OPM April 2015 | Vol 5 | No 3

april 2015

www.OncPracticeManagement.com

Title

Volume 5 • Number 3

Oncology Practice Management ™

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

Need Imaging?

Communication Is Essential

By Karna Morrow, CPC, RCC, CCS-P, PCS

H

ealthcare continues to move rapidly toward the direction of more collaborative care, with patient care being coordinated among specialties and anchored by a primary care provider. The pace of this change, however, does not minimize the opportunity to improve key workflows, especially in the area of imaging.

Every oncology patient will at some point in their course of treatment require

Leveraging Data to Improve Cancer Care

By Rosemary Frei, MSc

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ig data has the power to significantly speed up the process from discovery to clinical adoption, according to a presentation at the Association of Community Cancer Centers 2015 Annual Meeting in Arlington, VA. Amy Abernethy, MD, PhD, Chief Medical Officer and Senior Vice President of Oncology, Flatiron Health, New York, NY, and Director, Duke

Cancer Care Research Program, Duke Cancer Institute, Durham, NC, first described an Amy Abernethy, encounter she had MD, PhD in 2009 while working in a melanoma clinic with an emergency department nurse named Janet, who presented with Stage IIIB melanoma.

Continued on page 10

Expert Urges Discussions with Patients About Treatment Costs

By Ellen Martin

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atients with cancer are paying more now for treatment than they ever have before, and are draining retirement savings, selling homes, and cutting back on essentials such as food and clothing to make ends meet, according to a recent presentation by S. Yousuf

Zafar, MD, MHS, at the Association of Community Cancer Centers 2015 Annual Meeting in Ar- S. Yousuf Zafar, MD, MHS lington, VA. Studies have shown that these circum-

Continued on page 18

Continued on page 12 From the publishers of

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM

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

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

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

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

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

For more information, visit GRANIXhcp.com.

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

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

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

4 CONTRAINDICATIONS None.

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

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

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

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

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

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

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

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian.

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

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

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

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

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

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

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

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

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day.

Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day.

This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

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

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

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

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

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

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

GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

Table of Contents

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

The Lynx Group

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

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April 2015 • Volume 5 • Number 3

Oncology Practice Management ™

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

From The Editor Climbing the Ladder to Tomorrow, One Rung at a Time...................... 8

By Dawn Holcombe, MBA, FACMPE, ACHE

Features Best Practices Need Imaging? Communication Is Essential........................................... 1

By Karna Morrow, CPC, RCC, CCS-P, PCS

Association of Community Cancer Centers Leveraging Data to Improve Cancer Care..........................................1

By Rosemary Frei, MSc

Expert Urges Discussions with Patients About Treatment Costs............ 1

By Ellen Martin

Payment Reform Congress Acts to Repeal SGR Formula..................................................... 9

By Gail Thompson

Perspective The Imperative to Discuss Cost of Care with Patients with Cancer

By Michael Kolodziej, MD, FACP............................................................................ 14

Gastrointestinal Cancers Symposium Cost of Regorafenib versus Benefit Analyzed in Patients with Metastatic Colorectal Cancer...............................................................20

By Chase Doyle

Interview with the Innovators Confirming Diagnoses and Identifying Biomarkers Linked to Targeted Treatments with the bioT3 Approach.................................32 Continued on page 6

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

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

Oncology Practice Management

I April 2015

New from Bayer HealthCare and Onyx Pharmaceuticals

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

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

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

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Printed in USA

Table of Contents

April 2015 • Volume 5 • Number 3

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

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

Publication of an advertisement or other product mentioned in Oncology Practice Management ™ should not be construed as an endorsement of the product or the manufacturer’s claims.

Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned.

Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

Oncology Practice Management ™

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

Continued from page 4

DEPARTMENTS Patient and Provider Access Bringing the Oncology Care Model into Focus................................... 22

By Leah Ralph

Wealth Management Why You Need Disability Insurance: A Doctor’s Story........................ 37

By Stuart E. Lowenkron, MD

Clinical Trial Tracker Clinical Trials Under Way for Patients with Renal-Cell Carcinoma.................................................................................................. 44 Drug Update Lenvima (Lenvatinib), a Multireceptor Tyrosine Kinase Inhibitor, Approved by the FDA for the Treatment of Patients with Differentiated Thyroid Cancer.................................................................. 50

By Loretta Fala

Drug Coding FDA-Approved Medications Used for the Treatment of Colorectal Cancer................................................................................ 56

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

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

Oncology Practice Management

I April 2015

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

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

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

Nancy G. Payne, CMPE Executive Director Space Coast Cancer Center Titusville, FL

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

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

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

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

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

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From the Editor

Climbing the Ladder to Tomorrow, One Rung at a Time

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

N

o matter how high you want to go, you have to step on that first rung of the ladder. Every oncology practice in the country is making plans to move forward in some direction, and will have to climb a ladder, one step at a time.

Oncology care is delivered in myriad formats and systems, including through private, hospital-based, academic, and even commercial centers.

There is not one “right” solution.

Each setting has already evolved in a certain direction, and many of the models being tried are geared toward specific formats or health systems; these may or may not be adaptable to other settings.

Many pilots and programs are currently being utilized in the oncology community, yet those involve only a minority of practices. We read articles and hear stories about payer– provider collaborations, episode-­ ofcare pilots, oncology medical home projects, and others. The reality is that there are more regions without active models than there are regions with pilot programs in place. There are also tens of thousands of medical directors of employers and regional health plans who are responsible for oncology policy and who have not yet had one conversation with an oncology group about oncology care.

There are hundreds of oncology practices that have not yet had one conversation with a payer beyond traditional contracting negotiations.

It is easy for very good practices struggling to keep up with the vicis-

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situdes of daily operations to wonder if they are behind, or missing out on something.

Those medical directors and practices are not behind—they are just budding opportunities waiting to happen. We are learning that getting to the point of executing some of these pilots is a lengthy process.

Those journeys start with an initial meeting, then progress through a delicate dance of mutual learning and understanding, and finally the slow blossoming of trust between providers and those who pay for medical services (eg, employers or health plans).

It is important to know that this process does take time, and that the initial meeting is going to be awkward. Payers and providers are both affected by oncology care choices, but in different ways, and both hold the needs of—and impact on—the patient as the highest priority. Too often, payer medical directors have little direct understanding of oncology as a specialty. However, they will have opinions and concerns regarding the treatment of cancer.

Too often the first inclination of the provider preparing for that first meeting is to develop a litany of their own concerns, or examples of where payments are underwater or need to be increased. This is not a good conversation for the first meeting. A better strategy for all involved is to make the initial meeting last ≤1 hour, and to spend that time listening to each other and finding mutual ground.

Hot-button issues should be identified for the payer or employer, and the practice should express its interest and value as a partner and resource regarding oncology issues. These are

Oncology Practice Management

I April 2015

the building blocks of a relationship, and the essential first rung on the ladder toward collaboration and mutually supported oncology management for patients in the local market.

It is often useful to engage a neutral facilitator with a solid understanding and credibility in both the payer and oncology markets to help prepare for the first few meetings.

At the next meeting, both parties should come prepared with data they would like to share, based on the direction provided by earlier discussions. From these and subsequent discussions, projects, and eventually pilots, will evolve. These early meetings are not the time to jump into plans for oncology medical homes or episodic care payments. Those are far more complicated models that will evolve as possible solutions down the road, once a good relationship has been established.

If your group is watching the news and conference discussions about oncology medical homes or other pilot and payment reform models, and is not one of the early participants, take a deep breath. Watch and learn from the presentations, and start to evaluate what changes you would like to adopt in your own practice to prepare for eventual participation.

Then, stop and look at your own local market. What is going on?

Who are the top 3 to 5 business groups, employers, or health plans with whom you would like to develop a closer relationship? What can you offer them as a resource on cancer? Reach out to them and listen.

You will have just completed the first rung on the ladder toward your own local oncology market reform, and it is a strong start. l

Payment Reform

Congress Acts to Repeal SGR Formula

By Gail Thompson

T

he verdict is in: Congress has passed legislation to permanently repeal Medicare’s sustainable growth rate (SGR) formula.

The bill was approved by the US House of Representatives on March 26, and the 92-8 vote in the US Senate on April 14 now puts the legislation in the hands of President Barack Obama, who is expected to sign it. The $200-billion deal staves off a 21.2% cut to Medicare payment rates and extends the Children’s Health Insurance Program (CHIP) while repealing the nearly 20-yearold formula.

After the US House of Representatives passed the bipartisan SGR legislation on March 26, pressure then mounted on members of the Senate to sign and approve the deal as well before leaving on spring break. The March 31 deadline to

pass the bill came and went, however, with members of Congress heading home for a 2-week holiday recess.

Prominent senators shared their optimism that the issue would be addressed upon their April 13 return, although practice managers and administrators, wary from past experience, remain cautious.

A patch enacted in 2014 to the SGR formula expired on March 31, and, had the legislation not passed, the Centers for Medicare & Medicaid Services (CMS) would have been required to proceed as if the 21.2% cuts to Medicare payments had taken effect. Under current law, however, it would not actually have had to pay out April 1 claims under any fee schedule until April 14 at the earliest. In the past, CMS has also held claims for longer than the 14 days in anticipation of congressional

action on the SGR formula.

Medicare had been required to annually publish the Medicare conversion factor, the SGR update, and allowed expenditures for physicians’ services for the upcoming year. For years, the rise in physician services expenditures had resulted in an ever-increasing SGR correction against the targeted expenditures, and an annual announcement of a double-digit reduction in physician services rates—21.2% this year—scheduled for each April 1. Each year, the medical community has risen up, decrying the unsustainability of double-digit rate reductions in the physician fee schedule. l This is a developing story. Please visit www.OncPracticeManagement.com or see our upcoming May issue for more information.

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Association of Community Cancer Centers

Leveraging Data to Improve... Continued from the cover “We could predict her risk of death pretty well. I could say, ‘Well, you’ve got red hair and you look kind of Irish, but I don’t even know the number of patients in clinical trials who had backgrounds similar to yours or personal characteristics that are just like yours,’” recalled Dr Abernethy. “She wanted to help others. But her story—because she wasn’t in a clinical trial or an observational study—does not get entered into the data record forever for the future, nor can all of those stories of taking care of patients like Janet inform the care of other Janets in the future.”

In addition to this challenge, she noted other data challenges, including the fact that electronic health records don’t sync up with each other, and that even within electronic medical records (EMRs), much of the data is unstructured.

As conversations continue across healthcare about how to optimize healthcare delivery, improve quality and effectiveness, and tap into personalized medicine, Dr Abernethy said, a common theme emerges.

“Fundamentally, it’s about creating a foundation of linked, patient-level data that can be analyzed and reanalyzed, used and reused, to solve all these problems simultaneously,” Dr Abernethy said. “We’ve had this conversation for quite a while. How can we build this data substrate, this foundation of consistent information that we can draw upon?”

To help solve this problem, Flatiron has partnered with community oncology practices to have all patient-related information stored in a common, cloud-based database called OncoEMR. In addition, the company’s OncoAnalytics platform can be used to gather and parse clinical practice data. Approximately 220 cancer centers use these tools, with 1750 clinicians and 725,000

melanoma, adding unstructured data abstraction to information gleaned from the EMR resulted in 100% completeness of the records for whether the patients had a metastatic diagnosis, their testing status for BRAF mutation, and the date of that testing, along with results from those who were tested.

The software suites also can enable higher accuracy in, for example, finding patients with a particular diagnosis in a patient cohort. A search “We’ve had this can first be performed for patients conversation for quite a with relevant codes from the International Classification of Diseases, Ninth while. How can we Revision; chart data gathered via abbuild this data substrate, straction can be added to find other patients with the same specific conthis foundation of dition. This approach yields lower consistent information rates of false-positives and false-negathat we can draw tives, according to Dr Abernethy.

“Getting to a right group of paupon?” tients and having data to help dis—Amy Abernethy, MD, PhD cern the right cohort of patients is critically important for all of the questions in front of us, not just acapatients with active cancer in the demic questions,” she added.

Flatiron Health Cancer Center NetOne example is her team’s effort work, she reported. to bring together experts from many The systems normalize and har- disciplines to map patterns of cancer monize structured data into a com- treatments, including which medicamon data model to assemble consis- tions are used most commonly as tent patient information for each of first-line, second-line, and third-line the many patients in the network. therapy, she said. They can also reThey also uniformly cull and catego- fine the analyses by adding data, for rize the key pieces of unstructured example, on which patients receivinformation for each patient. ing each type of treatment have “This process then allows us to mutated or wild-type BRAF. pull out key data points that, as canAnother facet of the technolocer care providers, we know we need gies’ potential is to create dashto have; biomarkers, staging infor- boards and reports for practice manmation, performance status, smoking agement. These can highlight such status,” noted Dr Abernethy. “We information as how many patients call that, at Flatiron, technology-­ have not yet had their tumors enabled abstraction.” staged, or how many patients in Users could then “build [com- each practice location are on treatplete] individual patient journeys ments and what the associated that reflect what happened to the charges and revenues are, said Dr individual across time,” she said. For Abernethy. Practice administrators example, in a set of patients with could also sort the patient populaContinued on page 13

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Oncology Practice Management

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Oncology

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Association of Community Cancer Centers

Expert Urges Discussions with Patients... Continued from the cover stances affect patient well-being, quality of life, and adherence, said Dr Zafar, Associate Professor of Medicine, Duke University Medical School, Duke Cancer Center, Durham, NC, and providers should be taking steps now to address this issue of financial toxicity with their patients.

“As you think about the physical toxicity of your patients, and how we engage our patients on physical toxicity, also consider their financial toxicity,” Dr Zafar told the audience.

“The time has come to stop describing this problem of financial toxicity.

Now we need to start intervening.”

To demonstrate his point, Dr Zafar shared a case study about a male patient who was diagnosed with localized rectal cancer at a young age.

Although the patient was insured, he did not have prescription drug coverage, and had paid for his oral chemotherapy out of pocket. He tolerated treatment well, and did not demonstrate physical toxicities associated with his treatment. However, at the end of his treatment, his cancer had metastasized.

At first unaware of his patient’s coverage status, Dr Zafar discussed further treatment options with the patient, and was surprised and concerned when the patient expressed hesitation about moving forward.

When pressed, the patient explained that he did not have pre-

scription drug coverage, and had incurred substantial debt to pay for his oral chemotherapy.

“He had a job, and he had insurance, but he had no prescription drug coverage,” Dr Zafar said. “He paid for all that medicine fully out of pocket. Because I didn’t ask him

Patients with cancer are paying more now for treatment than they ever have before, and are draining retirement savings, selling homes, and cutting back on essentials such as food and clothing to make ends meet. the simple question of whether he has prescription drug coverage, I caused him to incur thousands of dollars in medical debt.

This patient taught me an impor­ tant lesson, and that lesson is that it’s very difficult to identify patients who are at risk of financial toxicity.”

Dr Zafar cited 2 reasons why patients may be paying more now for their cancer therapies than they used to: the cost of treatment has increased substantially over the past several years, and the amount that patients are asked to pay toward the cost of their treatment (ie, cost-sharing) has also increased. More specifically, he noted that the price of 1

KEY POINTS n Treatment costs affect patient well-being, quality of life, and adherence n The price of 1 month of chemotherapy has jumped from roughly $100 in 1970 to $10,000 in 2010 n Referring the patient to assistance programs or a financial counselor may be enough to help reduce costs without affecting the course of treatment n Consider financial toxicity as an important part of the treatment discussion, and be open to broaching a discussion with patients about costs of care.

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month of chemotherapy has jumped from roughly $100 in 1970 to $10,000 in 2010,1 and a survey from the Kaiser Family Foundation documented that deductibles, premiums, and worker contributions to premiums have been rising sharply since 1999.2 In addition, a connection be-

Oncology Practice Management

I April 2015

tween high out-of-pocket costs and nonadherence to prescription medicine—for example, patients not taking their drugs as prescribed, filling part of their prescriptions, or not filling their prescriptions at all, in order to save money—is documented in the literature, he said.

“Then there’s the form of cost-sharing that I think is most relevant to our patients, and that’s tiered formularies,” said Dr Zafar.

“Cancer patients have no choice but to reach for that top-shelf drug. As a result, they incur more costs out-ofpocket for a drug that is potentially life-saving and that patients are on for years.”

A significant part of the remedy, he believes, involves educating the patient population; this includes educating them on basic concepts about health insurance and healthcare such as copays and deductibles; and educating them about their diagnosis, prognosis, and treatment options. It is also important, he said, to look at the costs of treatment as well as new payment models. Finally, it is essential for providers to open the discussion with patients about costs.

Acknowledging that oncologists

Association of Community Cancer Centers

Leveraging Data to Improve... Continued from page 10 tion by individual diseases and the treatments being used for them. She added that “unstructured data could be overlaid on top of that” structured data.

The data can also be used to facilitate quality monitoring (eg, examining which patients are receiving the appropriate treatments based on their individual characteristics, including risk factors for adverse events and contraindications). Another use of the data is to support “discovery sciences” such as bioassessments and clinical annotations, and also to help practices identify which patients might be eligible for particular clinical trials.

“My point today is that Janet gave me a very, very strict task in 2009; she said, ‘Don’t let my story go

work that we do, nor the assessment of the work,” said Dr Abernethy.

“By partnering with you, and with

Dashboards and reports can highlight such information as how many patients have not yet had their tumors staged, or how many patients in each practice location are on treatments and what the associated charges and revenues are. away.’ I think that one of the things that we all see in clinical practice is the stories of the patients that we’re caring for shouldn’t go away, nor the

more and more insights about what tools will make us smarter in the future, we’ll be able to do this more and more.” l

Expert Urges Discussions with Patients... Continued from page 12 have a lot to cover during a patient’s appointment, he advised that referring the patient to assistance programs or a financial counselor may be enough to help reduce costs without affecting the course of treatment.

“The important thing I tell oncologists is that we’re not alone in this.

We have a lot of people we can turn to who can help patients find the resources,” he said. “But it is often our job to take that first step and let patients know that this is okay to talk about. Otherwise they may never do it.”

Dr Zafar also described a system he helped design called FinANCE— Financial Assistance, Navigation, and Communication Education— that focuses on educating patients about healthcare and finances. This includes video-based and interactive content on how patients can talk to healthcare providers about cost containment and resources for financial assistance, as well as a screening tool for financial distress.

A pilot test of 15 patients with cancer who were randomized to use

most all of those using the system reported that it improved their knowledge about financial aspects of cancer care and what can be done about it. His team aims to engage financial counselors as well as more providers in the discussion of costs.

Dr Zafar urged the audience to consider financial toxicity as an important part of the treatment discussion, and to be open to broaching a discussion with patients about the costs of care. Noting conversations he has had with financial counselors and social workers who help patients with cancer, he said, “It is much easier to help a patient find financial resources before they incur medical debt than it is to dig them out of that debt. We need to identify patients, and we need to identify them early.” l

“It is much easier to help a patient find financial resources before they incur medical debt than it is to dig them out of that debt.”

—S. Yousuf Zafar, MD, MHS

References

1. Memorial Sloan Kettering Cancer Center. Center for Health Policy & Outcomes. Cost of cancer drugs. www.mskcc.org/research/health-policy-outcomes/costdrugs. Accessed April 8, 2015.

2. The Henry J. Kaiser Family Foundation. 2013 Employer Health Benefits Survey. http://kff.org/privateinsurance/report/2013-employer-health-benefits/. Published August 20, 2013. Accessed April 8, 2015.

FinANCE and another 15 controls showed that the majority of those using FinANCE found it helped with their financial concerns, reported Dr Zafar. Furthermore, al-

April 2015

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Perspective

The Imperative to Discuss Cost of Care with Patients with Cancer

By Michael Kolodziej, MD, FACP, National Medical Director for Oncology Solutions, Aetna

I

grew up in a lower middle class household. My dad was an insurance salesman, and we needed to live within a budget. The thought that we might buy something without considering the cost was unfathomable. As a doctor now, I wonder how we expect our patients to make healthcare purchases without this information. Why do we need to even justify discussing cost with patients?

For a long time, patients have been insulated from the total cost of healthcare. Employer-subsidized health insurance, which came into its own after World War II, has been the predominant mechanism by which working-age Americans obtain healthcare. Employers historically paid the majority of the premium costs. Patients historically paid a portion of the premium, a modest deductible, and a copay and/or coinsurance in return for healthcare services and treatments. Medicare beneficiaries have been responsible for a 20% coinsurance for Medicare Part B benefits. Unless the cost of care became so great that it approached the maximum benefit, few people paid attention.

To make things more confusing, healthcare continues to be billed separately by each provider in a byzantine array of charges and discounts.

An explanation-of-benefits form may outline the majority of the costs, although most people cannot really understand these documents.

But healthcare insurance is changing. The financial stability of families, employers, and the government is impacted by escalating, unsustainable healthcare costs. The patient has much more financial responsibility and risk in the new healthcare system. Many employers who remain

committed to providing healthcare benefits have shifted financial responsibility to their employees. More of the premium cost is now borne by the employee. In addition, employ-

does all of this mean? Patients are feeling it in the pocketbook.

Patients with cancer are a special high-cost group. Active treatment is expensive. The deductible is almost always met in the first month of therapy. Coinsurance of many high-cost services requires that patients pay more out of pocket. Specialty pharmacy is especially expensive. Most patients are totally unprepared for these expenses, and many cannot afford them. Medical costs are now the most common cause of personal bankruptcy. Growing evidence (and common sense) suggests that concerns regarding cost of care have a significant impact on patient quality

Healthcare insurance is changing. The financial stability of families, employers, and the government is impacted by escalating, unsustainable healthcare costs. The patient has much more financial responsibility and risk in the new healthcare system. ees are responsible for more out-ofpocket expenses through higher deductibles, coinsurance, and copays.

Health plans have aggressively implemented solutions to help control these rising costs, such as creating networks of high-value providers and tiering pharmacy benefits. Medicare is also exploring novel delivery methods to increase value. The emergence of health exchanges has also aided a new influx of patients with insurance benefit designs that build on highly managed care to optimize value and benefit. Many of the plans include high deductibles and high copays. What

of life. This is such a widely recognized problem that it has even earned a name: â&#x20AC;&#x153;financial toxicity.â&#x20AC;?

In general, oncologists have been ill-equipped to manage this type of toxicity. Most physicians have a fundamental understanding of health insurance, but they do not always understand the difference between Medicare Part A, B, C, and D, or the relationship among patientsâ&#x20AC;&#x2122; deductibles, coinsurance, and copays. And in oncology, they almost never really know the cost of the treatment plan they recommend. They may know in a qualitative way what is expensive, Continued on page 16

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Oncology Practice Management

I April 2015

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Perspective

The Imperative to Discuss Cost of Care... Continued from page 14 and what is really expensive, but when the incredible variety of insurance benefit designs is added, they are incapable of providing even a ballpark quantitative estimate.

Many practices offer financial counseling services, which do allow patients the opportunity to review out-of-pocket costs after a plan has been formulated. But only in cases where patients really cannot afford the expense is this plan changed.

After all, patients trust that the doctor recommended the best personalized plan.

This view of the oncology world is wrong. There are many factors that contribute to a particular treatment plan, including efficacy and toxicity.

Cost should be one of them. This is

By the Numbers $124.6 billion

Estimated US cancer care expenditures in 2010

$134.8 billion

Mortality cost from the approximate 600,000 cancer deaths in 2005

$158 billion

Projected cost of cancer care by 2020 Source: National Cancer Institute.

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especially true when there are a number of equivalent options. Honesty and a fair presentation of effica-

the economics of healthcare. Less than 15% of oncologists will pursue academic careers, and the rest will be

Attention to cost is a patient-centric approach.

Patients must plan for out-of-pocket costs. Cost and quality should be discussed transparently with patients as a component of shared decisionmaking. Ignorance on the part of the physician is not an excuse. cy, toxicity, as well as cost is the moral responsibility of the physician.

Several immediate actions will help to achieve evaluation and transparency of costs. First, physicians need to have access to the cost of care at the point of care. Several electronic medical record systems and clinical pathway tools are offering this information now. Second, physicians need to be educated about the “value” of the many options available to patients. In other words, they need to understand the quality of care provided for the costs. The National Comprehensive Cancer Network and the American Society of Clinical Oncology have projects to objectively pre­ sent this information to oncologists.

Finally, medical students, residents, and fellows need education in

Oncology Practice Management

I April 2015

directly impacted by how healthcare is paid for in this country. Doctors are responsible for discussing how healthcare decisions affect the whole patient, and our next generation of physicians should learn this at the same time they learn to read electrocardiograms.

Attention to cost is a patient-centric approach. Patients must plan for out-of-pocket costs. Cost and quality should be discussed transparently with patients as a component of shared decision-making. Ignorance on the part of the physician is not an excuse. When patients can make decisions that are informed by all aspects of their care—from risks to benefits to costs—they will have more confidence in their path and with the physician guiding their care. l

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

Network with your oncology navigation team at the

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

“

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

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

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

Special Session in Partnership with the Association for Oncology Practice Management

Value-Based Strategies for Navigation

with:

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

Meeting Topics Include:

Who Should Attend:

Best practices in navigation

Continuing education units

Oncology nurse navigators

Oncology social workers

Nuances in providing valuebased care in oncology

Psychosocial care for cancer patients

Practice managers

Administrators

Impact of prehabilitation and rehabilitation

Commission on Cancer case studies

Financial Counselors

Case managers

Survivorship

Networking opportunities

Patient or non-clinically licensed navigators

Oncology nurses and nurse practitioners

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

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Best Practices

Need Imaging? Communication Is... Continued from the cover imaging services. As such, the workflow between an oncology practice and an imaging center or facility, and the accurate documentation of medication necessity, has a significant impact on 2 elements of value to every practice: time and patient satisfaction.

First, every practice values time.

The patient encounter is a welltuned process. Every effort is made to reduce additional phone calls for administrative tasks. But take a quick poll: how many times in a given day does the imaging center, or billing office for the imaging center, reach out to your clinical staff for more information? How often is a request made for a new or revised order?

How often is any other communication made that disrupts that welltuned process?

Second, every practice values patient satisfaction. One quick path to dissatisfaction is delayed or denied insurance claims, resulting in even higher balances on patient accounts.

When patients are sent for imaging studies that are essential to their treatment plan, they trust that the communication between your practice and the imaging center will address what the insurance company needs to process and pay the claim.

How are claims processing or charge capture challenges of the imaging facility your problem? After all, these stumbling blocks likely will not affect whether you get paid for your services. They will, however, affect a key component, and true focus, of your practice: the patient. Denial letters from insurance companies are stressful. Statements for past-due im-

The workflow between an oncology practice and an imaging center or facility, and the accurate documentation of medication necessity, has a significant impact on 2 elements of value to every practice: time and patient satisfaction. aging charges are stressful. Delays in preauthorization or denied authorizations for key imaging studies are stressful. Stressed patients usually are not satisfied patients.

What can you do to improve the process between your practice and the imaging department? Accurate communication of medical necessity is essential. Every corner of healthcare is now highlighting medical necessity, and when you clearly com-

KEY POINTS n Centers for Medicare & Medicaid Services’ current coverage guidelines allow for only 3 subsequent imaging scans per cancer site; if the patient has >1 type of cancer, there is a separate 3-scan limit for each cancer n When the clinical indication on the order is limited to the patient’s primary cancer (eg, lung cancer, breast cancer) without sharing the rest of the story, or scans are considered to be subsequent when they really are not, 2 valuable goals—time and satisfaction—are at risk n A history of cancer may be interpreted differently by various agencies that may use an insurance database for myriad reasons (ie, research, life insurance policies, commercial driver’s license) n Accurately demonstrating medical necessity for each and every order today will minimize additional phone calls between practices, as well as delayed or denied claims.

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municate why the imaging is needed, you improve the process for your office and your patient.

The communication tool between your practice and the imaging center is the order or requisition form.

Whether this communication tool is a piece of paper or a computer screen, it is worth considering the rest of the sentence regarding a positron emis-

Oncology Practice Management

I April 2015

sion tomography (PET) and computed tomography (CT) order, “We are requesting a PET/CT because....”

A PET/CT is the perfect place to start thinking about medical necessity. The Centers for Medicare & Medicaid Services’ current coverage guidelines allow for only 3 subsequent imaging scans per cancer site.

If the patient has >1 type of cancer, there is a separate 3-scan limit for each cancer. A subsequent scan is ordered by stating “restaging” or checking the box on the requisition form for “subsequent scan.” The imaging is needed because information is needed to determine the next step in a treatment course.

Think about a patient who has been treated for colon cancer. At some point in the treatment course, it is determined that the patient has also developed lung cancer. Is this scan really to determine the next step for the colon cancer? It is easy to categorize the patient with the first malignancy, and no one is questioning that the patient still has that malignancy, but this scan is

Best Practices

ordered because an initial strategy is needed for the new lung cancer— a new initial strategy that will not, however, take away from the 3-scan limit for the colon cancer. Answering accurately for the specific scan will ensure that the patient’s benefits are appropriately applied.

Remember, subsequent scans are very different from a scan ordered after a period of watchful waiting for recurrence. They are also different than scans ordered for surveillance purposes in a patient with previously treated cancer who has no clinical evidence to suggest active disease.

When the clinical indication on the order is limited to the patient’s primary cancer (eg, lung cancer, breast cancer) without sharing the rest of the story, or scans are considered to be subsequent when they really are not, 2 valuable goals—time and satisfaction—are at risk.

Consider an order requesting magnetic resonance imaging of the brain because of breast cancer. Perhaps this is the reason, but it is possible that there is another part to the story. The patient does have a primary malignancy, but is the imaging really being ordered because of a concern for metastatic disease in relation to the patient’s presenting signs and symptoms? Although you cannot assign a diagnosis to “rule out” metastatic disease, codes can be assigned for the variety of signs and symptoms (ie, headaches, blurred vision, slurred

speech) that are associated with that metastasis. In that setting, the primary malignancy becomes a secondary diagnosis supporting the complexity

cised/eradicated, (2) the primary site is no longer being treated, and (3) there is no evidence of remaining cancer at that primary site.

The term “history of” can be applied differently between a cancer center and the imaging center; the term is also reported differently to an insurance payer.

—Karna Morrow, CPC, RCC, CCS-P, PCS

of the case. Sharing a full clinical picture may also support the frequency at which scans may be requested (eg, because this patient has a complicated personal and family history of related cancers, and because the patient has had multiple treatment courses still without resolution).

The term “history of ” can be applied differently between a cancer center and the imaging center; the term is also reported differently to an insurance payer. A history of cancer may also, in turn, be interpreted differently by various agencies that may use an insurance database for myriad reasons (ie, research, life insurance policies, or commercial driver’s license). The patient may have a clinical history of prostate cancer, but the phrase “history of ” should only be used in an imaging requisition when (1) the primary site is ex-

April 2015

Unlike clinical protocols, there is no specific time frame for the cancer to be reported as “history of ” to an insurance payer. If the primary site is excised, there is no evidence of disease remaining at that site, and the patient elects to forego further treatment, the condition may be reported as “history of prostate cancer” within months of the biopsy.

Implementing the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10CM) will also directly impact the clinical data shared between the oncology practice and the imaging center. Accurately demonstrating medical necessity for each and every order today will minimize additional phone calls between practices, as well as the delayed or denied claims, as we move toward ICD-10-CM implementation on October 1. l

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Gastrointestinal Cancers Symposium

Cost of Regorafenib versus Benefit Analyzed in Patients with Metastatic Colorectal Cancer

By Chase Doyle

A

ccording to a recent cost-effectiveness analysis, thirdline therapy with regorafenib (Stivarga) in patients with previously treated metastatic colorectal cancer (CRC) far ­exceeded accepted willingness-to-pay thresholds based on incremental cost-effectiveness ratio (ICER) and quality-adjusted life-years (QALYs).

Presented at the 2015 Gastrointestinal Cancers Symposium, the results showed that regorafenib provided an additional 0.04 QALYs, at a cost of $39,391.

note its considerable side-effect profile and high cost.

“It has a lot of side effects—handfoot syndrome, fatigue, diarrhea— and patients who have already received 2 lines of treatment are often not in a high enough performance status to receive it,” he said.

In addition, when it is administered, there are extraordinary costs to payers. Citing the lack of any published US-based cost-effectiveness studies of regorafenib for the treatment of metastatic colorectal cancer, Dr Goldstein’s outcomes

“If there is not a precise number for willingness-­to-­ pay value, it’s been approximated in the past at around $50,000 per QALY, perhaps $100,000 per QALY, and maybe even $150,000 per QALY, but this number of $900,000 per QALY is way above that benchmark value.”

—Daniel A. Goldstein, MD

“The incremental cost-effectiveness ratio was almost $900,000 per QALY, which is way above the benchmark value,” said Daniel A. Goldstein, MD, Hematology Oncology Fellow at the Winship Cancer Institute, Emory University, Atlanta. “Basically, you’re not getting a lot of bang for your buck.”

Regorafenib was approved by the FDA in 2012 for patients with CRC and is now the standard of care as third-line therapy in patients with metastatic CRC, improving the median overall survival by only 1.4 months. Dr Goldstein was quick to

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were obtained by merging publicly available clinical trial data with publicly available cost data for Medicare.

According to estimates from the Centers for Medicare & Medicaid Services, the base-case value for the drug was $11,364 per cycle. (The drug is administered on the first 21 days of a 28-day cycle.) The management of adverse events included in Dr Goldstein’s assessment was based on accepted standards.

“We used the CORRECT trial data that were published for patients who were treated with regorafenib versus placebo in a third-

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I April 2015

line setting,” said Dr Goldstein, “and they found that regorafenib had a 6-week median overall survival benefit. And so, when you incorporate quality-adjusted life-years into that, because the quality of life for patients who are in third-line treatment is not great, the drug provided patients only 0.04 quality-adjusted life-years gained.”

And those 0.04 QALYs proved costly. Including adverse events, the price of regorafenib equaled $39,391 for the total treatment duration.

“In all 1-way sensitivity analyses,” noted Dr Goldstein, “the ICER of regorafenib was greater than $700,000 per QALY. And the ICER of regorafenib was greater than $200,000 per QALY in more than 99% of probabilistic sensitivity analyses.”

At a willingness-to-pay threshold of $100,000 per QALY, the use of regorafenib in patients with previously treated metastatic CRC is not cost-­effective.

“If there is not a precise number for willingness-to-pay value, it’s been approximated in the past at around $50,000 per QALY, perhaps $100,000 per QALY, and maybe even $150,000 per QALY,” emphasized Dr Goldstein, “but this number of $900,000 per QALY is way above that benchmark value….It’s the highest number I’ve ever seen in any of my personal studies.”

When asked whether this drug is still used at Emory, Dr Goldstein acknowledged, “When we do have patients who have run out of all FDA-approved options, we may offer this drug, although, admittedly, it doesn’t have that much benefit in unselected patients.” l

ACCC: MEETING YOUR NEEDS Gear up for a full menu of meetings with need-to-know information for the entire cancer care team. Don’t miss out on unparalleled opportunities to advance your learning in critical areas, and earn CE credits. Be sure to share this information with your colleagues who can benefit from these events.

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FINANCIAL ADVOCACY REGIONAL MEETINGS

ONCOLOGY REIMBURSEMENT MEETINGS

Bridging the Gap between Patient Needs and Financial Resources These FREE one-day meetings help sharpen the skills and knowledge base of financial advocates.

Any member of the cancer care team who deals with oncology business and reimbursement will benefit from these FREE one-day meetings. Gain a fullspectrum perspective with sessions on payment reform; the latest trends in coding and billing; proper management of financial data; and the practical application of radiation oncology CPT codes.

Tuesday, May 5, 2015 Tampa, Florida

Tuesday, June 2, 2015 Silver Spring, Maryland

Tuesday, June 23, 2015

Thursday, April 16, 2015

Burlingame, California

Chicago, Illinois

Tuesday, April 28, 2015 Raleigh, North Carolina

Tuesday, May 19, 2015 Scottsdale, Arizona

ONCOLOGY PHARMACY EDUCATION NETWORK REGIONAL MEETINGS

Tuesday, August 25, 2015 Indianapolis, Indiana

Tuesday, November 17, 2015 Boston, Massachusetts

These two-day meetings provide take-away tools and information to oncology pharmacists and members of the cancer care team in pharmacy operations.

Thursday, December 10, 2015 Birmingham, Alabama

May 15–16, 2015 New Brunswick, New Jersey

June 26–27, 2015

32ND NATIONAL ONCOLOGY CONFERENCE

Fort Lauderdale, Florida

July 10–11, 2015 Charlotte, North Carolina

Stay Tuned!

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

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

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

Patient and Provider Access

Bringing the Oncology Care Model into Focus

By Leah Ralph, Manager, Provider Economics and Public Policy, Association of Community Cancer Centers

O

n February 12, the US Department of Health & Human Services announced its much-anticipated Oncology Care Model, developed by the Centers for Medicare & Medicaid (CMS) Innovation Center as part of the broader effort to lower healthcare costs and tie reimbursement to quality and value. The Association of Community Cancer Centers has been conducting an in-depth analysis, and the model generally looks similar to the discussion draft made available in August last year; although the model contains many positive elements, many questions still remain.

At its core, the Oncology Care Model looks similar to a patient-­ centered oncology medical home or accountable care organization, with a target expenditure and shared savings component that encompasses the total cost of patient care during a particular period of treatment.

The model is a voluntary, 5-year program slated to begin in spring 2016. Physician group practices, hospital-based practices (except for prospective payment system–exempt hospitals), and solo practitioners who furnish cancer chemotherapy are eligible to participate.

Payments will be based on a 6-month episode of chemotherapy treatment that is triggered by the administration of a preset list of chemotherapy drugs, and will take into account all Part A and Part B, and some Part D expenditures for that patient during the episode. In addition to a fee-for-service payment, providers will receive a care coordination payment to improve quality of care ($160 per patient, per month during the episode) and, to incentivize lower costs, a perfor-

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mance-based payment that will be based on the difference between a risk-adjusted target price and actual expenditures during the episode.

The payment arrangement is 1-sided risk, with the option of converting to a 2-sided risk in the third year.

quirements, including effective use of electronic health records, providing 24-hour access to practitioners who can consult the patient’s medical record in real time, developing comprehensive patient care plans, offering patient navigation services, and targeting continuous quality improvement.

Although we were pleased to see much of the Association of Community Cancer Centers’ feedback incorporated into the final version of this model—and we appreciated the opportunity to provide meaningful input before the model was finalized—our dialogue with CMS is ongoing. Our members continue to have questions about the benchmarking methodology, specifics on

At its core, the Oncology Care Model looks similar to a patient-centered oncology medical home or accountable care organization, with a target expenditure and shared savings component that encompasses the total cost of patient care during a particular period of treatment.

Importantly, the care model is a multipayer model in which commercial payers and state Medicaid agencies are encouraged to participate. Aligning financial incentives by engaging multiple payers will leverage the opportunity to transform oncology care across a broader population. During its process of selecting practices to participate, CMS will favor those that participate with other payers in addition to Medicare. Practices will also have to meet certain quality metrics and undergo practice transformation re-

Oncology Practice Management

I April 2015

the quality metrics and practice transformation requirements, eligibility to participate in the model, and more. We continue to work with CMS to secure answers to these questions.

If your practice is interested in participating, or considering participation, we encourage you to submit a nonbinding letter of intent to CMS by the deadline of May 7, 2015. We anticipate that CMS will continue to provide additional guidance until the final application deadline of June 18, 2015. l

In mCRPC therapy…

Is there more to the story?

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

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

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

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

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

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

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

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

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

Please see additional Important Safety Information on the next page.

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

For men with mCRPC who progressed on ADT

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

More than 1,000 days.

And every day tells a story.

35.3 5.2 MONTHS IMPROVEMENT IN MEDIAN OVERALL SURVIVAL

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

compared with placebo plus prednisone.

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

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

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

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

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were overall survival (OS) and radiographic progression-free survival.

ADT = androgen-deprivation therapy.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2015 3/15 029979-150220

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

B:11.125 in

003307-150130

S:10.375 in

T:10.875 in

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

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA®.

Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA®.

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

Learn more today at

www.zytigahcp.com.

Every day tells a story.

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

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

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

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

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

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

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

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

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

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

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

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

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

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

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

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

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

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

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

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

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

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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

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

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

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

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

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

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

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

The median duration of treatment with ZYTIGA was 13.8 months.

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

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

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%).

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

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

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

Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

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

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

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine).

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

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate.

Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical Pharmacology (12.3) in full Prescribing Information].

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

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

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 ©Janssen Biotech, Inc. 2012 Revised: January 2015 028959-150203

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Interview with the Innovators

Confirming Diagnoses and Identifying Biomarkers Linked to Targeted Treatments with the bioT3 Approach An Interview with Ralph V. Boccia, MD, FACP, of Georgetown University

T

he current generation of oncologists has witnessed great advances in our understanding of tumor biology and biomarkers linked to treatments. Those advances started with research, but disseminating this information can be difficult given the myriad of obstacles in adoption to practice. The science behind these advances is fascinating and excites those in medicine Ralph V. Boccia, MD, with the possibility of providing meanFACP ingful, life-altering care to patients. But still there exists the reality of the vetting of each new discovery, starting with niche use among the early users, before it gets adopted more broadly.

With the advent of molecular medicine, we have novel options to detect and identify genetic mutations and other biomarkers to assist in selecting the appro­ priate therapy to target cancer cells. Combining this

knowledge with guidelines of how to treat based on tumor type can only serve to improve patient outcomes.

There are many options in selecting tests to gather pertinent information related to a patient’s genetic profile and the biology of their tumor. In this current installment of Interview with the Innovators, and with the intent to assist in the dissemination of impactful information, we focus on the bioT3 approach, which provides a molecular diagnosis for tumors with unclear diagnosis as well as comprehensive biomarker profiling, including mutational analysis and protein expression markers to assist oncologists in selecting site-specific and targeted therapy options for patients with metastatic cancer. The publishers of PMO had the pleasure of meeting with Dr Ralph V. Boccia from the Center for Cancer and Blood Disorders and Clinical Associate Professor at Georgetown University who participated in the research for these products and has first-hand experience with them in the clinic. To view the live interview, please visit www.PersonalizedMedOnc.com/videolibrary.

PMO Genomic tools such as next-generation sequencing are not widely adopted in community practices for metastatic patients. In your experience, what are the barriers to adoption?

Dr Boccia The low uptake in the community is primarily due to the fact that the first wave of tools was developed to meet the needs of academia and don’t adequately address the needs of community practices. More specifically, when it comes to next-gen sequencing, research-focused oncologists are interested in understanding all mutations associated with a given tumor type, even if no agents are currently available that can target the related pathways. Increasingly, there is interest among these academics in obtaining information across the entire genome in the hope of future actionability,

and often in the context of their collaborations with research divisions of pharmaceutical companies.

In sharp contrast, treatment-focused oncologists are primarily interested in current actionability and thus interested in biomarkers linked to Food and Drug Administration (FDA)-approved drugs and late-stage clinical trial candidates. Further, they are focused on getting the information fast in a simple and easy-to-understand tumor-specific report at a reasonable cost. Therefore, the use will increase when the needs of community practices are more directly addressed.

PMO Can you discuss the strengths and weaknesses of the various next-gen sequencing tests to detect actionable biomarkers?

Dr Boccia In terms of the first wave of tools developed for academia, there are 2 main approaches: 1) sequencing only, and 2) testing everything independent of tumor type. The strength of the “sequencing-only” approach is that it consumes very little tissue but, unfortunately, it is not a comprehensive platform. For some spe­cific biomarkers, IHC [immunohistochemistry] and

Dr Boccia is a founder and the Medical Director of The Center for Cancer and Blood Disorders. He is also Clinical Associate Professor of Medicine at Georgetown University, consulting Medical Director of the International Oncology Network (ION) Clinical Research Program, and Chairman of ION’s Medical Advisory Panel.

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Interview with the Innovators

Different needs related to

FISH [fluorescence in situ hybridmetasta/c disease management Different needs related to metastatic disease management ization] are the more appropriate platforms versus sequencing. IHC Treatment-focused oncologists Research-focused oncologists probes protein expression levels in the tumor, which cannot be • Research focused, and interested • Focused on patient care performed with sequencing. This in clinical trial enrollment is relevant both for traditionally • Often specialize in specific • More often see all cancers, with important biomarkers such as cancers specialization in select cases HER2, ER [estrogen receptor], and PR [progesterone receptor] • Interested in all targets, including • Interested in targets with FDA-approved those in the discovery stage drug or late-stage clinical trials expression, which are recognized candidates to be important in breast cancer, as well as relatively new biomark• Actionable now or in the future • Actionable now ers such as programmed death-­ • Cost not usually a limiting factor • Cost-focused (especially patient portion) ligand 1 (PD-L1), which may have a growing clinical relevance in melanoma, lung cancer, and other solid tumors.

Sequencing also probes genetic rearrangements and amplifications in a manner that is inconsistent with approved targeted therapy labels and inclusion criteria of many clinical trials. Recent ASCO/CAP mary site—otherwise called carcinomas of unknown [American Society of Clinical Oncology/College of primary site. In addition, there are certain ambiguous American Pathologists] guidelines for biomarker testing presentations where patients appear to have a certain in lung cancer clearly state that ALK rearrangement type of tumor; however, the overlap of the clinical pretesting should be done by FISH, in line with the pivotsentation with potentially different types of cancer al studies for crizotinib and the corresponding package makes the initial diagnosis unclear. insert. Rearrangements, in principle, can also be probed by sequencing, but the cutoff criteria and the test specifics are not identical. Unlike academia, where the When you run such a large number of remaining tests can be done by in-house pathology, it is not pragmatic for a community oncologist to work with biomarkers independent of the type of multiple testing facilities to obtain comprehensive biocancer, you end up with slower turnaround marker information. times, high costs, and significant tissue use, The “testing everything independent of tumor type” approach employs a very large number of biomarker tests. in conflict with the basic needs of The strength of this approach is that it is extremely comtreatment-focused oncologists. prehensive. However, when you run such a large number of biomarkers independent of the type of cancer, you end up with slower turnaround times, high costs, and significant tissue use, in conflict with the basic needs for a Data would suggest that the combination of carcinocommunity oncology practice. In addition, many biomas of unknown primary site and the ambiguous presenmarkers are only relevant within specific tumor types, so tations probably make up for around 100,000 patients this approach is not aligned with the clinical evidence newly diagnosed each year, which is ~15% of all newly behind many biomarkers. High-cost tests like this are diagnosed metastatic patients. So it’s no small number. better used as a last resort when a patient has exhausted It is important for clinicians to identify the primary all standard-of-care options. site, because the treatment that we render is dictated by PMO How common is the issue of unclear diagnosis where the tumor started, not where the tumor ends up. in metastatic cancer?

Accurate diagnosis of tumor type/subtype is necessary for Dr Boccia In clinical practice, patients can present selecting the proper site-specific chemotherapy and molecwith carcinomas for which we cannot identify their priularly targeted therapies. It is important to note that mo-

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Interview with the Innovators

bioT3 addresses needs for a broad group of metastatic patients

proach, and how it compares to other offerings that you are familiar with?

Dr Boccia I’ve had the opportunity to Clear work with bioTheranostics for a number of Diagnosis? years, first in the research setting and now in Yes No clinical practice. bioT3 was not commercially available when I first started doing research Dx + Rx Rx alone with them as part of a consortium looking at carcinomas of unknown primary site. I curOffering rently use bioT3 in my everyday practice for metastatic patients with clear as well as unclear diagnoses, from initial treatment through • Biomarkers linked to targeted • Help achieve definitive Value resistance and recurrence. treatments diagnosis of tumor type & proposition The bioT3 offering combines tumor type subtype • Concise actionable panel diagnosis and comprehensive biomarker pro• Biomarkers linked to targeted • Lower cost treatments filing for metastatic tumors. It is made up of • Lower rejection rates (QNS) • Reimbursement ease • Tumor-specific reports 2 components, the first being CancerTYPE • Logistical ease, minimal tissue • Time: 5-7 days ID, a gene expression–based molecular tumor use (low QNS) 4 classifier. CancerTYPE ID is necessary when • Time: 7-10 days we’re looking to identify a primary tumor type, specifically if we’re confronted with a carcinoma of unknown primary site or potentially one of those ambiguous states where Treatment driven by CancerTYPE resulted a 37% increase in overall TreatmentIDdriven by in CancerTYPE ID resulted in a there is a differential diagnosis. An example 37% increase in overall survival survival of that might be metastatic squamous cell carcinoma in the lung that could be a primaMedian Survival, months ry bronchogenic squamous cell carcinoma in 1.0 Assay directed the lung, or it could be a primary head and 12.5 0.9 (n = 194) neck squamous cell carcinoma metastatic to 0.8 Empiric* (n = 396) 9.1 0.7 the lung. If unidentified using regular tools, 0.6 CancerTYPE ID can help distinguish be0.5 tween these tumor types. Another example 0.4 might be a patient who presents with abdom0.3 inal carcinomatosis, and we don’t know if it’s 0.2 a GI [gastroin­testinal] or a GU [genitouri0.1 nary] primary. CancerTYPE ID can be useful 0.0 0 6 12 18 24 30 36 42 for cases in which the tumor type is unTime (months) known, and also in cases where there is diagnostic ambiguity and several tumor type Identified primary site of tumor in 98% of cases possibilities exist. * Based on historical control.

The second component is CancerTREATHainsworth et al. J Clin Oncol. 2013;31:217-223.

3 MENT NGS+, a comprehensive platform that includes next-generation sequencing, lecularly targeted therapies are indicated for specific FISH, and IHC that lends us the opportunity to select tumor types. For example, vemurafenib is FDA approved therapies. The biomarkers tested by CancerTREATfor metastatic melanoma patients harboring a BRAF MENT NGS+ are based on National Comprehensive V600E mutation, but it is not approved in metastatic Cancer Network and ASCO guidelines and major phase colorectal cancer with the same mutation and may not 2 and phase 3 clinical trials, resulting in more concise be effective in this case. So understanding the biomarker panels and reports. This is in contrast to the complicated profile in the context of tumor type is important. reports you receive when you do extensive next-generaPMO We understand that you have used bioT3 from tion sequencing that leave a lot of physicians in a posibioTheranostics in your clinical practice. Can you share tion where they don’t understand where to go next. with us the type of patient for whom you use this apPMO How do you view the strength of the clinical Overall Survival (probability)

bioT3 addresses needs for a broad group of metastatic patients

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Interview with the Innovators

Tumor specific panels designed to optimize cost, turn-around time, QNS Tumor-specific panels designed to optimize cost,and turnaround time, QNS rates, and rates, actionability actionability IHC/FISH tests

Next-Generation Sequencing panel (NGS) NSCLC

CRC

Breast

Melanoma

ALK (FISH)

PTEN (FISH)

HER2 (IHC)

PD-L1 (IHC)

Comprehensive panel

ABL1

EGFR

GNAS

KRAS

PTPN11

AKT

ERBB2

GNAQ

MET

RB1

ALK

ERBB4

HNF1A

MLH1

RET

APC

EZH2

HRAS

MPL

SMAD4

RET (FISH)

PTEN FISH)

ATM

FBXW7

IDH1

NOTCH1

SMARCB1

PDL1 (IHC)

ER (IHC)

EGFR (IHC)

BRAF

FGFR1

JAK2

NPM1

SMO

PR (IHC)

FGFR1 (FISH)

CDH1

FGFR2

JAK3

NRAS

SRC

CDKN2A

FGFR3

IDH2

PDGFRA

STK11

CSF1R

FLT3

KDR

PIK3CA

TP53

CTNNB1

GNA11

KIT

PTEN

ROS1 (FISH)

HER2 (FISH)

ALK (FISH) C-MET (IHC) C-MET (FISH)

HER2 (IHC) HER2 (FISH) RET (FISH) ROS1 (FISH)

PD-L1 (IHC)

VHL

PTEN (FISH)

• Concise list of FISH and IHC biomarkers for NSCLC, CRC, Breast, and Melanoma based on NCCN® recommended biomarkers and phase 2/3 clinical trials • In contrast, the comprehensive panel is designed to maximize “shots on goal”

validation evidence for the CancerTYPE ID, and how does it compare with other gene expression tests?

Dr Boccia In comparison to other gene expression tests, CancerTYPE ID covers a significantly larger number of tumor types, 50 tumor types compared with 15 and 42. In addition, several studies have validated its accuracy and clinical utility. Specifically, the Mayo Clinic, University of California Los Angeles, and Massachusetts General Hospital have done a blinded study and documented the accuracy of CancerTYPE ID (Clin Cancer Res. 2012;18:3952-3960). A head-to-head comparison of CancerTYPE ID versus IHC demonstrated that CancerTYPE ID was significantly better (J Mol Diagn. 2013;15:263-269). A prospective study in patients with carcinomas of unknown primary site that we published in the Journal of Clinical Oncology showed a 37% improvement in overall survival in those patients profiled with this assay and then treated based on the tumor type identified compared with empiric standardof-care chemotherapy (J Clin Oncol. 2013;31:217-223).

PMO For what types of patients do you see a role for CancerTYPE ID in clinical practice?

Dr Boccia We’ve used CancerTYPE ID in our clinical practice in a number of situations. When we get a pathology report back, the first thing we do is to look to

2

see how they document where the tumor that they’re describing appears to have originated from. Oftentimes there is a long account of immunohistochemical stains describing what they conclude. But sometimes pathology reports have an inconclusive or ambiguous diagnosis from a histologic and immunohistochemical standpoint.

I currently use bioT3 in my everyday practice for metastatic patients with clear as well as unclear diagnoses, from initial treatment through resistance and recurrence.

An example might be a patient with a suspected diagnosis of non–small cell lung cancer [NSCLC] based on clinical correlation, but the pathology report indicates that the tumor is TTF-1 [thyroid transcription factor-1] negative, whereas most lung cancers, but not all lung cancers, are TTF-1 positive. If we think it is NSCLC but can’t be absolutely certain, that would be a reason to use the CancerTYPE ID.

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Interview with the Innovators

Additionally, if the clinical presentation is atypical, or if there are multiple lesions at a distant point from any organ, and standard workup does not provide a definitive diagnosis, then CancerTYPE ID can be very helpful in these situations.

PMO Considering the second component of bioT3, for which patients do you see a role for CancerTREATMENT NGS+ in your clinical practice?

Dr Boccia We find CancerTREATMENT NGS+ to be helpful in several situations. The first would be at the time of diagnosis where we’re looking to profile that patient’s tumor and make sure that we have in fact identified actionable targets.

An example of that might be NSCLC, the nonsquamous variety, where we want to be sure that we have given the patient the best treatment options since there are several targeted therapies available based on the biomarker profile of the tumor. If, for instance, the tumor is EGFR, ALK-1, or ROS1 positive, that’s not a patient we want to be giving chemotherapy to at the outset, because randomized trials have clearly shown that the tyrosine kinase inhibitors offer the patient better response rates, better progression-free survival, and better overall survival. On the other hand, if these biomarkers are negative, then this patient is best suited for chemotherapy. So patients with a known diagnosis of metastatic NSCLC are candidates for CancerTREATMENT NGS+ in the up-front setting. CancerTREATMENT NGS+ is a great platform because it combines next-gen sequencing with

CancerTYPE ID can be useful for cases in which the tumor type is unknown, and also in cases where there is diagnostic ambiguity and several tumor type possibilities exist.

FISH and IHC testing, which is important for NSCLC if you are looking for ALK rearrangements because ASCO/ CAP guidelines recommend that ALK testing be performed by FISH. If you’re looking for PD-L1 expression, the best way to assess this is through IHC. CancerTREATMENT NGS+ is also very useful for those metastatic cases in which several lines of therapy have been implemented and the disease progresses. A good example of that would be a breast cancer patient with ER+/PR+ tumor type; we would offer several lines of endocrine therapy before moving on to chemotherapy. Once we’ve gotten beyond those first several lines of therapy and looking for additional actionable targets or

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clinical trial options, that would be a good time to use CancerTREATMENT NGS+ secondarily.

There are times when we would use the 2 components of bioT3 together. An example would be an unknown primary site, let’s say an ambiguous primary site or one that we thought might be lung. CancerTYPE ID would help us confirm this is an NSCLC, and that it is non-

As a treatment-focused community physician, it is very important for me to obtain actionable information in a costeffective manner, and I think the bioT3 approach takes this into account. squamous, to allow us to better understand whether there is an actionable target, specifically ALK, ROS1, RET, and EGFR. So combining them in this instance would be a perfect tool for us to set up a treatment program that we could carry through for many lines of therapy.

PMO An important theme at ASCO 2014 is the importance of managing costs of cancer care, particularly for metastatic patients. How important is it to lower cost from the perspective of community practices, and how does bioT3 address this critical need?

Dr Boccia We’re at a point in this society where healthcare costs are clearly out of control. The budget is unsustainable, and it’s important that all of us contribute to controlling costs the best we can. There is ongoing payment reform, and so the whole system is changing in the next several years. What this means is that we’re going to be sharing risks with the carriers, as well as showing value and quality with our treatment selection. Accountable care organizations are forming and will recruit members, and all will share risk. The upside potential here is enormous to begin to control the cost of some of these more expensive tests and provide actionable answers for more effective therapy. In looking at Explanation of Benefits coming in from my patients for the testing we have ordered, I’m sometimes appalled. I’ve seen bills for profiling as high as $30,000, certainly $5000, $6000, $7000, and $8000. As a treatment-focused community physician, it is very impor­ tant for me to obtain actionable information in a cost-effective manner, and I think the bioT3 approach takes this into account.

PMO Thank you very much for your time today, and our best wishes to you for continued success.

Dr Boccia Thank you, it was my pleasure. l

Wealth Management

Why You Need Disability Insurance: A Doctor’s Story

By Stuart E. Lowenkron, MD, Associate, Physician Financial Services

M

embers of the medical profession sacrifice their time and energy without reservation for the care of patients. All too often, however, it is done to the detriment of themselves and their families—especially in the areas of personal financial planning. Many physicians opine the cost of the various insurance policies we purchase, whether life insurance, homeowners insurance, or disability insurance.

We forget, as I almost did, that we need these policies to protect our most valuable asset: our ability to earn an income.

Early Career In the early 1990s I was completing my fellowship. The future seemed bright, and it was time to take the first steps toward short-term and long-term planning for my family. At that early stage of my career, I thought there would be plenty of time to take care of these things. Since I was still relatively young and in good health, I wanted to concentrate on the present, and the future would take care of itself. At the urging of my personal and financial advisors, however, I purchased life insurance and disabil­ ity insurance, and began putting money into tax-deferred accounts for

different story. I have been battling this disease a good part of my life, have been in and out of treatment and taking medication since I was in my 20s, and it has been an exhausting mental and physical endeavor.

the future. Unbeknownst to me, taking these steps, or more specifically, purchasing my disability insurance policy, would be among the most important and smartest decisions I would ever make.

Upon completion of my residency and fellowship training, I uprooted my young family to a small Southern town, where I had been recruited to set up shop as a specialist. Within 3 years, I had a thriving practice and started to build a comfortable lifestyle for myself and my family. Two years later, though, it was gone: my home, my family as a result of divorce, my practice, my money, and my friends.

The primary reason was my health. I had begun to suffer from major depression, a disease that would follow me and impact the rest of my life.

Purchasing my disability insurance policy would be among the most important and smartest decisions I would ever make.

The most significant of all the problems at the onset of the disease and at points throughout my medical career was an inability to work, with subsequent loss of income and the inability to support and care for myself and my family. In my third year of private practice, my health deteriorated significantly. I finally reached a point where I became overwhelmed and “paralyzed”; I was unable to work, and eventually I had to give up my practice. All of a sudden I had no income and an overwhelming number of problems, and I was barely able to function due to serious depression.

The Impact of Depression For me, depression has manifested in a number of ways, including profound sadness and severe fatigue, often with an inability to get out of bed.

Difficulty concentrating would result in mental paralysis, often impairing my ability to perform even the simplest of tasks. Taking care of patients always seemed to be the easy part of my job, but dealing with my depression and taking care of myself was a

The Silver Lining Despite these problems, I had 2 things going for me that essentially saved me. First, when I bought my disability and life insurance policies, I began a relationship with the agent who sold them to me that has lasted more than 20 years. He did not just sell me a policy and disappear. He kept in touch with me to see how things were going and whether there

Depression: Facts and Figures n Depression affects nearly 1 in 10 adults each year, and women are more likely to experience the disorder than men n Biochemistry, genetic, personality, and environmental factors can all play roles in a person’s depression n For a diagnosis of depression, symptoms must last for ≥2 weeks n Depression is one of the most treatable mental disorders, with 80% to 90% of people with depression eventually responding well to treatment.

Source: American Psychiatric Association.

Continued on page 42

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For patients with bone metastases from solid tumors

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

8.2

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

months longer vs zoledronic acid1

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

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

months

XGEVA VA® 120 mg Q4W (n = 2,862) VA

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

19.5

months

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

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

2 YEARS

P < 0.001†

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

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

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

Monitor calcium levels and calcium and vitamin D intake.

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

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

P value for superiority.

†

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

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

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

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

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

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

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

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

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

Learn more at XGEVA.com

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

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

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

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

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

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

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

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

www.XGEVA.com

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Brief Summary: Consult package insert for complete Prescribing Information

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

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

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

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

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

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

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

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

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

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

Monitor calcium levels and calcium and vitamin D intake.

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

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

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

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

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

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

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

Xgeva were osteonecrosis and hypocalcemia.

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

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

Maternal mammary gland development was normal.

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

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

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

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

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

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

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

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

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

DOUS14CDNY4736_A_XGEVA_Asize_BS_V10_8pt_r10.indd 2

Females and Males of Reproductive Potential.

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

OVERDOSAGE: There is no experience with overdosage of Xgeva.

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

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

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

Printed in USA.

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

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

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

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

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

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

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

Wealth Management

Why You Need Disability Insurance... Continued from page 37 was anything else he could help me with; he ultimately became a loyal friend. In fact, it was he who reminded me about the second thing I had going for me: the disability insurance policy that I had not wanted to purchase several years before.

The insurance policies that I complained about having to purchase, believing I was probably never going to need them, became of utmost importance. Like most physicians who deal with disabled patients, I found it hard to believe that I had become one of them. The monthly income from my disability insurance policy saved my life.

After a few years, I felt I was ready to return to work. I would need to return to employment as a new employee of either a hospital or someone’s private practice. How would I make it work financially? I was residing in an area with a higher cost of living; I had remarried and was granted custody of my children. I also needed to purchase a home. It appeared that if I wanted to continue to live where I was, I was going to have to work for a lot less money than I had been earning previously.

With income from my disability insurance policy, I was able to do this once again. It contained a rider that would pay benefits, proportionate to my loss of income, even though I was still working in my original field.

Although I believed I was no longer

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sick, my income was. With a little lifestyle adjustment, the salary I would earn plus the supplemental income I received from my disability policy allowed me to take a job at a hospital, followed by a move back into private practice. Both paid well below what I needed, but I was able to support my family until my salary increased to something more in line with my cost of living.

The insurance policies that I complained about having to purchase became of utmost importance.

A New Beginning Unfortunately, after working fulltime for 6 more years, I once again became too sick to work and had to claim total disability. After about a year and a half, and much discussion with family, friends, and medical professionals, I made a life-changing decision: I changed professions. Although I would always be a doctor, my medical condition would no longer allow me to actively practice clinical medicine, and I changed course to something that would provide a more favorable work environment.

Oncology Practice Management

I April 2015

I now devote my time and energy, using my experience, to make sure physicians and other healthcare professionals have the same type of income protection in place. Life has taught me a valuable lesson. Unfortunately, in the medical profession, we are too busy or do not realize that taking steps early in our career can help us avoid mistakes that can be financially devastating. Thankfully, my disability insurance policy contained a valuable “own occupation” definition of total disability that allows me to continue to receive monthly income until age 65 years, regardless of my ability to work in another profession. In addition, my benefits also increase annually due to the cost of living rider that I purchased.

I am now, once again, able to provide for my family while working in a profession more conducive to my medical issues. Without my disability policy, which I did not want to buy and cursed every time I paid a premium, I do not know how my family and I would have survived. I am so glad I never had to find out. l Stuart E. Lowenkron, MD, is an associate 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 Slowenkronmd@physicianfinancial services.com with comments or questions.

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

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

TM

Good Manufacturing Process

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

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

EHC388 Innovations ASize_120214

Clinical Trial Tracker

Clinical Trials Under Way for Patients with Renal-Cell Carcinoma

T

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

1

Dalantercept with or without Axitinib This phase 2, randomized, double-blind, 2-part study aims to evaluate the safety, tolerability, and recommended dose level of dalantercept in combination with axitinib in part 1, and compare progression-free survival (PFS) between the above combination therapy versus axitinib alone in part 2. Patients with clearcell renal-cell carcinoma who are aged ≥18 years may enroll if they have experienced disease progression after ≤3 lines of therapy, and if other criteria are met. Patients will receive axitinib orally twice a day with an injection of dalantercept or placebo once every 3 weeks.

The primary outcome of part 1 in the study is the number of patients with adverse events, and of part 2 is PFS. Part 2 has secondary outcome measures of overall survival (OS), time to tumor progression, objective response rate, duration of response, and disease control rate. Pharmacodynamic biomarker activities are also assessed. This study is expected to enroll 174 patients in many sites across the United States. For more information, contact the clinical trials manager at clinicaltrials041@ acceleronpharma.com. The NLM Identifier is NCT01727336.

2

Entinostat with Aldesleukin The objective of this phase 1/2 study is to determine the

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side effects and best dose of entino­ stat when given with aldesleukin to patients with metastatic or surgically unresectable renal-cell carcinoma.

Patients aged ≥18 years may enroll if they have received ≤2 therapies, have an Eastern Cooperative Oncology Group (ECOG) performance score of 0, and if other criteria are met. Patients will receive oral entin­ ostat once every 2 weeks starting 2 weeks before and throughout combination treatment with aldesleukin.

High-dose intravenous aldesleukin is given every 8 hours on days 1 to 5 and 15 to 19. Courses repeat every 84 days in the absence of disease progression or unacceptable toxicity.

Primary outcome measures include the recommended dose of entinostat when given in combination therapy and the overall response rate. Secondary outcomes include the incidence of toxicities in phases 1 and 2, and PFS and time to tumor progression in phase 2. Changes in level of specific T lymphocytes and tumor metabolisms are also assessed. This study is expected to enroll 54 patients in California, Maryland, New York, and Ohio. For more information, contact Roberto Pili, MD, at 716-845-3117 or roberto.pili@roswellpark.org. The NLM Identifier is NCT01038778.

3

AZD6094 (HMPL-504) for Papillary Renal-Cell Carcinoma This phase 2, open-label trial examines the efficacy of AZD6094 (HMPL-504) in treatment-naïve or previously treated patients with papillary renal-cell carcinoma. Patients aged ≥18 years may enroll if they have an ECOG performance score of 0 or 1, adequate hematologic and liver functions, a glomerular filtra-

Oncology Practice Management

I April 2015

tion rate of ≥40 mL/min, and if other criteria are met. All patients will receive oral AZD6094 600 mg daily.

The primary outcome measure is the antitumor activity of AZD6094 as defined by the percentage of patients with an incidence of complete or partial response that is confirmed ≥4 weeks later. The secondary measures include the PFS, safety and tolerability, and pharmacokinetics of the experimental drug.

Changes in target lesion tumor size from baseline, duration of response, and OS are also assessed. All outcomes are assessed for ≤7 months.

This trial is expected to enroll 75 patients in many locations throughout the United States. To locate a site, contact the Cancer Study Locator at 877-400-4655 or astrazeneca@ emergingmed.com. For more information, contact the AstraZeneca Clinical Study Information Center at 877-240-9479 or information. center@astrazeneca.com. The NLM Identifier is NCT02127710.

4

Adjuvant Axitinib Therapy in High-Risk Patients The purpose of this phase 3 trial is to determine whether adjuvant therapy with axitinib will prevent or delay the recurrence of renalcell carcinoma in patients with high risk for the disease after surgery. Patients aged ≥18 years who have been treated with nephrectomy and have no evidence of macroscopic residual disease or metastatic disease may enroll if other criteria are met. Patients are randomized in a 1:1 ratio to receive a placebo or 5 mg of axit­ inib twice a day.

The primary outcome is disease-free survival. Secondary outcomes include OS and the safety profile of both treatment arms. All

Clinical Trial Tracker

outcomes are assessed for 5 years.

This study is expected to enroll 592 patients in multiple locations throughout the United States. For more information, contact Rolf Linke, MD, at 650-954-0106 or rolf. linke@sfj-pharma.com, or Clinton White, PhD, at 925-963-8696 or clinton.white@sfj-pharma.com. The NLM Identifier is NCT01599754.

5

Pazopanib for Metastatic Non–Clear-Cell Renal-Cell Carcinoma The objective of this phase 2, open-label, single-arm trial is to study how well pazopanib hydrochloride works in treating patients with metastatic non–clear-cell renal-cell carcinoma. Patients aged ≥18 years with an ECOG performance score of 0, 1, or 2 who have received ≤1 treatment other than pazopanib may enroll if other criteria are met. All patients will receive oral pazopanib hydrochloride daily for 28 days. The course will repeat every 28 days in the absence of disease progression or unacceptable toxicity.

The primary objective is OS, defined as the percentage of patients who survive 12 months of treatment. Secondary outcome measures include tumor response rate, PFS, and adverse event rate, which are all assessed ≤2 years after treatment completion. This trial is expected to enroll 39 patients in Scottsdale, AZ, and Rochester, MN. For more information, contact the Clinical Trials Referral Office at 855-776-0015. The NLM Identifier is NCT01767636.

6

Autologous Dendritic-Cell Immunotherapy (AGS-003) plus Standard Treatment This phase 3, open-label, randomized trial compares the OS benefit

between patients who receive standard treatment plus AGS-003 and those who receive standard treatment alone; tumor collection will take place as part of this study. Patients aged ≥18 years with advanced renal-cell carcinoma may qualify for tumor collection if they are scheduled for cytoreductive or partial nephrectomy. Patients may receive treatment if they have been diagnosed within a year, have a Karnofsky performance status of ≥70, and a life expectancy of ≥6 months. All patients will receive standard treatment with sunitinib, and the experimental group will also receive AGS003, an intradermal injection of an autologous dendritic-cell product.

Primary outcome measures include OS, PFS, and tumor response.

The number of emergent adverse events that require treatment is also assessed. This trial is expected to enroll 450 patients throughout many locations in the United States. For more information, contact the Adapt Study Team at 877-573-9235 or contact@adapt-study.com. The NLM Identifier is NCT01582672.

The primary outcome measure is to compare recurrence-free survival between the 2 groups, and the secondary outcomes are to compare OS and toxicity between the 2 groups.

This study is expected to enroll 1218 patients at sites throughout the United States. For more information, contact Gilbert Carrizales at 210-614-8808 or gcarrizales@swog. org, or Dana Sparks, MAT, at 210614-8808 (extension 1004) or dsparks@swog.org. The NLM Identifier is NCT01120249.

8

Sunitinib versus Placebo The objective of this phase 3, randomized, double-blind, parallel-group study is to compare the disease-free survival rate and safety of sunitinib versus placebo in patients who receive adjuvant treatment and who are at high risk for recurrent renal-cell carcinoma after surgery. Patients aged ≥18 years with high-risk renal-cell carcinoma, an ECOG performance score of 0 to 2, and who are treatment-naïve may enroll if other criteria are met. Patients are randomized to sunitinib malate 50 mg orally or placebo in a 4-weeks-on, 2-weeks-off regimen for a year or until disease recurrence or occurrence of a secondary malignancy, significant toxicity, or withdrawal of consent.

The primary outcome measure is the disease-free survival comparison between the 2 groups, assessed for a time frame of 36 months. Secondary outcome measures include OS, safety, tolerability, and patient-reported outcomes. This study is expected to enroll 720 patients at sites throughout the United States. For more information, contact the Pfizer CT.gov Call Center at 800-718-1021. The NLM Identifier is NCT00375674. l

7

Everolimus Efficacy Postsurgery This phase 3, randomized, double-blind, parallel-group trial assesses the efficacy of everolimus in treating patients with renal-cell carcinoma who have received a partial or radical nephrectomy. Patients aged ≥18 years who had their first surgical resection within 84 days of study registration may enroll if other criteria are met. Patients are randomized to receive oral everolimus or placebo daily for 42 days, with the cycle repeating every 6 weeks. The treatment is given for up to 54 weeks in the absence of disease progression.

April 2015

I

www.OncPracticeManagement.com

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45

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

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

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

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

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

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

If co-administration of XTANDI cannot be avoided,

XTANDISupportSolutions.com

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

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

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

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

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

INDICATIONS AND USAGE

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

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

Respiratory Disorders

Table 1. Adverse Reactions in Study 1

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

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

XTANDI N = 800

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

Grade 1-4a (%)

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

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

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

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

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

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

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

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

General Disorders Asthenic Conditionsb Peripheral Edema

Placebo N = 399

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

50.6

9.0

44.4

9.3

15.4

1.0

13.3

0.8

Musculoskeletal And Connective Tissue Disorders Back Pain

26.4

5.3

24.3

4.0

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

2.5

17.3

1.8

1.3

11.5

0.3

1.5

6.8

1.8

0.3

0.3

0.0

21.8

1.1

17.5

0.3

Hot Flush

20.3

0.0

10.3

0.0

Hypertension

6.4

2.1

2.8

1.3

Diarrhea Vascular Disorders

Nervous System Disorders Headache

12.1

0.9

5.5

0.0

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

9.5

0.5

7.5

0.5

7.4

6.6

4.5

3.8

Epistaxis

3.3

0.1

1.3

0.3

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

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

Grade 3-4 (%)

Placebo N = 844 Grade 1-4 (%)

Grade 3-4 (%)

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

28.6

2.5

22.4

3.0

Arthralgia

21.4

1.6

16.1

1.1

Gastrointestinal Disorders

6.6

0.0

4.5

0.0

4.3

0.3

1.8

0.0

4.0

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

0.3

0.0

1.8

6.5

0.0

0.3

2.4

4.8

1.3

Insomnia

8.8

0.0

6.0

0.5

Anxiety

6.5

0.3

4.0

0.0

Renal And Urinary Disorders Hematuria

6.9

1.8

4.5

1.0

Pollakiuria

4.8

0.0

2.5

0.0

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

0.0 0.3

Pruritus

3.8

0.0

1.3

0.0

Dry Skin

3.5

0.0

1.3

0.0

Constipation

23.2

0.7

17.3

0.4

Diarrhea

16.8

0.3

14.3

0.4

Vascular Disorders Hot Flush

18.0

0.1

7.8

0.0

Hypertension

14.2

7.2

4.1

2.3

Nervous System Disorders Dizzinessc

11.3

0.3

7.1

0.0

Headache

11.0

0.2

7.0

0.4

Dysgeusia

7.6

0.1

3.7

0.0

5.7

0.0

1.3

0.1

2.1

0.1

0.4

0.0

0.6

8.5

0.6

0.0

10.5

0.0

1.5

4.7

1.1

0.1

5.7

0.0

Mental Impairment Disordersd Restless Legs Syndrome

Respiratory Disorders Dyspneae

11.0

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

8.2

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

Renal And Urinary Disorders Hematuria

8.8

1.3

5.8

1.3

Injury, Poisoning And Procedural Complications Fall

12.7

1.6

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

5.3

0.7

3.0

1.1

16.4

0.7

8.5

0.2

Investigations Weight Decreased

12.4

0.8

Reproductive System and Breast Disorders Gynecomastia

3.4

0.0

1.4

0.0

a b c d

CTCAE v4 Includes asthenia and fatigue.

Includes dizziness and vertigo.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

076-0472-PM

Drug Update

Lenvima (Lenvatinib), a Multireceptor Tyrosine Kinase Inhibitor, Approved by the FDA for the Treatment of Patients with Differentiated Thyroid Cancer

By Loretta Fala, Medical Writer

T

hyroid cancer, cancer that starts in the thyroid gland, accounts for 3.8% of all cancer cases in the United States.1 There were an estimated 62,980 new cases of thyroid cancer and 1890 deaths resulting from thyroid cancer in 2014.1 Thyroid cancer is most common in people aged 45 to 54 years (median age, 50 years),1 and it occurs 2 to 3 times more often in women than in men.2 The incidence of thyroid cancer has risen steadily in recent years.3 Although this increasing rate can be attributed largely to disease detection at an earlier stage, the incidence of larger tumors has also increased.3 Thyroid cancer is classified into 3 types—differentiated (includes papillary, follicular, and Hürthle tumors); medullary tumors; and anaplastic (aggressive undifferentiated tumors).2 Differentiated thyroid cancer accounts for more than 90% of all cases of thyroid carcinoma.2 An estimated 566,708 patients were living with thyroid cancer in the United States in 2011.1 Approximately 68.2% of patients are diagnosed at the local stage of thyroid cancer; for patients with localized thyroid cancer, the 5-year survival rate is currently 99.9%.1 However, 10% to 30% of patients who are thought to be disease-free after the initial treatment will have disease recurrence and/or metastases.4 For patients with differentiated thyroid cancer that is refractory to radioacCopyright © 2015 American Health & Drug Benefits. Used with permission. All rights reserved.

50

I

tive iodine [131-isotope, also known as 131I] therapy, the 10-year survival rate is only 10% from the time that metastatic disease is detected.5,6 According to a recent study, the estimated annual US healthcare costs (undiscounted) for thyroid cancer were $1.4 billion in 2010; these costs are projected to reach $2.1 billion in 2015 and to exceed $3.1 billion by 2019.7 The authors noted that thyroid cancer is a major public health issue, particularly for women, given the increasing incidence (especially of papillary carcinoma) of the disease among women.7 According to another study, differentiated thyroid cancer accounted for total societal costs of approximately $1.6 billion annually in the United States in 2013.8 Furthermore, the annual costs attributable to differentiated thyroid cancer were projected to approach $3.5 billion by 2030 in that study.8 The treatment of differentiated thyroid cancer generally includes surgery, when possible, followed by radioactive iodine treatment in appropriate patients, and thyroxine therapy. Systemic therapy, including the recently approved tyrosine kinase inhibitors, may be used for patients with significant disease progression, nonresectable tumors, or tumors that are nonresponsive to radioactive iodine therapy.2 The multitargeted tyrosine kinase inhibitors have demonstrated a clinical benefit in locally recurrent, unresectable and metastatic medullary thyroid cancer and in radioactive iodine–refractory differentiated thy-

Oncology Practice Management

I April 2015

roid cancer.2 Optimal management of the side effects associated with tyrosine kinase inhibitor therapy and/ or dose modification are key considerations when managing thyroid cancer with this class of drugs.2 The tyrosine kinase inhibitors represent an important advancement in the treatment of thyroid cancer, because they target multiple molecular pathways that are involved in the pathogenesis of thyroid tumors.5

Lenvatinib: A New Oral Option for Differentiated Thyroid Cancer On February 13, 2015, lenvatinib (Lenvima; Eisai), an oral, multireceptor tyrosine kinase inhibitor, was approved by the US Food and Drug Administration (FDA) to treat patients with locally recurrent or metastatic, progressive, radioactive iodine–refractory differentiated thyroid cancer.9 Lenvatinib was granted an expedited review by the FDA, using its priority review process, based on the drug’s potential to provide a significant improvement in safety or effectiveness in treating a serious condition over available medications. In addition, lenvatinib received an orphan drug designation, because it is designated to treat a rare condition.9 Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said, “The development of new therapies to assist patients with refractory disease is of high importance to the FDA. Today’s approval gives patients and healthcare profes-

Drug Update

rosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other receptor tyrosine kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including the fibroblast growth factor receptors FGFR1, 2, 3, and 4; and the platelet-derived growth factor receptor alpha, KIT, and RET.11

Table 1 E fficacy Results in the SELECT Study: Lenvatinib versus Placebo in Patients with Progressive Thyroid Cancer Lenvatinib cohort Placebo cohort Efficacy variable (N = 261) (N = 131) Progression-free survivala Events, N (%)

107 (41)

113 (86)

Progressive disease

93 (36)

109 (83)

Death

14 (5)

4 (3)

18.3 (95% CI, 15.1-NE)

3.6 (95% CI, 2.2-3.7)

Median progression-free survival, mo Hazard ratiob

0.21 (95% CI, 0.16-0.28) P <.001c

Objective response ratea Objective response rate, %

65 (95% CI, 59%-71%)

2 (95% CI, 0%-4%)

Complete response, %

2

0

Partial response, %

63

Dosing and Administration The recommended dose of lenvatinib is 24 mg orally, once daily. In patients with severe renal or hepatic impairment, the dose is reduced to 14 mg once daily.11 Lenvatinib is available in a 4-mg and a 10-mg capsule.11

2 P <.001

d

Overall survival

e

Deaths, N (%) Median overall survival

e

Hazard ratio

b

71 (27)

47 (36)

NE

NE

0.73 (95% CI, 0.50-1.07)

Clinical Studies The SELECT Trial The safety and efficacy of lenvatinib were evaluated in the SELECT trial, a multicenter, randomized (in a 2:1 ratio), double-blind, placebo-controlled study.5 The study included 392 patients with locally recurrent or metastatic radioactive iodine–refractory differentiated thyroid cancer and radiographic evidence of disease progression within 12 months before study randomization, as confirmed by an Independent Radiologic Review (IRR).5,11 Radioactive iodine–refractory was defined as (1) ≥1 measurable lesions with no iodine uptake on radioactive iodine scan, (2) iodine uptake with progression within 12 months of radioactive iodine therapy, or (3) having received cumulative radioactive iodine activity of >600 mCi (22 GBq) with the last dose administered at least 6­­ months before study entry.11 In this study, patients were randomized to receive lenvatinib 24 mg once daily (N = 261) or placebo (N =

P = .10b

Independent radiologic review.

Estimated with Cox proportional hazard model stratified by region (Europe vs North America vs other), age-group (≤65 vs >65 years), and previous VEGF/VEGFR-targeted therapy (0 vs 1). c Log-rank test stratified by region (Europe vs North America vs other), age-group (≤65 vs >65 years), and previous VEGF/VEGFR-targeted therapy (0 vs 1). d Cochran-Mantel-Haenszel chi-square test. e Not estimable.

CI indicates confidence interval; NE, not estimable; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Source: Lenvima (lenvatinib) capsules prescribing information; February 2015. a

b

sionals a new therapy to help slow the progression of DTC [differentiated thyroid cancer].” 9 Steven I. Sherman, MD, Associate Vice Provost, Clinical Research, M.D. Anderson Cancer Center, and principal investigator of a pivotal phase 3 study on lenvatinib led by researchers at the University of Texas M.D. Anderson Cancer Center, noted that advances in thyroid cancer treatment have been made in recent years, particularly for patients with metastatic disease who do not respond to radioactive iodine therapy.10 Dr Sherman stated, “For de-

cades, in this patient population, the treatment was often to repeat ineffective doses of radioactive iodine, and possibly salvage therapy with chemotherapy.” He added, “About 10 years ago, with the growing availability of novel targeted agents and multitargeted kinase inhibitors, we began to recognize potential for treating this subgroup of patients with antiangiogenic therapy and sought to enroll those with refractory disease in clinical trials.” 10

Mechanism of Action Lenvatinib is a multireceptor ty­

Continued on page 54

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MAY 18 – 20, 2015 • MOTIF SEATTLE HOTEL • SEATTLE, WASHINGTON The Academy of Oncology Nurse & Patient Navigators (AONN+) 2015 West Coast Regional Meeting offers navigation professionals access to a host of educational sessions, networking opportunities and poster presentations.

Conference Chair and AONN+ Program Director

EDUCATIONAL OBJECTIVES After completing this activity, the participant should be able to:

Lillie Shockney, RN, BS, MAS University Distinguished Service Associate Professor of Breast Cancer Administrative Director, The Johns Hopkins Breast Center Director, Cancer Survivorship Programs at the Sidney Kimmel Cancer Center at Johns Hopkins Associate Professor, JHU School of Medicine Departments of Surgery, Oncology & Gynecology and Obstetrics Associate Professor, JHU School of Nursing, Baltimore, Maryland

Conquer

myeloma OURNEY

the patie nt voice

YOUR CANCER JOURNEY – WORKING WITH YOUR NAVIGATOR

MY MU LTI PLE

“My blood prote remained stab in level until 2008 whenle for four years became eleva the number diagnosed withted and I was multiple myel Katie LePag oma.” e, multiple myeloma surviv or

aga zine

.com

UNDERSTAND ING COLORECTAL CANCER ACUPUNCTURE AS AN ADJUVANT THERAPY Official patien

t magazine

of

Assess strategies for navigating diverse patient populations by cancer type and environmental factors in this specific region Define methods for providing patient support and guidance in the age of personalized cancer care Evaluate best practices regarding survivorship and psychosocial care in this specific region Provide appropriate care and counsel for patients and their families Want to know more? Additional information about educational objectives and continuing education can be found at: AonnOnline.org/Regionals/West-Coast.

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PRIL 2015 • VOL. 1 • NO. 2

Discuss regional issues regarding the evolution of the role of navigation in healthcare

CONQUER™ magazine, featuring articles written by and for patients with cancer, survivors, nurse navigators and other oncology team members.

Subscribe today at Conquer-Magazine.com

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WHO SHOULD ATTEND: Oncology nurse navigators

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Financial counselors

Case managers

Patient or non-clinically licensed navigators

Oncology nurses and nurse practitioners

THANK YOU TO OUR SPONSORS Corporate Platinum Sponsors

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Corporate Gold Sponsors

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AGENDA* Monday May 18th 6:30 - 8 PM

Dinner and Multiple Myeloma Presentation (non–CE-certified activity)

Tuesday May 19th

Wednesday May 20th

AM Sessions

AM Sessions

6:45 - 8 8:15 - 8:30

(non–CE-certified activities)

Breakfast N.E.X.T. Session

9:30 - 10:30

8:15 - 8:30

8:30 - 9:30

General Session 2: Complete Care – The New Trend in Doctor Visits

Genetic Counselor and the Managing Director of the Breast Cancer

Development, Southern California Permanente Medical Group

Survivorship Center, University of Kansas Cancer Center

Kristen Andrews | Proactive Care Group Lead, Southern California

10:45 - 11:45

9:30 - 10:30

General Session 3: Value-Based Strategies for Navigation

Program, University of Colorado Health-North Kathleen Michie, PT, MT, CLT | Oncology Services Program Manager,

Community Medical Oncologist, Breast Cancer and Oncology

Oncology Rehabilitation and Integrative Therapies

Medical Home Specialist, City of Hope Medical Group

PM Sessions 1:15 - 2

2 - 2:45

Lunch N.E.X.T. Session - sponsored by Takeda Oncology

General Session 10: Fasting and the Ketogenic Diet: The Next Therapies for Cancer Treatment and Prevention?

Leonora Renda, RDN | Oncology Outpatient Dietician, University of Arizona Cancer Center (Oncology Nutrition Dietetic Practice Group)

Michele Webb, CTR | Cancer Registry Coach, Sample Meadow

General Session 11: Keynote: Back to Purpose – The “Heart” of Healing

Publishing LLC, Registry Mindset, National Cancer Registrars

Lee Tomlinson | Medical Consultant, Professor, UCLA School of

Association

Continuing Education, F. Lee Tomlinson & Associates, Los Angeles,

General Session 5: CoC Pillar Survivorship Care Plan Case Studies Jacqueline Casillas, MD, MSHS | Associate Professor, UCLA School of Medicine, Associate Director, UCLA-Livestrong Survivorship Center of Excellence

2:45 - 3:30

10:45 - 11:45

(CE-certified activities)

General Session 4: CoC Pillar Quality Standard Case Studies

General Session 9: Impact of Oncology Prehabilitation and Rehabilitation Patti Frelund, RN-BSN, OCN, CBCN | Supervisor, Patient Navigator

Linda Bosserman, MD, FACP | Assistant Clinical Professor,

11:45 - 1

General Session 8: Moving Beyond Patient Satisfaction: Tips to Measure Program Impact (Survivorship & Navigation) Jennifer Klemp, PhD, MPH, MA | Assistant Professor, Cancer and

Gail Lindsay, RN | Managing Director of Clinical Program

Permanente Medical Group

Welcome (Recap of day before) Lillie D. Shockney, RN, BS, MAS

General Session 1: Metastatic Breast Program Lillie D. Shockney, RN, BS, MAS

Breakfast N.E.X.T. Session (non–CE-certified activity)

Welcome Lillie D. Shockney, RN, BS, MAS

8:30 - 9:30

6:45 - 8

(CE-certified activities unless otherwise noted)

General Session 6: CoC Pillar Patient Navigation Process Case Studies

11:45 - 12:45

California PM Session 12:45 - 1

Closing Remarks Lillie D. Shockney, RN, BS, MAS

* Agenda subject to change. Complete agenda and faculty information available at AonnOnline.org

Danelle Johnston, RN, MS, OCN, CBCN | Coordinator, Oncology Services at St. Jude Medical Center 3:30 - 4

General Session 7: CoC Pillar Psychosocial Distress Screening Case Studies Matthew J. Loscalzo, LCSW | Professor and Executive Director, Supportive Care, City of Hope National Medical Center

4 - 4:45

Commission on Cancer Panel Discussion Nina Miller, MSSW, OSW-C - Moderator | Cancer Liaison Initiatives

JOIN AONN+ FOR ITS 2015 WEST COAST REGIONAL MEETING May 18 - 20, 2015 at the Motif Seattle Hotel in Seattle, Washington.

Manager, American College of Surgeons, Commission on Cancer Michele Webb, CTR • Jacqueline Casillas, MD, MSHS • Danelle Johnston, RN, MS, OCN, CBCN • Matthew J. Loscalzo, LCSW 5:00 - 6:30

Reception (non–CE-certified activity)

REGISTER TODAY AT: AonnOnline.org/Regionals/West-Coast

Drug Update

Lenvima (Lenvatinib), a Multireceptor... Continued from page 51 131) until disease progression. Randomization was stratified by geographic region, previous VEGF/ VEGFR-targeted therapy, and age.

The median age of the patients was 63 years. Overall, 99% of the patients had metastatic disease.11 The primary efficacy outcome measure was progression-free survival, as determined by a blinded IRR using Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).11,12 Secondary efficacy outcome measures included objective response rate and overall survival. Patients in the placebo group could receive lenvatinib after an independent review confirmation of disease progression.11 As shown in Table 1, a significant prolongation in progression-free survival was demonstrated in patients receiving lenvatinib compared with patients who received placebo. Patients in the lenvatinib group had a 14.7-month longer median progression-free survival than patients in the placebo group. Moreover, 65% of patients in the lenvatinib group had an objective response compared with 2% of patients in the placebo group.

Overall survival was not estimable in either group.5,11

Safety The most common adverse reactions (with an incidence of â&#x2030;Ľ30%) associated with lenvatinib are shown in Table 2. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).11 The most common adverse reactions (at least 1%) resulting in discontinuation of lenvatinib were hypertension (1%) and asthenia (1%).11 Lenvatinib has no known contraindications.11 Drug Interactions Effect of other drugs on lenvatinib.

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Table 2 Lenvatinib versus Placebo: Adverse Events (All Grades Incidence â&#x2030;Ľ30%) Lenvatinib 24 mg Placebo (N = 261) (N = 131) All grades, Grades All grades, Grades Adverse reaction % 3-4, % % 3-4, % Hypertensiona

73

44

16

4

Fatigue

67

11

35

4

67

9

17

0

Arthralgia/myalgia

62

5

28

3

Decreased appetite

54

7

18

1

Weight decreased

51

13

15

1

Nausea

47

2

25

1

Stomatitis (inflammation of the mouth and lips)

41

5

8

0

Headache

38

3

11

1

Vomiting

36

2

15

0

Proteinuria

34

11

3

0

Palmar-plantar erythrodysesthesia (hand-foot) syndrome

32

3

1

0

Abdominal paine

31

2

11

1

Dysphonia (voice impairment)

31

1

5

0

b

Diarrhea c

d

Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure. b Includes asthenia, fatigue, and malaise. c Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia. d Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation. e Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain.

Source: Lenvima (lenvatinib) capsules prescribing information; February 2015. a

CYP3A is one of the main metabolic enzymes of lenvatinib. No dose adjustment of lenvatinib is recommended when coadministered with CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein inhibitors and CYP3A and P-gp inducers.11

Warnings and Precautions Hypertension. Blood pressure should be controlled prior to treatment with lenvatinib. Lenvatinib should be withheld for grade 3 hypertension despite optimal hypertensive therapy. For patients with

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I April 2015

life-threatening hypertension, lenvatinib should be discontinued.11 Cardiac failure. Patients should be monitored for clinical symptoms or signs of cardiac decompensation. Lenvatinib should be withheld for grade 3 cardiac dysfunction. For patients with grade 4 cardiac dysfunction, lenvatinib should be discontinued.11 Arterial thromboembolic events.

Lenvatinib should be discontinued following an arterial thromboembolic event.11 Hepatotoxicity. Before initiation of lenvatinib and periodically through-

Drug Update

out treatment, liver function tests should be monitored. For patients with grade 3 or greater liver impairment, lenvatinib should be withheld.

Lenvatinib should be discontinued for patients with hepatic failure.11 Proteinuria. Before initiating lenvatinib therapy and periodically through treatment with lenvatinib, patients should be monitored for proteinuria. Lenvatinib should be withheld in patients with ≥2 g of proteinuria for 24 hours. Lenvatinib should be discontinued in patients with nephritic syndrome.11 Renal failure and impairment. Lenvatinib should be withheld for grade 3 or 4 renal failure or impairment.11 Gastrointestinal perforation and fistula formation. Lenvatinib should be discontinued in patients who develop gastrointestinal perforation or life-threatening fistula.11 QT interval prolongation. Electrolyte abnormalities should be monitored and corrected in all patients.

For patients who develop grade ≥3 QT interval prolongation, lenvatinib should be withheld.11 Hypocalcemia. Blood calcium levels should be monitored at least monthly and calcium should be replaced as necessary during treatment with lenvatinib.11 Reversible posterior leukoencephalopathy syndrome (RPLS). Lenvatinib should be withheld for patients with RPLS until the RPLS is fully resolved.11 Hemorrhagic events. Lenvatinib should be discontinued for patients with grade 3 hemorrhage. Lenvatinib should be discontinued for patients with grade 4 hemorrhage.11 Impairment of thyroid-stimulating hormone (TSH) suppression.

TSH levels should be monitored monthly and thyroid replacement medication should be adjusted as needed in patients with differentiated thyroid cancer.11 Embryofetal toxicity. Lenvatinib can cause fetal harm. Women of

reproductive potential should be advised about the potential risk to the fetus and the use of effective contraception.11

option became available to help slow the progression of differentiated thyroid cancer, the most common type of thyroid cancer, in patients with locally recurrent or metastatic, radioactive iodine–refractory disease.9 Treatment with lenvatinib, a multitargeted tyrosine ­kinase inhibitor, demonstrated a statistically significant prolongation in progression-free survival in patients with progressive, radioactive iodine–re­ fractory differentiated thyroid cancer. In the SELECT clinical study, the median progression-free survival in the lenvatinib group was 18.3 months versus 3.6 months in the placebo group (P <.001).5,11 l

Use in Specific Populations Lactation. It is not known whether lenvatinib is present in human milk. Because of the potential for serious adverse reactions in nursing infants from lenvatinib, women should be advised to discontinue breastfeeding during treatment with lenvatinib.11 Pregnancy. Lenvatinib can cause fetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the fetus.11 Females and males of reproductive potential. Lenvatinib may result in reduced fertility in women of reproductive potential. Lenvatinib may result in damage to male reproductive tissues leading to reduced fertility of unknown duration.11 Pediatric use. The safety and effectiveness of lenvatinib in pediatric patients have not been established.11 Geriatric use. In clinical studies, no overall differences in safety or effectiveness were observed between patients aged ≥65 years and those aged <65 years.11 Renal impairment. No dose adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended dose of lenvatinib is 14 mg taken once daily. Patients with end-stage renal disease were not studied.11 Hepatic impairment. No dose adjustment is recommended in patients with mild or moderate he­ patic impairment. In patients with severe hepatic impairment, the recommended dose of lenvatinib is 14 mg taken once daily.11

References

1. National Cancer Institute. SEER stat fact sheets: thyroid cancer. http://seer.cancer.gov/statfacts/html/ thyro.html. Accessed March 10, 2015.

2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): thyroid carcinoma. Version 2.2014. August 12, 2014. www.nccn.org/store/login/login.aspx?Return URL=http://www.nccn.org/professionals/physician_gls/ pdf/thyroid.pdf. Accessed March 10, 2015.

3. American Cancer Society. What are the key statistics about thyroid cancer? Revised February 13, 2015. www.cancer.org/cancer/thyroidcancer/detailedguide/­ thyroid-cancer-key-statistics. Accessed March 11, 2015.

4. National Cancer Institute. Thyroid cancer treatment (PDQ®). Updated February 25, 2015. www.cancer. gov/cancertopics/pdq/treatment/thyroid/Health Professional/page9. Accessed March 13, 2015.

5. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372:621-630.

6. Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab.

2006;91:2892-2899.

7. Aschebrook-Kilfoy B, Schechter RB, Shih Y-C, et al. The clinical and economic burden of a sustained increase in thyroid cancer incidence. Cancer Epidemiol Biomarkers Prev. 2013;22:1252-1259.

8. Lubitz CC, Kong CY, McMahon PM, et al. Annual financial impact of well-differentiated thyroid cancer care in the United States. Cancer. 2014;120:1345-1352.

9. US Food and Drug Administration. FDA approves Lenvima for a type of thyroid cancer. Press release.

February 13, 2015. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm434288.htm. Accessed March 14, 2015.

10. M.D. Anderson. Lenvatinib shows promise for patients with radioiodine-­refractory thyroid cancer. Press release. February 11, 2015. www.mdanderson.org/ newsroom/news-releases/2015/lenvatinib-promiseradioiodine-refractory-­thyroid-cancer.html. Accessed March 13, 2015.

11. Lenvima (lenvatinib) capsules [prescribing information]. Woodcliff Lake, NJ: Eisai Inc; February 2015.

12. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45: 228-247.

Conclusion With the FDA approval of lenvatinib, a new, once-daily oral treatment

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Drug Coding Supplied by RJ Health Systems

FDA-Approved Medications Used for the Treatment of Colorectal Cancer The following sections will assist healthcare professionals and payers by providing appropriate coding and billing information associated with the treatment of colorectal cancer.

The following sections include: • Associated ICD-9-CM codes used for the classification of colorectal cancer • Drugs that have been FDA approved in the treatment of colorectal cancer • Drugs that are Compendia-listed for off-label use for colorectal 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 colorectal cancer:

153 Malignant neoplasm of colon

Excludes: b enign carcinoid tumor of colon (209.50-209.56) malignant carcinoid tumor of colon (209.10-209.16)

153.0 Hepatic flexure

153.1 Transverse colon

153.2 Descending colon Left colon

153.3 Sigmoid colon Sigmoid (flexure) Excludes: rectosigmoid junction (154.0) 153.4 Cecum Ileocecal valve 153.5 Appendix

153.6 Ascending colon Right colon

153.7 Splenic flexure

153.8 Other specified sites of large intestine Malignant neoplasm of contiguous or overlapping sites of colon whose point of origin cannot be determined Excludes: ileocecal valve (153.4) rectosigmoid junction (154.0)

153.9 Colon, unspecified Large intestine, not otherwise specified 154 Malignant neoplasm of rectum, rectosigmoid junction, and anus

Excludes: b enign carcinoid tumor of rectum (209.57) malignant carcinoid tumor of rectum (209.17)

154.0 Rectosigmoid junction Colon with rectum Rectosigmoid (colon)

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Drug Coding

154.1 Rectum Rectal ampulla 154.8 Other Anorectum

Cloacogenic zone Malignant neoplasm of contiguous or overlapping sites of rectum, rectosigmoid junction, and anus whose point of origin cannot be determined

Generic (brand) name

HCPCS code - code description

FDA approved for colorectal cancer

Compendia off-label use for Possible CPT ® colorectal cancer administration codes

Bacillus Calmette–Guérin (BCG Vaccine)

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

√

90471, 90472

Bacillus Calmette–Guérin (TheraCys, Tice BCG)

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

√

51720

Bacillus Calmette–Guérin (TheraCys, Tice BCG)

J9031 - BCG (intravesical), per installation

√

51720

bevacizumab (Avastin)

J9035 - Injection, bevacizumab, 10 mg

√

96413, 96415

capecitabine (Xeloda)

J8520 - Capecitabine, oral, 150 mg

√

N/A

capecitabine (Xeloda)

J8521 - Capecitabine, oral, 500 mg

√

N/A

carmustine (BiCNU)

J9050 - Injection, carmustine, 100 mg

cetuximab (Erbitux)

J9055 - Injection, cetuximab, 10 mg

cisplatin (Platinol-AQ)

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

√

96409, 96413, 96415

doxorubicin (Adriamycin)

J9000 - Injection, doxorubicin hydrochloride, 10 mg

√

96409

floxuridine (FUDR)

J9200 - Injection, floxuridine, 500 mg

√

96422, 96423, 96425

fluorouracil (Adrucil)

J9190 - Injection, fluorouracil, 500 mg

√

96409

irinotecan (Camptosar)

J9206 - Injection, irinotecan, 20 mg

√

96413, 96415

leucovorin calcium (Wellcovorin)

J0640 - Injection, leucovorin calcium, per 50 mg

√

96372, 96374, 96409

levoleucovorin calcium (Fusilev)

J0641 - Injection, levoleucovorin calcium, 0.5 mg

√

96365, 96366

lomustine (CeeNu)

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

√

N/A

lomustine (CeeNu)

S0178 - Lomustine, oral, 10 mg

√

N/A

methotrexate

J9250 - Methotrexate sodium, 5 mg

√

96372, 96374, 96401, 96409, 96450

methotrexate

J9260 - Methotrexate sodium, 50 mg

√

96372, 96374, 96401, 96409, 96450

√

96413, 96415 96413, 96415

√

Continued on page 58

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Drug Coding

FDA-Approved Medications... Continued from page 57 mitomycin (Mutamycin)

J9280 - Mitomycin, 5 mg

√

96409

mitoxantrone (Novantrone)

J9293 - Injection, mitoxantrone hydrochloride, per 5 mg

√

96409, 96413

oxaliplatin (Eloxatin)

J9263 - Injection, oxaliplatin, 0.5 mg

√

96413, 96415

panitumumab (Vectibix)

J9303 - Injection, panitumumab, 10 mg

√

96413, 96415

pemetrexed (Alimta)

J9305 - Injection, pemetrexed, 10 mg

regorafenib (Stivarga)

C9399* - Unclassified drugs or biological (hospital outpatient use ONLY)

√

N/A

regorafenib (Stivarga)

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

√

N/A

topotecan (Hycamtin)

J8705 - Topotecan, oral, 0.25 mg

√

N/A

topotecan (Hycamtin)

J9351 - Injection, topotecan, 0.1 mg

√

96413

√

96409

√

vincristine (Vincasar PFS) J9370 - Vincristine sulfate, 1 mg ziv-aflibercept (Zaltrap)

J9400 - Injection, ziv-aflibercept, 1 mg

√

96409

96413

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

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

This information was supplied by

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www.RJHealthSystems.com

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