OPM Nov 2014 | Vol 4 | No 7 by Value-Based Cancer Care

NOVEMBER 2014

www.OncPracticeManagement.com

VOLUME 4 • NUMBER 7

Oncology Practice Management ™

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

Quality Care for Patients with Cancer Interview with Linda Bosserman, MD, FACP

Where Did My Data Go? By Teri U. Guidi, MBA, FAAMA, President and CEO Oncology Management Consulting Group

here is no denying the trend of medical oncology practices being acquired by hospitals, whether through professional service agreements, employer–employee agreements, or something in between. The 2013 Community Oncology Practice Impact Report1—published by the Community Oncology Alliance—

shows that in the past 6 years, 469 (35%) of 1338 responding practices have been acquired, and the rate of acquisition has increased 20% in the 15 months since the 2012 report. Across the country, educational sessions at numerous oncology-focused Continued on page 24

Influences on Rising Oncology Drug Costs Take a bite out of G-CSF By Ruth Lander, FACMPE

I T

he interview featured in this arti cle was conducted with Linda Bosserman, MD, FACP, at the 2014 conference of the Association for Value-Based Cancer Care.

acquisition costs*

recently tuned into 60 Minutes to have observed a strong watch a segment on oncology drugs. relationship between ® This episode was of interest to multiple of the healthcare sysGRANIX isgreat another option inlevels short-acting me since I have served as an adminis- tem that fuel drug costs and purchase G-CSF therapy trator at a large oncology practice in practices in community cancer centers Ohio for the past several decades. Long in the United States. The practice of before this segment aired, however, I pricing drugs is a complex and often With broadonformulary had been formulating my thoughts confusing coverage process, and there are several † the evolution of drug and purtrends that to contribute to rising GRANIX is pricing covered on the top 5seem plans nationwide chasing practices. During this time, I healthcare costs.

Continued on page 12

» Also covered through Medicare Part B

Continued on page 16

From the publishers of

Indication » GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive ER K anticancer drugs associated with a clinically significant incidence of febrile neutropenia. C INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM

A TR s L the al » Splenic rupture: Splenic rupture, including fatal cases, can occur following ri IA Discontinue R l T 32 administration of human granulocyte colony-stimulating factors (hG-CSFs). T a L nicwhoy…report GRANIX and evaluate for an enlarged spleen or splenic rupture in patients A li a upper abdominal or shoulder pain after receiving GRANIX. IC w C r W N de LI Ne and Please see reverse side for additional Important Safety Information C Un brief summary of Full Prescribing Information on page adjacent to our ad inside. Important Safety Information

* 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. † Top

5 by percentage of US insured lives (Commercial, Medicare Part D, Medicare Advantage, and managed Medicaid) as reported by Health Strategies Group, Inc., Strategic Accounts, 2013.

Important Safety Information (continued) » 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® (tbo-filgrastim) Injection, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Full Prescribing Information on page adjacent to our ad inside.

Brought to you by Teva—a global leader with significant experience in oncology and biologics.

Oncology

©2014 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-40393 October 2014. Printed in USA.

NOVEMBER 2014

www.OncPracticeManagement.com

VOLUME 4 • NUMBER 7

Oncology Practice Management ™

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

Quality Care for Patients with Cancer Interview with Linda Bosserman, MD, FACP

Where Did My Data Go? By Teri U. Guidi, MBA, FAAMA, President and CEO Oncology Management Consulting Group

Influences on Rising Oncology Drug Costs By Ruth Lander, FACMPE

I T

he interview featured in this arti cle was conducted with Linda Bosserman, MD, FACP, at the 2014 conference of the Association for Value-Based Cancer Care.

recently tuned into 60 Minutes to watch a segment on oncology drugs. This episode was of great interest to me since I have served as an administrator at a large oncology practice in Ohio for the past several decades. Long before this segment aired, however, I had been formulating my thoughts on the evolution of drug pricing and purchasing practices. During this time, I

have observed a strong relationship between multiple levels of the healthcare system that fuel drug costs and purchase practices in community cancer centers in the United States. The practice of pricing drugs is a complex and often confusing process, and there are several trends that seem to contribute to rising healthcare costs. Continued on page 16

Continued on page 12 From the publishers of

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM

C A TR s L al

IA l Tri 2 3 a

ic y… lin a C W IC N ew der I L N Un C

You put a lot of work into your treatment plan. We’ll do everything we can to support it.

Bristol-Myers Squibb Oncology is committed to helping appropriate patients get access to our medications by providing reimbursement support services for healthcare professionals.

Bristol-Myers Squibb Oncology Reimbursement Support It’s your patient. You have our commitment - 100% of requested services are returned to you in 24 hours.*

Access and Reimbursement Services Dedicated, in-person support from local Area Reimbursement Managers Benefit Investigation Prior Authorization and Appeals Support Secure provider portal for monitoring reimbursement cases

*Access Support enrollment form must be complete and have all required signatures.

Patient Affordability Services Choosing the appropriate therapy is the first step. Helping patients pay for it is another matter. BMS Access Support® can assist with reimbursement and co-pay issues.

Here’s how: Eligible, commercially-insured patients pay a $25 co-pay per infusion up to $25,000 per year per product Patients with insurance through Federal Healthcare Programs or patients that are otherwise underinsured or uninsured are referred to independent charitable organizations that may be able to provide assistance

On The Phone, Online, In Person For more details, visit www.BMSAccessSupport.com or call 1-800-861-0048.

Table of Contents

November 2014 • Volume 4 • Number 7

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

Oncology Practice Management ™

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

FROM THE EDITOR Taking a Deep Breath Before the Holidays..........................................7

By Dawn Holcombe, MBA, FACMPE, ACHE

FEATURES Interview with the Innovators Quality Care for Patients with Cancer..................................................1 Interview with Linda Bosserman, MD, FACP

Data Management Where Did My Data Go?........................................................................1 By Teri U. Guidi, MBA, FAAMA

Practice Finances Influences on Rising Oncology Drug Costs..........................................1 By Ruth Lander, FACMPE

Human Resources Tattletale or Whistleblower: What’s an Employer to Do?............... 17 By Robert D. Orzechowski, MBA, SPHR

Physician–Hospital Alignment Series Do’s and Don’ts in Physician–Hospital Alignment, Part 3............... 18 By Max Reiboldt, CPA

Electronics in Cancer Care Patient Portals Improve Healthcare, but Are Still Works in Progress.................................................................................... 20 By Chase Doyle

Continued on page 4

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 reimbursment, 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.

November 2014

www.OncPracticeManagement.com

Table of Contents

November 2014 • Volume 4 • Number 7

Oncology Practice Management™, ISSN 2164-4403 (print), is published 8 times a year by Engage Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. 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 hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in 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 3

DEPARTMENTS Wealth Management Investing: Where to Put Your Money Now........................................ 21 By W. Ben Utley, CFP®, and Lawrence B. Keller, CFP®, CLU®, ChFC®, RHU®, LUTCF

FDA Update Recent Drug Approvals........................................................................ 30 Clinical Trial Tracker New Clinical Trials Under Way............................................................. 32 Drug Update Beleodaq (Belinostat) Receives FDA Approval for the Treatment of Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma ........................................... 36 By Lisa A. Raedler, PhD, RPh

Drug Coding FDA-Approved Medications Used for the Treatment of Prostate Cancer............................................................ 47

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 Risë Marie Cleland President Oplinc, Inc Portland, OR

Ruth Linné Lander, FACMPE Practice Administrator Columbus Oncology & Hematology Associates, Inc Columbus, OH

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

Teri U. Guidi, MBA, FAAMA President and CEO Oncology Management Consulting Group Pipersville, 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

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

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

Patrick A. Grusenmeyer, ScD, FACHE President Christiana Care Health Initiatives Newark, DE

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

Mary Pat Whaley, FACMPE, CPC Physician Advocate and Consultant www.managemypractice.com Durham, NC

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

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

Indication

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

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colonystimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. February 2014.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40171 February 2014. Printed in USA.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40188 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

From the Editor

Taking a Deep Breath Before the Holidays By Dawn Holcombe, MBA, FACMPE, ACHE; President, DGH Consulting, South Windsor, CT Editor-in-Chief, Oncology Practice Management

t seems that throughout 2014, those of us in oncology have been moving at 100 miles an hour. New challenges hit us every day and can involve regulatory or reimbursement issues, patient or personnel concerns, operational setbacks, or any combination of the above. We turn to our colleagues, resources such as Oncology Practice Management, and association conferences and meetings to stay well informed and ready to guide our organizations through the next day, week, month, or year. Despite the speed at which we are moving, though, I am awestruck at how far we still have to go. We are in the midst of a major healthcare transformation, and a window into oncology practices offers a microcosmic view of the entire healthcare system. Our organizations are tasked daily with doing more with fewer resources. The changes now required of us and our practices challenge cultural norms, pitting physician against physician, and team members against one another. More than one practice has seen key staff members leave rather than accept the changes planned by a progressive group. The good news is that the remaining teams are definitely leaner and more focused. Change can be empowering, if you survive it. ‎Will we embrace accountable care affiliations, medical home models, patient-focused culture shifts, integration, affiliation, acquisitions, and the breakup of existing acquisitions? The answer is probably that many of these options will hit each one of us, if they haven’t already. Each change will take a piece of us, both personally and professionally. We have payers and employers who are understandably concerned about

oncology and who may have expectations regarding outcomes, data, and performance that are slightly ahead of where we are. It will take new and very tightly honed negotiating and analytical skills to push working collaborations.

opment are being lauded for their potential in targeted therapy, some are also being challenged as a gray area in evidence-based medical decision-making. There are so many new tools being developed that we don’t have the time to sort the wheat from the chaff. It will take more time before we have the answers we want for our patients, yet we are tasked and challenged by both payers and patients to understand, explain, and justify the options. This all seems overwhelming ‎and humanly impossible to accomplish. Patients continue to need us, however, and in some mechanism, we will provide for them. Our world may soon look dramatically different in ways we cannot at this point comprehend, but we will get there. What gives me hope is that, as I continue to attend conferences and meetings, I am surrounded by intelligent people who have an undeniable passion for their patients, their colleagues, and the prospect of beating cancer. Oncology leaders are a special group. We can reach our goals, and hopefully we can also take a deep breath and be proud of ourselves. I do think that we will need to reach out to each other through our professional associations, and even our mentally rejuvenating social media connections. As the holidays approach and we celebrate with our families, I’d also like to take a moment to celebrate our oncology family, all of whom keep moving forward despite the challenges we face. The holiday season draws closer, with all of its joys and obligations, but let’s also remember the beauty of our efforts, and not forget to stop, take a breath, and feel proud for a few moments. l

Our organizations are tasked daily with doing more with fewer resources. The changes now required of us and our practices challenge cultural norms, pitting physician against physician, and team members against one another.

In oncology, clinical issues are evolving and change is coming rapidly. We are rushing toward the concept of personalized medicine; however, while the tools, screenings, and biomarkers under devel-

November 2014

www.OncPracticeManagement.com

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.

• 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

S:6.875”

Brief Summary: Consult package insert for complete Prescribing Information

DOUS14CDNY4736_A_XGEVA_Asize_BS_V10_8pt_r10.indd 1

8/11/14 11:56 AM

S:9.875”

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.

S:6.875”

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.

8/11/14 11:56 AM

S:9.875”

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

Interview with the Innovators

Quality Care for Patients…Continued from the cover Q: What are the main value- based concerns for oncologists in the United States? Linda Bosserman, MD, FACP (LB): Oncologists are very concerned that the treatments they give to patients are actually going to improve their health. As we learn more about the growing costs of cancer care and the burden of patient copayments, we’re looking at, “Do we really understand the full impact of the treatment we’re giving to patients?” That means the outcome as far as progression-free survival and overall survival, as well as toxicities, side effects, the costs of those, and the costs to the patient of the overall regimen. Q: Should oncologists concern themselves with cost issues, or is this beyond their clinical focus? LB: In today’s environment, there is no way an oncologist can avoid understanding cost issues if we’re going to help our patients evaluate the regimens we’re recommending, the total treatment course, short-term and longterm toxicity, what the outcome is, and what their cost is going to be. Q: Are you concerned with the level of copayment that is faced by many patients with cancer? LB: As an active clinical oncologist and practice president [Wilshire Oncology Medical Group, Rancho Cucamonga, CA], I can tell you that patients’ copayments are a daily issue that our doctors, our staff, and I deal with. Particularly, even in senior advantage plans, patients are being asked for 20% copayments on increasingly expensive regimens; for many this is unaffordable. It’s not just a chemotherapy, biologic therapy, or oral drug copayment. It’s copayments for visits and for multiple treatment courses that are really becoming unaffordable to patients. More and more

of our patients are coming back and saying, “I can’t afford that regimen. What are the alternatives? What are the costs?” We as physicians have had to learn it. Our staff has had to learn it. Q: What can and should be done to alleviate the cost burden on patients with cancer? LB: When you look at the growing burden of individual patients paying for cancer care, we need to come together as payers, providers,

In today’s environment, there is no way an oncologist can avoid understanding cost issues if we’re going to help our patients evaluate the regimens we’re recommending, the total treatment course, short-term and longterm toxicity, what the outcome is, and what their cost is going to be. the pharmaceutical industry, the government, and ask, “Why do cancer patients have an unfair burden of copayments compared with other diseases, and what is a fair copayment for which treatments?” If we were an ideal world in a value-based system, we might have no copayments for things that were highly effective and increase cure, or markedly improve survival and quality of life. Perhaps as

we got into further lines of treatment with lesser, even questionable benefit, there would be more responsibility on the part of the patient. There are many ideas out there, but we have to come up with a solution, because right now it’s becoming unaffordable for patients in America. Q: There is a growing push toward involving patients in treatment decisions. Should this apply to oncology, or does the fact that cancer is often a life-and-death situation change the equation? LB: As an oncologist who has practiced for 35 years, and in the community where I really know my patients, when you listen to patients, you learn they want to be actively involved, they and their family, or a combination. Sometimes they appoint a family member, but they want to know the truth. They have marketing material, they go on the Internet, but they want to know from their doctor, “What is my health, what is my disease, what is the comprehensive treatment program, what can I expect from that short term and long term, and what will be my health outcome? Also, what is my copayment responsibility for this package?” In our practice, we have found it is essential that every patient who goes for individual chemotherapy teaching also has separate financial teaching. People don’t understand their health plans. They don’t understand their copayment responsibilities. They need to have a plan, think about that with their families, and make arrangements, or, when available, apply for copayment assistance. Q: Is there one theme that underlies patient care no matter where it is delivered in the United States? LB: There’s one theme that ought to underlie everything we do. Continued on page 14

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

Christine Celgene Patient Support ® Specialist

Your single source for personal support

Celgene Patient Support® offers you and your patients financial assistance and insurance-related services from a single Specialist assigned to your area. Co-pays for Celgene medications are reduced to $25 or less for eligible patients. Celgene Commercial Co-pay Programa

Financial assistance through third-party organizations

Celgene Free Medication Programa

Help with locating transportation assistance

Call Celgene Patient Support® at 1-800-931-8691 Monday – Friday, 8 AM – 7 PM ET

Online enrollment now available at www.celgenepatientsupport.com Or e-mail us: patientsupport@celgene.com a

Subject to eligibility requirements.

08/14

US-CELG140179

Interview with the Innovators

Quality Care for Patients…Continued from page 12 We in medicine went into medicine to improve our patients’ health, to use our scientific knowledge, our years of training (12-14 years for an oncologist), to work with our patients, meet their needs, educate them, and walk with them through the path of their treatment, whether it’s for prevention, cure, or end of life, to improve their health, or relieve their suffering. We have to get back to that as the main value. Q: There is continued concern regarding the consequences of community practices being absorbed into hospital settings. How does the setting in which care is offered impact the quality of care? LB: We’re hearing a lot about this change in the care side for oncology patients. Traditionally, 85% of patients in the past 10 years in America have received most of their treatment in the community. It was the largest side of clinical research, often with academic partnerships, and often using academic centers for super specialty, tertiary, or quaternary care. With the financial changes, we saw across the country a third of practices out of practice last year, and I believe this year will be even greater. It’s very regional. In Southern California, I’m not sure there will be many practitioners left within 2 years. They’re going to join academic centers, hospitals, or systems. In the big picture, this could ideally become very beneficial to patients. If you look at the Kaiser system in California, which has 40% market share, it’s a completely integrated system. Between the pharmacy, medical benefits, physicians, surgeons, oncologists, radiation oncologists, supportive care, rehabilitation, hospice, and survivorship, it’s all integrated on behalf of that patient. We’re see-

Linda Bosserman, MD, FACP

We all work as a team and try to divide the work to improve access, discussion, education, and treatment for our patients. No one doctor can do all this, and the team approach is critical.

ing several systems come together in some regional markets to compete with each other. Ultimately, a patient could understand the health outcomes, survival rates, quality of life, and cost in system A versus B or C. Right now, consumers have no way to know if the care they’re getting is in their best interest and for their best outcome. Q: What are the key components of high-quality breast cancer care? LB: I have been a breast cancer specialist for many years; there are many components to breast cancer

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

quality care, from the patient’s point of view, the health plan, and from the clinician. If you look at reengineering the care from day 1, when a woman is first diag nosed, is there someone to talk with her, comfort her, walk her through the system? Can she get into treatment immediately to begin dealing with whatever the aspects of her diagnosis are and get information about how she’s going to get through that, what her health outcome expectations would be, and what the treatment plan would be? It means, quoting the National Comprehensive Cancer Network, for most women, having a core biopsy, so, from day 1, they know whether they have cancer, as well as the initial types and features of that cancer. Therefore, how can she put a team together of medical oncologists, surgeons, radiation oncologists, plastic surgeons, or others, to begin putting a comprehensive treatment plan in place? Then, I think high quality means you have someone to navigate, whether it’s a medical oncologist or a nurse navigator, who helps you walk through and coordinate your care, understand the costs, and have the psychosocial, emotional, and family support that’s critical to caregivers and to patients. This is especially true for women, many of whom are mothers, wives, and now in the workforce, who have other competing concerns besides just the treatment details. Then it ensures that every patient, with her specific diagnosis, has a personalized care plan, treatment for her disease, its features, and her priorities and preferences. Are they of childbearing age? Are they menopausal? Are they already having menopausal symptoms? Do

Interview with the Innovators

they have bone loss? Do they have hyperlipidemia? How do we coordinate their overall health with their breast cancer treatment to achieve the best health outcome for that patient? Those are the quality metrics that patients want to know. If they have advanced disease, they want to know a team is going to help relieve their symptoms and help them with the emotional issues. If they’re breast cancer survivors, they have significant emotional challenges, concerns, and side effects that need long-term management and support, especially in the workplace, and that it’s supported by their clinicians.

and tried to find active-treatment protocols for patients. It’s more complicated than patients can sort through themselves…then when you think you have active clinical trials, and you make phone calls, you find out that they’re not available. That system, as a core nationally, needs to be improved. As we educate patients about clinical trials, we find they’re very open to them, but they want the trial to be integrated into their health plan, into their treatment routine, and as close to home as possible. It’s a very important value to patients, but the system itself needs to be revamped, even though we’re making people aware of it at the practice level.

Q: What can physicians and practice managers do to boost awareness and participation in clinical trials? LB: Our administration and team members promote clinical trials at the practice level. We also encourage patients to find out about clinical trials. In reality, the ClinicalTrials.gov website does not work well. I’ve done searches

Q: What tips would you share with members of the patient’s healthcare team—nurses, navigators, physician assistants, nurse practitioners—to facilitate access to care for their patients? LB: Most of us, whether we’re in an academic or community practice, are working with a team approach: teams of medical oncologists, surgeons, radiation oncologists, plastic

surgeons, and physical therapists, but also within our team in the practice. At the practice level we have secretaries who do intake, financial analysis, access, and authorization. We have medical assistants who enter data and talk to patients about medications and their vital signs. We have nurses who deliver chemotherapy. We have advanced practice practitioners, otherwise known as nurse practitioners, and physician assistants, the physicians themselves, and our administrators. We all work as a team and try to divide the work to improve access, discussion, education, and treatment for our patients. No one doctor can do all this, and the team approach is critical. That’s often a challenge to explain to patients and make sure they’re comfortable with the whole team being there to meet their needs. Q: What are the advantages of Commission on Cancer accreditation? What are the disadvantages of not being accredited? LB: Accreditation is important as setting standards…. Hospitals use the Commission on Cancer to certify their programs. It has certainly encouraged community hospitals to put resources toward the work, elevating the work of tumor boards, the documentation, educational outreach for the community, having special cancer screening days in the community and at academic centers. While I think it’s important, I don’t think patients pay much attention to the level of accreditation. As the money has dried up at the community hospitals, I have seen a significant cutback in their willingness to put up funding for the certification that no one’s requiring. Setting standards is wonderful, so we can all be on the page together and try to do our best as teams, but it also has to have realistic funding. l

INTERVIEW HIGHLIGHTS • In the current healthcare environment, oncologists cannot avoid understanding patients’ cost concerns when evaluating recommended treatment regimens. • For many patients, copayments for cancer treatments, including medicines and patient visits, are unaffordable. • Patients and family members want to be actively involved in the treatment process; it is essential that every patient who receives chemotherapy teaching also receives financial teaching so he or she better understands the costs associated with his or her treatment. • Recent trends indicate that community cancer centers will continue to merge with larger academic centers or hospitals, which may allow for more integrated systems of cancer care. • Patients are interested in participating in clinical trials; however, they would like the trial to be integrated into their health plan and treatment routine, and to be close to their home. • A team approach to cancer care is critical; it is important to explain this approach to patients and ensure they are comfortable with it.

November 2014

www.OncPracticeManagement.com

Practice Finances

Influences on Rising Oncology Drug Costs Continued from the cover Drug Pricing, Supply, and Demand I have recorded price increases over the past decade for drugs used by our oncologists. In reviewing these records, I found that, since enactment of the Medicare Modernization Act (MMA) in 2003, prices on branded oncology drugs have increased approximately 1 to 4 times a year based on average sales price (ASP). The only exception to this price pattern occurred in the first quarter after sequestration when the pharmaceutical industry struggled to forecast the impact of price increases on sales. The pricing of cyclophosphamide provides a clear example of this as well as the impact pricing volatility has on the industry at all levels. In the past, several drug manufacturers were producing this drug, and in this environment of ample supply and price competition, the price of cyclophosphamide declined. In 2008, it was available for approximately $20 per gram; over time, however, with minimized competitive dynamics in place, the cost of this drug has escalated to its current level, at the time of this writing, of approximately $600 per gram. Oncology centers have endured these price increases due to the centrality of this drug in the adjuvant treatment protocol for breast cancer and other key regimens, even though its cost has had a negative impact on the bottom line. Patterns such as these—ie, price increases in an unrestrained market environment— have a critical impact on healthcare industry costs, with primary service providers bearing the lion’s share of the burden. In another example, the pricing of monoclonal antibody blockbuster drugs like trastuzumab and rituximab have risen substantially. Since their introduction into the battle

against cancer many years ago, the prices for these 2 drugs have nearly doubled. Drugs that were—for a time—in short supply also add to this discussion. Current prices for some drugs are more than double the pricing levels at the time the shortages occurred. Simple drugs such as cyanocobalamin, dexamethasone, sterile water for injection, and normal saline are just a few examples

Ruth Lander, FACMPE

of drugs and/or solutions that have experienced dramatic price increases. Normal saline for infusions is still in short supply even though it is a basic, high-use product for treatment infusions. When it is available, pricing on high-use sizes is often elevated, thereby driving up the cost of healthcare in multiple sectors of the industry.

Drug Selection in Community Oncology Centers Drug purchasing takes place daily in community oncology practices across the country, and individuals making decisions about drug purchasing have to consider multiple factors other than just cost. The cause of including high-

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

priced drugs in oncology practices has very real roots: in addition to the MMA, which introduced a flawed ASP formula into the oncology world, sequestration, complex treatment infusion codes with few paying actual administration costs, and other regulations dictating coding and auditing requirements have driven up operating costs while eroding productivity. To combat some of the increased costs of doing business, oncology centers may select a higher-priced drug when lower-priced alternatives are available. Drug companies often provide incentives for selecting their higher-priced drug by offering cancer centers financial rebates that help with the center’s bottom line. To an oncology clinic struggling to stay fiscally viable in the face of so many regulatory mandates, selection of the higher-priced drug takes them one step closer to filling their own fiscal gap. This selection then filters down to patients, who may end up with higher copay fees, thus contributing to the cycle of escalating healthcare costs nationwide.

Conclusion I have enjoyed several decades of productive work in a successful oncology practice. As I approach my own retirement from practice management, I have growing concerns that we are inviting additional regulatory action by the government to interrupt the marketing, pricing, and ordering practices for oncology drugs plaguing the field today. Perhaps it is time for us to learn to self-regulate rather than wait for the government to step in. As the industry matures, managing our own operations so that even the purchasing of drugs is done through the lens of social responsibility will position us for greater success in the future. l

Human Resources

Tattletale or Whistleblower: What’s an Employer to Do? By Robert D. Orzechowski, MBA, SPHR, Chief Operating Officer, Lancaster Cancer Center

quick review of the evening news will often reveal stories of someone in an organization either doing wrong or blowing the whistle on someone else who did wrong. No organization is immune from having its reputation questioned when an employee or manager is caught violating ethical or legal standards, and the fallout can be damaging in many ways. We read almost daily about deliberate misdeeds, illegal behaviors, or unethical acts. Many of these behaviors have come to light because a current or former employee felt that pursuing corrective actions via internal avenues would be ineffective. Yet many people also remain silent out of fear of retaliation. When the wrongdoing is ultimately revealed, this act is referred to as “whistleblowing.” In certain cases, whistleblowing can be profitable. In a recent medical billing case in Kentucky, a physician was awarded $283,412.90 as part of a settlement.1 Some elements of this case and its settlement fell under the whistleblower provisions of the federal False Claims Act, which allows private citizens with knowledge of fraud to bring civil actions on behalf of the United States, and to share in any recovery.1 In other organizations (businesses, nonprofits, and government, small or large) opportunities exist daily for people to choose whether to behave in a legal and ethical manner. Those who choose not to usually have a financial need, an opportunity (access to cash, data, or other company assets), and a rationalization for their behavior. It is common to wonder why people make unethical or illegal

relevant topics for the organization’s sphere of operations, and provide a resource for employees to turn to, such as a specific executive or human resources leader. • Promulgate a policy and position for everyone to sign. Include a process for internally expressing concerns about suspected or witnessed questionable behavior. An ethics or “whistleblower” hotline can be especially valuable. All policies should receive legal review, address the company’s position and standards clearly, provide examples of prohibited behavior and for reporting possible violations, and clearly prohibit retaliation against anyone who reports possible violations. • Include in staff performance appraisals and job descriptions a section on level of compliance with company policies. Employee surveys can also support a compliance effort. • Clarify sanctions for all violators. Ethical behavior necessarily deals with the vagaries of human life, and it is important to remain flexible enough to account for variety and unexpected possibilities in the working world. Providing clear expectations, support, and processes to achieve an ethical culture is the real challenge for any organization seeking to create and sustain an engaged workforce. Executives, owners, and human resources professionals are especially suited to lead such efforts. l

choices, rather than adhere to the laws, regulations, and rules of common decency in their working lives. Another question, however, may be equally as relevant: Why do those who have knowledge of such acts remain silent? A recent National Business Ethics Survey found that about one third of workers who witness misconduct do not report it.2 So, what is an employer to do? High retaliation rates will dampen reporting and increase the likelihood that wrong behavior remains undiscovered. As such, there are tactical responses to the abovementioned question, keeping in mind that good tactics can never compensate for a bad strategy. The real challenge is to create a culture of ethical decision-making and behavior. Some suggestions to achieve this are presented below, and should only be implemented with the support of your upper management team. They include the following: • Manifest the organization’s position on ethical behavior through all available forms of communication; written standards are imperative. Meetings at all levels serve to maintain an aura of transparency, and can set an example for ethical expectations. • Train everyone on standards and

November 2014

References

1. The United States Attorney’s Office, Western District of Kentucky. Owners of Elizabethtown Hematology Oncology, PLC agree to pay over $3.7 million to settle false billings to government health care programs. www.justice.gov/usao/kyw/news/ 2014/20140603-03.html. Accessed November 10, 2014. 2. Ethics Resource Center. National business ethics survey of the US workforce. www.ethics.org/downloads/2013 NBESFinalWeb.pdf. Accessed November 6, 2014.

www.OncPracticeManagement.com

Physician–Hospital Alignment Series

Do’s and Don’ts in Physician–Hospital Alignment, Part 3 By Max Reiboldt, CPA, President/CEO, Coker Group, Alpharetta, GA

he alignment of physicians with hospitals and health systems can be challenging in today’s healthcare climate, yet interest in alignment continues to expand. In some instances, the necessity of maintaining a strong and diverse medical staff coupled with the threat of losing critical team members and the subsequent closure of a business line may result in hospitals and health systems making decisions and promises they may not otherwise make. Considering these concerns, this series of articles on physician–hospital alignments has explored topics relevant to those who are considering a relationship between practices and hospital systems. The first 2 articles in this series discussed pretransactional due diligence, structural design processes, governance, and compensation plans. In this third and final installment, ongoing and posttransactional relationships are explored; accountability, transparency, partnerships, and the use of information technology are discussed in detail.

Ongoing Relationships Once an alignment transaction takes place, the involved parties have to continue to work together. Sometimes, with the challenges of trying to put a deal together, efforts to provide a fully transparent and accountable posttransaction structure can be overlooked. In order for any such affiliation structure to stand the test of time, there must be a very clear and open process in place for sharing information, data, and overall performance. Accountability is an impor tant

facet of any posttransaction relationship; both parties must be accountable to each other. For example, the employed physician must be accountable to his

Sometimes, with the challenges of trying to put a deal together, efforts to provide a fully transparent and accountable posttransaction structure can be overlooked.

employer. This means everything from normal work performance to equipping oneself to meet the day-to-day responsibilities of the position. However, accountability also applies to the employer. In this case, the employer is often the hospital, and the hospital should realize and buy into the concept that they must fulfill the things

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

they committed to during the prealignment discussions. Anything less should result in some form of reconciliation between both parties. Transparency is also of great importance. Most employees (or physicians who are not fully aligned but significantly tied to a health system) seek some form of transparency. This may manifest as sharing of information and data (including performance) as well as openness in decision-making, not unlike the governance and leadership discussion considered in Part 2 of this series. Thus, an attitude of sharing appropriate information and data is key to building a long-term and sustaining relationship. Partnering actions are also an important part of the behavior of both parties posttransaction. So much work, effort, and emphasis are placed on getting the deal done that this issue often is overlooked. Consequently, people start to take others for granted, which inevitably compromises trust, transparency, and accountability. Although true partnering initiatives may not be the legal structure in each arrangement, an attitude of partnering is extremely important for the longterm sustainability of the alignment transaction. Another key to success in the ongoing relationship posttransaction is the level and degree of information technology (IT) use. This is related to transparency, but is really much greater than just sharing information. IT in the current healthcare environment is an absolute essential. It is imperative to be able to pull together data from a clinical standpoint that can be

Physician–Hospital Alignment Series

shared over a large number of participating providers. Such forms of clinical integration are critical to the long-term success of both the hospital and the physician going forward. Education is important in this process; that is, teaching and acquainting the physicians with some level of thoroughness relative to what IT is capable of doing as well as the nuances of how best to get information into the system. When physicians are under great stress to be productive (which can largely be tied to their compensation), the aggravation of working with an IT system that is only partly functional does not create a longterm trusting relationship or success in the alignment strategy. Building trust and respect, therefore, is a great way to summarize these matters. Understanding roles, keeping accountability well defined, and sharing information through a transparent mechanism is a sound

considered. This calls for cooler heads to prevail, with members of management of both the hospital and the physician group sitting down and doing what is best for the entire process. Often, this means reaching a compromised solution, maybe even one that is not quite as preferable to both compromising parties. Nonetheless, compromises are essential in the spirit of working together, now and in the future, postunwind.

formula for success as it relates to these alignment structures.

Planning for the Unwind Possibilities Although no one likes to talk about the potential for divorce, particularly prior to the marriage, these possibilities must be addressed and well documented prior to consummation of the alignment structure. There are ways to provide the physicians with a “soft landing” in an unwind that does not hurt the hospital, and, in the long run, could be very helpful. This should be the approach of the parties involved. Moreover, specific unwind protocols and policies should be defined so there are no misunderstandings as to how certain calculations will be completed or other matters resolved relevant to the unwind process. Assuming this has been done, inevitably issues will arise that have not been specifically

Summary Many do’s and don’ts apply to the entire concept of physician–hospital alignments, with variations from the very form or definition of the alignment model to the details of that model. Alignment requires a great deal of planning, expertise, and, in many instances, an independent party to help mediate the process. If these matters are addressed and appropriate agreements reached and then consistently applied, the chances for a most successful transaction are much enhanced for the hospital, health systems, and the physicians with whom they are aligning. l

KEY POINTS • With the challenges of putting a deal together, efforts to provide a fully transparent and accountable posttransaction structure can be overlooked. • Accountability is an important facet of any posttransaction relationship, and the physician and hospital must be accountable to each other. • Transparency, or an attitude of sharing appropriate information and data, is key to sustaining an alignment relationship. • An attitude of partnership is also extremely important to sustaining a long-term alignment relationship. • Effective use of information technology is essential, as is the ability to pull together data from a clinical standpoint that can be shared over a large number of providers. • Be prepared for issues that may arise from restructuring, and aim for trust, respect, and compromises.

ANNUAL CONFERENCE

M AY 3-6, 2015 Omni Shoreham Hotel Washington, DC

AN RSARY VE NI

This is the final article in a 3-part series on physician–hospital alignments. To review Part 1 and Part 2 of this series, which appeared in the June 2014 and October 2014 issues of Oncology Practice Management, respectively, visit www.OncPractice Management.com. Click on “Issues” for a drop-down selection of previous journal issues and select the appropriate issue.

AVBCConline.org/conference

November 2014

www.OncPracticeManagement.com

Electronics in Cancer Care

Patient Portals Improve Healthcare, but Are Still Works in Progress By Chase Doyle

San Diego, CA—Patient portals offer valuable benefits to providers and patients by enhancing patient– provider communication, increasing operational efficiencies, and empowering patients, according to data presented at the 2014 Association of Community Cancer Centers National Oncology Conference. “Patients report a sense of auton omy when they are given digitized access to their medical records,” said Cary A. Presant, MD, of Wilshire Oncology-US Oncology, who is Professor of Clinical Medicine, University of Southern California School of Medicine, Los Angeles. “By giving patients the metrics to monitor their own disease so they know to look for tumor markers, for example, or look for blood pressure, [they can] see how they’re actually doing.” Although in existence since 2002, the use of patient portals has been rising because of the Health Information Technology for Economic and Clinical Health (HITECH) Act, an increase in electronic medical record (EMR) incentive payments starting in 2011, and the threat of reduced payment for lack of EMR use in 2015. “Portals exist because digitization is universal,” said Dr Presant, “but we [healthcare professionals] have been among the last professions to get into digitization.” The recent push, however, has not come solely from legislative pressure or financial incentives. Rather, portals exist, in large part, as a result of patient preferences. “We have lots of patients who truly prefer digitized types of interactions; they also realize the inefficiencies in our offices that have existed in the past and the fact that having their

own portal may reduce this kind of frustration,” Dr Presant said. In a survey of 13,564 patients and 105 physicians, 82% of patients said they felt more in control and 99% of patients wanted OpenNotes to continue (Delbanco T, et al. Ann Intern Med. 2012;157:461-470). The results, however, were not entirely positive. Of physicians, 19% changed their documentation on account of patient viewership and 11% spent more time writing their notes, indicating a need for portals to become more efficient in the future. Whether portals can influence outcome also remains to be seen. Fourteen randomized controlled trials revealed insufficient evidence that patient portals improve health outcomes or cost (Goldzweig CL, et al. Ann Intern Med. 2013;159:677687). A separate study of the impact of portals on care delivery actually showed an increase in the number of emergency department and physician office visits by patients (Bates DW, et al. JAMA. 2012;308:20342036). In a 1000-patient practice, the use of portals resulted in 10 more patient visits per week, 5.5 additional phone calls per week, and increased workload for doctors. Yet, the appeal of direct and open informational exchange between patients and providers is undeniable. “Educational materials are the real gift of patient portals,” said Kim Woofter, RN, OCN, Chief Operat ing Officer at Michiana Hematology Oncology in northern Indiana. “I have the ability not just to share lab results in real-time but to link to websites and reliable resources…[so that] patients feel like they’re in control.” Another selling point for Ms Woofter is the appointment calen-

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

dar—anything scheduled in-house or at an outside facility is uploaded to a real-time calendar—and for patients who travel, the ability to upload personal health records makes for smoother transitions between treatment facilities. However, such immediate and shared access is not without its complications. “In the beginning, physicians were not happy with the thought of all lab results going directly to a patient in real-time,” said Ms Woofter, who has implemented a 4-day delay on tumor markers to allow physicians to contact their patients first. Despite the obvious benefits, registration remains an ongoing challenge for Ms Woofter, with only 40% of new patients adopting portals. The biggest incentive is family—the ability to share the treatment process with relatives eager to get involved. But if that does not work, there are free iPads, gifted with random drawings to 1 registered patient monthly. Clearly, patient portals are not perfect: there are user errors, crashes, and malfunctions, and there is a greater risk of malpractice as a result of in creased availability of information, as well as the possibility that a patient will not like the information. Dr Presant even cites the potential for a computer virus. But none of this can stop patients’ desire for access to information regarding their care—laboratories, x-rays, medications, the results of their recent visit—or their desire to communicate directly with their providers, the speakers maintained. “We have to find ways of improving outcomes and reducing overhead costs,” said Dr Presant, “but there is definitely improved patient satisfaction. Portals are here to stay. They are part of the future of healthcare.” l

Wealth Management

Investing: Where to Put Your Money Now By W. Ben Utley, CFP®, and Lawrence B. Keller, CFP®, CLU®, ChFC®, RHU®, LUTCF

ou make more money than you spend. It’s the right problem to have, but it’s a problem nonetheless. In fact, every new dollar of savings seems to call for a new investment strategy, but you don’t know where to begin. When you ignore the problem, cash piles up in your checking account—first $40,000, then 6 figures. Then you get nervous. If it was hard to invest a smaller sum, it seems impossible to invest more than $100,000. Then one day, you stumble upon the headline that brought you here, hoping to find the answer. And if this were any ordinary article, you might be well on your way to making the same mistake that most of your colleagues have made at least once in their careers: they pile their money into a hot investment touted at the time. First, they buy it. Then, they watch it drop like a rock. And, months later, when the promised results fail to materialize, they sell everything and feel foolish. It gets worse as the cash continues to pile up and your question goes unanswered: “Where do I put my money now?” The best investment strategies have nothing new about them and they work. Here are 3 investment strategies you can use over and over again, decade after decade, to make your savings last.

Stop Trading Stocks and Start Owning Markets We are sure that you have heard stories in the doctor’s lounge about how your colleagues doubled or tripled their money with their latest stock picks or how they nabbed a tax-free bond paying 5 full percentage points above average.

Sounds like they are making a killing, right? Not exactly. The chances are good that they have gotten killed on plenty of trades, but physician culture won’t allow them to tell you about their blunders. We’ve seen plenty of doctors who stock-picked their way to a small fortune, but

Single stocks can go bankrupt and single bonds can go into default, wiping you out completely. Index funds, which represent ownership in hundreds if not thousands of companies, make it easy to gain instant diversification, diluting the uncompensated or “bad” risk while retaining the “good” risk that leads to rewards over the long haul. Index funds are cheap. With operating expense ratios as low as 0.05%, you can buy an index fund and gain exposure to bonds or stocks around the world. That insignificant carrying cost also buys you the freedom to stop acting like a stockbroker and allows you to get back to serving as a healthcare provider. Savvy physicians prefer mutual funds for their tax efficiency. Since they follow a buy-and-hold approach to investing, index funds are more likely to realize tax-favored capital gains and tax-qualified dividends than more highly taxed short-term gains. This keeps your tax bill in check.

W. Ben Utley

We’ve seen plenty of doctors who stockpicked their way to a small fortune, but most started out with a much larger one. Instead of taking on substantial risk by betting on one stock, keep risk in check by owning a portfolio of them—the easy way.

Stop Timing the Markets and Start Owning Them (All) If you have heard about index investing, you probably know about the S&P 500, a basket of stocks that represents the 500 biggest companies in the United States. The index was made famous in the 1980s and 1990s as it ran up to the dotcom bubble, then vilified in the ensuing “lost decade” when the 10-year return on that index was close to zero. What index hecklers fail to realize, even to this day, is that there’s more than one index. In fact, you can gain exposure to practically all the stocks and bonds on the planet by owning as few as 4 mutual funds. Had investors done this during the past 10 years, they would have avoid-

most started out with a much larger one. Instead of taking on substantial risk by betting on one stock, keep risk in check by owning a portfolio of them—the easy way.

Continued on page 22

November 2014

www.OncPracticeManagement.com

Wealth Management

Investing: Where to Put Your Money Now Continued from page 21 ed some of the technology crash, found the lost decade, and enjoyed very decent returns after all. Unfortunately, the average investor seldom receives average returns. According to a recent study by mutual fund data company Morningstar, “the typical investor gained only 4.8 percent annualized over the ten years ended December 2013 versus 7.3 percent for the typical fund.” That’s a yawning 2.5% gap. Why did investors miss out on fully one third of the market returns? It’s simple. They did the same thing with their funds that your colleagues did with their stocks: they traded in and out of the market. To garner the returns advertised over the past decade, or even the last 3 decades, you would have to own them through thick and thin, no matter how dramatic or dire the news.

Invest Like a Nobel Prize Winner The main argument against an index-only strategy is that it generates merely average returns in the best-case scenario. This logic appeals to doctors who have never once settled for things that are merely average (and that’s pretty much all the physicians we’ve met). Thanks to the research of Nobel laureate Eugene Fama, we now know it’s possible to reliably beat the averages over the long run—but it’s not free. Mr Fama, a financial luminary who founded the first small cap index mutual fund, discovered that the smaller a company is, the more likely it is to outper form a larger one. This is known as the “small cap effect,” and it is robust, having been observed in US market history as well as the return series of developed foreign stock

markets and even emerging markets. Mr Fama and colleague, Kenneth French, both researchers who hail from the renowned University of Chicago Booth School of Business, also found that the stocks of cheap companies, known as “value stocks,” tend to outperform their more expensive “growth stock” peers in what is known as the “value effect.” This effect is also robust in markets domestic and foreign, and is available to investors using index funds.

Lawrence B. Keller

Remember, the answer to good investing is more than where you put your money now. It’s where you keep it over the long haul. While a small cap value tilt may add up to 4 percentage points more than the average untilted portfolio over long periods of time, it brings more volatility, too. When equity markets decline, those index funds filled with cheap little stocks take it hard, and you may wish you had

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

never owned them. The only way to reliably garner the higher expected returns from small cap value stocks is to remain fully invested and stay the course, even when times are tough. This, too, is old news. Even though Mr Fama won the Nobel Prize in economics just last year, his research on the small cap and value effects has been public knowledge since the 1980s.

Summary These perfectly decent strategies are so mundane—so incredibly boring—that you and your colleagues may never have heard of them. After all, words like “diversified,” “tax-efficient,” and “cost-effective” make lousy headlines. The good news is that you can start using a solid investment strategy and keep using it year after year, decade after decade, secure in the knowledge that you have found a permanent answer to a nagging question. Remember, the answer to good investing is more than where you put your money now. It’s where you keep it over the long haul. l 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. Contact him at 541-463-0899 or visit www.physician family.com. 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 at 800-481-6447 or by e-mail to Lkeller@physician financialservices.com with comments or questions.

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

“Better informed teams provide better care.” Matthew P. Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth Murray, UT

Value-Based Care IN Myeloma

™

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

Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues. Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.

Data Management

Where Did My Data Go? Continued from the cover society meetings and articles published in oncology-focused journals abound with topics on this subject. The vast majority of these presentations and publications discuss issues such as why a practice should consider acquisition, how an agreement should be structured, how compensation can be calculated, and so forth. Only a few thus far have told the detailed story of what actually happens once the ink on an alignment deal has dried. When any business owner sells to someone else, there will be significant changes for the previous owner as well as for staff. In the acquisition of a medical oncology practice, this is also true. Staff members will likely experience changes in compensation and performance expectations; physicians will cede some degree of control over daily operations; and payer and purchasing contracts will need to be changed. And, in all likelihood, data systems will change. The typical medical oncology practice has numerous data systems for insurance verification, scheduling, electronic medical records (EMRs), drug inventory handling, clinical trials, billing, and overall practice management. It is rare that a hospital will simply adopt a practice’s systems. Instead, new systems will be used, and with that comes a subtle change in control for physicians and practice managers who had been accustomed to having complete access to all of the detailed data residing in their various systems. When a hospital takes over those systems and converts them to different data systems, what happens to the old data? Unfortunately, in the best cases, the historical data are accessible, but difficult to compare with new data. In the worst cases, much of the data are simply lost for good. Let’s explore some of the impact that a hospital acquisition can have on data.

The loss of a patient’s scheduling history can be frustrating, al though not disastrous, since the information likely also resides, albeit less conveniently organized, in the medical record. Similarly, losing built-in scheduling templates creates headaches for staff members who may have to recreate those in a new system. This is irritating, but not insurmountable.

Since most acquisitions include moving a practice’s infusion business, including pharmacy, to a hospital’s domain, losing drug inventory data may not be a huge issue. Still, the hospital’s pharmacy systems often are not accessible to physicians, causing physicians to lose touch with their own utilization of various drugs. This, in turn, can thwart efforts to track adherence to guidelines or participation in quality programs like the Quality Oncology Practice Initiative (QOPI).

4 Teri U. Guidi, MBA, FAAMA

When any business owner sells to s omeone else, there will be significant changes for the previous owner as well as for staff.

Most practices today have EMRs; however, transferring data from one EMR to another can be very expensive if software interfaces must be purchased. Where interface is not possible, the transfer can be difficult, and there can be a nearly devastating impact: the information may have to be reentered by staff into a new system. The time required to make this transfer is enormous, as staff members comb through the old system or through paper copies and painstakingly enter it into the new system. That time is compounded by what may well be staff members’ steep learning curve for new software.

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

The loss of the above software system data (scheduling, EMRs, pharmacy) can prove calamitous for a clinical trials program. Data managers may lose all of the data necessary to monitor and report adherence to protocol requirements for physical exams, test orders and results, and treatments delivered. Without this information, compensation from study sponsors could be withheld.

Losing historical billing data may not seem, at first glance, to be a concern; however, it may have an impact on physician compensation. While a hospital cannot legally compensate physicians based directly on the infusion revenue that they generate, if the hospital’s staff are not properly trained and skilled in—and the billing system not designed for— the complexities associated with coding and billing for oncology services, revenue may suffer. That revenue is, at least in part, a source of funding for physician compensation and may affect physicians’ total income once an alignment agreement is implemented. In addition, the loss of historical billing data can also hamper efforts to track productivity.

Practice management systems are, in many ways, the backbone of a private practice; however, such

Data Management

systems do not generally exist in a hospital setting. Of particular concern is the lost ability to track all work relative value units (wRVUs). In an office-based setting, there are wRVUs associated with technical charge codes for the administration of drugs of all kinds, such as hydrations, infusions, and injections. In a hospital setting, it is literally impossible to attribute specific technical services to any individual provider. Therefore, physician productivity as measured by wRVUs will be lower when the infusion business transfers. In fact, data from the Oncology Management Consulting Group demonstrate an average wRVU differential of 17%. In other words, approximately 17% of a physician’s wRVUs come from the administration of treatments. This must be carefully examined prior to com-

pleting compensation packages that are based on wRVUs, particularly if benchmarked against external data. The loss of historical data of any kind brings with it the loss of the ability to follow trends. Those trends may be as simple as tracking a patient’s no-show history, or they can be as highly complex and important as trending clinical and diagnostic data. What, then, can a practice do to minimize the potentially catastrophic impact of a change in data systems? Obviously, in the ideal world, all of a practice’s data would be uploaded in a perfect format to new systems. But complete transfer of all data is not usually possible. Therefore, the practice should first be certain to retain access to its existing systems for a reasonable amount of time after a transition. This may result in unanticipated costs for soft-

ware licenses, hardware, and technical support. Second, consider “printing” all data to electronic files that could be utilized in the dire event of a total loss of functioning software. Software vendors may be able to do this, or the practice may need to engage temporary staff—either way, this step will likely incur unanticipated costs. Finally, for any practice staff members who will be transitioning to the new systems, ensure that the hospital provides adequate training and support, and that the hospital clearly recognizes that staff and physician productivity will be hampered by steep learning curves. l

Reference

1. Community Oncology Alliance. Community Oncology Practice Impact Report: The Changing Landscape of Cancer Care. www.communityoncology. org/pdfs/Community%20Oncology%20Practice%20 Impact%20Report%206-24-13F.pdf. Published June 25, 2013. Accessed November 3, 2014.

ONCOLOGY PRACTICE MANAGEMENT ™

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

A forum for members of the oncology team to have a discussion on the day-to-day operations of running a business. The goal is to share ideas and best practices, and provide a resource to ultimately help run a more efficient practice and improve patient care.

JOIN OUR LinkedIn GROUP TODAY

I I 25 www.OncPracticeManagement.com

November 2014

www.OncPracticeManagement.com

OPMin121213

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†

Uninsured or Underinsured Free XTANDI® (enzalutamide) capsules

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:

1-855-8XTANDI (855-898-2634) 8 AM – 8 PM ET

(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

0.0

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

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 7.4

6.6

4.5

3.8

6.6

0.0

4.5

0.0

4.3

0.3

1.8

0.0

4.0

0.3

1.8

0.0

6.5

0.3

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

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 g Infection 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 FDA Approves First Anti–PD-1: Pembrolizumab Indicated for Advanced Melanoma The FDA approved the first anti–programmed death receptor-1 (PD-1) therapy, pembrolizumab (Keytruda; Merck), for patients with unresectable or metastatic melanoma and disease progression after treatment with other melanoma therapy, such as ipilimumab, or, for a patient with BRAF V600 mutation, after BRAF inhibitor therapy. The FDA accelerated its approval for pembrolizumab based on early clinical data from the KEYNOTE-001 phase 1b trial showing a high tumor response rate and long durability of response rather than on actual improvements in survival or in disease progression. Ongoing phase 2 and 3 clinical trials are being conducted to provide confirmatory information that is expected to demonstrate clinically meaningful improved outcomes, including potential im provement in survival and/or reduction in disease progression. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is the first-ever anti–PD-1 therapy to re ceive FDA approval. The FDA also granted pembrolizumab a breakthrough therapy designation for advanced melanoma based on the positive early results from the phase 1b trial in 173 patients with unresectable or metastatic melanoma whose disease progressed after previous therapy, reflecting an unmet medical need for this patient population. The FDA approval was based on early results from the ongoing mul ticenter, open-label, randomized, dose- comparative KEYNOTE-001 phase 1b trial. A total of 89 patients received the 2-mg/kg dose every 3 weeks; other

patients received different doses, including a 10-mg/kg dose, which was just as effective. Overall, 411 patients were included in this trial. The overall response rate in the 89 patients receiving the 2-mg/kg dose was 24% (95% confidence interval, 15-34), including 1 complete response and 20 partial responses. At the time of the analysis, 86% of patients with objective responses had ongoing responses, with the duration of response ranging between 1.4 and 8.5 months. In addition, 8 of these patients are still showing ongoing responses of ≥6 months. All patients had received previous treatment with ipilimumab or a BRAF inhibitor in patients with a BRAF V600 mutation; the patients had disease progression within 24 weeks after the last dose of previous therapy. Patients were randomized to receive 2 mg/kg (N = 89) or 10 mg/kg (N = 84) of pembrolizumab every 3 weeks until unacceptable toxicity or until disease progression. The major efficacy outcomes analyzed were confirmed overall response rate and duration of response. The most common serious adverse events reported in ≥2% of patients who received pembrolizumab include renal failure, dyspnea, pneumonia, and cellulitis. The most common adverse events (reported in ≥20% of patients) were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. (September 4, 2014)

Bortezomib Receives New FDA Indication Bortezomib (Velcade; Millennium/ Takeda Oncology), which is already approved by the FDA as an intravenous (IV) or subcutaneous treatment for patients with multiple myeloma, recently received a supplemental new indication for the retreatment of adults with myeloma whose disease

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

had previously responded to bortezomib therapy and had relapsed (ie, progressed) at least 6 months after the last treatment with bortezomib. Retreatment with bortezomib can be restarted at the last dose the patient had tolerated previously. The new indication includes a labeling update with dosing guidelines and safety and efficacy data related to the use of bortezomib as a single agent or in combination with dexamethasone. The new supplemental indication was based on the results from a phase 2 clinical trial, RETRIEVE, as well as other supportive data. The single-arm, open-label, international RETRIEVE trial included 130 patients with myeloma (aged ≥18 years) who had previously responded to bortezomib-based therapy and whose disease relapsed at least 6 months after previous therapy. The overall response rate was 38.5%; 1 patient achieved a complete response and 49 patients achieved a partial response. The median duration of response was 6.5 months (range, 0.6-19.3 months). The safety of retreatment with bortezomib was consistent with the known safety profile of IV bortezomib in patients with relapsed myeloma; no cumulative toxicities were reported with retreatment. The most common adverse event was thrombocytopenia, which was reported in 52% of patients. The incidence of grade ≥3 thrombocytopenia was 24%. Peripheral neuropathy was observed in 28% of patients, and the incidence of grade ≥3 peripheral neuropathy was 6%. The incidence of serious adverse reactions was 12.3%. The most common serious adverse reactions were thrombocytopenia (3.8%), diarrhea (2.3%), herpes zoster (1.5%), and pneumonia (1.5%). Overall, 13% of patients discontinued bortezomib retreatment because of adverse events. (August 8, 2014) l

Now enrolling: MURANO study Investigating the Selective BCL-2 Inhibitor GDC-0199/ABT-199 in Chronic Lymphocytic Leukemia GDC-0199/ABT-199 is an investigational agent that has not been approved by regulatory agencies.

A Phase III Study of GDC-0199/ABT-199 Plus Rituximab Compared With Bendamustine Plus Rituximab in Patients With Relapsed or Resistant Chronic Lymphocytic Leukemia (CLL)

GDC-0199/ABT-199 + rituximab

Phase III Relapsed or resistant CLL (N=370)

GDC-0199/ABT-199 continued for 2 years or until disease progression

Bendamustine + rituximab Randomize Primary Endpoint

Secondary Endpoints

• Investigator-assessed progression-free survival, defined as time from randomization until disease progression or death from any cause

• Overall response rate • Incidence of adverse events

Key Inclusion Criteria

Key Exclusion Criteria

• Adult patients ≥18 years of age • Diagnosis of CLL per diagnostic criteria and relapsed or refractory CLL per the iwCLL guidelines • Previously treated with 1-3 lines of therapy (eg, completed ≥2 treatment cycles per therapy), including ≥1 standard chemotherapy-containing regimen • Previously treated with bendamustine, only if duration of response was ≥24 months • ECOG performance status of 0-1 • Adequate bone marrow function • Adequate renal and hepatic function

• Transformation of CLL to aggressive non-Hodgkin lymphoma or CNS involvement by CLL • Undergone an allogenic stem-cell transplant • A history of significant renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease • Hepatitis B, hepatitis C, or known HIV-positive • Receiving warfarin treatment • Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study drug • Received any anticancer or investigational therapy within 14 days prior to the first dose of study drug or has not recovered from previous therapy • Received CYP3A4 inhibitors (such as fluconazole, ketoconazole and clarithromycin) or inducers (such as rifampin, carbamezapine, phenytoin, St John’s Wort) within 7 days prior to the first dose of GDC-0199/ABT-199 • Prior GDC-0199/ABT-199 treatment

To learn more about this study, please visit www.ClinicalTrials.gov (NCT02005471, GO28667) or call the Trial Information Support Line at 1-888-662-6728.

GDC-0199/ABT-199 is being codeveloped by AbbVie and Genentech, a member of the Roche Group.

Reference: ClinicalTrials.gov, as of 5/2014. A2396579

Clinical Trial Tracker

New Clinical Trials Under Way

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

Erlotinib With or Without Bevacizumab The objective of this phase 2 study is to examine the efficacy of erlotinib with or without bevaciz umab in patients with stage IV non– small-cell lung cancer with epidermal growth factor receptor (EGFR) mutations. Patients aged ≥18 years with a life expectancy of ≥12 months, an Eastern Cooperative Oncology Group performance status 0 or 1, and a hemoglobin level of ≥9.0 g/dL may enroll if other criteria are met. Erlotinib is given orally once daily to both the comparator and experimental arms on days 1 through 21, and patients in the experimental arm receive a dose of intravenous bevacizumab for 30 to 90 minutes on day 1. Courses are repeated every 21 days for both arms until disease progression or unacceptable toxicity becomes evident. Patients are followed periodically for up to 5 years after study completion. The primary outcome is progression-free survival of patients with EGFR mutations being treated with erlotinib in combination with bevacizumab versus erlotinib alone. Secondary outcomes include overall rate of survival, complete or partial response rate to each treatment method, adverse events, and progression-free survival of patients with other mutation types. This study expects to enroll 118 patients in multiple locations across the United

States. For more information, contact Thomas Stinchcombe, MD, at 919-966-4431 or thomas_stinch combe@med.unc.edu. The NLM Identifier is NCT01532089.

Denosumab with Chemotherapy as First-Line Treatment This phase 2, randomized, double-blind study aims to study the effect of combining denosumab with standard chemotherapy in the treatment of patients with advanced lung cancer. Patients aged ≥18 years with stage IV, untreated non–small-cell lung cancer with or without bone metastasis may enroll if other inclusion criteria are met. Randomization occurs in a 2-to-1 ratio of patients receiving denosumab 120 mg to matching placebo subcutaneously every 3 or 4 weeks plus a loading dose on day 8 of the study. The first investigational product dose coincides with the patient’s first cycle of chemotherapy. Treatment continues until the time of the primary analysis, the patient is lost to follow-up, or the patient dies. All patients will receive daily dietary supplements of ≥500 mg of calcium and ≥400 IU of vitamin D. The primary outcome is the relative benefit on overall survival of receiving denosumab in combination with standard of care (SOC) versus SOC alone. The secondary outcomes aim to correlate tumor tissue RANK and RANKL expression with the objective response rate and/or overall survival. Serum denosumab trough levels, and safety and tolerability of denosumab are measured. The study expects to enroll 216 patients and will take place in multiple locations across the United States, including California, New York, and Tennessee. For more information, contact the Amgen Call Center at 866-572-6436. The NLM Identifier is NCT01951586.

Safety and Efficacy of Adding Talactoferrin to Standard Chemotherapy This is a phase 3, double-blind, safety and efficacy study comparing the combination of talactoferrin, carboplatin, and paclitaxel with the combination of paclitaxel and carboplatin in improving progression-free survival and overall survival in patients with non–small-cell lung cancer. Patients aged ≥18 years with at least 1 target lesion measurable by Response Evaluation Criteria in Solid Tumors are eligible if other criteria are met. In addition to carboplatin and paclitaxel, patients will receive 1.5 grams of twice-daily placebo or talactoferrin. The primary outcomes are overall and progression-free survival, and the secondary outcome measures include safety and tolerability, as well as objective response and disease stabilization rates. The study plans to enroll 1100 patients. For more information, contact Yenyun Wang, MD, at 713-552-1091 or ywang@agennix.com, or Rajesh Malik, MD, at 713-552-1091 or rmalik@agennix.com. The NLM Identifier is NCT00706862.

Bavituximab Plus Docetaxel versus Docetaxel Plus Placebo The purpose of this phase 3, double-blind study is to assess whether adding bavituximab to docetaxel will improve the results of treatment for patients with non–small-cell lung cancer (NSCLC). Patients must be aged ≥18 years, have histologic evidence of stage IIIB or IV nonsquamous NSCLC, have radiographic disease progression or recurrence during or after first-line, platinum-based doublet chemotherapy, and meet other criteria to enroll. Patients will receive docetaxel for 6, 21-day cycles with either bavituximab or a placebo on a weekly basis Continued on page 34

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

*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 ÂŠ 2010, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

V-10-0196

11/10

Clinical Trial Tracker

New Clinical Trials…Continued from page 32 in the absence of disease progression. The primary outcome is overall survival. Secondary outcomes include progression-free survival, overall response rate, and safety as measured by adverse event rates and laboratory procedures. The outcomes have a time frame of approximately 36 months. The study is expected to enroll 582 patients and be conducted at multiple locations across the United States, including Arizona, Oregon, and Wisconsin. For further information, contact Jennifer Lai, MBA, at 855-291-7867 or lungcan certrial@peregrineinc.com. The NLM Identifier is NCT01999673.

Carfilzomib with Irinotecan for Irinotecan-Sensitive Malig nancies This is a phase 1b/2 trial. Phase 1b is an open-label study determining the maximum tolerated dose of carfilzomib in combination with irinotecan in patients with relapsed small-cell lung cancer (SCLC) and non–small-cell lung cancer (NSCLC) or other irinotecan-sensitive cancers. Phase 2 assesses the 6-month survival of patients with relapsed SCLC treated with carfilzomib in combination with irinote can. Secondary outcomes include response rate, progression-free survival, safety and tolerability, and rates of specified adverse events for a time frame of up to 6 months. Phase 1b includes patients with advanced SCLC or NSCLC, or other cancers where irinotecan therapy has shown efficacy and for whom no curative therapy exists. Phase 2 includes patients with advanced-stage SCLC with progression or recurrence following 1 platinum-containing regimen. The trial plans to enroll 112 patients. For more information, contact Susanne M. Arnold, MD, at 859-3238043 or smarno0@uky.edu, or Grace Powell, BA, at 206-839-1790 or

g racep@crab.org. The NLM Identifier is NCT01941316.

Erlotinib Hydrochloride for Surgery-Removed Stage IB-II- IIIA NSCLC The objective of this phase 3, randomized study is to determine the efficacy of erlotinib hydrochloride in treating patients with stage IB, II, and IIIA non–small-cell lung cancer (NSCLC) that has been completely removed by surgery. Patients aged ≥18 years with completely resected stage IB to IIIA NSCLC with negative margins who meet additional inclusion criteria may enroll in the study. Patients are randomized to either erlotinib hydrochloride or placebo. Treatment is given once a day orally on days 1 through 21, and repeated every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. The primary outcome is overall survival from time of randomization until time of death, with up to 5 years of assessment. Secondary outcomes include disease-free survival at a 2-year follow-up, overall survival rate defined as the proportion of patients alive 5 years after the date of randomization, and incidence of adverse events associated with each study group. The study expects to enroll 450 patients in multiple locations across the United States, including Iowa, Maryland, and Nevada. For more information, contact Ramaswamy Govindan, MD, at 314-362-5737 or rgovinda@dom. wustl.edu. The NLM Identifier is NCT02193282.

Nintedanib for Advanced NSCLC This phase 2 trial studies the efficacy of nintedanib in treating patients with advanced non–smallcell lung cancer who have failed up

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

to 2 previous chemotherapy regimens. Patients aged ≥18 years with an Eastern Cooperative Oncology Group performance status of ≤1 may enroll if other inclusion criteria are met. All patients will receive nintedanib orally twice a day on days 1 through 28. Courses are repeated every 28 days in the absence of disease progression or unacceptable toxicity. The primary outcome is progression-free survival (PFS) rate of the fibroblast growth factor receptor 1 (FGFR1)-amplified patient group over a time frame of 6 months. The secondary outcomes include PFS rate for the FGFR1-amplified patient group compared with patients with wild-type FGFR1, PFS within each FGFR1-amplified group (low, intermediate, and high), overall survival, adverse events, and tumor response defined as partial or complete according to the Response Evaluation Criteria in Solid Tumors. This study expects to enroll 67 patients and will be conducted in New York at the Roswell Park Cancer Institute in Buffalo. For more information, c ontact Alex A. Adjei, MD, P hD, FACP, at 877-275-7724 or ASKRPCI@roswellpark.org. The NLM Identifier is NCT01948141.

Crizotinib for Stage IB-IIIA NSCLC Removed by Surgery This is a phase 3 study that evaluates whether crizotinib therapy adjuvant to surgical resection will result in improved overall survival (OS) compared with a placebo for patients with stage IB, II, and IIIA non–small-cell lung cancer with an anaplastic lymphoma kinase mutation. Patients aged ≥18 years without evidence of disease for 90 days in advance of randomization may enroll if other criteria are met. The experimental arm will receive crizotinib orally twice a day for days

Clinical Trial Tracker

1 through 21. Treatment is repeated every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. The placebo will be given in the same regimen. Primary outcomes measure OS from time of randomization to time of disease recurrence, new lung cancer appearance, or death, assessed for up to 10 years. Secondary outcomes are assessed for up to 10 years and include disease-free survival and toxicity rates measured according to the Common Terminology Criteria for Adverse Events. This study plans to enroll 378 patients and will be conducted in Philadelphia, PA. For more information, contact David E. Gerber, MD, at 214-648-7097 or david.gerber@ utsouthwestern.edu. The NLM Identifier is NCT02201992.

TH-302 or Placebo with Pemetrexed for Nonsquamous NSCLC This is a phase 2, randomized, double-blind study determining whether TH-302 in combination with pemetrexed is safe and effective as second-line treatment for nonsquamous non–small-cell lung cancer (NSCLC). Patients aged ≥18 years with stage IIIB or IV NSCLC with nonsquamous histology and other criteria are eligible for enrollment. Patients are randomized to either TH-302 400 mg/m2 or a matching placebo, intravenously

infused for 30 to 60 minutes on day 1 and day 8 of a 21-day cycle, and pemetrexed 500 mg/m2 intravenously infused on the first day, 2 to 4 hours after administration of TH-302 or placebo. The primary outcome is the efficacy of pemetrexed in combination with TH-302 as determined by overall survival over a time frame of 2 years in patients in the second- line chemotherapy setting with advanced, nonsquamous NSCLC compared with pemetrexed in combination with placebo. Secondary outcomes include the incidence and severity of adverse events, pharmacokinetics of TH-302 in study patients, and antitumor activity between the 2 groups as measured by progression-free survival and response rates. This study expects to enroll 440 patients at multiple locations across the United States, including Colorado, California, and Kentucky. For more information, contact Kristin Williams at 860-949-5311 or kristin. williams@psi-cro.com, or Mandeep Grewal at 650-474-8361 or mgrewal @thresholdpharm.com. The NLM Identifier is NCT02093962.

Custirsen for Patients with Stage IV NSCLC This is a phase 3 study that compares the overall survival of patients receiving custirsen and docetaxel (Arm A) versus docetaxel

alone (Arm B). Patients aged ≥18 years with stage IV non–small-cell lung cancer (NSCLC), a life expectancy >12 weeks from screening, and who received 1 previous line of platinum-based systemic anticancer therapy for advanced or metastatic NSCLC may enroll if other criteria are met. Both treatment arms will receive docetaxel 75 mg/m2 intravenously (IV) for 1 hour on the first day of every 21-day cycle. The experimental arm (Arm A) will also receive 3 loading doses of custirsen 640 mg IV for 2 hours administered 5 to 9 days prior to the first day of cycle 1, followed by custirsen 640 mg IV weekly every 21-day cycle. Treatment will continue until there is unacceptable toxicity, disease progression, withdrawal of consent, or protocol-specified parameters to curb treatment. The primary outcome is overall survival, defined as the time between date of randomization and date of death from any cause. Secondary outcomes include progression-free survival, rate and duration of objective response, duration and rate of disease control, and adverse events. Data are collected over 60 months. The study plans to enroll 1100 patients, and study locations include Florida, North Carolina, and Texas. For more information, contact Teva US Medical Information at 800-8965855. The NLM Identifier is NCT01630733. l

SUBSCRIBE NOW Don’t miss an issue of Oncology Practice Management, bringing you all the news, information, and practical advice you need to help you manage your practice. Go to www.OncPracticeManagement.com to subscribe today

November 2014

www.OncPracticeManagement.com

Drug Update

Beleodaq (Belinostat) Receives FDA Approval for the Treatment of Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma By Lisa A. Raedler, PhD, RPh, Medical Writer

eripheral T-cell lymphoma (PTCL) is a broad term that encompasses several rare and often aggressive types of non-Hodgkin lymphoma.1 The Leukemia & Lymphoma Society estimates that between 10% and 15% of patients with non- Hodgkin lymphoma have a T-cell lymphoma subtype.1 According to data from the Surveillance, Epidemiology, and End Results registry, the incidence of PTCL is less than 1 case per 100,000 individuals in the United States.2 PTCL is most often identified in patients aged ≥60 years.1 PTCL comprises multiple subtypes, each with unique clinical features.3 The most common PTCL subtypes include PTCL not otherwise specified (PTCL-NOS), anaplastic large-cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL); these subtypes account for approximately 70% of all PTCL cases in the United States.3 PTCL is typically characterized by enlarged lymph nodes in the neck, armpit, or groin.1 PTCL also affects the bone marrow, liver, spleen, stomach, and skin.1 Other symptoms of PTCL may include night sweats, fever, weight loss, and rash.1 Compared with patients with aggressive B-cell lymphomas, patients with PTCL have very poor outcomes.4 According to the International T-Cell Lymphoma Study, the overall survival at 10 to 15 years was 10% for patients with PTCL-NOS.5 Traditionally, treatment advances for patients with PTCL have been Copyright © 2014 American Health & Drug Benefits. All rights reserved.

slower than treatment advances in other types of lymphoma.4 Patients with newly diagnosed PTCL are often treated with single-agent drugs and drug combinations that are used in B-cell lymphomas, including the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and the EPOCH (etoposide, vin-

Belinostat was approved under the FDA’s accelerated approval program based on 2 surrogate end points—tumor response rate and duration of response. cristine, doxorubicin, cyclophosphamide, and prednisone) regimens.3,4 Because virtually all patients with PTCL will experience disease relapse, high-dose chemotherapy followed by autologous stem-cell transplantation is considered a treatment option for eligible patients.3 For relapsed or refractory PTCL, the relatively new treatment options include pralatrexate and romidepsin, both of which were approved by the US Food and Drug Administration (FDA) in 2009; older cytotoxic drugs and drug combinations include gemcita bine-based combinations, DHAP (dexamethasone, cytarabine, and cisplatin), and ICE (ifosfamide, carboplatin, and etoposide).3

In 2011, the FDA approved brentuximab vedotin, an antibody-drug conjugate, for the treatment of patients with relapsed or refractory systemic ALCL.6 Clinical trials are under way to assess the activity of this monoclonal antibody in other subtypes of PTCL.3 The cost burden associated with PTCL is significant. A recent retrospective cost analysis evaluated claims data for commercially insured patients with Medicare supplemental benefits to identify patients with PTCL.7 A total of 1000 patients with PTCL were included in the analysis. Results showed that patients with PTCL were hospitalized more often and experienced longer lengths of hospital stays compared with the matched controls without PTCL.7 In addition, patients with PTCL utilized more physician office visits, pharmacy services, emergency department visits, and hospice care compared with the matched control group.7 The mean annual healthcare costs were $75,934 for patients with PTCL compared with $4661 for the matched controls.7 The medical costs for patients with PTCL were primarily driven by hospitalizations (ie, 32% of the overall costs) and pharmacy services (ie, 20% of the overall costs).7 Overall, 11% of patients with PTCL underwent stem-cell transplantation compared with none of the patients in the control group. The average cost of stem-cell transplantation exceeded $126,000 per patient.7

Belinostat: A New Treatment Option for PTCL On July 3, 2014, the FDA approved belinostat (Beleodaq; Spectrum Continued on page 38

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

Your One Source for Patient Support IncyteCARES connects eligible patients taking Jakafi® (ruxolitinib) to ongoing support and resources during their treatment.

Reimbursement Assistance • Benefit verification • Prior authorization • Appeal support

Access

Education & Support

• Co-pay assistance

• Access to trained nurses

• Free medication program

• Educational information to help teach your patients about their condition

• Referrals and assistance with independent not-for-profit organizations

• Patient education packet

Connect Today Visit www.IncyteCARES.com or call 1-855-4-JAKAFI (1-855-452-5234) Monday–Friday, 8 AM–8 PM ET, to learn more about how to connect your patients to IncyteCARES.

Drug Update

Beleodaq (Belinostat) Receives…Continued from page 36 Pharmaceuticals) for the treatment of patients with relapsed or refractory PTCL.8 This approval was based on an open-label, single-arm, nonrandomized, international clinical trial conducted at 62 centers and included 129 patients with relapsed or refractory PTCL.8-10 The primary end point was overall response rate, including complete response and partial response, as assessed by an Independent Review Committee using the International Workshop Criteria.8-10 Belinostat, which is administered via intravenous infusion, was approved under the FDA’s accelerated approval program based on 2 surrogate end points—tumor response rate and duration of response.8,9 An improvement in survival or disease- related symptoms has not yet been established.9

Mechanism of Action Belinostat is a histone deacety lase inhibitor.9 Histone deacety lases are enzymes that facilitate the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins.9 In vitro, belinostat causes the accumulation of acetylated histones and other proteins, which results in cell apoptosis and/or cell-cycle arrest of some transformed cells. Belinostat demonstrates preferential cytotox-

icity toward tumor cells relative to normal cells.9

Dosing and Administration In patients with relapsed or refractory PTCL, the recommended dosage and schedule of belinostat is 1000 mg/ m2 administered intravenously on day 1 to day 5 of a 21-day cycle. Treatment with belinostat should be repeated every 21 days until disease progression or until unacceptable toxicity.9 Belinostat should be infused over 30 minutes. The infusion time may be extended to 45 minutes if infusion-site pain or other symptoms attributable to the infusion occur. In patients known to be homozygous for the UGT1A1*28 allele, the dose of belinostat should be reduced to 750 mg/m2.9 Belinostat is primarily metabolized by the liver. The data are insufficient to recommend a specific dose of belino stat in patients with moderate or severe hepatic impairment or in patients with creatinine clearance ≤39 mL/min.9 BELIEF: A Pivotal Phase 2 Clinical Trial The safety and efficacy of belin ostat in patients with relapsed or refractory PTCL were demonstrated in the BELIEF clinical trial, a single-arm, open-label, nonrandomized, international study.10 In this clinical

esponse Rates Associated with Belinostat in Patients with Table 1 R Relapsed or Refractory PTCL Response

Patients receiving belinostat (N = 120), N (%)

Overall response

31 (25.8) (95% CI, 18.3-34.6)

Complete response

13 (10.8) (95% CI, 5.9-17.8)

Partial response

18 (15.0) (95% CI, 9.1-22.7)

CI indicates confidence interval; PTCL, peripheral T-cell lymphoma. Source: Beleodaq (belinostat) injection prescribing information; July 2014.

trial, 129 patients with relapsed or refractory PTCL received belinostat 1000 mg/m2 administered intravenously over 30 minutes once daily on days 1 to 5 of a 21-day cycle.10 Patients received belinostat every 3 weeks until disease progression or until unacceptable toxicity.9,10 The primary efficacy end point was overall response rate, including complete response and partial response. Responses were assessed by an Independent Review Committee using the Cheson 2007 International Workshop Criteria.9,10 The duration of response was a secondary end point. Response assessments were performed every 6 weeks for the first 12 months of the trial, followed by every 12 weeks until 2 years from the initiation of the study treatment.9 The duration of response was measured from the first day of the documented response until disease progression or death. Disease progression was evaluated by the Independent Review Committee.9 The median duration of treatment with belinostat was 2 cycles (range, 1-33 cycles).9,10

Patient population The median age of the 120 patients evaluable for efficacy in the BELIEF trial was 64 years, with 62 patients (52%) aged ≥65 years.9,10 The majority (52%) of the patients enrolled were male; 88% were white, and 77% had an Eastern Cooperative Oncology Group performance status of 0 or 1.9,10 Furthermore, 64% of the patients had confirmed PTCL-NOS, 18% had AITL, and 11% had anaplastic lymphoma kinase-1 negative ALCL.9 Overall, 17% of the patients had platelet counts <100,000/μL.9,10 The median time from the initial PTCL diagnosis was 12 months (range, 2.6-266.4 months). The median number of previous systemic treatments for PTCL was 2 (range, 1-8).9,10 Continued on page 40

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

unc

FACES

her mot

The Academy of Oncology Nurse & Patient Navigators (AONN+) invites you to share your story of how cancer has affected you or a loved one. These stories will serve as a forum to build awareness and be a source of inspiration and reassurance to others. Select stories will be featured on the AONN+ website and in future issues of the Journal of Oncology Navigation & SurvivorshipÂŽ.

nephew

r siste

HopE

â&#x201E;˘

ndm oth er

YEA R A N N I V E RS A RY

YEAR A N N I V E R S A RY

ie t fr

bes

er broth AONNFacesofHopeAsize_53014

Share Your StorY With uS!

November 2014 I www.OncPracticeManagement.com I 39 AONNonline.org/community/aonn-faces-of-hope

Drug Update

Beleodaq (Belinostat) Receives…Continued from page 38 ll-Grade Adverse Events in ≥10% of Patients with Relapsed or Table 2 A Refractory PTCL Receiving Belinostat Patients receiving belinostat (N = 129) Adverse reactions All grades, % Grade 3 or 4, % 42 1 Nausea 37 5 Fatigue 35 2 Pyrexia 32 11 Anemia 29 1 Vomiting 23 1 Constipation 23 2 Diarrhea 22 6 Dyspnea 20 1 Rash 20 0 Peripheral edema 19 0 Cough 16 7 Thrombocytopenia 16 3 Pruritus 16 1 Chills 16 2 Increased blood lactate dehydrogenase 15 2 Decreased appetite 15 0 Headache 14 0 Infusion-site pain 12 4 Hypokalemia 11 4 Prolonged QT interval 11 1 Abdominal pain 10 3 Hypotension 10 1 Phlebitis 10 0 Dizziness PTCL indicates peripheral T-cell lymphoma. Source: Beleodaq (belinostat) injection prescribing information; July 2014.

Efficacy Among patients receiving belino stat, the overall response rate was 25.8% (Table 1). The response rate was 23.4% among patients with PTCL-NOS and 45.5% for patients with AITL.9,10 Among patients whose disease responded to belinostat, the median duration of response was 8.4 months (95% confidence interval, 4.5-29.4).9,10 The median time to response was

5.6 weeks (range, 4.3-50.4 weeks).10 Overall, 9 of the 120 patients proceeded to stem-cell transplantation after receiving belinostat.9,10

Adverse Reactions The safety of belinostat was assessed in 129 patients with relapsed or refractory PTCL in the BELIEF clinical trial. Adverse reactions of any severity level were observed in 97% of the patients.9,10

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

Table 2 summarizes the adverse reactions associated with belin ostat in patients with relapsed or refractory PTCL, regardless of causality.9 A total of 61 patients (47%) experienced serious adverse reactions while receiving belinostat or within 30 days after their last dose of belinostat. The most common (>2%) serious adverse reactions included pneumonia, pyrexia, infection, anemia, increased creatinine clearance, thrombocytopenia, and multiorgan failure.9 Overall, 25 (19%) patients discontinued belinostat treatment as a result of adverse reactions, which included anemia, febrile neutropenia, fatigue, and multiorgan failure. In addition, 12% of patients receiving belinostat had to have dosage adjustments because of adverse reactions.9,10 Overall, 1 treatment-relateddeath from hepatic failure was reported in the BELIEF trial.9,10 In addition, 1 treatment-related death from ventricular fibrillation was reported in another clinical trial with belino stat monotherapy. Echocardiogram analysis did not identify a QT interval prolongation.9

Warnings and Precautions Hematologic toxicity. Belinostat can cause thrombocytopenia, neutropenia, lymphopenia, and/or anemia. During treatment with belinostat, blood counts should be monitored weekly, and dosage modifications should be made as needed for hematologic toxicity.9 Infections. Pneumonia, sepsis, and other serious infections, including fatalities, have occurred with belinostat. Belinostat should not be administered to patients with an active infection.9 Hepatotoxicity. Fatal hepatotoxicity and liver function test abnormal-

Drug Update

ities have occurred with belinostat. Liver function tests should be assessed before initiating treatment and before the start of each cycle. Dose interruptions or adjustments are recommended until recovery. Belinostat should be permanently discontinued if the hepatic toxicity is severe.9 Tumor lysis syndrome. Tumor lysis syndrome has been associated with belinostat in patients with relapsed or refractory PTCL. Patients with advanced-stage disease and/or high tumor burden should be monitored carefully for this syndrome.9 Gastrointestinal toxicity. Nausea, vomiting, and diarrhea have been observed with the use of belinostat. Antiemetic and antidiarrheal medications may be required.9 Embryofetal toxicity. Belinostat can cause fetal harm when administered to a pregnant woman; teratogenicity and/or embryofetal lethality can occur. If belinostat is used during pregnancy, or if the patient becomes pregnant while taking belinostat, she should be counseled about the potential hazard to the fetus.9

Use in Specific Populations Pregnancy. Belinostat has been assigned pregnancy category D. Because it is a genotoxic drug and targets actively dividing cells, belin ostat may cause teratogenicity and/or embryofetal lethality. Women should avoid becoming pregnant while receiving belinostat.9 Nursing mothers. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing

infants from belinostat, either nursing or belinostat should be discontinued based on the importance of the drug to the mother.9 Pediatric use. The safety of belino stat in pediatric patients has not been established.9 Geriatric use. In the BELIEF clinical trial, approximately 50% of the patients were aged ≥65 years; these patients had a higher response rate to belinostat compared with patients aged <65 years (36% vs 16%, respectively). No meaningful differences in response rates were observed in patients aged ≥75 years compared with patients aged <75 years. No clinically meaningful differences in serious adverse reactions were observed based on patients’ age.9,10

The safety and efficacy of belino stat in combination with the CHOP regimen and with other agents are being explored for the treatment of patients with newly diagnosed PTCL and B-cell hematologic malignancies.11 The activity of belinostat is also being evaluated in solid tumors, including small-cell lung cancer.11 l

References

1. The Leukemia & Lymphoma Society. Peripheral T-cell lymphoma facts. Revised July 2014. www.lls.org/content/ nationalcontent/resourcecenter/freeeducationmaterials/ lymphoma/pdf/peripheraltcelllymphomafacts.pdf. Accessed August 13, 2014. 2. Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006;107:265-276. 3. Lymphoma Research Foundation. Peripheral T-cell lymphoma (PTCL). 2012. www.lymphoma.org/site/ pp.asp?c=bkLTKaOQLmK8E&b=6300159. Accessed August 13, 2014. 4. Foss FM, Zinzani PL, Vose JM, et al. Peripheral T-cell lymphoma. Blood. 2011;117:6756-6767. 5. Vose JM, Armitage J, Weisenburger D; for the International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/Tcell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26:4124-4130. 6. US Food and Drug Administration. FDA approves Adcetris to treat two types of lymphoma. Press release. August 19, 2011. www.fda.gov/NewsEvents/News room/PressAnnouncements/ucm268781.htm. Accessed August 14, 2014. 7. Potashman MH, Burudpakdee C, Wang W, et al. Clinical and economic burden of peripheral T-cell lymphoma in the United States. Blood. 2013;122. Abstract 2963. 8. US Food and Drug Administration. FDA approves Beleodaq to treat rare, aggressive form of non-Hodg kin lymphoma. Press release. July 3, 2014. www.fda. gov/newsevents/newsroom/pressannouncements/ucm 403929.htm. Accessed August 14, 2014. 9. Beleodaq (belinostat) for injection [prescribing information]. Irvine, CA: Spectrum Pharmaceuticals, Inc; July 2014. 10. O’Connor OA, Masszi T, Savage KJ, et al. Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): results from the BELIEF trial. J Clin Oncol (Meeting Abstracts). 2013;31(15 suppl). Abstract 8507. 11. ClinicalTrials.gov. Belinostat. Search results. http://clinicaltrials.gov/ct2/results?term=belinostat& Search= Search. Accessed August 15, 2014.

Conclusion Belinostat is an effective and safe treatment option for patients with relapsed or refractory PTCL. Belinostat joins pralatrexate and romidepsin as active single agents that are FDA approved for use in this rare and aggressive type of lymphoma. Similar to these previously approved agents, belinostat was approved under the FDA’s accelerated approval program based on surrogate end points. An improvement in survival or in disease-free survival has not yet been established for belinostat. Ongoing clinical trials may provide further survival outcomes. The relatively low incidence of myelosuppression that was observed with belinostat in patients with relapsed or refractory PTCL warrants further investigation of this drug in combination with other therapies.

Oncology Practice Management is now available online at: www.OncPracticeManagement.com

November 2014

www.OncPracticeManagement.com

NEW PHASE 3 DATA

IMBRUVICA® demonstrated single-agent survival in previously treated CLL INDICATIONS: IMBRUVICA® is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with: • Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy • CLL with 17p deletion

Significantly improved overall survival (OS)—secondary endpoint • 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA® arm (HR=0.43; 95% CI: 0.24, 0.79) • Median OS not yet reached in either treatment arm • 29% of ofatumumab patients crossed over to receive IMBRUVICA® upon progression

Significantly extended progression-free survival (PFS)—primary endpoint 78% statistically significant reduction in the risk of death or progression (independent review) 100

PFS (%)

80 60 40 Hazard ratio (HR) for progression or death: 0.22 (95% CI: 0.15, 0.32) P<0.0001 by log-rank test

20 0

183 161

116 83

Number at risk IMBRUVICA® 195 Ofatumumab 196

Months

Ofatumumab 9

38 15

7 1

0 0

Results from the randomized, multicenter, open-label, Phase 3 RESONATE™ trial of IMBRUVICA® vs ofatumumab in patients with previously treated CLL. Patients (N=391) were randomized 1:1 to receive either IMBRUVICA® 420 mg orally daily until disease progression or unacceptable toxicity or IV ofatumumab at an initial dose of 300 mg, followed 1 week later by a dose of 2000 mg weekly for 7 doses, and then every 4 weeks for 4 additional doses. Fifty-seven patients randomized to ofatumumab crossed over following Independent Review Committee-confirmed progression to receive IMBRUVICA®. Primary endpoint: PFS as assessed by an Independent Review Committee (IRC) according to modified International Workshop on CLL Criteria.

Significantly improved PFS in patients with previously treated del 17p CLL • 75% reduced risk of progression or death (HR=0.25; 95% CI: 0.14, 0.45) — Median PFS not reached with IMBRUVICA® vs 5.8 months with ofatumumab

In CLL studies, approximately 5% of patients discontinued due to adverse events Please review the Important Safety Information on adjacent page.

ORAL, ONCE-DAILY DOSING

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage - Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®. The mechanism for the bleeding events is not well understood. IMBRUVICA® may increase the risk of hemorrhage in patients receiving anti-platelet or anti-coagulant therapies. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding. Infections - Fatal and non-fatal infections have occurred with IMBRUVICA®. Twenty-six percent of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly. Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly. Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification. Second Primary Malignancies - Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%).

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA®. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. ADVERSE REACTIONS The most common adverse reactions (≥20%) in the clinical trials were thrombocytopenia (56%), neutropenia (51%), diarrhea (51%), anemia (37%), fatigue (28%), musculoskeletal pain (28%), upper respiratory tract infection (28%), rash (26%), nausea (25%), and pyrexia (24%). Approximately 5% of patients receiving IMBRUVICA® discontinued treatment due to adverse events. These included infections, subdural hematomas, and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. DRUG INTERACTIONS CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose. CYP3A Inducers - Avoid co-administration with strong CYP3A inducers. SPECIFIC POPULATIONS Hepatic Impairment - Avoid use in patients with baseline hepatic impairment. Please review the Brief Summary of full Prescribing Information on the following page.

To learn more, visit us at

www.IMBRUVICA.com

Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib) IMBRUVICA® (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Improvements in survival or disease-related symptoms have not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials [see Clinical Studies (14.1) in full Prescribing Information]. Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2) in full Prescribing Information]. Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in full Prescribing Information]. Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Twenty-five percent of patients with MCL and 26% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly. Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly. Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in full Prescribing Information]. Second Primary Malignancies: Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was nonmelanoma skin cancer (range, 4 to 8%). Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Cytopenias [see Warnings and Precautions] • Atrial Fibrillation [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.

IMBRUVICA® (ibrutinib) capsules The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2). The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1. Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) System Organ Class

Preferred Term

Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Infections and Upper respiratory tract infestations infection Urinary tract infection Pneumonia Skin infections Sinusitis Fatigue General disorders Peripheral edema and administrative Pyrexia site conditions Asthenia Skin and Bruising subcutaneous Rash tissue disorders Petechiae Musculoskeletal and Musculoskeletal pain Muscle spasms connective tissue Arthralgia disorders Respiratory, thoracic Dyspnea and mediastinal Cough disorders Epistaxis Metabolism and Decreased appetite nutrition disorders Dehydration Nervous system Dizziness disorders Headache Gastrointestinal disorders

All Grades Grade 3 or 4 (%) (%) 5 51 0 31 0 25 5 24 0 23 1 17 0 11 34 14 14 14 13 41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

0 3 7 5 1 5 3 1 3 0 3 0 1 0 0 4 0 0 2 4 0 0

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111)

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

Percent of Patients (N=111) All Grades Grade 3 or 4 (%) (%) 57 17 47 29 41 9

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included

IMBRUVICA® (ibrutinib) capsules

48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia. Approximately five percent of patients receiving IMBRUVICA in Study 1 and 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4.

Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1 System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions Skin and subcutaneous tissue disorders Respiratory, thoracic and mediastinal disorders Musculoskeletal and connective tissue disorders Nervous system disorders

Preferred Term Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection Fatigue Pyrexia Peripheral edema Asthenia Chills Bruising Rash Petechiae Cough Oropharyngeal pain Dyspnea Musculoskeletal pain Arthralgia Muscle spasms Dizziness Headache Peripheral neuropathy Decreased appetite

Metabolism and nutrition disorders Neoplasms benign, Second malignancies* malignant, unspecified Injury, poisoning Laceration and procedural complications Psychiatric disorders Anxiety Insomnia Vascular disorders Hypertension

All Grades Grade 3 or 4 (%) (%) 63 4 23 2 21 2 21 0 19 2 15 0 13 0 48 21 17 10 10 31 25 23 13 13 54 27 17 19 15 10 27 23 19 21 19 10 17

2 6 6 8 0 4 2 0 4 0 2 0 0 0 0 0 6 0 2 0 2 0 2

10*

10 10 17

0 0 8

*One patient death due to histiocytic sarcoma. Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

Percent of Patients (N=48) All Grades Grade 3 or 4 (%) (%) 71 10 54 27 44 0

* Based on laboratory measurements per IWCLL criteria and adverse reactions

Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2

System Organ Class ADR Term Gastrointestinal disorders Diarrhea Nausea Stomatitis* Constipation Vomiting General disorders and administration site conditions Fatigue Pyrexia Infections and infestations Upper respiratory tract infection Pneumonia* Sinusitis* Urinary tract infection Skin and subcutaneous tissue disorders Rash* Petechiae Bruising* Musculoskeletal and connective tissue disorders Musculoskeletal Pain* Arthralgia Nervous system disorders Headache Dizziness Injury, poisoning and procedural complications Contusion Eye disorders Vision blurred

IMBRUVICA Ofatumumab (N=195) (N=191) All Grades Grade 3 or 4 All Grades Grade 3 or 4 (%) (%) (%) (%)

48 26 17 15 14

4 2 1 0 0

18 18 6 9 6

2 0 1 0 1

28 24

2 2

30 15

2 1

16 15 11 10

1 10 1 4

11 13 6 5

2 9 0 1

24 14 12

3 0 0

13 1 1

0 0 0

14 11

1 0

6 5

0 0

Subjects with multiple events for a given ADR term are counted once only for each ADR term. The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms

IMBRUVICA® (ibrutinib) capsules Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2 IMBRUVICA Ofatumumab (N=195) (N=191) All Grades Grade 3 or 4 All Grades Grade 3 or 4 (%) (%) (%) (%) Neutrophils Decreased 51 23 57 26 Platelets Decreased 52 5 45 10 Hemoglobin Decreased 36 0 21 0 * Based on laboratory measurements per IWCLL criteria DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information]. CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions]. Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Nursing Mothers: It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65 versus 51% of younger patients) [see Clinical Studies (14.2) in full Prescribing Information].

IMBRUVICA® (ibrutinib) capsules Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions]. • Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions]. • Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions]. • Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions]. • Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions]. • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information]. • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information]. • Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration. Active ingredient made in China. Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA® is a registered trademark owned by Pharmacyclics, Inc. © Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 PRC-00524 07/14

Drug Coding Supplied by RJ Health Systems

FDA-Approved Medications Used for the Treatment of Prostate Cancer The following sections will assist healthcare professionals and payers by providing appropriate coding and billing information associated with the treatment of prostate cancer. The following sections include: • Associated ICD-9-CM codes used for the classification of prostate cancer • Drugs that have been FDA approved in the treatment of prostate cancer • Drugs that are Compendia-listed for off-label use for prostate cancer 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 prostate cancer: 185

Malignant neoplasm of prostate Excludes: seminal vesicles (187.8)

FDA approved for prostate cancer

Compendia off-label uses for prostate cancer

CPT ® administration codes

Generic (brand) name

HCPCS code – code description

abiraterone acetate (Zytiga)

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

√

N/A

abiraterone acetate (Zytiga)

C9399* – Unclassified drugs or biologicals (hospital outpatient use ONLY)

√

N/A

Bacillus CalmetteGuerin (Tice BCG)

90585 – Bacillus Calmette-Guerin (BCG) vaccine for tuberculosis, live, for percutaneous use

√

90471

Bacillus CalmetteGuerin (Tice BCG, TheraCys)

90586 – Bacillus Calmette-Guerin (BCG) vaccine for bladder cancer, live, for intravesical use

√

51720

Bacillus CalmetteGuerin (Tice BCG, TheraCys)

J9031 – BCG (intravesical), per installation

√

51720

bevacizumab (Avastin)

J9035 – Injection, bevacizumab, 10 mg

√

96413, 96415

bicalutamide (Casodex)

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

√

N/A

cabazitaxel (Jevtana)

J9043 – Injection, cabazitaxel, 1 mg

√

96413

cisplatin (Platinol-AQ)

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

√

96409, 96413, 96415

cyclophosphamide (Cytoxan)

J8530 – Cyclophosphamide, oral, 25 mg

√

N/A

November 2014

www.OncPracticeManagement.com

Drug Coding

FDA approved for prostate cancer

Compendia off-label uses for prostate cancer

CPT ® administration codes

√

96409, 96413, 96415

Generic (brand) name

HCPCS code – code description

cyclophosphamide (Cytoxan)

J9070 – Cyclophosphamide, 100 mg

degarelix (Firmagon)

J9155 – Injection, degarelix, 1 mg

dexamethasone (Decadron)

J8540 – Dexamethasone, oral, 0.25 mg

docetaxel (Taxotere, Docefrez)

J9171 – Injection, docetaxel, 1 mg

doxorubicin (Adriamycin)

J9000 – Injection, doxorubicin hydrochloride, 10 mg

enzalutamide (Xtandi)

C9399* – Unclassified drugs or biologicals (hospital outpatient use ONLY)

√

N/A

enzalutamide (Xtandi)

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

√

N/A

epirubicin (Ellence)

J9178 – Injection, epirubicin hydrochloride, 2 mg

estradiol valerate (Delestrogen)

J1380 – Injection, estradiol valerate, up to 10 mg

√

96372

estramustine (Emcyt)

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

√

N/A

estrogen (eg, estradiol, conjugated estrogen, esterified estrogen)

J8499* – Prescription drug, oral, nonchemotherapeutic, not otherwise specified

√

N/A

fluorouracil (Adrucil)

J9190 – Injection, fluorouracil, 500 mg

flutamide (Eulexin)

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

√

N/A

flutamide (Eulexin)

S0175 – Flutamide, oral, 125 mg

√

N/A

goserelin acetate (Zoladex)

J9202 – Goserelin acetate implant, per 3.6 mg

√

96372, 96402

histrelin (Vantas)

J9225 – Histrelin implant, 50 mg

√

11981, 11982, 11983

hydrocortisone (Solu-Cortef)

J1720 – Injection, hydrocortisone sodium succinate, up to 100 mg

√

96365, 96366, 96372, 96374

ixabepilone (Ixempra)

J9207 – Injection, ixabepilone, 1 mg

√

96413, 96415

ketoconazole (Nizoral)

J8499* – Prescription drug, oral, nonchemotherapeutic, not otherwise specified

√

N/A

leuprolide acetate (Eligard, Lupron Depot)

J9217 – Leuprolide acetate (for depot suspension), 7.5 mg

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

96402

√ √

96413

√ √

√

N/A

96409

96409, 96413

96409

96402

Drug Coding

FDA approved for prostate cancer

Compendia off-label uses for prostate cancer

CPT ® administration codes

Generic (brand) name

HCPCS code – code description

leuprolide acetate (Lupron)

J9218 – Leuprolide acetate, per 1 mg

medroxyprogesterone (Depo-Provera)

J1050 – Injection, medroxyprogesterone acetate, 1 mg

√

96402

melphalan (Alkeran)

J8600 – Melphalan, oral, 2 mg

√

N/A

melphalan (Alkeran)

J9245 – Injection, melphalan hydrochloride, 50 mg

√

96409, 96413

methylprednisolone (Medrol)

J7509 – Methylprednisolone, oral, per 4 mg

√

N/A

methylprednisolone (Depo-Medrol)

J1020 – Injection, methylprednisolone acetate, 20 mg

√

11900, 11901, 20600, 20605, 20610, 96372

methylprednisolone (Depo-Medrol)

J1030 – Injection, methylprednisolone acetate, 40 mg

√

11900, 11901, 20600, 20605, 20610, 96372

methylprednisolone (Depo-Medrol)

J1040 – Injection, methylprednisolone acetate, 80 mg

√

11900, 11901, 20600, 20605, 20610, 96372

methylprednisolone (Solu-Medrol)

J2920 – Injection, methylprednisolone sodium succinate, up to 40 mg

√

96365, 96366, 96372, 96374

methylprednisolone (Solu-Medrol)

J2930 – Injection, methylprednisolone sodium succinate, up to 125 mg

√

96365, 96366, 96372, 96374

mitoxantrone (Novantrone)

J9293 – Injection, mitoxantrone hydrochloride, per 5 mg

√

96409, 96413

nilutamide (Nilandron)

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

√

N/A

paclitaxel (Taxol)

J9265 – Injection, paclitaxel, 30 mg

√

96413, 96415

prednisolone (eg, Orapred, Millipred)

J7510 – Prednisolone, oral, per 5 mg

√

N/A

prednisone (Deltasone)

J7506 – Prednisone, oral, per 5 mg

√

N/A

radium Ra dichloride (Xofigo)

A9699 – Radiopharmaceutical, therapeutic, not otherwise classified

√

79101

radium Ra dichloride (Xofigo)

C9399* – Unclassified drugs or biologicals (hospital outpatient use ONLY)

√

79101

√

96413, 96415

sipuleucel-T (Provenge) Q2043 – Sipuleucel-T, minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF, including leukapheresis and all other preparatory procedures, per infusion (code price is per 250 mL) topotecan (Hycamtin)

96402

√

J9351 – Injection, topotecan, 0.1 mg

√

November 2014

96413

www.OncPracticeManagement.com

Drug Coding

Generic (brand) name

HCPCS code – code description

FDA approved for prostate cancer

trastuzumab (Herceptin) J9355 – Injection, trastuzumab, 10 mg

Compendia off-label uses for prostate cancer √

CPT ® administration codes 96413, 96415

triptorelin (Trelstar Depot, Trelstar LA)

J3315 – Injection, triptorelin pamoate, 3.75 mg

96372, 96402

vinBLAStine (Velban)

J9360 – Injection, vinblastine sulfate, 1 mg

√

96409

vinorelbine (Navelbine)

J9390 – Injection, vinorelbine tartrate, per 10 mg

√

96409

√

*When billing a nonclassified medication using a CMS 1500 claim form, you must include both the HCPCS code in Item 24D and the drug name, strength, and NDC (National Drug Code) in Item 19 or Item 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 2014 • Current Procedural Terminology (CPT ®) 2014 • CPT copyright 2014 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association • ICD-9-CM for Professionals Volumes 1 & 2, 2014 • 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) CPT ® indicates Current Procedural Terminology ; 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

ONCOLOGY PRACTICE MANAGEMENT

I November 2014

RJ Health Systems The Creators of ReimbursementCodes.com

RJ Health Systems â&#x20AC;&#x201D; the pharmaceutical specialists that healthcare professionals have turned to since 1983 for their drug information. We work with over 170 Payor organizations that touch approximately 110 million lives. RJ Health Systems has established and continuously maintains a Library of Drug Intelligence that provides the most comprehensive, trusted, and up-to-date coding and reimbursement information in the industry. 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. Please visit www.rjhealthsystems.com to learn more about our products and services listed below:

>> >> >> >> >> >> >> >> >>

ReimbursementCodes.com Drug Diagnosis Coding CMAC PartBorPartD.com NDC Conversion Database Min/Max Dosing Advisories Notations Clinical Consulting

rjhealthsystems.com