ&#x20AC;&#x201C; patient interactions to a more global care continuum focus. Increasing attention to the total cost of care will change discussions regarding the definition of appropriate treatments.

Pathways, while continuing to emerge as an essential element in the growing process of care delivery, will serve as just one tool in the larger discussion of relative value, efficacy, total cost, and impact of decisions on care outcomes. Manufacturers of cancer care drugs will need to equip their teams with the ability to adapt to rapidly changing delivery leaders in individual markets, and to tailor materials and support for a variety of perspectives.

Some leaders in providing care will be more focused on the role of products in the total cost of the care continuum, whereas health plan deContinued on page 16

14

I

Oncology Practice Management

I February 2015

Cancer Center Business Summit

The Future of Oncology Reimbursement

By Gail Thompson

C

hanges in oncology payment and reimbursement as well as delivery models were reviewed recently by an expert panel at the Cancer Center Business Summit (CCBS). Providers, payers, industry representatives, and thought leaders were on hand to share their thoughts and experiences.

Moderated by Marc Samuels, JD, MPH, Chief Executive Officer, ADVI, the panel included Michael Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna; Kavita Patel, MD, MS, Fellow and Managing Director, Engelberg Center for Health Care Reform, The Brookings Institution; Denise Pierce, President and Chief Executive Officer, DK Pierce & Associates; Larry Strieff, MD, Specialty Medical Director, Hill Physicians Medical Group; and Robin Zon, MD, FACP, FASCO, Michiana Hematology Oncology, and Chair, Clinical Practice Committee, American Society of Clinical Oncology (ASCO).

Dr Kolodziej shared with the audience that moving forward, transparency in care, pricing, utilization, and costs will be mandatory from all stakeholders: providers, payers, patients, and employers. While everything must be on the table for review in order to develop workable solutions, he noted that reform will not work unless physicians are holding the reins, so collaboration rather than conflict between payers and providers is essential. Aetna has explored several models for oncology, and has decided on the parameters of a model based upon the oncology medical home. This meets the companyâ&#x20AC;&#x2122;s needs and expectations for transparency and quality, and should allow oncology practices to meet those deliverables as well.

Dr Patel explored alternative pay-

ment models under review by the Centers for Medicare & Medicaid Services (CMS). One of the models CMS is considering identifies patients with specific cancers and builds an episode-based payment on a per-month basis, plus another payment that is risk-adjusted for care coordination. When an episode is complete, quality measures will be

value-based payment design, among other options to manage cancer treatment costs. In a specific example, she discussed collaborations between MD Anderson Cancer Center and Shell Oil Company through a voluntary program that offers cancer information and prevention services to Shell employees utilizing a case manager. She indicated that business

While everything must be on the table for review in order to develop workable solutions, Dr Kolodziej noted that reform will not work unless physicians are holding the reins, so collaboration rather than conflict between payers and providers is essential. reviewed with the potential for a bonus performance payment or a negative payment element for poor performance. CMS would like to include private payers in this implementation, but has not yet identified any collaborators. Some of the current challenges for this model include defining a cancer type, defining a finite period of time coverage, and other issues that have arisen with control of Medicare Part D, Part A, and Part B costs.

Employer perspectives on cancer management were presented by Ms Pierce, based upon qualitative and quantitative research completed recently with employers across the United States. Cancer has become one of the top 3 disease concerns for many employers, some of whom are starting to take action themselves, rather than to wait for a payment reform model. Ms Pierce discussed the efforts of employers that are exploring a solid tumor mapping program, the use of nurse navigators,

coalitions are also starting to become more engaged not just in contracting for services, but in benefit design and analytics coordination.

The Hill Physicians Medical Group has built a bundled payment model for oncology patients in California. Dr Strieff described the utilization experience, the development of the case rate, and the necessary addition of stop-loss programs to financially protect the physicians.

The group is monitoring quality by using ASCOâ&#x20AC;&#x2122;s Quality Oncology Practice Initiative program. To date, the model has led to performance improvements, increased satisfaction compared with a standard fee-for-service model, and improvements in cost.

Dr Zon outlined the details of Consolidated Payments for Oncology Care (CPOC), ASCOâ&#x20AC;&#x2122;s proposed payment reform model. This model would replace current codes with new codes that are billable for physician services for new patients, for Continued on page 16

February 2015

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Cancer Center Business Summit

Building the Oncology System... Continued from page 14 cision makers and policy makers may request proof of value to the employer or plan to better meet the needs of insured patients. Increasingly, patients, treating physicians, and health plans are likely to ask manufacturers of new products for comparisons to other market alternatives and even to other delivery or site-of-care models that may be supported by the treatment options (home care, oral medicines, pumps, self-administration, or even decisions to not treat).

During an audience question-and­ -answer session, one point summa-

rized the status of the future healthcare delivery model debate: there is a need to innovate in drugs, but also

py. All stakeholders need to come together to determine how to balance the needs of patients and pro-

All stakeholders need to come together to determine how to balance the needs of patients and providers with the efforts of the pharmaceutical industry and the concept of value. to recognize that a focus on the cost of drugs, especially multiple combinations of drugs, comes with reduced sustainability of cancer thera-

viders with the efforts of the pharmaceutical industry and the concept of value. We do not, however, have any definitive answers yet. l

The Future of Oncology Reimbursement Continued from page 15 each month of active treatment, for monitoring patients not in active treatment, for services related to transitions of care, and for additional payment adjustments related to utilization and performance on quality measures, adherence and use of certified pathways, resource utilization (oncology medical home, hospitalization, and emergency department admissions), and participation in clinical trials. The CPOC model is not yet tested; ASCO hopes to begin practice testing this year.

Presenters generally agreed that CMS will be a major driver of change for provider payments. It is likely that private payers will begin collaborating with CMS, increasing the rapidity of changes on oncology payments across a wide variety of markets. In addition, it is expected that

drug costs will be targeted and probably removed as a driver of cancer treatment choices; rather, patient outcomes and allowable cost param-

The consensus among presenters was that the current system is not sustainable, and private insurers and CMS have committed to change. eters will become targeted drivers of treatment choice. Several oncology payment reform models are under consideration by public and private

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entities, but none have been identified as primary solutions at this time.

The consensus among presenters was that the current system is not sustainable, and private insurers and CMS have committed to change.

In addition, employers were mentioned as a rising catalystâ&#x20AC;&#x201D;rather than a passive participantâ&#x20AC;&#x201D;in the oncology payment and management reform arena. Escalating prices for insurance premiums are pushing small to medium employers to turn to exchange plans for employee health insurance benefits, a move that has far-reaching implications for coverage and access.

Despite the variety of pilots and proposed models, the panel emphasized that the future of oncology reimbursement is a work in progress, and one clear solution is yet to emerge. l

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08/14

US-CELG140179

From the Editor

Pharmacy Benefit Managers and... Continued from the cover company is looking to find ways to eventually guide doctors toward preferred drugs in the PBM’s approved formulary in ways that do not cause patients to be upset.

These steps—indicative of a growing trend for entities outside of the oncology space to take control of oncology spend—portend a sea change in control and influence over the oncology space. So why should practices, physicians, patients, and cancer centers be concerned about what appears to be an approaching battle between drug manufacturers and PBMs? There is a new move toward managing medical care. PBMs are very interested in offering services to their customers (employers and health plans) to manage all of oncology, whether billed through the pharmacy benefit or the medical benefit. Such services would position PBMs as an arbiter of care choices between the payer and the treating physician and his or her patients. What experience and skill sets related to the comprehensive management of oncology qualify a PBM to manage board-certified oncology physicians?

Medical oncology management involves far more than drug choices. PBMs are not equipped to manage medical oncology and should not be the arbiters of oncology treatments prescribed by board-certified physicians. Drug formulary decisions for patients with cancer should be evaluated with input from practicing oncologists, and the utility of the drug should be given greater consideration than its cost structure. Even drugs in the same class have different side effects and mechanisms of action. Only the treating physician has direct access to patients, their records, and their health status, and can make the best decision for the patient.

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Narrow drug formularies can be pennywise but pound foolish for complex cancer treatments, and patients and health plans/employers will pay the price, whereas PBMs benefit from drug limitations based on bidding wars. Mandating the use

Accessing appropriate treatments for complex patients with cancer when formularies are built with such a narrow focus will be difficult at best, potentially leading to adverse consequences for the patient, as well as greater overall costs. of only 1 drug option that is selected from a discounted bidding war may yield financial benefits for a PBM, but will also likely cost patients and health plans/employers more for laboratory tests, emergency department visits, physician services, and increased side effect management, or even reduced effectiveness compared with a drug that is not on the accepted formulary.

There is no denying that we currently enjoy significant improvements in the battle against cancer, and that pharmaceutical advances have played a major role. There is also no denying that there is only so much money available to pay for healthcare, and that choices are and will continue to be made for all diseases. There is already great pressure on the pricing of cancer drugs, and that pressure will continue.

When developing a formulary,

Oncology Practice Management

I February 2015

however, the focus of third-party administrators of pharmaceuticals is ordinarily on the price of drug A versus drug B, not on the total cost of cancer treatment. When facing the complexities of cancer care, it is imperative to stay focused on the larger picture. Accessing appropriate treatments for complex patients with cancer when formularies are built with such a narrow focus will be difficult at best, potentially leading to adverse consequences for the patient, as well as greater overall costs.

Physicians see the patient, know the patient, and know the parameters of health status, family and work concerns, and psychosocial aspects of the patient and the patient’s caregivers. Medical benefits address the total costs of care and the fit of specific drugs within the whole con­ tinuum of care. Pharmacy benefit management focuses on the drug.

Management of medical benefits and pharmacy benefits are simply not interchangeable.

What can practices do? Engage local employers and health plans in discussions about oncology management. Review your own processes for cancer management and drug selection: are there opportunities for improvement that do not adversely affect the patient and can be managed better by your practice? Inform your state societies about this as an issue to watch and address. Engage the pharmaceutical companies with whom you work. The total cost of care is indeed a societal problem, and one that is hitting all of us right now.

Contracting and pricing negotiations will continue to happen. However, if and when such negotiations by third parties affect patient access and safety, and can lead to unintended financial, health, and medical consequences, the medical community should, and will, be heard. l

In mCRPC therapy…

Is there more to the story?

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

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

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

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

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

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

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

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

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

Please see additional Important Safety Information on the next page.

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

For men with mCRPC who progressed on ADT

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

More than 1,000 days.

And every day tells a story.

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

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

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

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

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

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

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

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

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

ADT=androgen-deprivation therapy.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 6/14 016819-140612

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

B:11.125 in

003307-130924

S:10.375 in

T:10.875 in

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

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

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

Learn more today at

www.zytigahcp.com.

Every day tells a story.

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

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

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

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information].

In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

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

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

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

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

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

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

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

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

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

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

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

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

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

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

Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Musculoskeletal discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

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

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 4 Includes

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

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

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo.

The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry 1 Hyperglycemia 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%).

Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

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

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

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

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

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

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

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine).

If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

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

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

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

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

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

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

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

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

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

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

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

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

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

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

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

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

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

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

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

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

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

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

Regulatory Update

FDA Issues Final Rule on Pregnancy and Lactation Labeling

By Rosemary Frei, MSc

T

he US Food and Drug Administration (FDA) is hoping that its December 4, 2014, final rule on pregnancy and breastfeeding labeling for prescription drugs and biological products1 will be helpful to patients and providers.

Clinicians are also optimistic about the changes but are waiting to see whether sufficient data will be available to truly clarify the risks of using each medication during conception, pregnancy, and lactation.

The new regulations state that as of June 30, 2015, labels for newly approved medications must have 3 subsections—Pregnancy, Lactation, and Females and Males of Reproductive Potential—describing the medication’s effects on women who are pregnant or breastfeeding, on the fetus and breast-fed children, and on men and women who are attempting to conceive. Labels must no longer include a labor and delivery subsection or the currently used A, B, C, D, or X pregnancy category designation for classifying teratogenicity.

Over the subsequent 3 to 5 years, products approved from 2001 to June 2015 will be required to comply with the new labeling rules. Labeling for medications approved before June 30, 2001, will not be required to include the new changes, but the letter designation, if any, must be removed within 3 years of the final rule’s effective date.

“We’ve been long aware that this section of the medical product labeling is probably one of the least informative sections of the drug labeling there is. It is rarely up to date, [and] we hear from clinicians that they don’t understand it [and that] there were long descriptions of animal data that were not interpreted well,” Sandy Walsh, FDA Press Officer, stated in an

ceived and will increase the clarity in understanding the labels. But there will be some adjustment on all sides getting used to the new system.”

The final rule stipulates that the Pregnancy subsection of the label will specify whether there is a scientifically acceptable pregnancy-exposure registry for the drug. This subsection also will include a summary of the risks to fetuses and mothers of using the drug during pregnancy, as well as any other available information to help clinicians counsel pregnant women about use of the medication.

The Lactation subsection will indicate whether the medication is absorbed systemically by the mother and, if so, what its effects are on milk production; how much of the drug reaches the breast milk; and what its effects are on breast-fed babies. Other information to be put in this subsection includes ways to minimize the amount of the drug ingested by children via breastfeeding and ways to monitor for and reduce side effects from the medication.

Information in the Females and Males of Reproductive Potential subsection will address whether pregnancy testing or contraception is needed or recommended before, during, or after medication use. Furthermore, if studies have indicated that the medication affects fertility, these data will also be included.

The opportunity for public comments regarding this measure closed on February 1, 2015. The FDA is now planning to finalize draft guidance for the industry. l

Richard L. Schilsky, MD

e-mail to Oncology Practice Management. “[A]nd studies...done by astute clinicians and researchers never made it to labeling. We’re hoping this new rule will allow for much more useful information to be added consistently.”

Richard L. Schilsky, MD, Chief Medical Officer, American Society of Clinical Oncology, commended the FDA for moving forward with the changes but said a large data gap remains. “The rule seems to deal with how the information should be presented in the label,” Dr Schilsky told Oncology Practice Management. “[But] the bigger issue is how we get the information that needs to be in those sections of the label that actually provides the guidance that physicians and their patients are looking for. The problem is the lack of information about what the risks of different drugs are to the developing fetus or the child who’s breastfeeding, particularly with some of the new targeting drugs that we don’t have much experience with.”

Urologist Philippe Spiess, MD, gives a passing grade to the changes.

“A, B, C, D, and X in the current labeling isn’t very clear to the lay public,” Dr Spiess, who practices at Moffitt Cancer Center, Tampa, FL, said in a telephone interview. “I think the changes will be well-re-

February 2015

Reference

1. Federal Register: The Daily Journal of the United States Government. Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. https:// federalregister.gov/a/2014-28241. Published December 4, 2014. Accessed February 11, 2015.

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Personalized Medicine

Payers Debate the Economics of Personalized Medicine in Oncology

By Wayne Kuznar

S

an Francisco, CA—The rising costs of biomolecular testing and targeted drugs have prompted many to ask whether the United States can afford personalized medicine in oncology. At the Third Annual PMO Live Conference, a Global Biomarkers Consortium Initiative, medical directors from 2 health plans tackled this question from the payer perspective.

Ken Schaecher, MD, Medical Director at SelectHealth, answered “it depends” to the key question. Dr Schaecher noted that healthcare costs in the United States now stand at 17.2% of gross domestic product.

The United States can afford personalized medicine “until we decide not to,” he said, pointing out that some targeted medicines cost upwards of $100,000 annually, because the United States has no threshold to pay for these medicines.

Most payers have defined sets of rules, Dr Schaecher said, but the problem in the United States is the large number of payers, each with their own set of rules. Sometimes, even within a plan, one set of rules may be applied, but different benefit structures mean that one patient can get a therapy that another cannot.

Is It Cost-Effective?

Gary Johnson, MD, MS, MBA, Regional Medical Director at Humana, said that paying for treatments and tests is always possible, but the real question is, “Should we pay?” As stewards of the premium dollar, insurers can cover anything they want to but they will have to raise premiums to do so.

The targeted approach to care allowed by personalized medicine creates the opportunity for greater

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cost-effectiveness, as in KRAS testing to select patients with colorectal cancer for targeted therapy. Being able to select the right treatment for the right patient improves health outcomes, said Dr Johnson.

Personalized medicine “shows us where treatments will be effective,

can reduce provider liability, said Dr Johnson. A well-defined treatment pathway linked with a diagnostic marker provides legal cover denial of a treatment.

“We can identify disease at an earlier state, and as a general rule, the earlier we treat various cancers,

“We can identify disease at an earlier state, and as a general rule, the earlier we treat various cancers, the more effective it is clinically, and, as important, the more cost-effective it is….

The answer to this question, ‘Can we afford personalized medicine?’ is a resounding ‘yes.’”

—Gary Johnson, MD, MS, MBA

and just as important, where treatments will not be effective so we can avoid toxicities and morbidities from treatments that, in essence, cause harm,” he said. “All of this is the goal of managed care and of clinical care.”

By reducing unnecessary risks of treatments not likely to work in a given patient, personalized medicine

Oncology Practice Management

the more effective it is clinically, and, as impor­tant, the more cost-effective it is,” he said. “BRCA testing, which has been around for decades, and Oncotype DX, for breast cancer are additional examples of why the answer to this question, ‘Can we afford personalized medicine?’ is a resounding ‘yes.’ ”

KEY POINTS • The rising cost of molecular testing and targeted drugs has raised the question whether the United States can afford personalized medicine in oncology • Personalized medicine enables providers to select the right treatment for the right patient, which improves health outcomes, and would be supported by payers, if used appropriately • Establishing a threshold for the annual costs of high-priced targeted medicines may make personalized medicine more cost-effective

I February 2015

Personalized Medicine

The higher price tags of targeted therapies reduce the cost-effectiveness of personalized medicine, said Dr Schae­cher.

“We’ve found that, typically, with more targeted therapies, the price tag goes up, and there’s only so much money in the bank,” he reasoned. “A great example is crizotinib. It has a $96,000 price, because it only works in 4% of the non–small-cell lung cancer [NSCLC] population that has the mutation. That price tag is much above most of the other therapies used in NSCLC.”

The Biomarkers Dilemma Biomarker costs are increasing as well, Dr Schaecher said, with some tests exceeding $3000.

The misapplication of information in directing therapy is another potential con to personalized medicine in oncology. Sometimes, tests with low sensitivity or specificity are being used to determine clinical utility. And, in some instances, providers select the same treatment they would have otherwise without the biomarker test.

There is also a risk that information from testing may be applied when evidence is not present, said Dr Schae­cher. “It’s arguable that there is adequate evidence for whole-genome sequencing in oncology, but for most

payers, they don’t believe that the evidence is there yet,” he said. “Using biomarkers in a one-off circumstance can help one patient but, unfortunately, as payers, we have to make broad payer-based decisions and not

A lack of process standardization across laboratories argues against the wholesale use of biomarker tests. “As much as we would like all of the tests to be FDA-approved, sometimes FDA approval can mean different things,”

“Provide payers with evidence that it’s useful, and that it would be no more costly or preferably less costly than the current approach to management, and you win the day. It’s that easy.”

—Ken Schaecher, MD

individual decisions. When there’s a lack of evidence we have to be consistent in our decisions. If I make an exception for one patient, that can bind us to make an exception for every patient going forward.”

Pharmacogenetic testing to identify drug metabolism may also add cost without utility. It is unproven that knowing that a patient may be a rapid metabolizer of an antidepressant medication is going to alter the therapy. That can occur in the oncology arena also, said Dr Schaecher.

Dr Schaecher said. “Many [tests] are home-brewed, done in university labs, and when you don’t have that standardization, it’s harder for us to want to approve having a test covered.”

Finally, a patient may still insist on a therapy anyway with a negative biomarker test.

“Provide payers with evidence that it’s useful, and that it would be no more costly or preferably less costly than the current approach to management, and you win the day,” said Dr Schaecher. “It’s that easy.” l

Clinician and Survivor Shares...Continued from page 9 most important things I can share with physicians is the importance of spending time with the patient.

If I asked them to do only one thing while they are having a discussion, I want them to hold that patient’s hand. I want them to feel connected to this individual and not just focus on the cancer, but to look at the patient and see someone who is an individual, someone who has a life outside of the world of cancer.

I also realize that we are facing a

shortage of oncology specialists in the United States. That does not mean that the patient deserves less of the oncologist’s time. Oncologists really do need to identify what they need to prioritize in their discussion, and then utilize mid-level clinicians as well as nurse navigators to pick up where they have left off in doing education, psychosocial support, and barrier assessment, and then provide patients with the resources that they need.

Above all, I want to make sure

February 2015

that the physician is talking about hope: what is this patient hoping for from the perspective of what the treatment is going to accomplish and where the patient sees his or her life going forward, including for individuals with metastatic disease. What is the patient hoping for, and how can we help that patient transition through hope? Most importantly, provide that patient a good death.

That is something I will hold an oncologist responsible for. l

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Wealth Management

How to Choose a 529 College Savings Plan

By W. Ben Utley, CFP®, and Lawrence B. Keller, CFP®, CLU®, ChFC®, RHU®, LUTCF

W. Ben Utley

S

Lawrence B. Keller

ection 529 College Savings plans are tax-advantaged college savings vehicles, and one of the most popular ways to save for college today. Known officially as “qualified tuition programs,” 529 college savings plans have changed the world of tuition savings, much like the way 401(k) plans changed the world of retirement savings a few decades ago. While a 529 plan may be the best vehicle to save for college, you will need to understand the basics in order to make the right choice.

The Basics of 529 Plans Congress created 529 plans in 1996 and named them after Section 529 of the Internal Revenue code. A 529 plan is state-operated and offers tax advantages as well as other potential incentives to ease saving for college or postsecondary training for a designated beneficiary, such as a child or grandchild. Eligible educational institutions generally include colleges, universities, vocational schools, or other postsecondary educational institutions eligible to participate in a student aid program administered by the US Department of Education.

When establishing a 529 plan, you can name anyone as a beneficiary, including a relative, a friend, or yourself. There are no income restrictions on you as the contributor, or on the beneficiary, and there is also no limit

to the number of 529 plans you can establish. College savings plans are established by individual states and typically managed by an experienced financial institution that the state has designated. All 50 states and the District of Columbia sponsor at least 1 type of 529 plan.

The main advantage to these plans is that earnings are not subject to federal tax—and generally not subject to state tax—when the designated beneficiary uses the money for “qualified higher education expenses” (eg, tuition, fees, books, room and board). If you make a nonqualified withdrawal (ie, a withdrawal used for something other than the beneficiary’s qualified higher education expenses), then the earnings portion of the withdrawal will be taxed at the federal level at the rate of the person who receives the distribution (usually the account owner). State taxes will likely apply in addition to a penalty; specifically, the earnings portion of the withdrawal will be subject to a 10% federal penalty.

The majority of plans are open to residents of any state. This means you can shop for the plan with the best money manager, overall performance record, investment options, fees, and customer service. Keep in mind, however, that many states limit their tax benefits to residents who participate in an in-state college savings plan.

Opening a 529 plan is simple: complete a short application, designate a beneficiary, and contribute the required minimum amount. Most plans also offer automatic deductions or electronic fund transfers to make future saving even easier. Once the account is open, you or anyone else can contribute as much money to the account as you wish, subject to the plan’s specific limits. Some plans

may require a minimum amount to open the account, have a minimum amount for each contribution, or restrict the total contributions allowed per year. All plans have total lifetime contribution limits; however, most states generally have limits in excess of $300,000.

You can roll over your existing college savings plan account to a new 529 plan account once every 12 months without any federal tax penalty and without having to change the beneficiary. There may be state income tax consequences (and, in some cases, state-imposed penalties) that result from such a rollover. This option lets you leave a plan with few investment choices or one that has earned poor returns for a plan with more investment flexibility or a better track record. If you are satisfied with the plan but want to change the way your existing assets are invested, this can be done twice each calendar year, or whenever the account beneficiary changes. You do have the ability to change how your future contributions are allocated at any time.

If your child receives a college scholarship, you can withdraw money without penalty as long as your withdrawals during the year don’t exceed the annual scholarship amount. However, you will owe federal and state income taxes on the earnings portion of each withdrawal.

If the beneficiary doesn’t use the money in the account for college, you can use the savings for graduate school or other higher education later, transfer the balance without penalty to another eligible family member (including a parent, step-sibling, half-sibling, or, in some cases, an inlaw of the original beneficiary), or simply make a nonqualified withdrawal as described earlier.

Continued on page 30

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Oncology Practice Management

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ACCC: MEETING YOUR NEEDS Gear up for a full menu of meetings with need-to-know information for the cancer care team. Don’t miss out on unparalleled opportunities to advance your learning in critical areas.

Be sure to share this information with your colleagues who can benefit from these events.

ONCOLOGY REIMBURSEMENT MEETINGS

$

Any member of the cancer care team who deals with oncology business and reimbursement will benefit from these FREE one-day meetings. Gain a fullspectrum perspective with sessions on working with new payment models; the latest information on documentation, coding, and billing; achieving ROI on quality certification; and a legislative and regulatory update.

ACCC 41st

ANNUAL MEETING

CANCERSCAPE Policy, Value & Quality

Thursday, April 16, 2015

March 16–18, 2015

Chicago, Illinois

Arlington, Virginia

Tuesday, April 28, 2015

Decode the complexity of healthcare policy reform, and discover the nuances of demonstrating value and quality in cancer care delivery.

Raleigh, North Carolina

Tuesday, May 19, 2015 Scottsdale, Arizona

Tuesday, August 25, 2015 Indianapolis, Indiana

Tuesday, November 17, 2015

Register Today!

www.accc-cancer.org/cancerscape

Boston, Massachusetts

Thursday, December 10, 2015 Birmingham, Alabama

32ND NATIONAL ONCOLOGY CONFERENCE Stay Tuned!

The ACCC National Oncology Conference delivers innovative ideas, solutions, and strategies to implement in your cancer program.

October 21–24, 2015 Portland Marriott Downtown Waterfront Portland, Oregon

For details on all ACCC meetings go to www.accc-cancer.org/meetings

Wealth Management

How to Choose a 529... Continued from page 28 Section 529 plans yield another valuable break: estate taxes. Contributions to the plan are considered a completed gift under estate tax code, so your contribution qualifies for the $14,000 annual gift tax exclusion amount. In fact, you can contribute up to $70,000 per child and then elect to treat the contribution as if it were made over a 5-year period.

This means a physician’s family with 2 children could move as much as $280,000 into the plan, and out of their estate, in a year.

Now that you understand the basics, let’s look at the steps you will need to take as you do your financial planning for college.

1

Determine whether your state offers a tax advantage for 529 plan contributions. Colorado, Georgia, Idaho, Iowa, Kansas, Louisiana, Maryland, Michigan, Mississippi, Missouri, Montana, Nebraska, New Mexico, New York, Ohio, Oklahoma, Oregon, Rhode Island, South Carolina, Utah, Virginia, West Virginia, and Wisconsin offer tax benefits for 529 contributions made by taxpayers residing in those states.

2

Learn how your state’s tax break works. Contact your tax specialist and ask these 3 questions: • How much money do I need to contribute to my state’s 529 plan to get the maximum tax benefit?

• How much will I save in taxes when I make my contribution?

• What is the deadline for making a contribution?

Note that some states will only allow you to deduct calendar year contributions from your tax return, while others will allow you to contribute up until the time your return is filed (as is the case with IRA contributions). If you discover this article in March, this means you might still have a chance to save taxes if

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you forgot (or didn’t know) to make a contribution last year.

3

Research investment results and expenses for in-state and out-of-state plans. If your state offers a tax break for 529 plan contributions, it might seem like this is the best option. But what if the performance of your state’s plan is poor? The cost of lower returns may outweigh the benefit of the tax break, so do a little digging and run a quick calculation.

The majority of plans are open to residents of any state. This means you can shop for the plan with the best money manager, overall performance record, investment options, fees, and customer service.

4

Calculate the performance gap: this is the difference in total return between your in-state plan and the out-of-state plan.

5

Think about the amount of money you will have in the plan.

If you are targeting a 4-year private university at a cost of $200,000 per student, and your family has nothing saved today, the average balance between now and then will probably be about $100,000.

6

Calculate the opportunity cost of using the in-state plan: multiply the average amount you’ll have invested by the performance gap.

Amount Invested × Performance Gap = Opportunity Cost

Oncology Practice Management

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Let the opportunity cost help you choose your plan. If the tax benefit outweighs the opportunity cost, consider using your state’s plan. If the opportunity cost is much larger than the tax benefit, then the out-of-state plan might be a better choice. We say “might be” because there’s one more thing you need to consider as you choose your plan: asset protection.

Some state plans confer a measure of protection against the claims of creditors, and in some states this protection only extends to physicians who live in that state and contribute to the instate 529 plan. The law on this issue varies from state to state, so you might want to seek legal counsel if you are at all concerned about the protections your plan may (or may not) afford.

Joseph F. Hurley, CPA, founder of www.savingforcollege.com and the nation’s expert on saving for college, hails the 529 plan as the best way to save for college. Even though the tax benefits, creditor protection, and kid-friendly usability were intended for everyone’s benefit, these features make 529 plans the best way for families of physicians to save for college, too. Choosing the right 529 plan is not as easy as it appears, but these steps will help you make the right choice for your family. l Lawrence B. Keller, CFP®, CLU®, ChFC®, RHU®, LUTCF, is the founder of Physician Financial Services, a New York–based firm specializing in income protection and wealth accumulation strategies for physicians. He can be reached by calling 516-677-6211 or by e-mail to Lkeller@physicianfinancialservices.com.

W. Ben Utley, CFP®, is the lead advisor with Physician Family Financial Advisors, a fee-only financial planning firm helping doctors throughout the United States to save for college and invest for retirement.

He can be reached by calling 541-463-0899 or by e-mail to ben@physicianfamily.com.

Clinical Trial Tracker

New Clinical Trials Under Way

T

he following clinical trials are currently recruiting patients with prostate cancer for inclusion in several investigations. Each trial description includes the NLM Identifier to use as reference with ClinicalTrials.gov.

1

Radiation Therapy With or Without Androgen Deprivation Therapy This phase 3, parallel assignment, open-label study examines the effectiveness of radiation therapy when it is given with or without androgen deprivation therapy comprising a lutein­ izing hormone-releasing hormone (LHRH). Patients aged ≥18 years with prostate cancer may enroll if other criteria are met. Patients are randomized to receive (1) external-beam radiation therapy once daily on days 1 to 5 or (2) an LHRH agonist subcutaneously or as an injection every 1 to 3 months with oral flutamide or bicalu­ tamide for 6 months. Beginning 8 weeks after the first LHRH injection, patients will undergo radiotherapy as in the non-LHRH group.

The primary objective is overall survival (OS), measured from the date of randomization to the date of death due to any cause. Secondary outcome measures include biochemical failure, local or regional disease recurrence, and distant metastasis. This study is expected to enroll 1520 patients at sites throughout the United States. For more information, contact Alvaro Martinez, MD, FACR, at 248-5530606 or alvaro.martinez@rtsx.com.

The NLM Identifier is NCT00936390.

2

Safety and Efficacy of Enzalutamide This phase 3, parallel-assignment, double-blind study assesses the safety and efficacy of enzalutamide in patients with nonmetastatic prostate cancer. Patients aged ≥18 years who

have ongoing androgen deprivation therapy with a gonadotropin-releasing hormone agonist/antagonist or prior bilateral orchiectomy may enroll if other criteria are met. Patients are randomized to placebo or 160 mg of enzalutamide daily.

The primary outcome measure is metastasis-free survival. Secondary outcome measures include OS, time to pain progression, or time to opiate use for prostate cancer pain. Time to first use of cytotoxic chemotherapy or new antineoplastic therapy, and time to prostate-specific antigen (PSA) progression are also collected. This study is expected to enroll 1560 patients at sites throughout the United States. For more information, contact Mohammad Hirmand, MD, at 415543-3470 or mohammad.hirmand@ medivation.com, or Kristina Wilson at 415-543-3470 or kristina.wilson@ medivation.com. The NLM Identifier is NCT02003924.

progression and skeletal-related events. This trial is expected to enroll 1170 patients at several sites throughout the United States. For more information, contact Richard Kapsa at kapsa@sotio.com. The NLM Identifier is NCT02111577.

4

Enzalutamide and Mifepristone This phase 1/2 trial studies the side effects, efficacy, and best dose of enzalutamide and mifepristone combination therapy. Patients aged ≥18 years with metastatic hormone-resistant prostate cancer, an Eastern Cooperative Oncology Group performance status of ≤2, and evidence of castrate testosterone levels at <50 ng/dL may enroll if other criteria are met. Patients are randomized to receive either enzalutamide alone or in combination with mifepristone.

Primary outcomes are the recommended phase 2 dose, defined as the highest mifepristone dose in combination with enzalutamide, and PFS. Secondary outcome measures include OS, radiographic PFS, pharmacokinetic parameters of the 2 drugs, and the androgen and glucocorticoid receptors’ expressions within circulating tumor cells. This study is expected to enroll 108 patients in Chicago, IL. For more information, contact Kelly O’Connor at 773-7024653 or koconnor@medicine.bsd. uchicago.edu. The NLM Identifier is NCT02012296.

3

DCVAC Added to Standard Chemotherapy The objective of this phase 3, parallel-assignment, double-blind study is to determine whether DCVAC/PCa added to standard-ofcare chemotherapy can improve survival times for patients with metastatic castration-resistant prostate cancer. Patients aged ≥18 years with disease progression despite androgen deprivation therapy, a life expectancy of ≥6 months, and an Eastern Cooperative Oncology Group performance status of 0 to 2 may enroll if other criteria are met. Patients are randomized to receive either DCVAC or placebo with standardof-care therapy consisting of docetaxel and prednisone.

The primary outcome is OS, measured over a time frame of 124 weeks.

Secondary outcome measures include radiographic progression-free survival (PFS), and duration to PSA

5

Enzalutamide plus Dutasteride as First-Line Treatment The objective of this phase 2, open-label, single-group assignment study is to determine the effect of enzalutamide and dutasteride on the time to PSA level increase. Patients aged 65 to 85 years with prostate cancer who have a serum testosterone level of >1.7 nmol/L at time of screening and an Eastern Cooperative Oncology Group performance status of Continued on page 32

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Clinical Trial Tracker

New Clinical Trials... Continued from page 31 0 to 2 may enroll if other criteria are met. All patients will receive daily enzalutamide and dutasteride orally.

The primary outcome measure is PSA levels, measured from blood drawn every 6 weeks for 103 weeks.

This trial is expected to enroll 40 patients in Rochester, NY, and Milwaukee, WI. For more information, contact Chunkit Fung, MD, at 585- 275-9319 or chunkit_fung@urmc.rochester.edu, or Ayesha Khan at 585-275-3351 or ayesha_khan@urmc.rochester.edu. The NLM Identifier is NCT02213107.

6

Safety, Efficacy, and Pharmacokinetic Behavior of Leuprolide Mesylate The purpose of this phase 3, openlabel, single-group assignment trial is to evaluate if leuprolide mesylate for injectable suspension (LMIS) is safe and effective in the treatment of advanced prostate carcinoma. Patients aged ≥18 years with a baseline morning serum testosterone level of >150 ng/dL and an Eastern Cooperative Oncology Group performance score of ≤2 may enroll if other criteria are met.

All patients will be given 2 injections with a depot formulation of LMIS 50 mg at 6 months apart, and are followed until day 336.

The primary outcome measure is efficacy of the study drug. Secondary outcome measures include postsuppression excursions of serum testosterone, and the pharmacokinetics, safety, and tolerability of LMIS. This study is expected to enroll 130 patients at multiple sites throughout the United States. For more information, contact John Mao, PhD, at 650-421-1016 or john.mao@foresee pharma.com. The NLM Identifier is NCT02234115.

7

Calcitriol, Ketoconazole, and Hydrocortisone This single-arm, phase 1/2 trial studies the side effects, best dose, and

32

I

efficacy of calcitriol when given in combination with ketoconazole and hydrocortisone in patients with advanced or recurrent prostate cancer.

Patients aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0 to 2 or a Karnofsky performance score of 60% to 100%, a life expectancy >3 months, and hemoglobin ≥8 g/dL may enroll if other criteria are met. All patients will receive oral calcitriol daily according to protocol. Patients will receive ketoconazole orally 3 times a day on days 1 to 24 and days 4 to 24 in phase 1 and 2 of the trial, respectively. Oral hydrocortisone is given in phase 1 of the trial only. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Primary outcome measures include the maximum tolerated dose of calcitriol as well as PSA response rate. Secondary outcome measures are toxicity and objective tumor response as measured by a monthly physical exam and radiographic evaluation every 12 weeks. This study is expected to enroll 51 patients in Buffalo, NY. For more information, contact Donald L. Trump, MD, FACP, at 877-275-7724 or askrpci@ roswellpark.org. The NLM Identifier is NCT00536991.

8

Metformin Prostate Cancer Adjuvant Trial This open-label, phase 2 trial will determine whether metformin can increase the PSA doubling time for patients with prostate cancer who have failed primary treatment with radiation, or surgical patients who are at high risk for recurrence based on surgical pathology. Patients aged ≥18 years with hemoglobin A1c <7.0% who are able to swallow and retain oral medication may enroll if other criteria are met. All patients will receive metformin hydrochloride extended release 750 mg twice a day for

Oncology Practice Management

I February 2015

9 months, and are randomized to receive either surgery or radiation.

The primary outcome measure is PSA doubling time. The secondary outcome measure is the decrease in PSA levels. All end points are measured for a time frame of 9 months.

This study is expected to enroll 70 patients in Mineola, NY. For more information, contact Kaitlin Tietjen, MS, at 516-663-4721 or ktietjen@ winthrop.org, or Andrew Ho, BSc, at 516-535-1900 or aho@winthrop.org.

The NLM Identifier is NCT02176161.

9

Enzalutamide plus Leuprolide The purpose of this phase 3, parallel-assignment, double-­ blind study is to assess the combination of enzalutamide and leuprolide in patients with high-risk, nonmetastatic prostate cancer that progresses after radical prostatectomy, radiotherapy, or both. Patients aged ≥18 years with PSA doubling time ≤9 months and a serum testosterone level of ≥150 ng/dL may enroll if other criteria are met. Patients are randomized to receive enzalutamide plus leuprolide, enzalutamide monotherapy, or placebo plus leuprolide.

The primary outcome measure is metastasis-free survival, measured for up to 56 months. Secondary outcomes include OS, the proportion of patients per group who remain treatment free 2 years after suspension of study drug treatment, and the time to castration resistance. Prostate cancer–specific survival, time to first symptomatic skeletal event, and safety and adverse event profiles are also measured. This trial is expected to enroll 1860 patients in Tucson, AZ; Omaha, NE; and Myrtle Beach, SC. For more information, contact William Novotny, MD, at 415-983-3066 or william. novotny@medivation.com, or Christian Lopez at 415-829-4159 or christian. lopez@medivation.com. The NLM Identifier is NCT02319837. l

FDA Update

Recent Drug Approvals Jakafi Gets New Indication for Use in Patients with Polycythemia Vera The FDA approved ruxolitinib (Jakafi; Incyte Corporation) for the treatment of patients with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea. The FDA approval was based on Protocol CINC424B2301, a multicenter, openlabel, active-control trial of 222 patients with PV whose disease was resistant to or who were intolerant of hydroxyurea. The composite end point was durable hemat­ocrit control and spleen volume reduction, and a durable hemat­ ocrit control that obviated the need for regular phlebotomy. Patients were ran­ domized to ruxolitinib 10 mg twice daily (N = 110) or to best available care (N = 112).

Ruxolitinib was superior to best available therapy in durable hematocrit control and in spleen volume reduction at week 32 (21% vs 1%; P <.001) and at week 48 (19% vs 1%; P <.001), as well as in a relatively high rate (55%) of durable hematocrit control at week 48.

The most common hematologic adverse reactions (incidence >20%) through week 32 were thrombocytopenia and anemia. The most common nonhematologic adverse events (incidence >10%) were headache, abdominal pain, diarrhea, dizziness, fatigue, pruritus, dyspnea, and muscle spasms. Overall, 4% of patients discontinued therapy with ruxolitinib because of adverse events.

(December 14, 2014) Cyramza Approved in Combination with Docetaxel for Metastatic NSCLC Ramucirumab (Cyramza; Eli Lilly) received a new indication for use in combination with docetaxel for the treatment of patients with

Blincyto First Immunotherapy Approved for B-Cell Acute Lymphoblastic Leukemia The FDA approved blinatumo­ mab (Blincyto; Amgen) for the treatment of patients with relapsed or refractory Philadelphia chromosome (Ph)-negative precursor B-cell acute lymphoblastic leukemia (ALL), a rare and rapidly growing form of ALL. Blinatumomab is intended for use in patients with B-cell ALL. Blinatumomab is the first immunotherapy approved by the FDA for patients with leukemia. The drug acts as a connector between the CD19 protein (which is found on the surface of most B-cell lymphoblasts) and the CD3 protein found on T-cell lymphocytes, using the body’s T-cells to destroy the leukemia cells.

The FDA had initially granted this drug a breakthrough therapy designation, and applied its priority review and accelerated approval program to approve the drug 5 months ahead of the scheduled date. Blinatumomab has an orphan drug designation. The FDA is now requiring the manufacturer to conduct a new clinical trial to show a survival benefit with blinatumomab in patients with relapsed or refractory Ph-negative precursor B-cell ALL. The approval was based on the safety and efficacy of blinatumomab in a clinical trial of 185 adults with Ph-negative relapsed or refractory precursor B-cell ALL. All patients received an infusion of blinatumo­ mab for at least 4 weeks. The results showed a 32% complete remission rate lasting approximately 6.7 months. The trial was not designed to show improvement in survival.

Blinatumomab is associated with significant risks, including cytokine release syndrome, encephalopathy, and nervous system adverse events.

The most common side effects reported were pyrexia, headache, pe-

metastatic non–small-cell lung cancer (NSCLC) whose disease is progressing with or after platinum-based chemotherapy. In patients with EGFR or ALK mutations, disease progression should be considered for treatment with an FDA-approved medication for these genetic mutations before administering ramucirumab. Earlier in the year, the FDA approved ramucirumab alone and in combination with paclitaxel for the treatment of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma after disease progression while using first-line therapy.

The approval of ramucirumab in combination with docetaxel for patients with NSCLC was based on results of the multicenter, double-blind, placebo-­ controlled study of 1253 patients with previously treated metastatic NSCLC that showed improved overall survival (OS). Patients were randomized to ramucirumab in combination with docetaxel on day 1 of a 21-day cycle (N = 628) or to placebo plus docetaxel (N = 625). The median OS was 10.5 months in the ramucirumab plus docetaxel arm and 9.1 months in the placebo plus docetaxel arm, a significant difference (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.98; P = .024).

Progression-free survival (PFS) was also significantly longer with ramucirumab than with placebo (HR, 0.76; 95% CI, 0.68-0.86; P <.001).

Among 1245 patients who received at least 1 dose of ramucirumab plus docetaxel, the most frequent adverse reactions (incidence ≥30%) were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation.

The most common serious adverse reactions with the active combination were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). (December 12, 2014)

Continued on page 38

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Your Patients, Your Practice…

Helping Your Practice This comprehensive financial assistance program offers ongoing support across the reimbursement spectrum to help you help your patients.

Complete Provider Assistance Benefits verification Prior authorization tracking Regionally dedicated case managers Local access and reimbursement specialists Denied claims assistance Indication XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Important Safety Information Contraindications XTANDI (enzalutamide) capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of patients who were treated with XTANDI and 0% treated with placebo. In Study 2, conducted in patients with chemotherapy-naïve metastatic CRPC, seizure occurred in 0.1% of patients who were treated with XTANDI and 0.1% treated with placebo. Patients experiencing a seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited clinical trial experience in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold, whereas Study 2 permitted the use of these medications.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Adverse Reactions The most common adverse reactions (≥ 10%) reported from the two combined clinical trials that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/ vertigo.

Other Adverse Reactions include: • Laboratory Abnormalities: In the two studies, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI

We’ve Got You Covered Helping Your Patients Financial assistance is available for patients.* Private Insurance $5000/month copay assistance, up to $12,000/year

Medicare/Medicaid Referrals to Independent Copay Foundations†

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New Patients Awaiting Coverage Decision Free XTANDI through XTANDI Quick Start+™ Program

*Subject to eligibility. Void where prohibited by law. Restrictions may apply. † XTANDI Support SolutionsSM has no control over the decisions made by and does not guarantee support by these independent copay foundations.

To learn more about XTANDI Support Solutions or enroll your patients today:

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(0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).

• Infections: In Study 1, 1% of XTANDI versus 0.3% of placebo patients and in Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

• Falls: In the two studies, falls including fall-related injuries occurred in 9% of XTANDI patients vs 4% treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas.

• Hypertension: In the two studies, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of XTANDI or placebo treated patients.

Drug Interactions • Effect of Other Drugs on XTANDI – Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible.

If co-administration of XTANDI cannot be avoided,

XTANDISupportSolutions.com

reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers may alter the plasma exposure of XTANDI and should be avoided if possible.

• Effect of XTANDI on Other Drugs – XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

PLEASE SEE BRIEF SUMMARY OF COMPLETE PRESCRIBING INFORMATION ON FOLLOWING PAGES.

XTANDI Support SolutionsSM, a component of Astellas Access ServicesSM 1-855-8XTANDI (1-855-898-2634); Fax 1-855-982-6341; XTANDISupportSolutions.com ©2014 Astellas Pharma US, Inc. All rights reserved. 076-0329-PM 9/14 Printed in USA XTANDI, Astellas, and the flying star logo are trademarks of Astellas Pharma, Inc.

XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information.

INDICATIONS AND USAGE

Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in Study 1 (cont.)

Respiratory Disorders

Table 1. Adverse Reactions in Study 1

Study 2: Chemotherapy-naive Metastatic CastrationResistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDItreated patients and 37% of placebo-treated patients.

Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

XTANDI N = 800

XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Grade 1-4a (%)

CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)].

WARNINGS AND PRECAUTIONS Seizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience readministering XTANDI to patients who experienced seizure.

Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

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

Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids.

The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

General Disorders Asthenic Conditionsb Peripheral Edema

Placebo N = 399

Grade Grade Grade 3-4 1-4 3-4 (%) (%) (%)

50.6

9.0

44.4

9.3

15.4

1.0

13.3

0.8

Musculoskeletal And Connective Tissue Disorders Back Pain

26.4

5.3

24.3

4.0

Arthralgia 20.5 Musculoskeletal 15.0 Pain Muscular 9.8 Weakness Musculoskeletal 2.6 Stiffness Gastrointestinal Disorders

2.5

17.3

1.8

1.3

11.5

0.3

1.5

6.8

1.8

0.3

0.3

0.0

21.8

1.1

17.5

0.3

Hot Flush

20.3

0.0

10.3

0.0

Hypertension

6.4

2.1

2.8

1.3

Diarrhea Vascular Disorders

Nervous System Disorders Headache

12.1

0.9

5.5

0.0

Dizzinessc Spinal Cord Compression and Cauda Equina Syndrome Paresthesia Mental Impairment Disordersd Hypoesthesia

9.5

0.5

7.5

0.5

7.4

6.6

4.5

3.8

Epistaxis

3.3

0.1

1.3

0.3

a CTCAE v4 b Includes asthenia and fatigue. c Includes dizziness and vertigo. d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Table 2. Adverse Reactions in Study 2 XTANDI N = 871 Grade 1-4a (%)

Grade 3-4 (%)

Placebo N = 844 Grade 1-4 (%)

Grade 3-4 (%)

General Disorders Asthenic 46.9 3.4 33.0 2.8 Conditionsb Peripheral 11.5 0.2 8.2 0.4 Edema Musculoskeletal And Connective Tissue Disorders Back Pain

28.6

2.5

22.4

3.0

Arthralgia

21.4

1.6

16.1

1.1

Gastrointestinal Disorders

6.6

0.0

4.5

0.0

4.3

0.3

1.8

0.0

4.0

Infections And Infestations Upper Respiratory Tract 10.9 Infectione Lower Respiratory 8.5 Tract And Lung f Infection Psychiatric Disorders

0.3

0.0

1.8

6.5

0.0

0.3

2.4

4.8

1.3

Insomnia

8.8

0.0

6.0

0.5

Anxiety

6.5

0.3

4.0

0.0

Renal And Urinary Disorders Hematuria

6.9

1.8

4.5

1.0

Pollakiuria

4.8

0.0

2.5

0.0

Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 Non-pathologic 4.0 1.4 0.8 Fractures Skin And Subcutaneous Tissue Disorders

0.0 0.3

Pruritus

3.8

0.0

1.3

0.0

Dry Skin

3.5

0.0

1.3

0.0

Constipation

23.2

0.7

17.3

0.4

Diarrhea

16.8

0.3

14.3

0.4

Vascular Disorders Hot Flush

18.0

0.1

7.8

0.0

Hypertension

14.2

7.2

4.1

2.3

Nervous System Disorders Dizzinessc

11.3

0.3

7.1

0.0

Headache

11.0

0.2

7.0

0.4

Dysgeusia

7.6

0.1

3.7

0.0

5.7

0.0

1.3

0.1

2.1

0.1

0.4

0.0

0.6

8.5

0.6

0.0

10.5

0.0

1.5

4.7

1.1

0.1

5.7

0.0

Mental Impairment Disordersd Restless Legs Syndrome

Respiratory Disorders Dyspneae

11.0

Infections And Infestations Upper Respiratory 16.4 Tract Infectionf Lower Respiratory Tract And 7.9 Lung Infectiong Psychiatric Disorders Insomnia

8.2

Table 2. Adverse Reactions in Study 2 (cont.)

Renal And Urinary Disorders Hematuria

8.8

1.3

5.8

1.3

Injury, Poisoning And Procedural Complications Fall

12.7

1.6

NonPathological 8.8 2.1 Fracture Metabolism and Nutrition Disorders Decreased 18.9 0.3 Appetite

5.3

0.7

3.0

1.1

16.4

0.7

8.5

0.2

Investigations Weight Decreased

12.4

0.8

Reproductive System and Breast Disorders Gynecomastia

3.4

0.0

1.4

0.0

a b c d

CTCAE v4 Includes asthenia and fatigue.

Includes dizziness and vertigo.

Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes dyspnea, exertional dyspnea, and dyspnea at rest. f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4).

The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).

Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls and Fall-related Injuries In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo.

Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible.

Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology (12.3)].

Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl

enzalutamide by 1.3-fold in healthy volunteers [see Clinical Pharmacology (12.3)].

The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo.

Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible.

Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology (12.3)].

Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category X [see Contraindications (4)].

Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryofetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).

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

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

Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical

experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted.

Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)].

Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function.

The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)].

OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.

Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Revised: September 2014 14B006-XTA-BRFS Rx Only © 2014 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

076-0472-PM

FDA Update

Recent Drug Approvals Continued from page 33 ripheral edema, febrile neutropenia, nausea, hypokalemia, fatigue, constipation, diarrhea, and tremor.

Blinatumomab was approved with a Risk Evaluation and Mitigation Strategy (REMS) program to inform healthcare providers about the serious risks associated with this medication. The product information also carries a boxed warning to alert providers of the risks and serious side effects associated with the use of blinatumomab. (December 3, 2014)

Avastin plus Chemotherapy for Platinum-Resistant Gynecologic Cancers

The FDA approved a new indication for bevacizumab solution (Avastin; Genentech) to be used in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for the treatment of patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The approval is based on the results of the AURELIA study, an international, randomized trial with investigator-assessed PFS. AURELIA compared bevacizumab plus chemotherapy versus chemotherapy alone. Overall, 179 patients were randomized to bevaciz­ umab plus chemotherapy and 182 patients received chemotherapy alone with 1 of the 3 chemotherapies.

Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal.

All the patients had received ≤2 previous chemotherapy regimens, had ECOG performance status of 0 to 2, and had disease recurrence within <6 months of the platinum-­ based therapy.

Bevacizumab plus chemotherapy had a significant PFS improvement compared with chemotherapy alone

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(HR, 0.38; 95% CI, 0.30-0.49; P <.001), with a median PFS of 6.8 months versus 3.4 months, respectively; however, the OS was not significantly different, with a median OS of 16.6 months versus 13.3 months, respectively (HR, 0.89; 95% CI, 0.69-1.14).

The most common adverse reactions (≥15%) with bevacizumab plus chemotherapy were neutropenia, peripheral sensory neuropathy, and hypertension. Gastrointestinal perforations were reported in 1.7% of patients who received bevacizumab.

(November 14, 2014)

FDA Approves Nivolumab for Advanced Melanoma

The FDA recently approved nivolu­ mab (Opdivo; Bristol-Myers Squibb Company), a human programmed death receptor-1 blocking antibody, for the treatment of patients with unresectable or metastatic melanoma that no longer responds to ipilimumab. The drug was also approved for the treatment of patients with melanoma with a BRAF V600 mutation that no longer responds to ipilimumab and BRAF inhibitor therapy.

The FDA accelerated its approval of nivolumab based on interim data from the CheckMate 037 phase 3 trial showing a 32% (N = 38) objective response rate (ORR) in the first 120 patients who received the drug.

This response lasted for >6 months in approximately one third of the patients. The 32% ORR (95% CI, 23,41) was based on data from 4 patients (3%) who achieved a complete response and 34 patients (28%) who achieved a partial response.

Efficacy of the drug was evaluated during a planned, interim, single-arm analysis of data from the phase 3, randomized, open-label CheckMate

Oncology Practice Management

I February 2015

037 trial. A total of 268 patients received the 3-mg/kg intravenous dose every 2 weeks; patients in the comparator arm (N = 102) received an investigator’s choice of chemotherapy: single-agent dacarbazine or a combination of carboplatin plus paclitaxel. The primary objectives in this trial are ORR and OS. The study is ongoing but no longer recruiting patients.

The most common adverse reaction reported among patients receiving the study drug was rash (21%).

Grade 3/4 adverse reactions occurred in 42% of the patients receiving the study drug. The most frequent of these—reported in 2% to <5% of patients receiving the study drug— were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.

The FDA granted breakthrough therapy designation, priority review, and orphan product designation for nivolumab because (1) preliminary clinical evidence demonstrated that the drug may offer a substantial improvement over available therapies; (2) the drug has the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition; and (3) the drug is intended to treat a rare disease, respectively.

“Opdivo is the seventh new melanoma drug approved by the FDA since 2011,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The continued development and approval of novel therapies based on our increasing understanding of tumor immunology and molecular pathways are changing the treatment paradigm for serious and life-threatening diseases.”

(December 22, 2014) l

Drug Update

Nivolumab (Opdivo): Second PD-1 Inhibitor Receives FDA Approval for Unresectable or Metastatic Melanoma

By Lisa A. Raedler, PhD, RPh, Medical Writer

A

lthough less common than other skin cancers, melanoma is the most dangerous form of skin cancer.1 According to data collected between 2004 and 2010, the 5-year relative survival rate for Americans with distant melanoma is only 16% for all ages, races, and sexes.2 The National Cancer Institute estimated that there were 76,100 new cases of skin melanoma in 2014, and more than 9700 patients died from this disease during the same period.2 The incidence of melanoma continues to rise, particularly among children and adolescents.3 Analysis of first-time melanoma diagnoses between 1970 and 2009 in patients aged 18 to 39 years showed that the number of new cases of skin melanoma increased 8-fold among young women and 4-fold among young men.3 Using data from 1973 to 2009, another study documented an average increase in melanoma of 2% annually in individuals aged between 0 and 19 years.4 The potential effect on healthcare resource use is just one reason for concern regarding these trends.

Based on an assessment of Medicare administrative claims data between 1991 and 2005, patients with melanoma, particularly those with metastatic disease, accrued an average of more than $11,000 monthly in total healthcare costs5; the majority of these costs were related to inpatient hospital services.5 This cost analysis was conducted in 2009, before the approval of novel targeted therapies for metastatic melanoma.

Copyright Š 2015 American Health & Drug Benefits. All rights reserved. Used with permission.

rates with limited response durability, and the use of ipilimumab, which offers a relatively low response rate but very durable responses.7 On September 4, 2014, the US Food and Drug Administration (FDA) approved pembrolizumab, the first PD-1 inhibitor for the treatment of patients with unresectable or metastatic melanoma.8 This agent demonstrated objective and durable responses in a large phase 1b study that involved patients with unresectable or metastatic melanoma and disease progression after treatment with ipilimumab and, if the patient had the BRAF V600 mutation, after treatment with a BRAF inhibitor.8,9 To increase the proportion of patients with metastatic melanoma who achieve durable responses with immunotherapy, researchers are exploring potential synergies between immune checkpoint inhibitors that target CTLA-4, PD-1, PD-L1, and kinase-targeted therapies, as well as the concurrent and sequential use of CTLA-4, PD-1, and PD-L1 inhibitors.7

As evidenced by its low 5-year survival rates, metastatic melanoma is difficult to cure.6 Surgery and radiation therapy are feasible options for tumors that are localized to the skin or to the lymph nodes. Depending on their number and location, the surgical removal of melanoma metastases in internal organs is also an option.6 In the past, the management of patients with advanced stages of melanoma was very challenging.

Today, however, the development and the introduction of targeted agents have significantly changed the treatment landscape. The current armamentarium of systemic treatments for metastatic melanoma features immunotherapy agents (ie, ipilimumab, pembrolizumab) and BRAF inhibitors (ie, vemurafenib, dabrafenib, trametinib), in addition to traditional chemotherapy.6 Several of these novel agents offer superior efficacy compared with older cytotoxic drugs.6 Immune checkpoint blockade with monoclonal antibodies that are directed toward cytotoxic T-lymphocyte antigen (CTLA)-4, such as ipi­ limumab, as well as programmed-cell death (PD)-1 and PD ligand 1 (PDL1), have emerged as successful treatment options in the treatment of patients with melanoma.7 Ipilimumab was the first CTLA-4 inhibitor to demonstrate an overall survival benefit and highly durable objective tumor responses in patients with advanced melanoma.7 Specifically in the management of patients with metastatic melanoma and the BRAF V600 mutation, a contrast has been observed between the use of BRAF inhibitors, which offer high response

A Novel PD-1 Inhibitor for Unresectable or Metastatic Melanoma On December 22, 2014, the FDA approved nivolumab (Opdivo; Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma and disease progression after ipilimumab therapy and, if the patient is positive for a BRAF V600 mutation, after treatment with a BRAF inhibitor.10,11 Nivolumab is a monoclonal antibody that blocks PD-1 and is administered via intravenous infusion. This agent was approved under the accelerated approvContinued on page 40

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Drug Update

Nivolumab (Opdivo): Second PD-1... Continued from page 39 al program based on the surrogate end points, overall response rate, and duration of response.10,11 When discussing data supporting the efficacy of nivolumab in relapsed metastatic melanoma, Jeffrey S. Weber, MD, PhD, Director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at Moffitt Cancer Center, stated, “These data are important as they mark the first presentation of results from a phase 3 randomized study for the PD-1 immune checkpoint inhibitor class.” He further commented, “the response rate and duration of response in patients treated with Opdivo are consistent with findings from the early phase 1 trial in previously treated advanced melanoma.”12

Dosing and Administration The recommended dosage of nivol­ umab is 3 mg/kg administered as an intravenous infusion for 60 minutes every 2 weeks. Nivolumab should be administered until disease progression or until unacceptable toxicity.11 No dose adjustment of nivolumab is required for patients with renal impairment or for patients with mild hepatic impairment, defined as total bilirubin upper limit of normal or less and aspartate aminotransferase (AST) more than upper limit of normal or total bilirubin <1 to 1.5 times upper limit of normal and any AST.11 Mechanism of Action Nivolumab is a monoclonal antibody that binds to the PD-1 receptor and blocks interaction with its ligands, PD-L1 and PD-L2. This binding releases PD-1 pathway-mediated immune responses against tumor cells. Blocking PD-1 activity resulted in decreased tumor growth in syngeneic mouse tumor models.11 Clinical Trial: Checkmate-037 The approval of nivolumab was

based on the results of Checkmate-037, a phase 3 randomized, controlled, open-label study of nivolumab versus investigator’s choice chemotherapy in patients with advanced melanoma who previously received ipilimumab.11 A total of 370 patients with previously treated unresectable or metastatic melanoma enrolled in the Checkmate-037 clinical trial.11 All patients’ disease had progressed after previous therapy with ipilimumab and, if the patients were positive for a BRAF V600 mutation, after treatment with a BRAF inhibitor.11 These patients were randomized to receive nivolumab 3 mg/kg (N = 268) or investigator’s choice chemotherapy (N = 102) with dacarbazine 1000 mg/m2 every 3 weeks or with carboplatin (area under the curve, 6 mg•min/ mL) plus paclitaxel 175 mg/m2 every 3 weeks until disease progression or until unacceptable toxicity.11 The efficacy of nivolumab was evaluated in a single-arm, noncomparative, planned interim analysis of the first 120 patients who received nivolumab in the Checkmate-037 clinical trial and in whom the minimum duration of follow-up was 6 months.11 The primary efficacy end points were confirmed overall response rate according to the Response Evaluation Criteria in Solid Tumors, as assessed by a blinded independent review committee, and duration of response. Tumor assessments were conducted 9 weeks after randomization, followed by every 6 weeks for the first year, and then every 12 weeks.11 The Checkmate-037 clinical trial excluded patients with an autoimmune disease, medical conditions requiring systemic immunosuppression, ocular melanoma, active brain metastasis, or a history of grade 4 ipilimumab-related adverse reactions (except for endocrinopathies) or

grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled after 12 weeks.11 Patient Population Among the 120 patients who received nivolumab, the median age was 58 years.11 The majority of the patients were male (65%) and white (96%). All the patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. The patients’ disease characteristics included stage M1c disease (76%), 2 or more previous therapies for advanced or metastatic disease (68%), elevated lactate dehydrogenase (56%), positive for a BRAF V600 mutation (22%), and a history of brain metastases (18%).11 Efficacy The planned interim analysis of the Checkmate-037 clinical trial documented a 32% overall response rate for nivolumab 3 mg/kg in patients with unresectable or metastatic melanoma who previously received ipilimumab therapy and, if relevant, a BRAF inhibitor (95% confidence interval, 23%-41%).11 Of the 38 patients whose disease responded to nivolumab therapy, 4 patients achieved complete responses and 34 patients achieved partial responses.11 The majority (87%) of patients responding to nivolumab had ongoing responses with durations ranging from 2.6+ to 10+ months, including 13 patients with ongoing responses of at least 6 months.11 Objective responses were observed in patients with and without BRAF V600 mutation–positive melanoma.11 Safety The cohort of 268 patients with previously treated unresectable or metastatic melanoma in Checkmate-037 received a median of 8 doses Continued on page 42

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Oncology Practice Management

I February 2015

Promote the value of oncology navigation to your organization and bottom line

Network with your oncology navigation team at the

AONN+ West Coast Regional Meeting May 18 – 20, 2015 in Seattle, Washington

“

Financial Navigators a new buzz word is circling cancer centers right now. Navigators and patient advocates need to make sure that there is a clear understanding on the part of the patient what the cost of care means for them. Start talking with your oncology navigation team and see what the plans are for obtaining cost information for patients going forward, and get to know the financial navigator who will be involved in your clinic by attending the AONN+ West Coast Regional Meeting.”

Lillie Shockney, RN, BS, MAS, CBPN-IC, Program Director, Academy of Oncology Nurse & Patient Navigators (AONN+)

TUESDAY | MAY 19, 2015 10:45 AM - 11:45 AM

Special Session in Partnership with the Association for Oncology Practice Management

Value-Based Strategies for Navigation

with:

LINDA BOSSERMAN, MD, FACP Assistant Clinical Professor Community Medical Oncologist Breast Cancer and Oncology Medical Home Specialist City of Hope Medical Group

Meeting Topics Include:

Who Should Attend:

Best practices in navigation

Continuing education units

Oncology nurse navigators

Oncology social workers

Nuances in providing valuebased care in oncology

Psychosocial care for cancer patients

Practice managers

Administrators

Impact of prehabilitation and rehabilitation

Commission on Cancer case studies

Financial Counselors

Case managers

Survivorship

Networking opportunities

Patient or non-clinically licensed navigators

Oncology nurses and nurse practitioners

Visit AonnOnline.org to find out more and register today!

NON-MEMBERS EARLY BIRD REGISTRATION (ends 1/31/15) $135 Clinically Licensed | $110 Non-Clinically Licensed MEMBERS (ends 5/18/15) $115 Clinically Licensed | $100 Non-Clinically Licensed

Drug Update

Nivolumab (Opdivo): Second PD-1... Continued from page 40 elected Adverse Reactions in ≥10% of Patients Receiving Nivolumab Table S (and at a Higher Incidence than in the Chemotherapy Arm)

Adverse reaction

Nivolumab 3 mg/kg every 2 weeks (N = 268) All Grade grades, % 3-4, %

Chemotherapy (N = 102) All Grade grades, % 3-4, %

Skin and subcutaneous tissue disorders Rasha

21

0.4

7

0

Pruritus

19

0

3.9

0

17

0

6

0

11

0

2.0

0

5

0

Respiratory, thoracic, and mediastinal disorders Cough Infections and infestations Upper respiratory tract infectionb

General disorders and administration site conditions Peripheral edema

10

0

Including maculopapular, erythematous, pruritic, follicular, macular, papular, pustular, or vesicular rash, and dermatitis acneiform. b Including rhinitis, pharyngitis, and nasopharyngitis.

Source: Opdivo (nivolumab) injection prescribing information; December 2014. a

(range, 1-31 doses) of nivolumab (3 mg/kg).11 The patients’ median duration of exposure to nivolumab was 5.3 months (range, 1 day-9.6 months).11 In this clinical trial, 24% of patients were exposed to nivolumab for more than 6 months, and 3% of patients were exposed to nivolumab for more than 1 year.11 The Table summarizes the adverse reactions that occurred in ≥10% of patients and at a higher incidence rate compared with patients who received chemotherapy.11 Grade 3 and 4 adverse reactions occurred in 42% of nivolumab recipients.11 These events included abdominal pain, hyponatremia, elevated AST levels, and increased lipase levels; these adverse reactions occurred at rates ranging from 2% to <5%.11 Nivolumab was discontinued as a result of adverse reactions in 9% of patients, and 26% of patients who received nivolumab experienced a

drug delay for an adverse reaction.11 Nivolumab has no contraindications.

Warnings and Precautions Immune-mediated pneumonitis.

Overall, 5 (0.9%) fatal cases of pneumonitis occurred among 574 patients with solid tumors who received nivolumab in clinical trials.11 Pneumonitis, including interstitial lung disease, occurred in 3.4% of patients who received nivolumab in the Checkmate-037 clinical trial.11 Immune-mediated pneumonitis, which requires the use of corticosteroids and has no clear alternate etiology, occurred in 6 (2.2%) patients who received nivolumab. The median time to onset for these 6 cases was 2.2 months (range, 25 days-3.5 months).11 Grade 2 pneumonitis led to the interruption or the permanent discontinuation of nivolumab in 4 patients. The other 2 patients discontinued nivolumab for other reasons. In all 6 patients, immune­

mediated pneumonitis improved to grade 0 or 1 with corticosteroids.11 Patients who received nivolumab should be monitored for signs and symptoms of pneumonitis. Corticosteroids should be administered if grade 2 or higher pneumonitis is detected.11 Nivolumab should be withheld for moderate (grade 2) pneumonitis, and permanently discontinued for severe (grade 3) or life-threatening (grade 4) pneumonitis.11 Immune-mediated colitis. Colitis or diarrhea occurred in 21% of patients who received nivolumab, and in 18% of patients who received chemotherapy in the Checkmate037 clinical trial.11 Immune-mediated colitis was observed in 6 patients who received nivolumab. The median time to onset of immune-mediated colitis was 2.5 months.11 Patients who receive nivolumab should be monitored for signs and symptoms of colitis. Corticosteroids should be administered for grade 2 or higher colitis. Nivolumab should be withheld for moderate (grade 2) or severe (grade 3) colitis, and permanently discontinued for life­ threatening (grade 4) colitis or recurrent colitis upon restarting nivolumab therapy.11 Immune-mediated hepatitis. An increased incidence of liver test abnormalities was observed in the nivolumab group compared with the chemotherapy group, including increases in AST levels (28% vs 12%, respectively), alkaline phosphatase levels (22% vs 13%, respectively), alanine aminotransferase levels (16% vs 5%, respectively), and total bilirubin levels (9% vs 0%, respectively).11 Overall, 1.1% of patients who received nivolumab had immune-mediated hepatitis, which requires the use of corticosteroids and has no clear alternate etiology.11 Patients who receive nivolumab should be monitored for changes in Continued on page 44

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Oncology Practice Management

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Innovations in Oncology Management A newsletter series for oncology practice administrators, administrative staff, advanced practice clinicians, and oncology pharmacists.

The series will provide concise, up-to-date information on current issues that are impacting the business of oncology.

TM

Good Manufacturing Process

Topics include: Part 1: Patient Support Services Part 2: Oral Parity Legislation Part 3: Emerging Payment and Delivery Models Part 4: Working Collaboratively with Local Payers TO VIEW THE SERIES ONLINE PLEASE LOG ON TO:

InnovationsInOncologyManagement.com anagement.com Supported by funding from Celgene Corporation and Celgene Patient Support. Manufacturer did not influence content.

EHC388 Innovations ASize_120214

Drug Update

Nivolumab (Opdivo): Second PD-1... Continued from page 42 liver function. Corticosteroids should be administered for grade 2 or higher hepatitis. Nivolumab should be withheld if grade 2 hepatitis is observed, and discontinued for grade 3 and grade 4 immune-mediated hepatitis.11 Immune-mediated nephritis and renal dysfunction. An increased incidence of elevated creatinine levels was observed in patients who received nivolumab compared with patients who received chemotherapy (13% vs 9%) in the Checkmate-037 clinical trial.11 Grade 2 or 3 immune-mediated nephritis or renal dysfunction, defined as grade 2 or higher increased creatinine levels, need for corticosteroids, and no clear etiology, occurred in 0.7% of patients after 3.5 months and 6 months of nivolumab therapy, respectively.11 Patients should be monitored for elevated serum creatinine levels before and during treatment with nivolumab.11 If grade 4 elevation in serum creatinine levels is observed, corticosteroid therapy should be tapered and nivolumab should be permanently discontinued. Nivolumab therapy should be withheld if grade 2 or 3 elevation in serum creatinine levels is observed.11 Immune-mediated hypothyroidism and hyperthyroidism. Thyroid function was evaluated for all patients at baseline and during the Checkmate-037 clinical trial.11 Grade 1 or 2 hypothyroidism occurred in 8% of patients who received nivolumab and was not observed among patients who received chemotherapy. The median time to onset was 2.5 months (range, 24 days-11.7 months). The majority of patients with hypothyroidism received levothyroxine and restarted nivolumab therapy.11 Grade 1 or 2 hyperthyroidism occurred in 3% of patients who received nivolumab and in 1% of patients who received chemotherapy.

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The median time to onset in patients who received nivolumab was 1.6 months (range, 0-3.3 months).11 Thyroid function should be monitored before and during treatment with nivolumab. Hormone replacement therapy for hypothyroidism should be administered as needed, and hyperthyroidism should be controlled. There are no recommended dose adjustments for nivolumab.11 Other immune-mediated adverse reactions. Other clinically impor­ tant immune-mediated adverse reactions can occur while patients with unresectable or metastatic melanoma are receiving nivolumab.11 Clinically significant, immune-­ mediated adverse reactions that were observed in <1% of patients who received nivolumab included pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, and facial and abducens nerve paresis.11 When nivolumab was administered at doses of 3 mg/kg and 10 mg/ kg, clinically significant, immune-­ mediated adverse reactions were observed, including hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome.11 If an immune-mediated adverse reaction is suspected, patients who receive nivolumab must be evaluated to exclude other causes.11 Nivolu­ mab therapy should be withheld, and corticosteroid therapy should be administered based on the severity of the reaction. Upon improvement of the immune-mediated adverse reaction to grade 1 or less, a corticosteroid taper can be started and continued for at least 1 month. Depending on the severity of the event, nivolu­ mab can be restarted.11 Embryofetal toxicity. Nivolumab therapy may cause fetal harm when it is administered to a pregnant woman.11 Women of reproductive

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potential should use effective contraception during nivolumab therapy and for at least 5 months after the last dose. Women who become pregnant while taking nivolumab should be made aware of the potential risk of nivolumab to the fetus.11

Use in Specific Populations Pediatric patients. The safety and efficacy of nivolumab in pediatric patients have not been established.11 Geriatric use. The clinical studies of nivolumab did not include sufficient numbers of patients aged ≥65 years to determine whether they respond differently compared with younger patients.11 Pregnancy. There are no human data to describe the risk associated with nivolumab use during pregnancy. Pregnant women should be advised of the potential risk of nivolu­ mab therapy to the fetus.11 Nursing mothers. It is not known whether nivolumab is present in human milk. Because many drugs, including antibodies, are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from nivolumab, women should be advised to discontinue breastfeeding during treatment with nivolumab.11 Conclusion Nivolumab is the second PD-1 inhibitor approved by the FDA for the treatment of patients with un­resectable or metastatic melanoma. Based on an interim analysis of phase 3 clinical data, this novel agent is an effective and safe alternative for patients with unresectable or metastatic melanoma and disease progression after ipilimumab therapy, and if the patient is positive for a BRAF V600 mutation, after treatment with a BRAF inhibitor.

Nivolumab was approved under the FDA’s accelerated approval program based on the response rate data. As a

Drug Update

condition of accelerated approval, the FDA requires confirmatory trials to verify the agent’s clinical benefit. The Checkmate-037 clinical trial is designed to compare the overall survival rate of patients who receive nivolumab therapy with the overall survival rate of patients who receive chemotherapy.

An interim analysis of overall survival was not performed at the time of the response rate analysis.

The efficacy and safety of nivolu­ mab are being evaluated in several other tumors; these include metastatic nonsquamous non–small-cell lung cancer, metastatic breast cancer, metastatic colon cancer, follicular lymphoma, Hodgkin lymphoma, and non-Hodgkin lymphoma.13 l

References

Cancer Res. 2013;19:5300-5309.

8. US Food and Drug Administration. FDA approves Keytruda for advanced melanoma. Press release. September 4, 2014. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm412802.htm. Accessed January 29, 2015.

9. Keytruda (pembrolizumab) for injection [prescribing information]. Whitehouse Station, NJ: Merck & Co; January 2015.

10. US Food and Drug Administration. FDA approves Opdivo for advanced melanoma. Press release. www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm 427716.htm. Accessed January 29, 2015.

11. Opdivo (nivolumab) injection [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; December 2014.

12. Bristol-Myers Squibb. Positive phase 3 data for Opdivo (nivolumab) in advanced melanoma patients previously treated with Yervoy (ipilimumab) presented at the ESMO 2014 Congress; first phase 3 results presented for a PD-1 immune checkpoint inhibitor. September 29, 2014. http://news.bms.com/press-release/rd-news/positivephase-3-data-opdivo-nivolumab-advanced-melanomapatients-previously-t. Accessed January 27, 2015.

13. ClinicalTrials.gov. Nivolumab. Search results. http:// clinicaltrials.gov/ct2/results?term=nivolumab&Search= Search. Accessed January 27, 2015.

1. Skin Cancer Foundation. What is melanoma? www. skincancer.org/skin-cancer-information/melanoma.

Accessed January 23, 2015.

2. National Cancer Institute. SEER stat fact sheets: melanoma of the skin. http://seer.cancer.gov/statfacts/ html/melan.html. Accessed January 23, 2015.

3. Reed KB, Brewer JD, Lohse CM, et al. Increasing incidence of melanoma among young adults: an epidemiological study in Olmsted County, Minnesota. Mayo Clin Proc. 2012;87:328-334.

4. Wong JR, Harris JK, Rodriguez-Galindo C, Johnson KJ. Incidence of childhood and adolescent melanoma in the United States: 1973-2009. Pediatrics. 2013;131: 846-854.

5. Davis KL, Mitra D, Kotapati S, et al. Direct economic burden of high-risk and metastatic melanoma in the elderly: evidence from the SEER-Medicare linked database. Appl Health Econ Health Policy. 2009;7:31-41.

6. American Cancer Society. Treatment of melanoma skin cancer by stage. Revised December 23, 2014. www. cancer.org/cancer/skincancer-melanoma/detailedguide/ melanoma-skin-cancer-treating-by-stage. Accessed January 23, 2015.

7. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/ PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin

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Drug Coding Supplied by RJ Health Systems

FDA-Approved Medications Used for the Treatment of Renal Cell Carcinoma The following sections will assist healthcare professionals and payers by providing appropriate coding and billing information associated with the treatment of renal cell carcinoma.

The following sections include: • Associated ICD-9-CM codes used for the classification of renal cell carcinoma • Drugs that have been FDA approved in the treatment of renal cell carcinoma • Drugs that are Compendia-listed for off-label use for renal cell carcinoma based on clinical studies that suggest beneficial use in some cases. Please note: If a check mark appears in the FDA column, it will NOT appear in the Compendia off-label use column • Corresponding HCPCS/CPT® codes and code descriptions

Associated ICD-9-CM codes for the treatment of renal cell carcinoma: 189

Malignant neoplasm of kidney and other unspecified urinary organs Excludes: b enign carcinoid tumor of kidney (209.64) malignant carcinoid tumor of kidney (209.42) 189.0 Kidney, except pelvis

Kidney, not otherwise specified

Kidney parenchyma

Generic (brand) name

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HCPCS code - code description

FDA approved for renal cell carcinoma

Compendia off-label uses for renal cell carcinoma

Possible CPT ® administration codes

aldesleukin (Proleukin)

J9015 - Injection, aldesleukin, per single-use vial

√

96409

axitinib (Inlyta)

J8999* - Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

bevacizumab (Avastin)

J9035 - Injection, bevacizumab, 10 mg

√

96413, 96415

capecitabine (Xeloda)

J8520 - Capecitabine, oral, 150 mg

√

N/A

capecitabine (Xeloda)

J8521 - Capecitabine, oral, 500 mg

√

N/A

carboplatin (Paraplatin)

J9045 - Injection, carboplatin, 50 mg

√

96409, 96413, 96415

cisplatin (Platinol-AQ)

J9060 - Injection, cisplatin, powder or solution, per 10 mg

√

96409, 96413, 96415

cyclophosphamide (Cytoxan)

J8530 - Cyclophosphamide, oral, 25 mg

√

N/A

Oncology Practice Management

I February 2015

Drug Coding

cyclophosphamide (Cytoxan)

J9070 - Cyclophosphamide, 100 mg

dactinomycin (Cosmegen)

J9120 - Injection, dactinomycin, 0.5 mg

√

96409

doxorubicin HCl (Adriamycin)

J9000 - Injection, doxorubicin hydrochloride, 10 mg

√

96409

etoposide (VePesid)

J8560 - Etoposide, oral, 50 mg

√

N/A

etoposide (Etopophus, Toposar)

J9181 - Injection, etoposide, 10 mg

√

96413, 96415

everolimus (Afinitor)

J8999* - Prescription drug, oral, chemotherapeutic, not otherwise specified

floxuridine (FUDR)

J9200 - Injection, floxuridine, 500 mg

√

96422, 96423, 96425

fluorouracil (Adrucil)

J9190 - Injection, fluorouracil, 500 mg

√

96409

gemcitabine (Gemzar)

J9201 - Injection, gemcitabine hydrochloride, 200 mg

√

96413

ifosfamide (Ifex)

J9208 - Injection, ifosfamide, 1 gram

√

96413, 96415

interferon alfa-2b (Intron A)

J9214 - Injection, interferon, alfa2b, recombinant, 1 million units

√

96372, 96401

interferon alfa-n3 (Alferon N)

J9215 - Injection, interferon, alfa-n3 (human leukocyte derived), 250,000 IU

√

11900, 11901

interferon gamma-1b (Actimmune)

J9216 - Injection, interferon, gamma-1b, 3 million units

√

96372

√

96409, 96413, 96415

N/A

√

medroxyprogesterone J1050 - Injection, acetate (Depo-Provera medroxyprogesterone acetate, 1 mg 400 mg ONLY)

√

96372, 96402

pazopanib (Votrient)

J8999* - Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

peginterferon alfa-2a (Pegasys)

J3590* - Unclassified biologics

√

96372

peginterferon alfa-2a (Pegasys)

S0145 - Injection, pegylated interferon alfa-2a, 180 mcg per mL

√

96372

pemetrexed (Alimta)

J9305 - Injection, pemetrexed, 10 mg

√

96409

sargramostim (Leukine)

J2820 - Injection, sargramostim (GM-CSF), 50 mcg

√

96365, 96366, 96372

sorafenib (Nexavar)

J8999* - Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

sunitinib (Sutent)

J8999* - Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

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Drug Coding

temsirolimus (Torisel)

J9330 - Injection, temsirolimus, 1 mg

96413

thalidomide (Thalomid)

J8999* - Prescription drug, oral, chemotherapeutic, not otherwise specified

√

N/A

topotecan (Hycamtin)

J9351 - Injection, topotecan, 0.1 mg

√

96413

vinBLAStine (Velban)

J9360 - Injection, vinblastine sulfate, 1 mg

√

96409

vinCRIStine (Vincasar PFS)

J9370 - Vincristine sulfate, 1 mg

√

√

96409

*When billing a nonclassified medication using a CMS 1500 claim form, you must include both the HCPCS code (eg, J8999 Inlyta) in Item 24D and the drug name, strength, and NDC (National Drug Code) in Item 19 or 24A (shaded area) in order to ensure appropriate reimbursement. Please note: Check with payer regarding correct placement of medication information.

References • HCPCS Level II Expert 2015 • Current Procedural Terminology (CPT ®) 2015 • CPT copyright 2015 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association • ICD-9-CM for Professionals Volumes 1 & 2, 2015 • FDA-approved indication (product Prescribing Information) • Compendia references available upon request • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC, Rocky Hill, Connecticut • CMS (Centers for Medicare & Medicaid Services) GM-CSF indicates granulocyte-macrophage colony-stimulating factor; HCPCS, Healthcare Common Procedure Coding System.

This information was supplied by

30 Cold Spring Road, Rocky Hill, CT 06067 T: (860) 563-1223 F: (860) 563-1650

www.RJHealthSystems.com

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RJ Health Systems â&#x20AC;&#x201D; the pharmaceutical specialists that healthcare professionals have turned to since 1983 for their drug information.

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ReimbursementCodes.com incorporates the CMS HCPCS and AMA CPT Drug codes into a system that crosswalks each drug code with the drugâ&#x20AC;&#x2122;s NDC and brand/generic name.

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