PMO April 2013 Vol 2 No 2

April 2013 Volume 2 • Number 2 A Peer-Reviewed Journal

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BIOMARKERS Physician-Reported Clinical Utility of the 92-Gene Molecular Classifier in Tumors With Uncertain Diagnosis Following Standard Clinicopathologic Evaluation.......................Page 68

INTERVIEW WITH THE INNOVATORS Promoting the Adoption of Personalized Medicine Concepts: An Interview With Edward Abrahams, PhD, of the Personalized Medicine Coalition.................Page 79

CONTINUING MEDICAL EDUCATION Considerations in Multiple Myeloma.

Ask the Experts: Frontline and Retreatment Settings.................................. Page 82

VALUE-BASED CANCER CARE Introducing the Third Annual Conference of the Association for Value-Based Cancer Care............................................... Page 90

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he Global Biomarkers Consortium™ (GBC) is a community of worldrenowned healthcare professionals who will convene in multiple educational forums in order to better understand the clinical application of predictive molecular biomarkers and advanced personalized care for patients.

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BIOMARKERS Physician-Reported Clinical Utility of the 92-Gene Molecular Classifier in Tumors With Uncertain Diagnosis Following Standard Clinicopathologic Evaluation PAGE 68 Benjamin Kim, MD, MPhil; Brock E. Schroeder, PhD; Catherine A. Schnabel, PhD; Mark G. Erlander, PhD; Jennifer L. Malin, MD, PhD The authors provide the findings from a study designed to assess the characteristics and clinical decision outcomes of medical oncologists who have ordered the 92-gene molecular classifier (CancerTYPE ID) and determine how they view the clinical value of the test in their practice.

INTERVIEW WITH THE INNOVATORS Promoting the Adoption of Personalized Medicine Concepts: An Interview With Edward Abrahams, PhD, of the Personalized Medicine Coalition

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PMO talks with Edward Abrahams, PhD, about the vital role the PMC plays in the adoption of personalized medicine principles in our healthcare systems.

6.7%

CONTINUING MEDICAL EDUCATION Considerations in Multiple Myeloma.

Ask the Experts: Frontline and Retreatment Settings

3.2% 6.7%

1-3 years 3-5 years 5-10 years 10-20 years >20 years

Volume 2 • No 2

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David Siegel, MD, PhD; Elizabeth Bilotti, MSN, BSN, APN-C; Greg Eskinazi, RPh, MAS, BCOP

VALUE-BASED CANCER CARE Introducing the Third Annual Conference of the Association for Value-Based Cancer Care PAGE 90 Burt Zweigenhaft, BS Mr Zweigenhaft reviews the objectives of the AVBCC Annual Conference.

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PUBLISHING STAFF Senior Vice President/Sales & Marketing Philip Pawelko phil@greenhillhc.com Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Publisher Russell Hennessy russell@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Strategic Editor Robert E. Henry

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THE LAST WORD The Affordable Care Act and Oncology Personalized Medicine: Compatibility and the Governing Dynamics of Healthcare Robert E. Henry Mr Henry poses thoughtful questions as to how the ACA will affect personalized medicine.

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OUR MISSION The mission of Personalized Medicine in Oncology is to deliver practice-changing information to clinicians about customizing healthcare based on molecular profiling technologies, each patient’s unique genetic blueprint, and their specific, individual psychosocial profile, preferences, and circumstances relevant to the process of care.

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OUR VISION Our vision is to transform the current medical model into a new model of personalized care, where decisions and practices are tailored for the individual – beginning with an incremental integration of personalized techniques into the conventional practice paradigm currently in place.

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Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 6 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935.

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Editorial Board Editor in Chief Al B. Benson III, MD Northwestern University Chicago, Illinois

SECTION EDITORS Breast Cancer Edith Perez, MD Mayo Clinic Jacksonville, Florida

Drug Development Igor Puzanov, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee

Hematologic Malignancies Gautam Borthakur, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Gastrointestinal Cancer Eunice Kwak, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts

Lung Cancer Vincent A. Miller, MD Foundation Medicine Cambridge, Massachusetts

Pathology David L. Rimm, MD, PhD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut

Melanoma Doug Schwartzentruber, MD Indiana University Simon Cancer Center Indianapolis, Indiana

Predictive Modeling Michael Kattan, PhD Case Western Reserve University Cleveland, Ohio

Prostate Cancer Oliver Sartor, MD Tulane University New Orleans, Louisiana

EDITORIAL BOARD Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania

K. Peter Hirth, PhD Plexxikon, Inc. Berkeley, California

Hope S. Rugo, MD University of California, San Francisco San Francisco, California

Gregory D. Ayers, MS Vanderbilt University School of Medicine Nashville, Tennessee

Howard L. Kaufman, MD Rush University Chicago, Illinois

Danielle Scelfo, MHSA Genomic Health Redwood City, California

Lyudmila Bazhenova, MD University of California, San Diego San Diego, California

Katie Kelley, MD UCSF School of Medicine San Francisco, California

Lee Schwartzberg, MD The West Clinic Memphis, Tennessee

Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona

Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota

John Shaughnessy, PhD University of Arkansas for Medical Sciences Little Rock, Arkansas

Kenneth Bloom, MD Clarient Inc. Aliso Viejo, California

Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington

Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts

Mark S. Boguski, MD, PhD Harvard Medical School Boston, Massachusetts Gilberto Castro, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil Madeleine Duvic, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland

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Afsaneh Motamed-Khorasani, PhD Radient Pharmaceuticals Tustin, California Nikhil C. Munshi, MD Dana-Farber Cancer Institute Boston, Massachusetts

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio Stephen Gately, MD TGen Drug Development (TD2) Scottsdale, Arizona

Gene Morse, PharmD University at Buffalo Buffalo, New York

Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida Darren Sigal, MD Scripps Clinic Medical Group San Diego, California David Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee Moshe Talpaz, MD University of Michigan Medical Center Ann Arbor, Michigan

Steven O’Day, MD John Wayne Cancer Institute Santa Monica, California

Sheila D. Walcoff, JD Goldbug Strategies, LLC Rockville, Maryland

David A. Proia, PhD Synta Pharmaceuticals Lexington, Massachusetts

Anas Younes, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois

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NOVEMBER 15-17, 2013 CONFERENCE CO-CHAIRS Lillie D. Shockney, RN, BS, MAS AONN Program Director University Distinguished Service Associate Professor of Breast Cancer Departments of Surgery and Oncology Administrative Director, Johns Hopkins Clinical Breast Programs Administrative Director, Johns Hopkins Cancer Survivorship Programs Department of Surgery and Oncology Associate Professor, JHU School of Medicine Departments of Surgery, Oncology, and Gynecology Associate Professor, JHU School of Nursing Johns Hopkins Avon Foundation Breast Center Baltimore, MD

Sharon Gentry, RN, MSN, AOCN, CBCN Breast Health Navigator Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

REGISTER TODAY

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Letter From the Board

Information Overload – the Search for Clinical Relevance in the Oncology Literature Dear Colleague,

T

he field of oncology is changing at an unprecedented rate. Not that long ago, a few dozen chemotherapeutic agents were used to treat a wide variety of tumor types – and most of them were used empirically. It used to be relatively easy to keep current on advances as only a handful of randomized trials were published or presented each year for the most common disease sites. Now, there are well over 100 commercially available anticancer agents, many of which have targeted applications, and it seems that new FDA-approved indications are Al B. Benson III, MD being announced on a weekly basis. Every day, oncologists are inundated with information touting the results of the latest randomized trials for both common and uncommon malignancies. Even for an academic oncologist, it is challenging to keep current on the constant flow of new data.

It can be even more challenging to determine which results actually represent clinically meaningful advances. Many of the recent advances in oncology are truly remarkable scientific achievements, and we remain hopeful that they will translate into greater clinical gains. However, trials with statistically significant results that are of marginal clinical benefit do not justify the empiric use of expensive, state-of-theart treatments in all patients with an advanced, incurable disease. This approach is neither scientifically rational nor economically sustainable. What such studies tell us is that some patients do benefit from newer targeted therapies. It is now incumbent upon us to take these findings a step further by defining the predictive factors that will prospectively identify those patients who will benefit so we can begin to direct our treatments in a more rational, effective, and fiscally sound manner.

That is why Personalized Medicine in Oncology exists. We offer articles, interviews, and news exploring the best ways to effectively personalize oncology treatments. And now, we want your feedback. Please visit and bookmark us at www.personalizedmedonc.com to weigh in on the topics presented in our pages and on our Web site. We are looking forward to hearing from you and maintaining a meaningful dialogue.

Sincerely,

Al B. Benson III, MD Northwestern University PMO Editor in Chief

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Volume 2 • No 2

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• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma • Squamous Cell Carcinoma • Merkel Cell Carcinoma

July 26-28, 2013

Hyatt Regency La Jolla • San Diego, California

PROGRAM OVERVIEW

CONFERENCE CO-CHAIRS

A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carcinoma, and Merkel cell carcinoma, including: • Epidemiology and genetic/environmental factors • Molecular biology and cytogenetics related to the pathogenesis of cutaneous malignancies • Risk stratification based on patient and tumor characteristics • Principles of cancer prevention of melanoma and basal cell carcinoma • Current treatment guidelines • Emerging treatment options for personalized therapy • Future strategies in management based on translational data from current clinical trials and basic research

LEARNING OBJECTIVES Upon completion of this activity, the participant will be able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as they relate to the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, Merkel cell tumors, and malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

TARGET AUDIENCE This activity was developed for medical and surgical oncologists, dermatologists, radiation oncologists, and pathologists actively involved in the treatment of cutaneous malignancies. Advanced practice oncology or dermatololgy nurses, oncology pharmacists, and researchers interested in the molecular biology and management of cutaneous malignancies are also encouraged to participate.

DESIGNATION OF CREDIT STATEMENTS SPONSORS This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Luke’s Cancer Center Bethlehem, Pennsylvania

REGISTERED NURSE DESIGNATION Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.0 contact hours.

REGISTERED PHARMACY DESIGNATION The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.0 contact hours (1.2 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION EARLY BIRD REGISTRATION NOW OPEN! $175.00 UNTIL APRIL 30, 2013

www.CutaneousMalignancies.com

Professor Dr. Med. Axel Hauschild Professor, Department of Dermatology University of Kiel Kiel, Germany

AGENDA* FRIDAY, JULY 26, 2013 3:00 pm – 7:00 pm

Registration

5:30 pm – 7:30 pm

Welcome Reception/Exhibits

SATURDAY, JULY 27, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Welcome to the Second Annual World Cutaneous Malignancies Congress — Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD

8:30 am – 11:45 am General Session I: A Clinician’s Primer on the Molecular Biology of Cutaneous Malignancies • Keynote Lecture Understanding the Basic Biology and Clinical Implications of the Hedgehog Pathway • Keynote Lecture Pathogenesis of Merkel Cell Carcinoma: An Infectious Etiology? - Paul Nghiem, MD, PhD 12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm – 1:15 pm

BREAK

1:15 pm – 4:30 pm

General Session II: Current Treatment Guidelines in Cutaneous Malignancies • Case Studies Optimal, Value-Based Therapy of Cutaneous Malignancies: The Expert’s Perspective on How I Treat My Patients • Panel Discussion Management Controversies and Accepted Guidelines for the Personalized Management of Cutaneous Malignancies • Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Anti–PD-1

4:30 pm – 6:30 pm

Meet the Experts/Networking/Exhibits

PHYSICIAN CREDIT DESIGNATION The Medical Learning Institute Inc designates this live activity for a maximum of 12.0 AMA PRA Category 1 Credits ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Steven J. O’Day, MD Hematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center Clinical Associate Professor of Medicine USC Keck School of Medicine Los Angeles, California

SUNDAY, JULY 28, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Review of Saturday’s Presentations and Preview of Today’s Sessions

8:30 am – 11:45 am General Session III: Review of Emerging Treatment Options for Cutaneous Malignancies General Session IV: Challenges for the Cutaneous Malignancies Clinician • Panel Discussion How Can the Healthcare Team Work Best Together to Deliver Value-Based Care in Cutaneous Malignancies?

12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm – 1:15 pm

BREAK

1:15 pm – 2:45 pm

General Session V: “Hot Data� — What I Learned at Recent Meetings: Focus on Cutaneous Malignancies

2:45 pm – 3:00 pm

Closing Remarks - Steven J. O’Day, MD

*Agenda is subject to change.

For complete agenda please visit www.CutaneousMalignancies.com

2012 ASH Annual Meeting

Liposomal Vincristine Allows for Greater Dose Density Without Increased Neurotoxicity Caroline Helwick

I

n August 2012, vincristine sulfate LIPOSOME injection (VSLI; Marqibo) was granted accelerated approval by the FDA for the treatment of adult patients with Philadelphia chromosome–negative acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed after 2 or more antileukemia therapies.1 At the 2012 American Society of Hematology (ASH) Annual Meeting, investigators further described the pharmacokinetics and neurotoxicity profiles of the new drug and reported data in pediatric patients.

Dosing of VCR is limited by significant neurotoxicity, which occurs at doses higher than 1.4 mg/m2 and has led to capping of the total dose at 2.0 mg.

Standard vincristine sulfate (VCR) is a component of treatment regimens for pediatric and adult hematologic and solid malignancies,2 including ALL, non-Hodgkin lymphoma, Hodgkin lymphoma, Wilms’ tumor, sarcomas, and brain tumors. Dosing of VCR is limited by significant neurotoxicity, which occurs at doses higher than 1.4 mg/m2 and has led to capping of the total dose at 2.0 mg.2 The newly approved vincristine product is a sphingomyelin/cholesterol liposome–encapsulated formulation of VCR.2 Liposomal carriers are capable of increasing the therapeutic index of anticancer drugs by altering the pharmacokinetic behavior of standard agents. VSLI is administered at 2.25 mg/m2 by IV infusion over 1 hour once every 7 days with no dose cap.1

Increased Delivery of Vincristine to Target Tissue Dose capping is intended to reduce the risk of

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drug-induced neuropathy but may also limit clinical efficacy, said Jeffrey A. Silverman, PhD, vice president of clinical pharmacology and translational research at Talon Therapeutics.

“In addition to dose capping, standard VCR is limited by a very rapid distribution half-life and large volume of distribution that suggests there is wide and diffuse tissue distribution,” he said.

“VSLI is designed to overcome the dosing and pharmacokinetic limitations of standard VCR. It is intended to take advantage of fenestrated (leaky) vasculature found in bone marrow, lymph nodes, the spleen, and many tumors…to preferentially penetrate, accumulate, and deliver VCR to cancer tissues,” he pointed out.

Silverman described plasma pharmacokinetics in rats that received standard VCR or VSLI 2 mg/m2 by slow IV bolus.3 VSLI increased VCR plasma circulation time and area under the curve, delivered more VCR to tissues that are important in hematologic malignancies, and slowly released VCR in tumors over days, he reported.

Neurotoxicity Profile Stable in Spite of High Doses Delivered Peripheral neuropathy is the major toxicity associated with the use of VCR, and this limits the individual dose, cumulative exposure, and dose density of the drug.

“Attempts to increase the dose [of standard VCR] have been met with a 100% incidence of peripheral neuropathy,” Silverman said.

Due to VCR’s dose-dependent antitumor activity, it would be beneficial to be able to increase the dose and dose density without increasing neuropathy, he added.

Investigators dosed VSLI at 2.25 mg/m2 (the FDA-approved dose) without a dose cap and evaluated the emergence of neuropathy in 83 adults with relapsed/ refractory ALL and prior VCR exposure; 80% of the

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2012 ASH Annual Meeting

subjects had residual neuropathy.2 Peripheral neuropathy was proactively assessed weekly with a detailed evaluation of 16 signs and symptoms.

The investigators observed that the occurrence of peripheral neuropathy was consistent with the labeled dose of standard VCR, despite the delivery of larger, normally unachievable individual and cumulative doses of VCR. Peripheral neuropathy of any grade occurred in 23% of patients, but only 1% was grade 4 and 22% was grade 3 despite a dose density of 4.04 mg/week (2.25 mg/m2/week). This included peripheral motor neuropathy, pain in the extremity, areflexia, decreased vibratory sense, gait disturbance, hypoethesia, muscular weakness, neuralgia, paresthesia, and peripheral sensory neuropathy.

In comparison, previous studies of VCR showed much higher paresthesia rates at much lower dose densities4,5: • 78% with a dose density of 0.84 mg/week (1.4 mg/ m2 every 3 weeks) • 34% with a dose density of 0.67 mg/week (2 mg every 3 weeks) • 60% at a dose density of 1.33 mg/week (4 mg every 3 weeks) VSLI facilitated more than a 2-fold higher dose density without a concomitant increase in paresthesia rate.

“One of the advantages of VSLI is no dose cap, so we can administer more vincristine, and what we saw in this study is that higher dosing does not translate into greater neurotoxicity. With the conventional drug, we see more neurotoxicity even at much lower doses and lower dose density,” Silverman said.

There were no new or unexpected toxicities observed with VSLI dosed at 2.25 mg/m2, he added.

He acknowledged that the study compared neurotoxicity with VSLI to historical data on VCR. “A headto-head study is ongoing,” he added.

VSLI in Pediatric Patients “The pediatric experience with VSLI has been limited,” said Nirali N. Shah, MD, of the National Insti-

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tutes of Health Pediatric Oncology Branch, Bethesda, Maryland.

At ASH, Shah presented the results of a phase 1 single-institution dose escalation trial of 10 children and young adults (2-20 years old) with relapsed or refractory ALL or solid tumors.6 Seven of 10 received a VSLI dose that exceeded the 2-mg dose cap for standard VCR. Of 7 patients evaluable for response, 1 patient achieved a complete remission, 3 had stable disease, 2 had progressive disease, and 1 was too early to assess for response.

“VSLI appears to be safe and tolerable. The toxicity spectrum appears similar in children and adults,” Shah said. “VSLI may allow for intensification of vincristine therapy in children with cancer.”

Most treatment-related adverse events were grade 1 and 2 and reversible, the most common of which were hepatic transaminase elevations, paresthesias, neutropenia, and fatigue. No patient discontinued treatment due to neurotoxicity.

“Clearance of total vincristine in our study was approximately 100-fold lower in comparison to previously observed values for the administration of standard vincristine,” she added.

Accrual at the adult recommended dose is ongoing, and an expanded phase 2 cohort in pediatric patients with ALL is being planned. u

References

1. Marqibo [package insert]. South San Francisco, CA: Talon Therapeutics, Inc; August 2012.

2. Deitcher SR, Silverman JA; on behalf of the RALLY Trial investigators. Neurotoxicity profile of vincristine sulfate liposome injection (VSLI, Marqibo®) monotherapy in adults with relapsed acute lymphoblastic leukemia and universal prior standard vincristine exposure. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 3568.

3. Silverman JA, Deitcher SR. Vincristine sulfate liposome injection (VSLI, Marqibo®) facilitates increased delivery of vincristine sulfate to target cancer tissues. Blood (ASH Annual Meeting Abstracts). 2012;120.

Abstract 2457.

4. Haim N, Epelbaum R, Ben-Shahar M, et al. Full dose vincristine (without 2-mg dose limit) in the treatment of lymphomas. Cancer.

1994;73:2515-2519.

5. Verstappen CC, Koeppen S, Heimans JJ, et al. Dose-related vincristine-induced peripheral neuropathy with unexpected off-therapy worsening. Neurology. 2005;64:1076-1077.

6. Shah NN, Merchant M, Cole D, et al. Vincristine sulfate liposomes injection (VSLI, Marqibo): interim results from a phase I study in children and adolescents with refractory cancer. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 1497.

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HOPA Annual Conference

Comprehensive Gene Analysis Allows for Personalization of 5-FU to Reduce Risk of Toxicity Wayne Kuznar

A

bout 3% to 5% of the general population is believed to have a mutation in the gene that encodes a major 5-fluorouracil (5-FU) metabolizing enzyme. This mutation can extend the half-life of 5-FU, leading to increased plasma concentrations and potential toxicities, said Colleen Rock, PharmD, PhD, at the Hematology/Oncology Pharmacy Association 9th Annual Conference.

Comprehensive analysis of the gene – DPYD – can be used to personalize a patient’s 5-FU/capecitabine therapy, she said.

The rate-limiting enzyme in the metabolism of 5-FU (and its oral prodrug capecitabine) is dihydropyrimidine dehydrogenase (DPD), which is encoded by the DPYD gene. “A mutation in the gene can lead to drug accumulation; approximately 80% of 5-FU is rapidly metabolized by DPYD in the liver,” said Rock, clinical research associate at Myriad Genetic Laboratories, Inc, Salt Lake City, Utah. “If there’s a mutation that affects the protein function, it’s not going to be metabolized. There’s going to be accumulation, and this can lead to toxicity.”

Analyzing the DPYD gene “can allow us to decide whether to potentially reduce the dose of 5-FU in a patient or even switch to a different drug,” she said.

The data she presented were from an analysis of full gene sequencing test results from 3083 patients. DPYD analysis was performed by polymerase chain reaction and DNA sequencing. Genetic variants were tested using multiple variant classification techniques, including comparison with a consensus wild-type DPYD sequence.

“Because of the large number of patients included in this analysis, we have good information regarding prevalence, and found that the prevalence for the common DPYD mutations in the testing population is 7.3%,” said Rock.

The 3 common high-risk mutations were IVS14+1G>A

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(52.0%), D949V (40.5%), and 1560S (7.5%).

Full sequence analysis of the gene allowed for detection of a unique variant – E412E – that has been linked with a deleterious mutation in DPYD in some cases (N=12). “When we take the E412E variant into account, along with the common mutations, the potential exists for an almost 11% prevalence of gene mutation,” she said. “These patients who have a mutation are at risk for toxicity. Only full gene sequencing allows for identification of both common and novel mutations that may be associated with 5-FU toxicity.”

In a subset of 24 patients who were tested for DPYD mutations in response to an elevated 5-FU plasma level, gene variants were identified in 7 of the 24. In this population, the E412E variant occurred with similar frequency as that of the common high-risk mutations.

DPYD mutations were found with greater frequency in patients who suffered a greater number of 5-FU toxicities prior to DPYD gene testing. While the majority of patients were tested after experiencing at least one 5-FU toxicity, among those without pretest toxicities, the prevalence of DPYD mutations was 4.7%, which increased to 31.6% in patients with 4 toxicities.

Among the 5-FU toxicities, the prevalence of mutations (18.5%) was greatest for hematopoietic events, followed by hand-foot syndrome and stomatitis (12.6% each).

Most providers choose to submit a sample for testing after a 5-FU toxicity has occurred, said Rock. “I think that the preference would be to prevent toxicities and therefore test ahead of time, including for the E412E mutation,” she said.

The prevalence of mutations also varied by ancestry, with mutations most common among European and Latin American patients. u

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SNPs Identified for Further Study in Association With QOL in Men With Prostate Cancer Treated With Radiation Phoebe Starr

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nvestigators at Harvard Medical School have identified candidate single nucleotide polymorphisms (SNPs) in genes associated with inflammation that will be explored further with regard to their associations with long-term quality-of-life (QOL) effects of radiation therapy (RT) in men with prostate cancer.

The authors found 7 SNPs significantly associated with long-term QOL outcomes after RT, but these SNPs did not retain statistical significance in a comparator group of men treated with radical prostatectomy.

“Men with prostate cancer have significant decrements in quality of life, which may be related to genetic differences. In particular, inflammation-related genes may impact long-term toxicity following radiation therapy, including esophagitis and pneumonitis,” stated presenting author Jonathan Schoenfeld, MD, Harvard Radiation Oncology Program, Boston, Massachusetts.

“We have confirmed significant associations with SNPs and quality of life in men treated with radiotherapy, and these associations require prospective assessment regarding their relationship to QOL.” The study was based on blood samples collected from men diagnosed with prostate cancer and treated with RT between 1982 and 2006. All men were enrolled in the prospective US Physicians’ Health Study (USPHS), a randomized trial of aspirin and beta-carotene. Fortythree SNPs in 10 inflammation-related genes (previously found to be associated with prostate cancer) were genotyped and analyzed using the additive model.

Men with confirmed cases of prostate cancer (n=264) were given questionnaires at intervals during the years 2005 and 2007, a median of 6 years after diagnosis. The questionnaires followed QOL outcomes for the following symptoms experienced over the years since diagnosis and RT: decreased force of urinary stream, increased urinary frequency or urgency, rectal urgency, and impotence.

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Medical records were obtained and reviewed as well.

The first cohort was specifically limited to men with nonmetastatic prostate cancer treated with definitive RT. A second cohort of 337 men treated with definitive radical prostatectomy served as a comparison group.

“We limited excluded analysis to Caucasian men, and excluded other races,” said Dr Schoenfeld.

The first cohort of 264 men treated with RT had a median age of 72 years and were predominantly low-risk patients. Sixty-one percent had Gleason scores <7; 98% were early clinical stage.

The investigators identified 13 SNPs significantly associated with QOL. On multivariate analysis, 7 remained statistically significant. The SNPs were found on the following genes: IL8 (1 SNP), NFKB (2 SNPs), RNASEL (2 SNPs), CRP (1 SNP), and TLR10 (1 SNP).

Between 20% and 29% reported severe urinary and rectal symptoms, and 72% reported severe impotence.

Between 71% and 80% reported mild/never urinary and rectal symptoms, and 28% reported mild/never impotence.

In the second cohort of 337 men from the USPHS treated with radical prostatectomy, 71% had Gleason scores <7 and 95% were early stage.

Unfortunately, baseline characteristics and QOL results between the RT and surgical patients were not comparable. Between 9% and 15% had urinary or rectal symptoms and 82% had moderate to severe impotence.

“None of the 7 SNPs that were statistically significantly associated with the 4 parameters of QOL retained their statistical significance in men treated with radical prostatectomy,” Schoenfeld said.

Schoenfeld told the audience that the study had several limitations, including lack of pretreatment data and no correction for multiple testing. “The study is hypothesis generating. The mechanism of action of the selected genes is currently unknown. We performed incomplete sequencing of SNPs we tested.” u

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Targeted Therapies Added to Docetaxel Do Not Extend Survival in Metastatic Prostate Cancer Phoebe Starr

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he latest in a string of failed trials of targeted therapies added to docetaxel in metastatic castration-resistant prostate cancer (mCRPC) were presented at the 2013 Genitourinary Cancers Symposium. No survival benefit was observed with the addition of aflibercept to docetaxel/prednisone in the VENICE trial1 or with the addition of dasatinib to docetaxel/prednisone in the READY trial.2 These trials are expensive to mount and manage, and the medical community, including patients, invests a great deal of time and energy into these trials in the hope of identifying a treatment that improves outcomes.

Formal discussant of these trials, William Oh, MD, Mt. Sinai School of Medicine, New York City, stated that much stronger phase 2 evidence is needed before mounting yet another trial of a new agent added to docetaxel in this setting. He suggested that novel trial designs based on molecular-guided enrollment would be a step forward.

VENICE Trial The large multinational double-blind VENICE trial randomized 1224 men with mCRPC with progressive disease on hormonal therapy or surgical castration to first-line therapy with aflibercept plus docetaxel versus docetaxel. Aflibercept is a potent antiangiogenic fusion protein that binds VEGF-A, VEGF-B, and placental growth factor, with preclinical data to support its use.

At a median follow-up of 35 months, no difference in overall survival (OS), the primary end point, was observed.

OS was 22.1% in the aflibercept arm versus 21.1% in the placebo arm. Progression-free survival (PFS) was a median of 6.9 months versus 6.2 months, respectively. Time to first skeletal-related event (SRE) was almost identical: median of 15.3 months versus 15 months, respectively.

Patients in the aflibercept arm had a higher rate of toxicities, including serious adverse events, compared with the placebo arm. Grade 3/4 adverse events were

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reported in 77% of the aflibercept arm versus 48.5% in the placebo arm.

“This study provides a lesson that when we design large phase 3 trials, we need strong evidence of improved activity with the agent we want to study. As yet, no added agent has improved upon docetaxel plus prednisone in men with mCRPC,” stated presenting author Ian Tannock, MD, Princess Margaret Cancer Centre,Toronto, Canada.

READY Trial Based on preclinical data showing synergy for dasatinib, an Src kinase inhibitor, plus docetaxel and phase 2 safety data, the READY trial randomized 1522 patients with progressive mCRPC to dasatinib or placebo; all patients were treated with docetaxel plus prednisone.

“It is disappointing, but dasatinib did not improve median OS versus docetaxel alone,” said presenting author John Araujo, MD, MD Anderson Cancer Center, Houston, Texas.

Survival curves were virtually identical: 21.5 months for dasatinib and 21.2 months for docetaxel. No OS benefit was observed for dasatinib in any of the subgroups analyzed.

No meaningful changes were seen between the arms in response rates, bone turnover markers, PFS, or pain reduction. However, time to first SRE was a median of 31.1 months in the placebo group and not reached in the dasatinib group.

Treatment-emergent adverse events were observed in 18% of patients on the dasatinib arm versus 9% on the placebo arm.

Thirty percent of patients in both arms had serious adverse events. u

References

1. Tannock I, Fizazi K, Ivanov S, et al. Aflibercept versus placebo in combination with docetaxel/prednisone for first-line treatment of men with metastatic castration-resistant prostate cancer (mCRPC): results from the multinational phase III trial (VENICE). J Clin Oncol. 2013;31(suppl 6). Abstract 13.

2. Araujo JC, Trudel GC, Saad F, et al. Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): results from the randomized phase III READY trial. J Clin Oncol. 2013;31(suppl 6). Abstract LBA8.

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Prostate and Kidney Cancer News From the 2013 Genitourinary Cancers Symposium Alice Goodman

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Adjuvant Radiotherapy Reduces Risk of PSA Failure Compared With Wait-and-See Approach in Locally Advanced Prostate Cancer

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xtended follow-up of the German ARO 96-02 trial adds to the evidence that adjuvant radiotherapy reduces the risk of biochemical failure following radical prostatectomy in locally advanced prostate cancer (stage T3) versus a wait-and-see (WS) approach. Adjuvant radiotherapy reduced the risk of biochemical failure (rising prostate-specific antigen [PSA] level) by 49% at 10 years in this trial.

“Our long-term follow-up shows that it is incorrect to say that adjuvant radiation for patients with positive surgical margins stage is overtreatment. It is clear that adjuvant radiotherapy reduces biochemical evidence of disease after 10 years. It is quite important that we had a low rate of side effects, with only 1 case of grade 3 late toxicity,” stated presenting author Thomas Wiegel, MD, from the University of Ulm, Germany.

The study randomized 385 men with stage T3 prostate cancer following radical prostatectomy in a 1:1 ratio to adjuvant radiotherapy versus a WS approach.

A unique feature of this study – compared with other

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Photo by © ASCO/Todd Buchanan 2013.

pproximately 2350 urologists, oncologists, surgeons, radiation oncologists, and other oncology healthcare professionals gathered in Orlando, Florida, to attend the 2013 Genitourinary Cancers Symposium. The symposium, sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology, allows attendees to learn about the latest strategies for preventing, detecting, and treating cancers arising in the genitourinary organs. Following are summaries of some of the noteworthy abstracts presented at the symposium.

Thomas Wiegel, MD phase 3 trials in this setting – was that patients randomized to adjuvant radiotherapy received treatment following surgery before they were found to have an undetectable PSA level (<.05 ng/mL). The median number of positive nodes was 8; median follow-up was 112 months.

After exclusions for a variety of reasons, an intentto-treat analysis was based on 114 patients in the adjuvant radiotherapy arm and 159 in the WS arm. All patients had stage T3 disease; 27% had T3c (extension of cancer to the seminal vesicles). The majority of patients had Gleason scores ranging from 7 to 9.

The rate of 10-year freedom from biochemical failure was 56% in the adjuvant radiotherapy arm versus 35% in the WS arm, a significant absolute difference of 21% favoring adjuvant treatment (P=.00002).

No significant benefit was observed for adjuvant radiotherapy regarding metastasis-free survival or overall survival, although the trial was not powered to show this benefit.

The relative risk of biochemical failure was reduced for patients with positive surgical margins, higher PSA level, stage T3a/b, and higher Gleason scores.

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Wiegel said that late toxicity rates were low compared with previous trials conducted by SWOG and EORTC in this setting.

Formal discussant Anthony D’Amico, MD, PhD, of the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, said that until results of 2 ongoing trials evaluating adjuvant radiotherapy versus delayed radiotherapy are available, the decision to initiate adjuvant radiotherapy should be based on the number of risk factors, including Gleason score, surgical margins, extension into the seminal vesicles, and nodal status. u

Reference

Wiegel T, Bottke D, Bartkowiak D, et al. Phase III results of adjuvant radiotherapy (RT) versus wait-and-see (WS) in patients with pT3 prostate cancer following radical prostatectomy (RP)(ARO 96-02/AUO AP 09/95): ten years follow-up. J Clin Oncol. 2013;31(suppl 6). Abstract 4.

Photo by © ASCO/Todd Buchanan 2013.

Eighteen Months of Hormone Therapy Leads to Survival Similar to 36 Months in Combination With Radiation

Abdenour Nabid, MD

P

atients with high-risk prostate cancer who received radiation and hormone therapy as their primary treatment had similar survival with 18 months of hormone therapy compared with 36 months, according to results of a randomized phase 3 study.

“Hormone ablation therapy makes most men’s lives miserable,” stated presenting author Abdenour Nabid,

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MD, of the Centre Hospitalier Universitaire de Sherbrooke in Sherbrooke, Canada. Specifically, he said that the “castration syndrome” (lack of libido, erectile dysfunction, and hot flashes) compromises quality of life. Other symptoms include fatigue, weight gain, and mood irritability, and a small number of men have cardiovascular effects.

“Shorter-term hormone therapy could have a big impact on the lives of men with prostate cancer, reducing the quantity and intensity of its unpleasant side effects as well as treatment costs. We hope these results will convince doctors that they can stop hormone therapy after 1.5 years instead of 2 to 3 years,” he told listeners.

The optimal duration of androgen ablation therapy in high-risk prostate cancer is controversial. An EORTC study conducted in 2009 found that 6 months of androgen ablation in this setting was inferior to 36 months. The present study was designed to show that 18 months was superior to 36 months.

The study randomized 630 patients with node-negative, high-risk prostate cancer to radiotherapy to the pelvic area and prostate bed plus either 18 or 36 months of androgen ablation therapy (bicalutamide 1 month plus goserelin every 3 months).

Demographic and disease characteristics of the study population were well balanced between the arms. The median age was 71 years, the median PSA was 16 ng/ mL, and the median Gleason score was 8. Most patients had stage T2-T3 disease.

“These were truly high-risk patients,” Nabid noted.

At a median follow-up of 77 months, mortality was similar in the 2 arms: 22.9% in the shorter-duration hormone therapy arm versus 23.8% in the longer-duration arm. Among 147 deaths reported, 116 were due to causes other than prostate cancer.

At 5 years, overall survival rates were 92.1% versus 86.8% for the 2 arms, respectively, and 10-year survival rates were 63.6% versus 63.2%, respectively.

Disease-specific survival rates at 5 years were 97.6% versus 96.4%, respectively, and 10-year disease-specific survival rates were 87.2% in both arms.

“Importantly, the number of men dead due to pros-

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tate cancer was identical at 10 years,” Nabid stated.

Bruce Roth, MD, of Washington University in St. Louis, Missouri, was encouraged by these findings. He said that he wanted to examine the full peer-review publication of the study, but he was hopeful that the study would be practice changing. u

Reference

Nabid A, Carrier N, Martin A-G, et al. High-risk prostate cancer treated with pelvic radiotherapy and 36 versus 18 months of androgen blockade: results of a phase III randomized study. J Clin Oncol. 2013;31(suppl 6).

Abstract 3.

African Americans and Elderly Are at Increased Risk of High-Risk Prostate Cancer

E

lderly men and African American men whose prostate cancer was detected by PSA are at increased risk of having high-risk prostate cancer, according to a large, population-based, retrospective study. The findings imply that PSA testing may be warranted in elderly and African American men to find and treat high-risk cancers early, but more research is needed to demonstrate that early detection and treatment for high-risk prostate cancer can improve outcomes.

These findings are interesting in light of the US Preventive Services Task Force (USPSTF) recommendation to curtail routine PSA testing.

“If we stop PSA screening altogether [as recommended by the USPSTF], there is no other method to detect this form of prostate cancer sufficiently early to have the best chance of helping this group of high-risk patients. The findings of this study will help physicians and certain patients make more informed decisions on whether they want to proceed with PSA testing, although more research (and longer follow-up) is needed to determine the effects of early detection and intervention on outcome in these high-risk patients,” stated lead author Hong Zhang, MD, PhD, of the University of Rochester, New York.

The study found that about 40% of cases of highrisk, PSA-detected prostate cancer occur in men older than 75 years, and elderly men are 9.4 times more likely

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than men younger than 50 years to be at high risk. African American men of any age are more likely than white men to have high-risk disease.

The study identified 70,345 men from the Surveillance, Epidemiology, and End Results (SEER) registry data diagnosed with early-stage (T1c), node-negative, prostate cancer between 2004 and 2008. The investigators determined the probability of developing low-, intermediate-, and high-risk prostate cancer based on PSA criteria and Gleason stage. Low risk was defined as PSA <10 mg/L and Gleason score ≤6; intermediate risk was defined as PSA 10 to 20 mg/L and/or Gleason score 7; and high-risk disease was defined as PSA ≥20 mg/L and/or Gleason score ≥8; 47.6% were found to have low-risk disease, 35.9% intermediate-risk, and 16.5% high-risk.

Men older than 75 years accounted for 11.8% of the entire study population but comprised 24.3% of intermediate- and 26.1% of high-risk disease. African American men had a 50% higher chance of developing intermediate-stage prostate cancer and an 84% increased likelihood of developing high-risk prostate cancer compared with white men (P<.01 for both comparisons). u

Reference

Zhang H, Travis LB, Messing EM, et al. PSA-detected prostate cancer in the United States: a population-based study of 70,345 men with AJCC stage T1cN0M0 disease. J Clin Oncol. 2013;31(suppl 6). Abstract 50.

Detection of Prostate Cancer Increases With 10 to 12 Biopsy Specimens

U

rologists across the United States have largely adopted the evidence-based practice of obtaining 10 to 12 core biopsies of the prostate for the diagnosis of prostate cancer, and this practice has led to an increase in the rates of detection of prostate cancer, according to the results from one of the largest studies ever done in this setting.

“Segregation of prostate biopsy cores into 10 to 12 unique vials per biopsy has been adopted by urologists across sites of service, and it appears to be the de facto national standard of care,” stated presenting author

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Carl A. Olsson, MD, of Integrated Medical Professionals, LLC, New York City.

The massive study included more than 4.2 million specimens collected from about 440,000 biopsies. Data were collected from an annual mean of 1756.7 urologists in 765.6 practices in the United States. Biopsy rates and core sampling patterns were assessed in patients whose biopsies were submitted to either a national reference library (NRL) or a laboratory integrated into a urology practice lab (UPL).

The investigators analyzed the association between the rates of positive biopsies and the number of specimens per biopsy according to needle biopsy and anatomic pathology sampling. The analysis excluded saturation biopsies. For each year studied, the positive biopsy rate and the number of specimens per biopsy were recorded for both NRL and UPL, separately and combined.

In 2005, the positive biopsy rate was 38.2%, and the number of specimens per biopsy was 7.9; by 2011, the positive biopsy rate was 42.6%, and the number of specimens per biopsy was 10.7.

“The transition point was in 2008, suggesting that urologists were responding to published literature and guidelines recommending increased prostate sampling.

Physicians utilizing UPLs adopted these changes earlier than those using the NRL,” Olsson indicated in the poster.

The steepest increase in the number of specimens obtained occurred between 2005 and 2008, which was during the development of core sampling regimens.

The number of specimens obtained did not differ significantly across practice settings. u

In elderly patients in whom small asymptomatic kidney masses are found on imaging, surveillance is as safe and effective as surgery, especially in patients who are not good surgical candidates and/or who have comorbidities. In a retrospective analysis of more than 8300 elderly patients with small kidney masses, surveillance and surgery led to comparable kidney cancer–specific mortality, but surgery was associated with a higher risk of cardiovascular complications and all-cause mortality.

“Our analysis indicates that physicians can comfortably tell an elderly patient, especially a patient that is not healthy enough to tolerate anesthesia and surgery, that the likelihood of dying of kidney cancer is low and that kidney surgery is unlikely to extend their lives. However, since it is difficult to identify which tumors will become lethal, elderly patients who are completely healthy and have an extended life expectancy may opt for surgery,” stated lead author William C. Huang, MD, of the New York University School of Medicine, New York City.

The study used SEER registry data linked to Medicare claims for patients aged 66 years or older to identify 8317 patients diagnosed with small renal masses (ie, under 1.5 inches in diameter); 5706 (69%) underwent surgery and 2611 (31%) underwent surveillance.

At a median follow-up of 4.8 years, 2078 deaths were reported (25% of the population); 277 deaths (3%) were due to kidney cancer. The rate of kidney cancer­–specific death was identical with surveillance and surgery.

In an analysis adjusted for patient and disease characteristics, patients who were managed with surveillance had a significantly lower risk of death from any cause as well as a lower risk of a cardiovascular event.

The authors concluded that surveillance with modern imaging techniques is a safe option for management of small renal masses in elderly patients. u

Reference

Reference

For each year studied, the positive biopsy rate and the number of specimens per biopsy were recorded for both NRL and UPL, separately and combined.

Olsson CA, Kapoor DA, Mendrinos SE, et al. Utilization and cancer detection by U.S. prostate biopsies (2005-2011). J Clin Oncol. 2013;31(suppl 6). Abstract 107.

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Huang WC, Pinheiro LC, Russo P, et al. Surveillance for the management of small renal masses: utilization and outcomes in a population-based cohort. J Clin Oncol. 2013;31(suppl 6). Abstract 343.

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Biomarkers

Physician-Reported Clinical Utility of the 92-Gene Molecular Classifier in Tumors With Uncertain Diagnosis Following Standard Clinicopathologic Evaluation Benjamin Kim, MD, MPhil University of California San Francisco School of Medicine San Francisco, California Brock E. Schroeder, PhD Catherine A. Schnabel, PhD Mark G. Erlander, PhD bioTheranostics, Inc, San Diego, California Jennifer L. Malin, MD, PhD Veterans Affairs Greater Los Angeles Healthcare System UCLA Jonsson Comprehensive Cancer Center Los Angeles, California

Key Points • Tumor classification remains unknown or uncertain in a quarter to a third of newly diagnosed metastatic cancer • Defining and evaluating the clinical utility of molecular diagnostic assays is an evolving field • Given the complexity of genomic medicine, decision support tools may be needed to help physicians determine when testing is indicated and how to interpret results • Medical oncologists reported that use of the assay helped them make both diagnostic and treatment decisions

A

dvances in understanding the genetic basis of many cancers and the development of molecularly targeted therapies are increasing the need for diagnostic resolution. Patient outcomes have improved with the use of predictive biomarker testing, targeted therapies, and site-specific chemotherapy regimens.1,2 However, tumor classification

remains unknown or uncertain in a quarter to a third of newly diagnosed metastatic cancer,3,4 particularly in cases that are poorly differentiated or undifferentiated, contain limited biopsy tissue for immunophenotypic analysis, and/or are associated with atypical clinical presentation. Despite innovations in imaging and pathologic techniques, challenges with difficult-to-

Dr Kim is Assistant Professor of Clinical Medicine at the University of California San Francisco School of Medicine.

Dr Schroeder is Director, Medical & Scientific Affairs of bioTheranostics, Inc. Dr Schnabel is Vice President, Medical, Clinical & Regulatory Affairs of bioTheranostics, Inc. Dr Erlander is Chief Scientific Officer of bioTheranostics, Inc. Dr Malin is Associate Professor of Medicine at the UCLA Jonsson Comprehensive Cancer Center and continues her clinical practice by volunteering at the Veterans Affairs Greater Los Angeles Healthcare System.

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diagnose metastatic cancers are often compounded by molecular classification with the 92-gene assay reported the nonstandardized approaches traditionally employed interim overall survival results that compared favorably by clinicians to solve diagnostic dilemmas using iterwith previous trials of empiric treatment regimens for ative immunohistochemical (IHC) staining. FurtherCUP.16 more, this approach may delay diagnosis and incur An analysis of real-world clinical testing demonconsiderable costs,5,6 as well as deplete strated broader uptake of molecular tissue that may be essential for downclassification in recent years to restream predictive biomarker analysis. solve differential and confirm susIn recent years, molecular assays have pected diagnoses in challenging cases.7 been developed and are currently utiHowever, insight into how molecular lized as diagnostic complements to classification is being utilized in clinstandard clinicopathologic evaluation ical care and how it impacts oncoloin difficult-to-diagnose cases. Cancers gists’ clinical assessments and decision with unknown or uncertain primary making have not been evaluated. sites of origin is an area in oncology This study was designed to assess the that may significantly benefit from the characteristics and clinical decision use of molecular-based assays, in terms outcomes of medical oncologists who Benjamin Kim, MD, MPhil of improving both the accuracy and efhave ordered the 92-gene molecular ficiency of diagnostic classification, as classifier (CancerTYPE ID) and dewell as more tailored treatment recommendations. termine how they view the clinical value of the test in Molecular classifiers have been clinically validated, their practice.

7-10 with overall sensitivities ranging from 83% to 89%.

The accuracy and potential utility of molecular classiPatients and Methods fication in patients diagnosed with cancer of unknown This is a retrospective, survey-based study of medical primary (CUP) have been examined in several studoncologists who ordered the 92-gene assay as part of ies,11,12 and molecular classification has been incorporoutine clinical care. A 61-question survey was devel3,13 rated into diagnostic algorithms for CUP. Studies oped by the investigators for use in this study. The priexamining patient outcomes have demonstrated famary objectives of the study were to examine whether vorable outcomes in patients treated based on their the results of the 92-gene assay aided in: 1) the determolecular diagnosis. In a retrospective study, patients mination of a clinical diagnosis of the primary site of predicted to have a colorectal site of origin by molecorigin for their patient’s tumor, and 2) the therapeutic ular classification and treated with site-specific regidecision making for their patient. Additional assessmens had a median survival of 27 months, similar to ments included physician and patient characteristics; 14 patients with known metastatic colorectal cancer. In pre-assay diagnostic tests, diagnosis, and treatments (if a study combining retrospective cases from Sarah Canany); factors considered when ordering the 92-gene non Research Institute and prospective cases from The assay; circumstances under which physicians considered University of Texas MD Anderson Cancer Center, paordering the 92-gene assay; and how the 92-gene assay tients with a colon cancer molecular profile had better helped in the diagnosis of tumors and treatment planresponses to colon cancer–specific treatment regimens ning for patients, or why it was not helpful. The survey than those who were treated with empiric regimens (ie, was uploaded to a secure Web-based portal, pretested taxane/platinum).15 Finally, a prospective trial assessby multiple reviewers and on several Internet browsers, ing outcomes in patients with CUP treated based on and activated for use.

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To obtain the study sample population, a database of clinical cases maintained by bioTheranostics was queried to generate a file of 1105 medical oncologists based on the following inclusion criteria: 1) the oncologist must have had a tumor sample analyzed using the second generation of the 92-gene assay,7 2) the patient’s tumor sample must have had sufficient quantity and quality of RNA to pass quality control standards, 3) the 92-gene assay must have provided a prediction for the primary site of origin (ie, not unclassifiable by assay), and 4) the ordering physician’s name and contact information were available. Cases analyzed as part of clinical trials were excluded.

Carcinomas (26%) and adenocarcinomas (55%) were the most frequent histologic types based on pathologic evaluation prior to the 92-gene assay.

Physician participation was solicited via direct mail communication from investigators (BK and JLM), and physicians were directed to a secure Web site to complete the survey. To minimize selection and recall biases, participating physicians were asked to complete the survey questions as they pertained to the first patient for whom they ordered the 92-gene assay after a specified date (March 15, 2010) and to review the patient’s medical record prior to initiation of the survey. Thus, each physician only completed the survey for 1 patient. The survey was estimated to take 30 to 45 minutes, and physicians were offered $250 to complete the survey. Second and third contacts were made via direct mail or telephone to nonresponders. A third-party contract research organization (Percolation) provided operational support for the study.

The protocol was reviewed and approved by an independent institutional review board (Western Institutional Review Board); informed consent was not required for the study. Physicians were instructed that the survey was to be completed based only on materials (ie, data, documents, records) that had already

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been collected. No new patient-level data or patient identifying information were collected for the purposes of the survey. All statistical analyses were descriptive in nature, summarizing frequency and percentage distributions.

Results Physician and Patient/Tumor Baseline Characteristics Of 1105 physicians receiving invitations, 103 (9.4%) completed the Web-based survey. Physician and baseline patient/tumor characteristics are reported in the Table. The majority of respondents (82%) worked in community-based practices. Respondents had a median of 10 years of practice experience (range, 1-39 years), and most (77%) had utilized the 92-gene assay multiple times in the previous 12 months (median, 3; range, 0-20). The majority of patients had multiple sites of disease, most frequently involving lung (43%), liver (38%), lymph nodes (34%), and bone (10%). Carcinomas (26%) and adenocarcinomas (55%) were the most frequent histologic types based on pathologic evaluation prior to the 92-gene assay. The majority of tumors were poorly differentiated or undifferentiated; only 1 case involved a well-differentiated tumor.

Pre–92-Gene Assay Diagnostic Testing and Treatment Planning Patients underwent extensive diagnostic testing prior to physicians ordering the 92-gene assay. The mean number of IHC stains performed was 6.2 (median, 6; range, 1-17). Most patients (87%) had undergone a chest, abdomen, and/or pelvis CT scan, 61% a PET scan, 21% an MRI, 21% a colonoscopy, and 21% an esophagogastroduodenoscopy. In addition, 45% had serum tumor marker tests ordered.

Physicians were asked to report all clinically suspected primary sites of origin prior to ordering the 92-gene assay.

The mean number of clinically suspected sites of origin was 2.6; however, there were varying degrees of diagnostic certainty pre-assay: 34% of respondents reported a single suspected site, 66% had 2 or more suspected sites,

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Table. Medical Oncologist Respondent and Patient/Tumor Characteristics Medical Oncologist Characteristics

Patient/Tumor Characteristics

Practice setting, % Small to medium community practice (1-10 physicians)

51

ECOG performance status at time of first treatment, % 0

32

Large community practice (>10 physicians)

31

1

46

Regional medical center

3

2

17

Health maintenance organization

0

3

3

Academic medical center

14

4

1

VA medical center

1

Time practicing oncology, years Mean (SD)

12.6 (8.7)

Median

10

Range

1-39

New patients per month, No.

Sites of disease presentation, No. Mean (SD)

2.5 (1.7)

Median

2

Range

1-14

Frequent sites of disease presentation, % Lung

43

Mean (SD)

32.3 (22.7)

Liver

38

Median

30

Lymph nodes

34

8-170

Bone

10

Range

Biopsy site sent for CancerTYPE ID testing, %

New patients with metastatic cancer, % Mean (SD)

29.5 (19.8)

Liver

31

Median

25

Lung/pleura

16

Range

5-90

Lymph node

15

Histologic subtype of biopsy sample, %

Use of the 92-gene assay in past 12 months, No. Mean (SD)

3.8 (3.4)

Median

3

Range

0-20

Use of other molecular tests, %

Carcinoma

26

Adenocarcinoma

55

Squamous cell carcinoma

5

Unable to be determined

10

Other

4

KRAS mutation

95

BRAF mutation

81

Well differentiated

1

EGFR mutation

93

Moderately differentiated

17

ALK rearrangement

79

Poorly differentiated

50

BRCA1/2 mutation

85

Undifferentiated

8

Not otherwise specified

14

Unable to be determined/not known

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Histologic grade of biopsy sample, %

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To assess the circumstances under which physicians considered ordering the 92-gene assay, physicians were asked about their confidence in selecting the most appropriate treatment before ordering the assay and where in the treatment course they ordered it. A minority of physicians (18%) indicated high or very high confidence in being able to select the most appropriate treatment regimen prior to ordering the 92-gene assay (35% reported very low or low confidence and 47% moderate confidence). For therapeutic decision making, 31% of respondents ordered the assay after the patient had received at least 1 line of therapy, while the majority of physicians did not begin treatment until after the 92-gene assay results were received: 24% reported that they had a specific regimen in mind but did not begin treatment, while 45% did not have a single regimen in mind before ordering the 92-gene classifier.

Figure 1. Change in Clinically Suspected Sites of Origin and Concordance With Final Clinical Diagnosis Figure 1A A

Number of clinically-suspected sites of origin, %

Pre-92-gene assay

Post-92-gene assay

re 1B

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Percentage of Cases Number of clinicallysuspected sites of origin

1

2

3

4

5

6

7

8

9

10

B Concordance between 92-gene assay prediction and final clinical diagnosis

92-gene assay prediction considered in pre-assay diagnosis

Postâ&#x20AC;&#x201C;92-Gene Assay Impact on Clinical Diagnosis The 92-gene assay predicted 26 different tumor types, including both common (eg, No lung, breast, colorectal) and rare tumor types Yes 33% Yes 84% No 16% 67% (eg, cholangiocarcinoma, islet cell carcinoma; Figure 2A). The impact of the 92-gene assay on diagnostic certainty was assessed by comparing suspected tumor origin sites before and after the assay. Compared with before the assay, the number of clinically suspected sites A. Number of clinically suspected sites of origin before and after the 92-gene assay.

B. Concordance between the 92-gene assay prediction and final clinical diagnosis, and withof origin following the 92-gene assay decreased in concordant cases, the percentage of cases in which the 92-gene prediction was considered in the majority of cases (63% decreased, 33% in the initial pre-assay diagnosis. had the same number, and 4% increased), resulting in an overall decrease in the mean and 21% suspected 4 or more sites (Figure 1A). The most number of clinically suspected sites of origin from 2.6 to frequent clinically suspected primary sites of origin prior 1.2. Following incorporation of the 92-gene assay results, to ordering the 92-gene assay were lung (46%), gallbladmost physicians (84%) reported that they were able to der/biliary tree (26%), pancreas (26%), colon (25%), elucidate a single tumor site of origin (Figure 1A). breast (18%), and liver (17%).

The clinical utility of the 92-gene assay was also as-

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sessed by evaluating physician incorporation of the 92-gene assay prediction into their final clinical diagnosis. The 92-gene assay prediction was concordant with the final clinical diagnosis in 84% of cases (Figure 1B). Notably, in one-third of these cases, the molecular diagnosis provided by the 92gene assay had not been clinically considered prior to molecular testing (Figure 1B).

In most cases (80%), no additional diagnostic evaluations were performed following the 92-gene assay. In cases with additional post-assay evaluations, the most commonly conducted test was a PET scan.

Most physicians indicated that the 92gene assay was helpful in determining a final clinical diagnosis for the primary site of tumor origin (Figure 2B), with 78% of respondents answering “strongly agree” or “agree.” Of these, 45% indicated that the test result increased their confidence in an existing diagnosis, 30% reported that it aided in making an initial diagnosis, 20% said it helped to change the diagnosis, and 6% provided other responses. Among respondents who answered “disagree” or “strongly disagree,” the most common reason was that the test result was inconsistent with the clinical presentation or the oncologist’s impression of the primary tumor origin site.

Figure 2. Tumor Type Predictions and Physician-Reported Figure 2A Clinical Utility A

Lung - adenocarcinoma/large cell Cholangiocarcinoma Gallbladder - adenocarcinoma Breast - adenocarcinoma Gastroesophageal - adenocarcinoma Melanoma Ovary - serous Intestine - large Kidney - papillary cell carcinoma Urinary bladder - transitional cell carcinoma Germ cell - nonseminomatous Kidney - clear cell Neuroendocrine - pancreatic islet cell Skin - squamous cell Cervix - adenocarcinoma Intestine - small Liver Lung - squamous cell Ovary - mucinous Pancreas - adenocarcinoma Cervix - squamous cell Head/Neck - salivary gland Neuroendocrine - gastrointestinal carcinoid Neuroendocrine - small/large cell lung Sarcoma - malignant fibrous histiocytoma Urinary bladder - adenocarcinoma

Figure 2B

0

5

10

15

20

of92-Gene 92-gene Classifier %%of Classifier Predictions Predictions

B Strongly Agree

Agree

Neutral

Disagree Diagnostic Utility Therapeutic Utility

Strongly Disagree 0%

10%

20%

30%

40%

50%

Impact on Treatment Decision Making Respondents indicated that the 92-gene A. Tumor types predicted by the 92-gene assay in this study. B. Physician-reported clinical assay provided clinical utility for therapeuutility in response to questions asking whether the 92-gene assay helped determine a clinical diagnosis for primary site of origin (diagnostic utility) or helped in the treatment decisiontic decision making, with 81% of physicians making process (therapeutic utility). answering “strongly agree” or “agree” that the assay was helpful in the treatment decision-making process (Figure 2B). Among these respontreatment, and 6% stated that the test result allowed dents, 52% indicated that the assay guided the selection them to exclude a treatment regimen. Among responof an initial treatment regimen, 29% reported that it dents who did not agree that the 92-gene assay helped confirmed the appropriateness of a previously deterin the treatment regimen decision-making process, mined regimen, 10% said that it informed a change in the most common reason was that the test result was

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inconsistent with clinical presentation or impression.

Discussion There has been a rapid introduction of molecular diagnostic tests in oncology in recent years; however, to date, the value of molecular classification tests on diagnostic certainty and treatment decision making in routine clinical care have not been established. In the study reported here, the 92-gene molecular classification assay was generally ordered to characterize high-grade metastatic tumors that had undergone extensive clinical and pathologic evaluation prior to submission. Physicians reported using the assay to address a broad range of issues surrounding diagnostic uncertainty, including independent confirmation of a suspected diagnosis prior to treatment initiation, reassessment of an initial diagnosis following treatment failure, resolution of narrow differential diagnoses, and identification of primary

The value of molecular classification tests on diagnostic certainty and treatment decision making in routine clinical care have not been established. tumor site for patients diagnosed with CUP. Physicians reported strong diagnostic impact of the 92-gene assay.

The final clinical diagnosis was narrowed (in cases with a differential diagnosis pre-assay) or changed (in cases with a single suspected diagnosis pre-assay) in the vast majority of cases examined, and there was high concordance between the assay prediction and the final clinical diagnosis. Notably, in 41% of the cases, the molecular diagnosis was not clinically considered in the initial diagnosis prior to the assay; however, the physicianâ&#x20AC;&#x2122;s final diagnosis was changed to reflect the molecular diagnosis in two-thirds of these cases. In addition, few additional diagnostic tests were ordered after the molecular test, suggesting that most oncologist respondents viewed the results of the assay as being definitive. These findings highlight the difficulty in obtaining a definitive diagnosis for many high-grade metastatic cancers and the potential

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role of using an objective molecular diagnostic test to resolve a differential diagnosis or identify a primary site that was not considered following typical clinicopathologic characterization.

Difficult-to-diagnose tumors present a challenge to oncologists in terms of therapeutic decision making, as knowledge of tumor type and primary site of origin inform treatment selection from both an efficacy and safety standpoint. In the absence of a confirmed diagnosis of tumor type, patients are traditionally treated with empiric, broadly acting cytotoxic chemotherapy regimens that are associated with modest response, toxicity, and median survival times of only 6 to 10 months.3,17 The data reported in this study highlight the clinical impact of this challenge, as the 6 most common final clinical diagnoses (lung, pancreaticobiliary, ovary, kidney, breast, and melanoma; data not shown) require different treatment strategies, and several have approved, targeted therapies available.18 While not directly assessed in this study, multiple studies have provided evidence that optimizing treatment plans based on accurate tumor site of origin and targeting activated molecular pathways can improve patient outcomes compared with an empiric therapeutic approach.15,19-23 In particular, in a recently published prospective clinical trial, patients with metastatic CUP who were treated with sitespecific chemotherapy based on the 92-gene assay prediction had prolonged overall survival compared with historical controls from prior CUP trials from the same clinical trial network (median overall survival, 12.5 vs 9.1 months).16 Finally, the data reported here complement previous studies evaluating the clinical utility of genomic testing in the real-world setting. For example, studies investigating the clinical utility of the 21-gene recurrence score assay have shown that between 21% and 51% of physicians changed their recommendation for adjuvant breast cancer treatment following receipt of the assay results.24-27 In the present study, over half of respondents reported that the 92-gene assay either guided initial treatment choice, changed the treatment, or excluded a treatment.

The heterogeneity of different tumor types presents a

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challenge to prospectively evaluate the impact of incorporating molecular assays into diagnostic algorithms for metastatic cancer. Novel research designs are needed to help quantify the impact of these technologies.

Pragmatic trial designs, which have been proposed for comparing and evaluating the effectiveness of medical interventions in real-world settings,28-30 may have utility in assessing the associated impact of molecular diagnostic testing on clinical outcomes. For instance, patients could be randomized to receive usual diagnostic care or incorporation of a multigene molecular assay.

Diagnostic and therapeutic decisions would be at the discretion of the treating physician. While this design would not provide data regarding the efficacy of treatment based on specific genomic characteristics, such an approach would provide an assessment of the impact of a novel strategy (vs current standard of care) on a broad range of health outcomes, including survival, time to treatment, biopsy tissue preservation, total cost of care, and quality of life. Such studies are urgently needed so policies can be developed to ensure the optimal uptake of genomic medicine in clinical practice.

Several limitations should be considered when evaluating the results of this study. First, as a voluntary survey, there is the potential for a systematically different impression of clinical utility in survey responders versus nonresponders. Thus, the results of the study may not be generalizable to all test users. We attempted to mitigate for this possibility by collecting survey results from a large number of physicians (>100 individual oncologists) and only allowing 1 case per physician. Second, survey answers could be affected by recall error.

To address this issue, physicians were asked to review their patientâ&#x20AC;&#x2122;s medical record prior to completing the survey. Finally, we attempted to address the possibility of patient selection bias by instructing physicians to complete the survey for the first patient after a defined date, rather than allowing the physician to choose a particular case to review.

Conclusion Defining and evaluating the real-world clinical util-

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ity of molecular diagnostic assays is an evolving field.

More research into how oncologists incorporate the use of these testing modalities, make clinical assessments and treatment recommendations, and impact patient outcomes through their use will be important for assessing their place in standard clinical practice. Additional

This study was designed to assess the clinical indications and utility of molecular classification in real-world clinical practice. prospective studies incorporating molecular diagnostic assays will further help to define their clinical utility.

Moreover, given the complexity of genomic medicine, decision support tools may be needed to help physicians determine when testing is indicated and how to interpret results. This study was designed to assess the clinical indications and utility of molecular classification in real-world clinical practice. The 92-gene assay was utilized across an array of diagnostically challenging tumors, and medical oncologists reported that use of the assay resulted in more specific diagnoses for primary site of tumor origin and helped them make both diagnostic and treatment decisions.

Disclosures This study was funded by bioTheranostics, Inc. Study funding included support for the third-party contract research organization, as well as research support provided to BK and JLM. BES, CAS, and MGE are employees and stockholders of bioTheranostics, Inc. u

References

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2. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663-671.

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4. Hillen HF. Unknown primary tumours. Postgrad Med J. 2000;76:690-693.

5. Schapira DV, Jarrett AR. The need to consider survival, outcome, and expense when evaluating and treating patients with unknown primary

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carcinoma. Arch Intern Med. 1995;155:2050-2054.

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7. Erlander MG, Ma XJ, Kesty NC, et al. Performance and clinical evaluation of the 92-gene real-time PCR assay for tumor classification. J Mol Diagn. 2011;13:493-503.

8. Kerr SE, Schnabel CA, Sullivan PS, et al. Multisite validation study to determine performance characteristics of a 92-gene molecular cancer classifier. Clin Cancer Res. 2012;18:3952-3960.

9. Pillai R, Deeter R, Rigl CT, et al. Validation and reproducibility of a microarray-based gene expression test for tumor identification in formalin-fixed, paraffin-embedded specimens. J Mol Diagn. 2011;13:48-56.

10. Rosenwald S, Gilad S, Benjamin S, et al. Validation of a microRNA-based qRT-PCR test for accurate identification of tumor tissue origin. Mod Pathol. 2010;23:814-823.

11. Greco FA, Spigel DR, Yardley DA, et al. Molecular profiling in unknown primary cancer: accuracy of tissue of origin prediction. Oncologist.

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12. Greco FA. Evolving understanding and current management of patients with cancer of unknown primary site. Commun Oncol. 2010;7:183-188.

13. Greco FA, Oien K, Erlander M, et al. Cancer of unknown primary: progress in the search for improved and rapid diagnosis leading toward superior patient outcomes. Ann Oncol. 2012;23:298-304.

14. Hainsworth JD, Schnabel CA, Erlander MG, et al. A retrospective study of treatment outcomes in patients with carcinoma of unknown primary site and a colorectal cancer molecular profile. Clin Colorectal Cancer.

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Guidelines in Oncology (NCCN Guidelines). www.nccn.org/professionals/ physician_gls/f_guidelines.asp#site. Accessed August 15, 2012.

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22. Pentheroudakis G, Pavlidis N. Serous papillary peritoneal carcinoma: unknown primary tumour, ovarian cancer counterpart or a distinct entity?

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23. Hainsworth JD, Fizazi K. Treatment for patients with unknown primary cancer and favorable prognostic factors. Semin Oncol. 2009;36:44-51.

24. Oratz R, Kim B, Chao C, et al. Physician survey of the effect of the 21-gene recurrence score assay results on treatment recommendations for patients with lymph node-positive, estrogen receptor-positive breast cancer. J Oncol Pract. 2011;7:94-99.

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30. Roland M, Torgerson DJ. What are pragmatic trials? BMJ. 1998;316:285.

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For indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen

Established treatment, demonstrated results Single-agent TREANDA® (bendamustine HCl) for Injection provided durable responses that lasted a median of 9 months Median DR

9.2 months (95% CI: 7.1, 10.8)

All responders (n=74) Patients who achieved a CR/CRu

10.4 months (95% CI: 9.3, 13.6)

1

8.3 months (95% CI: 6.3, 10.8)

Patients who achieved a PR

1

0

2

4

6

Months

8

10

12

The efficacy of TREANDA was evaluated in a single-arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

In 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176), the most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%).

TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

• TREANDA is administered with a convenient dosing schedule – The recommended dose is 120 mg/m² administered intravenously over 60 minutes on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA • The most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥15%) are lymphopenia, leukopenia, anemia, neutropenia, and thrombocytopenia

Learn more at www.TREANDAHCP.com

Please see accompanying brief summary of full Prescribing Information.

Reference: 1. Data on file. Teva Pharmaceuticals.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2577b January 2013

Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkin Lymphoma That Has Progressed INDICATION AND USAGE: TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression (see Table 2). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports.

Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death.

Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain.

Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.

ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles.

The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176).

System organ class, preferred term, and number (%) of patients* are shown.

Total number of patients with at least 1 adverse reaction— All Grades: 176 (100); Grade 3/4: 94 (53).

Cardiac disorders, All Grades and Grade 3/4—Tachycardia: 13 (7), 0.

Gastrointestinal disorders, All Grades and Grade 3/4—Nausea: 132 (75), 7 (4); Vomiting: 71 (40), 5 (3); Diarrhea: 65 (37), 6 (3); Constipation: 51 (29), 1 (<1); Stomatitis: 27 (15), 1 (<1); Abdominal pain: 22 (13), 2 (1); Dyspepsia: 20 (11), 0; Gastroesophageal reflux disease: 18 (10), 0; Dry mouth: 15 (9), 1 (<1); Abdominal pain upper: 8 (5), 0; Abdominal distension: 8 (5), 0.

General disorders and administration site conditions, All Grades and Grade 3/4—Fatigue: 101 (57), 19 (11); Pyrexia: 59 (34), 3 (2); Chills: 24 (14), 0; Edema peripheral: 23 (13), 1 (<1); Asthenia: 19 (11), 4 (2); Chest pain: 11 (6), 1 (<1); Infusion site pain: 11 (6), 0; Pain: 10 (6), 0; Catheter site pain: 8 (5), 0.

Infections and infestations, All Grades and Grade 3/4—Herpes zoster: 18 (10), 5 (3); Upper respiratory tract infection: 18 (10), 0; Urinary tract infection: 17 (10), 4 (2); Sinusitis: 15 (9), 0; Pneumonia: 14 (8), 9 (5); Febrile Neutropenia: 11 (6), 11 (6); Oral Candidiasis: 11 (6), 2 (1); Nasopharyngitis: 11 (6), 0.

Investigations, All Grades and Grade 3/4—Weight decreased: 31 (18), 3 (2).

Metabolism and nutrition disorders, All Grades and Grade 3/4—Anorexia: 40 (23), 3 (2); Dehydration: 24 (14), 8 (5); Decreased appetite: 22 (13), 1 (<1); Hypokalemia: 15 (9), 9 (5).

Musculoskeletal and connective tissue disorders, All Grades and Grade 3/4—Back pain: 25 (14), 5 (3); Arthralgia: 11 (6), 0; Pain in extremity: 8 (5), 2 (1); Bone pain: 8 (5), 0.

Nervous system disorders, All Grades and Grade 3/4—Headache: 36 (21), 0; Dizziness: 25 (14), 0; Dysgeusia: 13 (7), 0.

Psychiatric disorders, All Grades and Grade 3/4—Insomnia: 23 (13), 0; Anxiety: 14 (8), 1 (<1); Depression: 10 (6), 0.

Respiratory, thoracic and mediastinal disorders, All Grades and Grade 3/4—Cough: 38 (22), 1 (<1); Dyspnea: 28 (16), 3 (2); Pharyngolaryngeal pain: 14 (8), 1 (<1); Wheezing: 8 (5), 0; Nasal congestion: 8 (5), 0.

Skin and subcutaneous tissue disorders, All Grades and Grade 3/4—Rash: 28 (16), 1 (<1); Pruritus: 11 (6), 0; Dry skin: 9 (5), 0; Night sweats: 9 (5), 0; Hyperhidrosis: 8 (5), 0.

Vascular disorders, All Grades and Grade 3/4—Hypotension: 10 (6), 2 (1). *Patients may have reported more than 1 adverse reaction.

NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients Hematology Variable All Grades Grade 3/4 Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. 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: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat.

Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known.

Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration.

• Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes.

If particulate matter is observed, the reconstituted product should not be used.

• Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution.

After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light.

Administration of TREANDA must be completed within this period.

DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.

HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

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Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ©2008-2012 Cephalon, Inc., or its affiliates.

TRE-2486c November 2012 (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDA full Prescribing Information.

Interview With the Innovators

Promoting the Adoption of Personalized Medicine Concepts: An Interview With Edward Abrahams, PhD, of the Personalized Medicine Coalition Edward Abrahams, PhD Personalized Medicine Coalition Washington, DC

T

he Personalized Medicine Coalition (PMC) is The PMC has 4 goals: 1) to provide opinion leadership an organization representing innovators, scienon public policy issues that affect personalized medicine; tists, patients, providers, and payers. PMC pro2) to help educate the public, policymakers, government motes the understanding and adoption of personalized officials, and private sector healthcare leaders about the medicine concepts, services, and prodpublic and personal health benefits of ucts for the benefit of patients and the personalized medicine; 3) to serve as health system. It has grown from its a forum for identifying and informing original 18 founding members in 2004 others of those public policies that may to over 225 members today. impede the ability to deliver the promThe mission of the PMC is to edise of personalized medicine; and 4) to ucate federal and state policymakers create a structure for achieving consenand private sector healthcare leaders sus positions on crucial public policy about personalized medicine â&#x20AC;&#x201C; helping issues and supporting changes needed them to understand the science, the to further the public interest in personcomplex issues associated with implealized medicine. mentation, and the requirements for Personalized Medicine in Oncology Edward Abrahams, PhD the positive evolution of personalized (PMO) recently had the great pleasure medicine. The PMC has demonstrated of meeting with the president of the its unique role in the field by encompassing all sectors PMC, Edward Abrahams, PhD, to discuss his views of of the biomedical enterprise within its membership and personalized medicine and the vital role the PMC plays effectively framing the debate around the key obstacles in the adoption of personalized medicine principles in to adoption of personalized medicine. our healthcare systems.

PMO Thank you so much for taking the time to speak with us, Dr Abrahams. To start, how does personalized medicine (PM) empower both the cancer patient and the physician regarding its broadening of clinical options that it offers them? Does this broaden-

ing of options require oncologists to invest more time in dialogue with patients and caregivers? And finally, does the financial system currently reimburse oncologists for these added cognitive services?

Dr Abrahams Personalized medicine, as the Per-

Dr Abrahams is President of the Personalized Medicine Coalition. Previously he has served as Executive Director of the Pennsylvania Biotechnology Association, Assistant Vice President for Federal Relations at the University of Pennsylvania, and in a senior administrative position at Brown University. Dr Abrahams also worked for 7 years for the US Congress as a legislative assistant to Senator Lloyd Bentsen, as an economist for the Joint Economic Committee under the chairmanship of Representative Lee Hamilton, and as an AAAS Congressional Fellow for the House Committee on the Interior.

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sonalized Medicine Coalition envisions it, incorporates new discoveries in biology and the development of new diagnostic tools to enable physicians to target treatments more precisely, thereby improving their efficacy and sparing unnecessary and adverse side effects. The evolution of medicine away from one-size-fits-all to one that is personalized is likely to require physicians to engage in a more complex dialogue with patients and caregivers than what has been necessary in the past. It has been said that a good doctor treats the disease, while a great doctor treats the patient. However, the current system of reimbursement for oncologists might not yet recognize this increased demand on physicians’ time.

We expect more progress in the future as key decision makers in academia, industry, and government continue to invest in personalized medicine.

PMO What tactics have proven most successful in bringing the advances of PM out of the research laboratory and into practice for the oncologist?

Dr Abrahams While science points us toward a better appreciation of the understanding of the heterogeneity of cancer as well as patients, we know that how products are regulated and, more importantly, how they are reimbursed make an enormous difference regarding their adoption by oncologists.

PMO Your Web site mentions that the Personalized Medicine Coalition is dedicated to overcoming the obstacles to PM. What would you regard as the leading obstacle to the proliferation of oncology PM? Dr Abrahams There are a number of obstacles that slow down the emergence of personalized medicine.

Chief among them are an evolving regulatory system that does not yet ideally review combined therapeutic and diagnostic products; a reimbursement system that does not clearly define what levels of evidence are necessary to make payment decisions, (reimbursement sometimes does not cover the cost of performing

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the test, much less the R&D for it), and a time lag by medical societies to adopt new approaches into their guidelines.

PMO Can you name an outstanding example of overcoming an obstacle to PM? Dr Abrahams There has been enormous progress in overcoming obstacles to personalized medicine, including the recent and rapid approvals of new targeted therapeutics for non–small cell lung cancer, for melanoma, and for cystic fibrosis. Clearly science points us in the direction of linking diagnosis and therapy. We expect more progress in the future as key decision makers in academia, industry, and government continue to invest in personalized medicine.

PMO How supportive are the industry, government, and clinical sectors regarding PM? Is the climate between these sectors essentially cooperative, adversarial, or indifferent to one another?

Dr Abrahams Given that all 3 sectors have been mired in a one-size-fits-all/trial-and-error world for decades, it is understandable that they are not able to turn on a dime. We have a lot of work to do to convince each that investing in personalized medicine will pay dividends for patients and the health system. But we need more evidence to convince them.

PMO Is the Affordable Care Act (ACA) financially compatible with the growth of PM overall and specifically in oncology, or will its additional costs reduce the spread of PM overall and in oncology in particular?

Dr Abrahams By creating accountable care organizations, which will be under considerable pressure to produce better outcomes while lowering overall costs, the ACA could put a premium on prescribing the right drugs for the right patients and avoiding the inefficiencies that result from one-size-fits-all/trial-anderror medicine. It will be very hard to maintain progress while lowering costs if we do not look to personalized medicine to provide answers that patients are going to want. So on balance, we are optimistic about healthcare reform.

PMO Value is more than cost – it is the balance of cost, quality, and access. What percent of oncology

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Interview With the Innovators

healthcare expenditures go to PM treatment and diagnostics, and how long will it take for PM to begin “paying dividends” economically (it already pays dividends clinically) and become attractive to payers by showing “value”? And finally, how would you articulate the value proposition justifying the cost of PM – in cancer, and overall – to the clinical, business, and government sectors…and to patients?

Dr Abrahams These are the key questions. Beginning with the last first: We believe that even if the cost of individual products increases, by increasing efficacy and decreasing inefficiency we can increase value both to the individual patient and to the system. While it is hard to determine what percentage of oncology healthcare expenditures are personalized, we do know that 75% of current treatments in oncology don’t work as intended for a given patient. That’s a lot of room for improvement. We believe that payers understand this, and we hope that they will work with us to get the right drugs to the right patients as we move away from a onesize-fits-all world.

PMO Is the pricing methodology of manufacturers for PM therapies and diagnostics becoming more sophisticated/skillful and less arbitrary, so as to balance necessary profit with product affordability?

Dr Abrahams Price and value should be correlated, something industry and payers both understand. If society wants innovation, it has to be willing to pay for it and be patient enough to facilitate its sometimes incremental development.

PMO If a biologic is developed that treats a cancer with a large patient population so well that it keeps the patient alive for the rest of their normal life expectancy, how do we avoid bankrupting the healthcare system?

Dr Abrahams The question overlooks the value of a patient returning to work, and becoming a productive person again who pays for the treatment he or she receives. That should be the goal of the healthcare system.

PMO How can manufacturers and payers work

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together to avoid this cost/quality clash of PM? Dr Abrahams Again, we believe that manufacturers and payers are on the same page regarding a common wish to develop and pay for products that prevent illness, cure disease when it occurs, and keep citizens productive.

PMO Dr Vicki Seyfert-Margolis, formerly of the FDA, has stated that the current reward system causes research of biologics to be repeated many times, resulting in a large attrition for pioneer products and greatly increasing developmental costs of biologicals. What is the remedy for this problem of nontransparency?

In the future, we expect that we will not refer to personalized medicine at all because all medicine will be personalized.

Dr Abrahams As Dr Seyfert-Margolis notes, there are many things the FDA could do to increase the efficacy of clinical trials and reduce their costs, including allowing smaller sample sizes, not requiring trials of biomarker-negative populations for lifesaving products until after approval, and permitting, if not encouraging, “adaptive” trials based on early results.

PMO How prominent a role do you expect PM to play in treating conditions in indications outside oncology? Are there any impediments to PM’s application in them?

Dr Abrahams In the future, we expect that we will not refer to personalized medicine at all because all medicine will be personalized. Obviously, we have a lot of work to do before that happens. Because of the obvious heterogeneity of cancer, more progress has been made in oncology to personalize treatment, but this does not mean that CNS disorders, for example, will not lend themselves to same sort of sophisticated diagnoses in the future. Progress depends on it. u

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CONTINUING EDUCATION 6th Annual

APRIL 2013 • VOLUME 6 • NUMBER 1

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Frontline and Retreatment Settings PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen Grants/Project Associate Susan Yeager The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattanonont Ferris Vice President of Finance Andrea Kelly Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino

LETTER

FROM THE

EDITOR-IN-CHIEF

Over the past decade, significant progress has been made in the management of multiple myeloma (MM), including new standards of care and the development and approval of several novel, effective agents. Despite this progress, more work needs to be done and numerous questions remain regarding the application and interpretation of recent clinical advances.

In this sixth annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this first issue, experts from the John Theurer Cancer Center at Hackensack University Medical Center answer questions related to the management of patients with newly diagnosed and relapsed/refractory myeloma in the era of novel agents.

Sincerely, Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean Digital Programmer Michael Amundsen

FACULTY David Siegel, MD, PhD Chief, Myeloma Division John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Elizabeth Bilotti, MSN, BSN, APN-C Nurse Practitioner, Multiple Myeloma Division John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Greg Eskinazi, RPh, MAS, BCOP Oncology Research Pharmacist John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Business Manager Blanche Marchitto

Supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company.

Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

Center of Excellence Media, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512

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April 2013

CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company.

Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM).

Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-007-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss existing and emerging therapeutic options for patients with newly diagnosed or relapsed/refractory MM and how to tailor therapy for individual patients • Describe the pharmacokinetics and pharmacodynamics of novel

agents when integrating these agents into treatment regimens for MM • Evaluate adverse event management strategies for patients with MM receiving novel therapies and multidrug regimens

Board for Celgene Corporation and on the Research Advisory Board for Eli Lilly. He does intend to discuss either non–FDAapproved or investigational use for the following products/devices: MLN9708, oprozomib, BT062, CC-223, and BHQ880.

Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships.

Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred.

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months.

Planners’ and Managers’ Disclosures William J. Wong, MD, MLI Reviewer, has nothing to disclose.

Bobbie Perrin, RN, OCN, MLI Reviewer, has nothing to disclose.

Nancy Nesser, JD, PharmD, MLI Reviewer, has nothing to disclose.

Faculty Disclosures Sagar Lonial, MD, is on the Advisory Board for and is a Consultant to Bristol-Myers Squibb, Celgene Corporation, Millennium: the Takeda Oncology Company, Novartis, Onyx Pharmaceuticals, and sanofi-aventis. He does not intend to discuss any non-FDA-approved or investigational use for any products/devices.

David Siegel, MD, PhD, is on the Speaker’s Bureau and Advisory Boards for Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals. He does intend to discuss either non–FDA-approved or investigational use for the following products/devices: MLN9708, oprozomib, daratumumab, and Arry-520.

Elizabeth Bilotti, MSN, BSN, APN-C, is on the Advisory Board and Speaker’s Bureau for and is a Consultant to Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals. She does not intend to discuss any non– FDA-approved or investigational use for any products/devices.

Greg Eskinazi, RPh, MAS, BCOP, is on the Pharmacist Advisory

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13008A. html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online.

If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org.

For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net.

Estimated time to complete activity: 1.0 hour Date of initial release: April 11, 2013 Valid for CME/CPE/CE credit through: April 11, 2014 SCAN HERE to Download the PDF or Apply for Credit.

To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone

Recent Advances in the Management of Multiple Myeloma David Siegel, MD, PhD

Chief, Myeloma Division, John Theurer Cancer Center Hackensack University Medical Center, Hackensack, NJ

Introduction The positive impact of novel therapies on newly diagnosed and relapsed/refractory multiple myeloma (MM) has been observed in both transplant-eligible and -ineligible patients. The development of next-generation agents, as well as new dosing schedules and modes of administration, have also contributed to greater efficacy and tolerability for many patients. In this article, David Siegel, MD, PhD, discusses some of the latest advances in myeloma treatment and offers insights on therapy selection and future directions in the management of the disease.

Given the wide array of choices available, is there a standard of care for the frontline treatment of transplant-eligible patients with MM? In myeloma, the main goal of induction therapy is disease cytoreduction.

This is important for improving performance status in newly diagnosed patients, which makes them more viable candidates for autologous stem cell transplantation (ASCT). It is critical during induction to reduce the tumor burden and increase the amount of healthy bone marrow to optimize stem

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cell mobilization. As shown in Table 1a, there are numerous options for treating newly diagnosed transplant-eligible patients.1 Among these choices, I think the most commonly used regimens, at least in larger cancer centers, are lenalidomide/bortezomib/dexamethasone (RVD) and cyclophosphamide/bortezomib/dexamethasone (CyBorD), which have both demonstrated good efficacy and ease of use. In a phase 1/2 study in newly diagnosed patients, treatment with RVD resulted in a partial response (PR) or better rate of 100%, with a 74% very good partial response (VGPR) or better rate in the phase 2 population.2 In a phase 2 study, CyBorD also demonstrated significant activity in newly diagnosed MM, including an overall response (OR) rate of 88% and a VGPR or better rate of 61% after 4 cycles of therapy.3 In the phase 2 EVOLUTION study, CyBorD and RVD were shown to have similar activity4; complete response (CR) was achieved in 22% and 47% of patients treated with 2 different schedules of CyBorD and 24% of patients treated with RVD. The fact that we are now able to offer patients subcutaneous (SQ) bortezomib has decreased the incidence and severity of peripheral neuropathy (PN) with these and other bortezomib-containing regimens. The 2012 approval of SQ bortezomib by the US Food and Drug Administration (FDA) was based on data from a few different studies, including the MMY-3021 trial, which compared the safety and efficacy of SQ versus intravenous (IV) administration in the relapsed myeloma setting.5 Rates of CR and VGPR after 4 cycles, OR after 8 cycles, time to response, duration of response, time to progression, progression-free survival (PFS), and 1-year overall survival (OS) were similar between treatment arms. However, the SQ route demonstrated improved tolerability compared with the IV route, especially in terms of PN.

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Table 1a. NCCN Recommendations: Initial Therapy for Transplant-eligible Patients1 Preferred Regimens

Category

Other Regimens

Category

VD

1

Dexamethasone

2B

PAD

1

DVD

2B

VTD

1

TD

2B

Rd

1

CRd

2A

CyBorD

2A

RVD

2A

Which regimens are being used for newly diagnosed patients who are not eligible for transplant?

CRd indicates carfilzomib/lenalidomide/dexamethasone; CyBorD, cyclophosphamide/bortezomib/dexamethasone; DVD, liposomal doxorubicin/vincristine/dexamethasone; NCCN, National Comprehensive Cancer Network; PAD, bortezomib/doxorubicin/dexamethasone; Rd, lenalidomide plus low-dose dexamethasone; RVD, lenalidomide/bortezomib/dexamethasone; TD, thalidomide plus dexamethasone; VD, bortezomib plus dexamethasone; VTD, bortezomib/thalidomide/dexamethasone.

Table 1b. NCCN Recommendations: Initial Therapy for Transplant-ineligible Patients1 Preferred Regimens

Category

Other Regimens Dexamethasone

Category

VD

2A

Rd

1

DVD

2B 2B

VMP

1

MP

2A

MPR

1

TD

2B

MPT

1

VAD

2B

DVD indicates liposomal doxorubicin/vincristine/dexamethasone; MP, melphalan plus prednisone; MPR, melphalan/prednisone/lenalidomide; MPT; melphalan/prednisone/thalidomide; NCCN, National Comprehensive Cancer Network; Rd, lenalidomide plus low-dose dexamethasone; TD, thalidomide plus dexamethasone; VAD; vincristine/doxorubicin/dexamethasone; VD, bortezomib plus dexamethasone; VMP; bortezomib/melphalan/prednisone.

There are clinical scenarios in which a 2-drug regimen may be a better option than a 3-drug regimen. For example, in patients who present with significant preexisting PN caused by diabetes or the myeloma itself, clinicians may choose to use lenalidomide plus low-dose dexamethasone (Rd), which has been shown to be active in newly diagnosed MM.6 Conversely, in patients who have significant renal dysfunction, bortezomib plus dexamethasone (VD), which has also demonstrated good clinical activity in the frontline setting,7 may be the preferred option, as physicians may be concerned about adequately dose-adjusting lenalidomide. There is a fear of using lenalidomide in the setting of renal insufficiency, which is based on the false perception that it is going to impact renal function. Physicians do, however, need to carefully follow dose-adjustment recommendations when using lenalidomide in renally impaired patients, because myelosuppression will be impacted by renal function.8 Another 3-drug regimen that is showing impressive results is carfilzomib/ lenalidomide/dexamethasone (CRd), which is the most recent addition to the National Comprehensive Cancer Network (NCCN) recommendations for frontline treatment of transplant-eligible patients.1 This combination was recently evaluated in a multicenter phase 1/2 trial, in which newly diagnosed patients (N=53) received carfilzomib at 20, 27, or 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for 8 cycles. The 20- and 27-mg/m2 doses were infused over 5 to 10 minutes, whereas the 36-mg/m2 dose was infused over 30 minutes. Patients also received lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly for cycles 1 to 4, and 20 mg weekly for cycles 5 to 8.9 Transplant-eligible patients who achieved ≥PR could proceed to stem cell collection after 4 cycles. All patients received 4 more cycles of CRd, with transplant-eligible patients having the option to proceed with ASCT. Patients who continued therapy beyond 8 cycles received maintenance CRd in 28-day cycles at the doses tolerated at the end of 8 cycles.

Results showed that patients experienced a rapid and good initial response to CRd, and their responses improved as the trial continued. Of the 49 pa-

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tients who completed 4 treatment cycles, 67% achieved at least near-complete response (nCR), with 45% in stringent complete response (sCR), defined as no detectable tumor cells or myeloma protein in the blood or bone marrow. Of the 36 patients who completed 8 or more treatment cycles, 78% achieved nCR with 61% achieving sCR. The investigators also reported PFS rates of 97% at 12 months and 92% at 24 months. This regimen was well tolerated, and PN rates were low. However, I think it is important to remember that this was a relatively small study, and more follow-up with larger cohorts of patients is warranted.

Again, we are fortunate to have numerous combinations to treat this population of patients (Table 1b).1 RVD, although not listed as an NCCN recommendation in the nontransplant setting, is now being widely used, at least here in the United States, where there is less pressure to use melphalan plus prednisone (MP). To date, there are no clinical trial data that clearly show an advantage with MP compared with dexamethasone or other corticosteroids. If you look at results from the large UPFRONT trial

by Niesvizky and colleagues, which compared VD versus bortezomib/thalidomide/dexamethasone (VTD) versus bortezomib/melphalan/prednisone (VMP) as initial therapy in nontransplant patients, you will see that there was no advantage in terms of response or tolerability with VD versus VMP.10 Furthermore, after 22 months of follow-up, median PFS rates were 13.8 months for VD, 14.7 months for VTD, and 17.3 months for VMP; these are not statistically different. One-year OS rates were also similar (87.4%, VD; 86.1%, VTD; 88.9%, VMP).

At our center, we routinely recommend ASCT for patients up to 75 years of age, and in some cases, offer transplant to those between 75 and 80 years. It is important to consider which factors make an individual “transplant-eligible,” not just at the time when initial therapeutic decisions are being made, but later in the course of treatment as well. If you have a patient whose disease is refractory to RVD, it may become necessary to consider them for transplant in the secondary setting. Hence, we want to avoid MP whenever possible even in these patients, so we do not compromise stem-cell reserve.

Beyond that, even if a patient is never transplanted, given the improved efficacy seen with novel therapies, he or she may live many years, even decades, after diagnosis. Therefore, it is important to consider the bone marrow injury and risk of secondary malignancies associated with alkylating agents11 and the impact this may have on survival and quality of life.

Which investigational agents are showing the most promise in MM treatment?

I think that MLN9708, which is a next-generation oral proteasome inhibitor, has the potential to be a game-changing drug. This agent is being combined with lenalidomide and dexamethasone in a phase 1/2 trial of newly diagnosed patients.12 After establishing the maximum tolerated dose (MTD) of the drug, 65 patients were evaluated in the study. In the 20 patients who were to undergo ASCT, stem cells were successfully collected. Overall, 52 patients were evaluable for response after a median of 6 cycles of treatment; of these patients, 58% achieved at least a VGPR, 32% achieved a PR, and 23% had a CR. Twenty-one patients (32%) reported neuropathy, which was grade 1 in 20% of patients, grade 2 in 9%, and grade 3 in 3%. Mild rash, fatigue, nausea, vomiting, and diarrhea were reported in 40% of patients. These were well managed with dose reductions and supportive care. Two grade 4 adverse events (AEs) were observed, including end-stage renal disease in 1 patient (resulting from disease progression) and deep vein thromboembolism in 1 patient. In light of the promising results seen with MLN9708, this drug has entered a phase 3 trial, and 2 other trials are planned in newly diagnosed patients and in those with relapsed and refractory disease.

Another second-generation oral proteasome inhibitor that is showing good activity is oprozomib. In a phase 1b study, this agent was administered on days 1 to 5 of a 14-day cycle with a standard 3 + 3 dose-escalation scheme.13 Treatment was initiated at 120 mg/day, with 4 to 6 hours between doses. To date, 13 patients with hematologic malignancies (MM and chron-

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Table 2. Common Grade 3/4 Adverse Events in ≥15% of Patients in the Phase 2 MM-002 Trial19 POM + LoDex (%)

POM Alone (%)

Neutropenia

38

47

Anemia

21

22

Thrombocytopenia

19

22

Pneumonia

23

16

Toxicity

LoDex indicates low-dose dexamethasone; POM, pomalidomide.

ic lymphocytic leukemia [CLL]) have been treated. Treatment duration up to 38 weeks has been observed thus far, and MTD has not been reached up to a 210-mg/day dose. Ten patients were evaluable for antitumor activity (9 with MM, 1 with CLL), and PRs were seen in 2 patients with MM and 1 patient with CLL. Researchers also are excited about daratumumab, a humanized anti-CD38 monoclonal antibody with broad-spectrum killing activity, which is showing promise as a single agent in relapsed/refractory MM,14 and Arry-520, a novel kinesin spindle protein inhibitor, which is showing activity alone and in combination with dexamethasone in patients refractory to bortezomib and lenalidomide.15 Can you comment on recent advances in the relapsed/refractory setting?

We now have 2 new agents available for the treatment of relapsed/refractory MM: carfilzomib and pomalidomide. Carfilzomib, a next-generation IV proteasome inhibitor, is currently FDA approved for patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory drug (IMiD), and who have demonstrated disease progression on or within 60 days of therapy completion.16 This agent represents an important advance in treatment, given its proven efficacy and good safety profile. In the phase 2 PX-171-003-A1 trial, heavily pretreated patients (N=266) received single-agent IV carfilzomib, given over 2 to 10 minutes on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle, for up to 12 cycles. The dose for cycle 1 was 20 mg/m2, which was escalated to 27 mg/m2 for all cycles thereafter provided that patients tolerated the initial dose level of 20 mg/m2.17 Of the evaluable patients, 95% were refractory to their last therapy, and 80% were refractory to both bortezomib and lenalidomide. The OR rate was 23.7%, median duration of response was 7.8 months, and median OS was 15.6 months.

Reported AEs included fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). The rate of treatment-related PN was only 12.4%, and this was almost exclusively grade 1 and 2.

Pomalidomide, a next-generation oral immunomodulator, is also approved for patients who have received at least 2 prior therapies, including bortezomib and an IMiD, and who have demonstrated disease progression on or within 60 days of therapy completion.18 This approval was based on data from the multicenter phase 2 MM-002 trial of patients with relapsed/ refractory MM who had previously received lenalidomide and bortezomib and were refractory to their last therapy. The treatment arms were pomalidomide plus low-dose dexamethasone (POM/LoDex) or pomalidomide alone (POM).19 Of the 221 patients evaluated for response, 29.2% achieved a PR or better with POM/LoDex versus 7.4% with POM. The most common grade 3/4 AEs in both arms are shown in Table 2. At a median follow-up of 14.2 months, median PFS was 4.6 months in the POM/LoDex arm and 2.6 months in the POM arm.20 Pomalidomide is also being evaluated in combination with carfilzomib and dexamethasone in a heavily pretreated, lenalidomide-refractory population with prior bortezomib exposure.21 Preliminary results show that this regimen is well tolerated and, among the 30 evaluable patients, the OR rate was 50%, including a VGPR rate of 13% and a PR rate of 37%. A phase 1 trial of pomalidomide, bortezomib, and low-dose dexamethasone in relapsed/refractory MM is also under way.22 This regimen shows good activity,

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with 73% of 15 evaluable patients responding to treatment (VGPR, 27% and PR, 46%). The most common AEs were fatigue (60%), edema (40%), and low platelet counts (40%).

I think that myeloma treatment will continue to evolve with the use of these agents, as well as monoclonal antibodies and other kinds of immunomodulatory manipulators, like the anti-PD1 antibodies that are making an impact on solid tumors. We are definitely going to see immunomanipulation as a breakthrough area in MM in the relatively short-term future. ♦ References

1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. Version 2.2013. http://www.nccn.org. Accessed March 25, 2013.

2. Richardson P, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116: 679-686.

3. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib, and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23:1337-1341.

4. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012;119:4375-4382.

5. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, noninferiority study. Lancet Oncol. 2011;12:431-440.

6. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomized controlled trial. Lancet Oncol. 2010;11:29-37.

7. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621-4629.

8. Niesvizky R, Naib T, Christos PJ, et al. Lenalidomide-induced myelosuppression is associated with renal dysfunction: adverse events evaluation of treatment-naïve patients undergoing frontline lenalidomide and dexamethasone therapy. Br J Haematol. 2007;138:640-643.

9. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120:1801-1809.

10. Niesvizky R, Flinn IW, Rifkin R, et al. Efficacy and safety of three bortezomib-based combinations in elderly, newly diagnosed multiple myeloma patients: results from all randomized patients in the community-based, phase 3b UPFRONT study. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 478.

11. Alkeran [package insert]. Rockville, MD: ApoPharma USA, Inc.; November 2011.

12. Kumar SK, Berdeja JG, Niesvizky R, et al. Phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 332.

13. Savona MR, Berdeja JG, Lee SJ, et al. A phase 1b dose-escalation study of split-dose oprozomib (ONX 0912) in patients with hematologic malignancies. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 203.

14. Lokhorst H, Gimsing P, Nahi H, et al. Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma - preliminary efficacy and pharmacokinetics data from a dose-escalation phase I/II study. Program and abstracts of the 17th Congress of the European Hematology Association; June 14-17, 2012; Amsterdam, the Netherlands. Abstract 1143.

15. Shah JJ, Zonder JA, Cohen A, et al. The novel KSP inhibitor ARRY-520 is active both with and without low-dose dexamethasone in patients with multiple myeloma refractory to bortezomib and lenalidomide: results from a phase 2 study. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 449.

16. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012.

17. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120: 2817-2825.

18. Pomalyst [package insert]. Summit, NJ: Celgene Corporation; 2013.

19. Richardson PG, Siegel DS, Vij R, et al. Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 634.

20. Jagannath S, Hofmeister CC, Siegel DS, et al. Pomalidomide (POM) with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior therapy with lenalidomide (LEN) and bortezomib (BORT): updated phase 2 results and age subgroup analysis. Blood (ASH Annual Meeting Abstracts). 2012;120: Abstract 450.

21. Shah JJ, Stadtmauer EA, Abonour R, et al. A multi-center phase I/II trial of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 74.

22. Richardson PG, Hofmeister CC, Siegel D, et al. MM-005: a phase 1, multicenter, open-label, dose-escalation study to determine the maximum tolerated dose for the combination of pomalidomide, bortezomib, and low-dose dexamethasone in subjects with relapsed or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 727.

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Nursing Considerations in the Frontline and Relapsed/Refractory Settings Elizabeth Bilotti, MSN, BSN, APN-C

Nurse Practitioner, Multiple Myeloma Division John Theurer Cancer Center Hackensack University Medical Center, Hackensack, NJ

Introduction Patients with multiple myeloma (MM) present with numerous disease- and treatment-related symptoms that require supportive care.

Monitoring for these complications and intervening with appropriate nursing strategies is critical for maintaining the delicate balance of therapeutic efficacy and tolerability. This requires a thorough knowledge of the toxicity profiles of agents currently used to treat the disease, as well as the latest guidelines for dose adjustments and other interventions. In this article, Elizabeth Bilotti, MSN, BSN, APN-C, discusses approaches used at her center for managing common adverse events (AEs) in both the newly diagnosed and relapsed/ refractory settings.

How do you manage common toxicities related to the use of lenalidomide/bortezomib/dexamethasone (RVD)?

Every time a patient comes into the clinic, we conduct an assessment for AEs related to the drugs used in the RVD regimen. Importantly, we compare how patients are currently feeling with how they were feeling at their last appointment and prior to starting treatment. We inform patients of the common toxicities that may develop and encourage them to contact the office immediately if they are unsure how to manage them or feel that they cannot wait until the next follow-up visit.

Toxicities related to dexamethasone used in RVD can be variable and extensive. Some of the subjective symptoms that patients report include insomnia, which may occur for a few days after treatment, as well as a “let-down effect,” which is characterized by an increase in energy for 1 or 2 days, followed by a “drained” feeling.1 We advise patients to be aware of their energy levels throughout the day, and if possible, look for patterns, so that they can modify their schedules around tasks they need to accomplish and when they have the ability to do them.

Treatment with dexamethasone can also increase a patient’s blood glucose levels, which may remain elevated for 24 to 48 hours after each dose.1,2 If a patient is receiving dexamethasone twice weekly as part of a standard RVD regimen, it is not unusual for glucose levels to be compromised 4 or more days each week. When treating a diabetic patient with MM, we notify his or her endocrinologist or primary care physician, so that necessary adjustments in medications can be made. In patients who are not diabetic, we still carefully monitor blood glucose levels throughout each treatment cycle. In addition, we watch for other signs and symptoms of elevated glucose levels, such as increased thirst or urination.

It is also important to evaluate for myopathies or muscle weakness, especially in the quadriceps, hamstrings, gluteal, and upper arm muscles, as these areas can be affected by the long-term use of dexamethasone, especially in elderly patients who are at greater risk for muscle wasting.1 We encourage individuals to exercise these muscles to reduce the risk of injuries due to falls.

The RVD regimen combines dexamethasone with the immunomodulatory drug (IMiD) lenalidomide, which increases the risk of venous thromboembolism (VTE).3 Therefore, it is important for patients to be educated on the potential signs and symptoms of this complication, which usually includes pain in the calf muscles (while walking or at rest), and in some cases, unilateral

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swelling or warmth.3 We tell our patients that anything out of the ordinary should be reported immediately so that we can determine whether further evaluation is necessary.

In patients receiving IMiDs in combination with steroids, it is critical to provide effective VTE prophylaxis.3-7 There are several risk factors, both patient and treatment related, that must be considered when evaluating for this risk in MM. Guidelines on risk assessment and prophylaxis of VTE have been established (Table),4-7 and we follow these recommendations, using aspirin or anticoagulation with low-molecular-weight heparin or warfarin, based on the number of risk factors and the regimen being administered.

One of the common AEs related to the use of lenalidomide is myelosuppression.8,9 When patients become anemic during therapy, they may feel fatigue throughout the day, or it may be evident only when they exert themselves.

For example, individuals may report that they need to stop and catch their breath after climbing a flight of stairs, which they never had to do before.

Interestingly, aside from these types of symptoms, patients often do not know that their blood counts are low until we make a formal assessment.

We also urge patients to immediately report any unusual bleeding or signs of infection, including a fever higher than 101°F (or higher than 100.5°F that occurs twice during a 24-hour period), which can signal infection or febrile neutropenia.8 Other possible signs of infection may include cough and increased frequency of (or burning during) urination. When necessary, the dose or schedule of lenalidomide may need to be adjusted until blood counts return to normal. Growth factor support may also need to be initiated.

Gastrointestinal (GI) toxicities that patients experience while on lenalidomide include constipation, diarrhea, and bloating.9 It is important to gauge how a patient’s condition has changed since he or she started treatment so that proper interventions, including laxatives, antidiarrheals, adequate fluid intake, or changes in the diet, can be initiated. Immediately addressing these toxicities helps to prevent further complications, such as weight loss, dehydration, bowel obstruction, and electrolyte disturbances.

Patients can also develop a low-grade rash from lenalidomide.9 This is more common during the first and second cycles of treatment and usually manifests as itching and redness of the scalp, which can be treated with an over-thecounter antihistamine. If patients report a whole-body rash, we ask that they come into the clinic to be assessed. In some cases, newly diagnosed patients are receiving prophylactic antibiotics, which may also lead to rash. Therefore, it is important to determine which medication is causing the problem so that the appropriate intervention can be chosen.

In patients receiving immunomodulatory drugs in combination with steroids, it is critical to provide effective VTE prophylaxis.

A well-known and challenging AE related to bortezomib use is peripheral neuropathy (PN).10 However, our ability to administer this drug subcutaneously (SQ) has helped to reduce the risk and severity of this toxicity, although some patients still experience it to some degree. Our center has completely switched over to SQ bortezomib, based on results of the phase 3 noninferiority trial by Moreau and colleagues.11 Our approach to monitoring and managing PN has not changed with this new route of administration. Assessing for neuropathy includes posing questions to the patient each time they come in, to determine whether there has been a change in sensation, pain, or function since baseline. When necessary, we withhold or dose-reduce as recommended until we see improvement in symptoms. Fortunately, bortezomib-based PN is often reversible when managed promptly.12

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Table. Risk Assessment for VTE Prophylaxis in Patients Treated with Immunomodulatory Drugs4-7 Individual Risk Factors

Treatment-Related Risk Factors

Obesity (BMI ≥30 kg/m2)

High-dose dexamethasone (≥480 mg/month or 120 mg/week)

Previous VTE

Doxorubicin

Central venous catheter or pacemaker

Combination chemotherapy

Chronic renal disease (CrCl <40 mL/min) Diabetes Medications (erythropoietin, estrogen) Immobility General surgery Trauma (major or lower extremity) Blood-clotting disorders Number of Risk Factors

Prophylaxis

0-1

Aspirin 81-325 mg daily

2+

LMWH (enoxaparin 40 mg SQ daily, or equivalent) Warfarin (INR 2-3)

BMI indicates body mass index; CrCl, creatinine clearance; INR, international normalized ratio; LMWH, low-molecular-weight heparin; SQ, subcutaneously; VTE, venous thromboembolism.

Bortezomib use can increase the risk of herpes zoster reactivation.13 Therefore, for patients being treated with RVD, we always include antiviral prophylaxis with acyclovir or another agent in its class. Similar to lenalidomide, bortezomib can also cause GI toxicities,10 which are managed with the interventions discussed earlier.

What are some of the important nursing considerations related to the use of carfilzomib and pomalidomide in the relapsed/ refractory setting?

When considering the use of carfilzomib for relapsed/refractory MM, the oncology team needs to ascertain whether the patient will be able to travel back and forth to the center for the necessary infusions. Fortunately, there is assistance available through nonprofit groups that help with transportation and lodging expenses for those who live far from the clinic. It is important for patients and their families to be made aware of these resources, to ensure that they have access to necessary treatment. Some of the organizations that provide useful information are Cancer Support Community (www.cancer supportcommunity.org), Chronic Disease Fund (www.cdfund.org), International Myeloma Foundation (www.myeloma.org), and Multiple Myeloma Research Foundation (www.themmrf.org).

When treating patients in the relapsed/refractory setting, myelosuppression is often a concern because patients have received multiple lines of therapy.

Baseline blood counts may be problematic in all cell lines as these patients may be older, are heavily pretreated, and many have been transplanted.

Although carfilzomib and bortezomib are both proteasome inhibitors, their effects on complete blood cell counts are different. Bortezomib causes transient cyclical thrombocytopenia; platelet counts predictably nadir following the last dose of each cycle (day 11), then typically recover prior to the next cycle.10,14 The platelet reduction with carfilzomib is also transient and cyclical, but the nadir occurs on day 8 of treatment.15 This is important to remember, as the most significant drop in platelet count occurs after 2 doses of this drug.

In some instances, a patient with relapsed disease will have bone marrow that is packed with myeloma cells. However, we may see improvement in blood counts if we can get the disease under control. For this reason, we try to forge

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ahead with carfilzomib treatment despite low counts, knowing that we can give blood products and growth factor support to help patients get through to their next cycle of therapy.

Carfilzomib may cause infusion-related reactions, including myalgias, arthralgias, shaking, chills, fever, and shortness of breath.15 These typically occur 6 to 8 hours after initial exposure to the drug or after the dose is escalated for the first time, which is typically on day 1 of cycle 2. When reactions do occur, they are usually transient and dissipate within 24 hours. It is important to recognize, however, that symptoms can develop at any time, not just during the first few cycles. To lower the incidence of these infusion reactions, patients must be premedicated with dexamethasone 4 mg prior to all doses during cycle 1, prior to all doses during the first cycle of dose escalation to 27 mg/m2, and thereafter if infusion reaction symptoms occur during subsequent cycles.15 One of the advantages of pomalidomide is that it is an orally administered agent.16 This can be an attractive option for patients with relapsed or refractory MM, who have already spent a lot of time in the clinic. One of the disadvantages with an oral agent, however, is patient adherence to therapy.

Once individuals leave the clinic, there is no guarantee that they are taking all of their doses as prescribed.

It is important for the nursing staff to maintain regular contact with patients on pomalidomide or other oral medications, to assess how they are doing. The recommendation with pomalidomide is to perform weekly blood counts for the first 8 weeks of treatment, as one of the most common toxicities is neutropenia.16 We like to see patients very frequently during the first 2 cycles of therapy. After that, it really depends on how well they are tolerating the drug.

The resources listed earlier in this article can be used to help patients who are concerned about the high out-of-pocket costs or copayments associated with pomalidomide. In some cases, patients may be eligible to receive treatment at a reduced cost or for free if they have no insurance or are underinsured. It is primarily the responsibility of the nurse, nurse navigator, or social worker to make sure that patients are aware of these and other services. ♦ References

1. Faiman B, Bilotti E, Mangan PA, Rogers K; IMF Nurse Leadership Board. Steroidassociated side effects in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):53-63.

2. Clore JN, Thurby-Hay L. Glucocorticoid-induced hyperglycemia. Endocr Pract. 2009;15: 469-474.

3. Rome S, Doss D, Miller K, Westphal J; IMF Nurse Leadership Board. Thromboembolic events associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):21-28.

4. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423.

5. Klein U, Kosely F, Hillengass J, et al. Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone. Ann Hematol. 2009;88:67-71.

6. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. 7. Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin prophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011;29:983-993.

8. Miceli T, Colson K, Gavino M, Lelleby K; IMF Nurse Leadership Board. Myelosuppression associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):13-20.

9. Revlimid [package insert]. Summit, NJ: Celgene Corporation; 2012.

10. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; June 2012.

11. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomized, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440.

12. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24:3113-3120.

13. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917.

14. Lonial S, Walter EK, Richardson PG, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood.

2005;106:3777-3784.

15. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012.

16. Pomalyst [package insert]. Summit, NJ: Celgene Corporation; 2013.

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Pharmacologic Considerations in the Era of Novel Therapies for Multiple Myeloma Greg Eskinazi, RPh, MAS, BCOP

Oncology Research Pharmacist John Theurer Cancer Center Hackensack University Medical Center, Hackensack, NJ

Introduction The development and approval of more effective drugs have led to better response rates and prolonged survival in multiple myeloma (MM). When choosing among these novel therapies, it is essential to consider factors such as pharmacologic profiles and dosing requirements and to identify the needs of each patient to promote individualized care. In this article, Greg Eskinazi, RPh, MAS, BCOP, discusses new directions in the treatment of myeloma and answers questions related to the evaluation of new agents in clinical trials.

What are some of the promising investigational agents being evaluated in clinical trials at your center?

We have a very robust clinical research department at the John Theurer Cancer Center, with just under 200 studies available to our patients.

Approximately 70% of these studies have a pharmacy component and many of them include the treatment of MM. We were deeply entrenched in the studies leading to the recent US Food and Drug Administration (FDA) approvals of carfilzomib and pomalidomide, which are indicated for the treatment of relapsed and/or refractory MM.1,2 The approvals have afforded us the opportunity to continue the evaluation of these agents in other settings, including frontline and maintenance, and as early therapy for the management of smoldering myeloma. Our center currently has 6 open trials of carfilzomib that are accruing patients. We are also evaluating several investigational agents that have shown evidence of antimyeloma activity.

MLN9708 is a selective inhibitor of chymotrypsin-like proteolytic (β5) site of the 20S proteasome with IC50 and Ki of 3.4 nM and 0.93 nM, respectively.3 In an upcoming phase 3 trial, patients with relapsed and/ or refractory MM will be randomized to receive lenalidomide (25 mg) on days 1 through 21, dexamethasone (40 mg) on days 1, 8, 15, and 22 every 28 days, and MLN9708 (4 mg orally) on days 1, 8, and 15; or the same dose and schedule of lenalidomide and dexamethasone plus placebo.4 The primary end point of this trial is progression-free survival (PFS), and secondary end points include overall survival (OS), rate of complete and very good partial response, duration of response, time to progression, safety profile, pain response, change in global health status, OS and PFS in the high-risk population, and pharmacokinetic data.

The immunoconjugate BT062 is comprised of the anti-CD138 chimeric monoclonal antibody nBT062 and the cytotoxic agent maytansinoid DM4.5 The proposed mechanism of action of BT062 is mediated by binding to CD138-positive myeloma cells. Once the immunoconjugate is internalized into the target cell, DM4 is released from the targeting molecule, thereby restoring the original toxicity of the drug. Thus, BT062 is considered a tumor-activated prodrug because the conjugation of DM4 to nBT062 keeps the cytotoxic drug inactive until it is released within the CD138-expressing target cell. A phase 1/2a study is under way to determine dose-limiting toxicities (DLTs) and/or the maximum tolerated dose (MTD)/recommended phase 2 dose of BT062 in combination with lenalidomide and dexamethasone in patients with relapsed and/or refractory MM.6 The mammalian target of rapamycin (mTOR) is a serine/threonine kinase related to the lipid kinases of the phosphoinositide 3-kinase family. It

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functions as a sensor of mitogen, energy, and nutrient levels and is a central controller of cell growth.7 In a phase 1/2 study, investigators are assessing the safety and tolerability of the mTOR kinase inhibitor CC-223 when administered orally and will try to define the MTD and the nontolerated dose.

They will also be determining the preliminary pharmacokinetics of CC-223 following both single and multiple oral dosing.8 What are some of the challenges related to the evaluation of novel agents in clinical trials?

Depending on a patient’s condition at the time of diagnosis, the need for immediate disease control must be addressed. Patients with symptomatic disease requiring treatment may present with 1 or more of the following: hypercalcemia, renal insufficiency, anemia, and/or bone lesions (Table).9 Advances in screening procedures (ie, serum protein electrophoresis, urine protein electrophoresis, and serum free light chain assays) and diagnosis and prognostic indicators based on the Durie-Salmon staging system10 and the International Staging System11 enable us to more accurately assess patients to determine the best course of treatment. Being able to offer our patients a wide variety of approved treatments or the opportunity to take part in clinical trials allows us greater leeway in terms of options. There are, however, challenges related to treating patients in clinical trials, as outlined below.

• Screening and enrollment of patients into clinical trials is a very labor intensive process. Patients must meet extremely detailed inclusion and exclusion criteria. Many times, due to advanced age and concomitant disease states, patients will not be eligible for participation.

• Laboratory reports, scans, and test results must be ordered as mandated by the sponsors of the trial. In some cases, these are performed more frequently than some insurance companies deem necessary, and valuable time is spent trying to obtain permissions.

• Adverse events (AEs) and admissions to the emergency department or other outside facility must be documented and reported to the appropriate agencies. Oftentimes, these admissions may be disease related and not based on the clinical treatment. Strict, detailed instructions are typically included in the protocols, including dose interruptions and/or reductions and procedures for infusion-related reactions.

Differentiating treatment-related versus disease-related symptoms is also extremely important, because overlapping toxicities may develop.

• Many agents are still in the development phase and not yet commercially available. Careful attention to AEs related to these medications is imperative. Differentiating treatment-related versus disease-related symptoms is also extremely important, because overlapping toxicities may develop.

• Risk Evaluation and Mitigation Strategies (REMS), often based on the FDA-regulated “Black Box warnings,” involve specialized educational aspects that patients must be aware of prior to consenting to treatment.

For most agents, the REMS address fertility/pregnancy concerns, which fortunately do not affect most of our patient population but still create issues related to drug procurement.

• The newest oral agents in development require strict adherence to be effective. Compliance is a concern because directions are very specific regarding the way that these drugs must be taken. To improve adherence, we encourage patients to keep diaries to help them remember when to take their medications.

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CONSIDERATIONS IN MULTIPLE MYELOMA • Transportation issues need to be addressed because many patients must be available for day-long pharmacokinetic sampling and frequent office visits.

From a pharmacy perspective, we must stay informed of the differences that exist between approved and investigational agents, as well as the doses and schedules that are used outside of standard treatment regimens.

Pharmacies may have multiple studies using the same investigational product at different dosages, routes of administration, and treatment schedules.

Accountability concerns are addressed by separating drugs by study or by investigational versus commercial supply. Single- and double-blind studies may require the pharmacist to handle the final step in the randomization process to determine the patient’s actual treatment.

The educational needs of the pharmacy and nursing staff must also be met. Study-specific educational documents derived from the protocol and investigator’s brochure are prepared for every study with specific instructions for the staff.

How does the multidisciplinary team approach at your center contribute to better patient outcomes?

The John Theurer Cancer Center is comprised of 14 specialized divisions, featuring teams of experts for specific types of cancer. This allows each patient to be evaluated and treated by a specialist in the field. The myeloma division is staffed by oncologists, advanced practice nurses, a research team, and support personnel that focus solely on this disease. The patient will stay with this unit throughout their treatment and will have access to the most comprehensive therapies available, including clinical trials when appropriate. If transplant is an option, appropriate strategies will be followed while patients are prepared for this procedure, at which time they will be transferred to our transplant division.

We provide a mandatory multidisciplinary class that all patients and caregivers must attend prior to transplant.

Our Blood and Marrow Transplant program has performed more than 3000 transplants since its inception. We provide a mandatory multidisciplinary class that all patients and caregivers must attend prior to transplant.

The class is taught by advanced practice nurses, staff nurses, nutritionists, pharmacists, and psychosocial workers, who are all dedicated to the education of transplant patients and their families.

Toxicities must be closely monitored and handled expediently. An evidence-based guidelines tool for symptom management has been developed to promote standardized and appropriate management of several of the commonly observed AEs related to therapy. These guidelines were recently published in an issue of the Clinical Journal of Oncology Nursing.12 Our center has an onsite chemotherapy pharmacy that is open 7 days a week. It is staffed by 13 pharmacists, 4 pharmacy assistants, and 1 research pharmacist (myself). All outpatient treatments are prepared in our facility.

A specialty retail pharmacy is located in the lobby to handle patients’ pre-

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Table. Diagnostic Criteria for Multiple Myeloma9 Clonal bone marrow plasma cells >10% Presence of serum and/or urinary monoclonal protein (except in cases of true nonsecretory myeloma) Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder (specifically CRAB): • Calcium elevation: serum calcium ≥11.5 mg/dL or • Renal insufficiency: serum creatinine >2 mg/dL • Anemia: hemoglobin >2 g/dL below lower limit of normal or value <10 g/dL • Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures

scription needs. As a specialty pharmacy, we can provide access to many medications that are not available in most standard pharmacies.

We offer consultations with our board-certified nutritional staff, and our center boasts a test kitchen in which weekly demonstrations are held to teach patients better nutritional habits. We also have an on-site meditation room and a resource library that addresses patient needs and provides literature search requests from the staff. ♦ References

1. US Food and Drug Administration announcements. FDA approves Kyprolis® (carfilzomib) for some patients with multiple myeloma. July 20, 2012. http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm312920.htm.

2. US Food and Drug Administration announcements. FDA approves Pomalyst® (pomalidomide) for advanced myeloma. February 8, 2013. http://www.fda.gov/Drugs/Information OnDrugs/ApprovedDrugs/ucm339286.htm.

3. Ocio EM, Mateos MV, San-Miguel JF. Novel agents derived from the currently approved treatments for MM: novel proteasome inhibitors and novel IMIDs. Expert Opin Investig Drugs. 2012;21:1075-1087.

4. ClinicalTrials.gov. A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708 Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients with Relapsed and/or Refractory Multiple Myeloma. http://clinicaltrials.gov/ct2/show/NCT01564537.

5. Ikeda H, Hideshima T, Fulciniti M, et al. The monoclonal antibody nBT062 conjugated to cytotoxic maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin Cancer Res. 2009;15:4028-4037.

6. ClinicalTrials.gov. A Phase I/IIa Multi-dose Escalation Study of BT062 in Combination With Lenalidomide and Dexamethasone in Subjects with Relapsed or Relapsed/refractory Multiple Myeloma. http://www.clinicaltrials.gov/ct2/show/NCT01638936.

7. Keen H, Ricketts S-A, Bales J, et al. The mTOR kinase inhibitor AZD8055 modulates 18F-FDG uptake in vivo in the human glioma xenograft model U87-MG. Mol Cancer Ther. 2009;8(suppl 1):Abstract A225.

8. ClinicalTrials.gov. A Phase 1/2, Multi-center Open Label, Dose Finding Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the mTOR Kinase Inhibitor CC-223 Administered Orally to Subjects with Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Multiple Myeloma. http://clinicaltrials.gov/show/ NCT01177397.

9. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749-757.

10. Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36:842-854.

11. Griepp PR, San Miguel J, Durie BGM, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412-3420.

12. Weber MS, Eskinazi G. The development of evidence-based supportive therapy guidelines for symptom management. Clin J Oncol Nurs. 2012;16:343-345.

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Value-Based Cancer Care

Introducing the Third Annual Conference of the Association for Value-Based Cancer Care Burt Zweigenhaft, BS Chief Executive Officer and Chairman, Onco360 Co-chair of the AVBCC Conference

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s we know, the American healthcare system is going through exorbitant changes, changes that will affect all providers and all stakeholders in the cancer care ecosystem.

The goal of the Association for Value-Based Cancer Care (AVBCC) is to bring together all the cancer care stakeholders in one unified meeting to discuss the many issues facing us today. One of the main objectives of the AVBCC Annual Conference is to be able to map out and help guide our members and attendees through the various changes in the US healthcare system.

this business today. This is rapidly changing as managed market payers’ control and oversight of cancer care are taking hold and are influencing the outcomes of decisions, pathways, formulas, reimbursement, and prior authorization.

It is very important that your staff gets to meet and see all of the stakeholders and decision makers in this chain of rapidly changing events that impact cancer care today. Without that, you and your organization are not going to be prepared for the market changes, and the impact on your brand could be tremendous.

Then again, if you attend the meeting and you observe and understand Burt Zweigenhaft, BS Changes in the changes, enter into the discussion Reimbursement and Purchasing and debate, and lastly, you have the foresight to plan We are at an inflection point in cancer drug distribufor the changes: hence you will be more successful in tion and management. We are seeing the typical wholethe long run. saler-to-physician channel control change rapidly.

Managed market payers are stepping up and exerting An All-Inclusive Agenda more control over what happens in oncologist offices.

We have an all-inclusive agenda. It allows us in the The landscape is changing in terms of reimbursement mornings, over the couple of days that we meet, to have and their contracting capabilities as Managed Market all the “big-ticket” topics discussed by some of the greatPayers are responding as we experiment and move into est thought leaders – the people who are driving change an accountable care organization (ACO) world. in the oncology space today – whether it is regulatory, It is very important that the AVBCC Annual Conreimbursement, coverage, policy, benefits, healthcare ference convenes an agenda and forum to guide and systems, hospital systems, or the large community pracmentor people through the changes, and to be able to tices that are changing the way we operate in cancer inflect strong opinions and to encourage people to parcare. ticipate in helping flush out important changes in the This allows all of the stakeholders, main issues, and chain to ensure that we can impact change in a very agendas to be discussed in an open forum. We have positive way. panels, channel experts, and key opinion leaders. This It is no longer the traditional wholesaler-to-physiis important; you never see such a mix in this business. cian group purchasing organization (GPO) model in Our afternoon tracks allow you to have breakouts,

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depending on whether it is reimbursement, genetics, product launch, pathways, or care management that is important to you. These are all separate tracks that allow you and your staff to move around with flexibility in the afternoon, and to make sure that you all cover the wide array of topics that we have available to enjoy and learn from.

We all know how important networking is. I know that we are in an e-mail and health information exchange market. But meeting key opinion leaders and exchanging in open dialogue, and being able to sit with them at lunch, at breakfast, or between sessions and hear what their thoughts are, is very important.

This is the only conference where the key people in the channel are at the meeting, and they are available for you to meet and to have personal time with. There is no better way to get ahead and to stay ahead in cancer care than to be at the AVBCC Annual Conference in its third year, in Hollywood, Florida.

This is your chance to see some of the greatest key opinion leaders, the people who are truly driving change in cancer care today.

Meeting Key Opinion Leaders Who are these key opinion leaders specifically? For the most part, they are the medical directors of the big insurance plans, the ones who are leading the change in cancer care, whether in Medicare, Medicaid, or in commercial plans. We have certain leaders that you may recognize, because you have read about them frequently in many publications, including the Association’s publication – Value-Based Cancer Care. We have coding experts. We have advocacy experts. We have policy experts. This is why the AVBCC Annual Conference is a very inclusive meeting, because we bring all the stakeholders together.

When we put together the agenda, our goal was to make sure that we had the right people, the right health plans, the right health systems, and the right leaders.

We did not want to see ourselves with another small, myopic view of this industry. We knew that the only way to effect change in a positive way is to get everyone

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and every voice in the room together to share information. That is the overall goal of the AVBCC Annual Conference – inclusiveness.

I have always believed that it is very important to meet face to face with the key people who are driving change in the business. One of the goals of our association is to make sure that we have a cast that includes

There is no better way to get ahead and to stay ahead in cancer care than to be at the AVBCC conference in its third year.

This is your chance to see some of the greatest key opinion leaders, the people who are truly driving change in cancer care today. everyone who is leading that change. We have people from Aetna, and people from the University of Pittsburgh Medical Center. We have people from hospital systems, such as the “Roswells” and the “Dana-Farbers” of the world. We have employer groups and coalitions, such as Caterpillar, Delta, the National Business Group on Health, UnitedHealthcare, and many others.

The goal of the AVBCC Annual Conference is to bring them all together to make sure that we all have access to each other and that we can share ideas in an open forum and help chart the future of cancer care in America. This is why you want to be with us at this meeting, and this is why you need to have your staff attend the conference.

This is the only meeting I am aware of that affords this type of inclusive venue, where everyone in the space can get to meet those important leaders who are driving change in cancer care.

One of the most important things that we know is changing is the distribution model as we are moving from the typical manufacturer to the wholesaler through GPO to community-based or system-based oncologists. The system is changing and manufacturers are now finding that they are no longer totally dependent on the wholesale channel or on GPOs to make and

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control the influential buying decisions to drive their products to market. Today it is being heavily influenced by the managed care channels and by payers’ coverage and reimbursement decisions.

In this meeting, in addition to having all the managed market payers represented, we also have the new stakeholders in the distribution channel. We have specialty pharmacies, we have oncology pharmacies, and we have hospital systems and others that are now taking hold of a new distribution model in cancer care.

As this business is changing, what we have done at the AVBCC is to make sure that we have at this Third Annual Conference all of the people who are effecting change, so that they can discuss that change and what it means to the healthcare markets. One of the major challenges that most manufacturers have to address in the cancer marketplace today will be now dealing in a comparative world of clinical and cost-effectiveness, where evidence is increasingly being weighed to come up with the value-based purchasing proposition.

The “New World” of Healthcare Part of the mission of the AVBCC is to come up with a formula for value-based purchasing that will include not only clinical elements but economic elements of overall cost as well. Part of our agenda is to make sure that the Association can put forth a framework for “value-based purchasing” and the corresponding proper process and formula for evaluating effectiveness so appropriate contracting for cancer drug therapies is in the marketplace.

The timing of the Third AVBCC Annual Conference could not be better. We are coming right off a national election. We did not know whether ObamaCare was going to last. Now we know that health information exchanges, state exchanges, and the novel products of the “new world” of healthcare are going to take effect and are here to stay, and change is permanent.

Obviously, we are moving from a utilization-focused model to a quality model of healthcare. These changes are going to be dramatic. These issues are part of the

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agenda of change that we are going to be discussing this year at the AVBCC Annual Conference in the various segments and forums.

Community- Versus Hospital-Based Care Also at this year’s AVBCC conference, we are going to explore one of the biggest changes in cancer care – the move from community oncology to hospital-based cancer care. We have representatives from the Community Oncology Alliance, the Association of Community Cancer Centers, the National Comprehensive Cancer Network, the American Society of Clinical Oncology, and others who are going to be discussing these changes.

We have seen a tremendous consolidation in the purchase of hematology and oncology practices by hospital systems as they are getting ready for ACO opportunities. This is going to have a dramatic impact on our marketplace. We are going to explore this critical change in depth in some of the sessions. Anyone who is involved in this oncology space must know what is going on, and must be able to predict the new models of distribution and service, given the consolidation and the changes in cancer care as we go forward.

Personalized Medicine Personalized medicine is probably going to be launched through cancer care. Why? Because cancer is so expensive, and all of the molecular tests that can really make a difference in clinical utility and drive change are going to be the companion diagnostics to cancer care. Thus, given the effect on comparative effectiveness research and the value-based approach of cancer care purchasing, the economics around personalized medicine make economic sense to embrace beyond the quality drivers.

This is a hugely important topic, and it is part of our agenda at the Third Annual Conference of AVBCC, where we have experts who will be speaking on the impact of personalized medicine, companion diagnostics, and molecular pathways as we move forward in improving patient care in America. u

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THIRD ANNUAL

Association for Value-Based Cancer Care Conference Influencing the Patient-Impact Factor

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida CONFERENCE CO-CHAIRS

AGENDA* THURSDAY, MAY 2, 2013 8:00 am - 5:00 pm

Registration

FRIDAY, MAY 3, 2013

Craig K. Deligdish, MD Hematologist/Oncologist Oncology Resource Networks

Gary M. Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS President and CEO OncoMed

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am

Session 1: Welcome, Introductions, and Opening Remarks Conference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am

Keynote Address

10:15 am - 10:30 am

Break

10:30 am - 11:45 am

Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder Collaborations Marcus Neubauer, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm

Session 3: Cost of Cure: When, How, and How Much?

John Fox, MD; John Hennessy

2:00 pm - 2:45 pm

Session 4: Where Is Oncology Care Headed in the Future?

Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

Upon completion of this activity, the participant will be able to: • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery.

• Define the barriers associated with cost, quality, and access as they relate to healthcare reform and what solutions are currently being considered.

• Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively.

• Examine the current trends in personalized care and companion diagnostics.

• Analyze the patient issues around cost, quality, and access to care.

2:45 pm - 3:30 pm

Session 5: What Will the Cancer Delivery System Look Like in 2015?

Ted Okon; John D. Sprandio, MD

TARGET AUDIENCE

PROGRAM OVERVIEW

Following on the success of our Second Annual Conference, AVBCC will be coming to Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies. Our goal is to be able to assist them in implementing, improving, and sustaining their organizations and institutions, while improving access for patients and ultimately quality patient care.

LEARNING OBJECTIVES

This conference is intended for medical oncologists, practice managers/administrators, and managed care professionals. Stakeholders in a position to impact cancer patient care, such as advanced practice nurses, pharmacists, and medical directors, are also invited to join this exciting forum.

DESIGNATION OF CREDIT STATEMENTS SPONSORS

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

3:30 pm - 3:45 pm

Break

3:45 pm - 4:30 pm

Session 6: Employers and Oncology Care F. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm

Session 7: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD; Thomas Smith, MD, FACP, FASCO

5:15 pm - 5:45 pm

Summary/Wrap-Up of Day 1

6:00 pm - 8:00 pm

Cocktail Reception in the Exhibit Hall

SATURDAY, MAY 4, 2013 7:00 am - 8:00 am

Opening Remarks

8:30 am - 9:15 am

Session 8: The Role of Government in the Future of Oncology Care Jayson Slotnick, JD, MPH

9:15 am - 10:00 am

Session 9: Medicaid: A Healthcare Delivery System Review Matthew Brow

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality Kip Piper

11:00 am - 11:45 am

Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence Issues Pat McKercher; Lillie Shockney, RN, BS, MAS

PHYSICIAN CREDIT DESIGNATION

The Medical Learning Institute Inc designates this live activity for a maximum of 17.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

REGISTERED NURSE DESIGNATION

Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm

Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm

Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling, Genome Sequencing—The Impact on Cost, Treatment, and the Value Proposition Mark S. Boguski, MD, PhD; Gary Palmer, MD, JD, MBA, MPH

3:45 pm - 4:15 pm

Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm

Cocktail Reception in the Exhibit Hall

Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

SUNDAY, MAY 5, 2013

REGISTERED PHARMACY DESIGNATION

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship Care Julie Silver, MD

9:15 am - 10:00 am

Session 15: Current and Future Considerations for the Oncology Practice Manager Dawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE $375.00 until March 15, 2013 REGISTRATION $425.00 after March 15, 2013 REGISTER TODAY AT

www.regonline.com/avbcc2013

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 16: Access to Drugs—Shortages, Biosimilars Douglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am

Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and Challenges Thomas Marsland, MD; David Eagle, MD

11:45 am - 12:00 pm

Summary and Conclusion of Conference

*Agenda is subject to change.

AVBCCAsize20413

Economic Outlook

The RomneyCare Bill Comes Due Deval Patrick proposes a huge tax increase on the middle class

T

he health reform that Mitt Romney passed in 2006 in Massachusetts presaged President Obama’s, and its results are showing what we can expect nationwide.

The latest warning comes in a huge new tax increase proposed by Governor Deval Patrick.

The second-term Democrat followed his party’s recent habit and proposed an increase in the state’s single-rate income tax to 6.25% from 5.25%, the first in more than 20 years. The Bay State constitution requires a flat rate, so the Governor is sticking it to all taxpayers.

Mr. Patrick will try to add progressivity by raising the personal exemption, which taxpayer groups will challenge as unconstitutional. His plan would also eliminate 45 income-tax deductions, for such things as the capital-gains exemption on the sale of a home, adoption fees and college scholarships. This is the left’s idea for tax reform: raise rates and limit deductions – a revenue twofer.

To help this bad medicine go down, Mr. Patrick would lower the state sales tax to 4.5% from 6.25%.

He says the sales levy “is widely regarded to be the most regressive tax that states impose,” which is funny given that Mr. Patrick is the same guy who raised the rate to 6.25% from 5% in 2009. Then he said raising the rate was essential to pay state bills and wouldn’t hurt the economy. Now he says it’s regressive and must be cut.

Business taxes would also rise under the Patrick revenue raid, and Bay State residents would pay higher gas taxes, turnpike tolls and car taxes. All told it’s a $1.9 billion a year net tax hike.

Mr. Patrick says the money will fund the usual array of liberal programs. But this is salesmanship to disguise that the state’s real spending driver is the exploding cost of RomneyCare. That law was supposed to save

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the state money. But last August Beacon Hill was forced to impose new price controls and a cap on overall state health spending because “health-care spending has crowded out key public investments,” as Mr. Patrick puts it in his budget.

He’s right about that: Health care was 23% of the state fisc in 2000, and 25% in 2006, but it has climbed to 41% for 2013. On current trend it will roll past 50% around 2020 – and that best case scenario assumes Mr. Patrick’s price controls work as planned. (They won’t.)

In real terms the state’s annual health-care budget is 15% larger than it was in 2007, while transportation has plunged by 22%, public safety by 17% and education by 7%. Today Massachusetts spends less on roads, police and schools after adjusting for inflation than it did in 2007.

Mr. Romney expanded coverage without a tax increase at first, but Democrats quickly passed one anyway and now they are tripling down. Call it the return of Taxachusetts, the state’s old moniker from the 1970s and 1980s before a string of GOP Governors were elected to hold the line.

Republicans can offer only token resistance now because Democrats hold 127 of the 160 House seats and 36 of 40 Senate seats on Beacon Hill. But will the voters buy it? In the late 1970s Massachusetts helped launch the national tax revolt with property tax measure 2½, and as recently as 2000 59% of voters approved a ballot initiative to cut the state income tax rate to 5%.

Mr. Patrick is gambling that Mr. Obama has so changed the politics of taxes that he can get away with anything.

He may also figure that he may skip town soon enough for the Obama Administration – think AG after Eric Holder – that he needn’t worry about the political fallout. The lesson for voters is that universal health care is going to have universally large costs. The middle class will pay the bill, as they are starting to do in Massachusetts. u Reprinted with permission of The Wall Street Journal © 2013. Dow Jones Company. All rights reserved.

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PMPM O C

ERSONALIZED EDICINE IN ONCOLOGY

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Our vision is to transform the old medical model of stratified medicine into a new model of personalized care where all decisions and practices are tailored to the individual.

The goal of Personalized Medicine in Oncology is to sensitize practitioners to the performance realities of new diagnostic and treatment discoveries and to clarify molecular profiling technologies as they relate to diagnostic, prognostic, and predictive medicine. PMO will feature diagnostic and clinical treatment information concerning these 3 root aspects of personalized medicine in oncology.

Readers are invited to submit articles for consideration in the following categories:

Biologicals in Trial •

Exploring the challenges of clinical trial design and patient enrollment

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Presentation of emerging clinical data

Predictive Models and Diagnostics •

A look at available diagnostic technologies and implementation in the community practice setting

Genetics and Biomarkers •

Exploring genetic discoveries and impact on predictors of disease and therapeutic response

The Cost of Personalized Medicine •

Personalized medicine policy drivers

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Payer coverage of diagnostics and biologics

Genetic Profiling Technologies •

What technologies are available to clinicians and consumers and their impact on diagnostic, prognostic, and predictive medicine

In Practice •

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Healthcare Economics

The Doctor Won’t See You Now. He’s Clocked Out.

ObamaCare is pushing physicians into becoming hospital employees.

The results aren’t encouraging.

Scott Gottlieb, MD American Enterprise Institute

B

ig government likes big providers. That’s why ObamaCare is gradually making the local doctor-owned medical practice a relic. In the not too distant future, most physicians will be hourly wage earners, likely employed by a hospital chain.

Why? Because when doctors practice in small offices, it is hard for Washington to regulate what they do.

There are too many of them, and the government is too remote. It is far easier for federal agencies to regulate physicians if they work for big hospitals. So ObamaCare shifts money to favor the delivery of outpatient care through hospital-owned networks.

The irony is that in the name of lowering costs, ObamaCare will almost certainly make the practice of medicine more expensive. It turns out that when doctors become salaried hospital employees, their overall productivity falls.

ObamaCare’s main vehicle for ending the autonomous, private delivery of medicine is the hospital-owned “accountable care organization.” The idea is to turn doctors into hospital employees and pay them flat rates that uncouple their income from how much care they deliver. (Ending the fee-for-service payment model is supposed to eliminate doctors’ financial incentives to perform extraneous procedures.) The Obama administration also imposes new costs on physicians who remain independent – for example, mandating that all medical offices install expensive information-technology systems.

The result? It is estimated that by next year, about

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50% of U.S. doctors will be working for a hospital or hospital-owned health system. A recent survey by the Medical Group Management Association shows a nearly 75% increase in the number of active doctors employed by hospitals or hospital systems since 2000, reflecting a trend that sharply accelerated around the time that ObamaCare was enacted. The biggest shifts are in specialties such as cardiology and oncology.

Estimates by hospitals that acquire medical practices and institutions that track these trends such as the Medical Group Management Association show that physician productivity falls under these arrangements, sometimes by more than 25% (more on this below).

The lost productivity isn’t just a measure of the fewer back surgeries or cardiac catheterizations performed once physicians are no longer paid per procedure, as ObamaCare envisions. Rather, the lost productivity is a consequence of the more fragmented, less accountable care that results from these schemes.

Once they work for hospitals, physicians change their behavior in two principal ways. Often they see fewer patients and perform fewer timely procedures.

Continuity of care also declines, since a physician’s responsibilities end when his shift is over. This means reduced incentives for doctors to cover weekend calls, see patients in the ER, squeeze in an office visit, or take phone calls rather than turfing them to nurses. It also means physicians no longer take the time to give detailed sign-offs as they pass care of patients to other doctors who cover for them on nights, weekends and days off.

Most hospitals exacerbate these strains by measuring the productivity of the physician practices they purchase in “Relative Value Units.” This is a formula that Medicare already uses to set doctor-payment rates.

RVUs are supposed to measure how much time and

PERSONALIZED MEDICINE

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Healthcare Economics

physical effort a doctor requires to perform different clinical endeavors.

Medicare assigns each clinical procedure a different RVU and then multiplies this figure by a fixed amount of money to arrive at how much it will pay a doctor for a given task. A routine office visit has an RVU of about 1.68, while removing earwax has one of 1.26. Setting a finger fracture rates a 3.48.

This system misses all of the intangible factors that help gauge the quality and efficiency of the care being delivered. It focuses physicians on the wrong goals for promoting health, such as how well they code charts to capture higher-value “units.”

Hospitals are beholden to the RVU system only because that is how they get paid by the government. Data from the Medical Group Management Association shows that physician productivity in these employed relationships, measured simply by RVUs, declines up to 25% compared with independent practices. The Advisory Board Company, a health-care consulting firm, estimates that when hospitals last went on a physician-acquisition binge in the late 1990s, productivity fell by as much as 35%. Those arrangements mostly failed, and the hospitals divested the stakes they had in individual doctor practices. The physicians went back to practicing out of their own offices.

All of this reduced productivity translates into the loss of what should be a critical factor in the effort to offer more health care while containing costs. Yet hospitals aren’t buying doctors’ practices because they want to re-

REPRINTS

form the delivery of medical care. They are making these purchases to gain local market share and develop monopolies. They are also exploiting an arbitrage opportunity presented by Medicare’s billing schemes, which pay more for many services when they are delivered at a hospital instead of an outpatient doctor’s office.

ObamaCare pushes this folly largely based on a naive assumption that models that worked well in one community can be made to work everywhere.

This billing structure exists because hospitals are politically favored in Washington. Their mostly unionized workforces give them political power, as does their status as big employers in congressional districts.

ObamaCare pushes this folly largely based on a naive assumption that models that worked well in one community can be made to work everywhere. President Obama has touted “staff models” like the Geisinger Health System in Pennsylvania and the Mayo Clinic in Minnesota that employ doctors and then succeed in reducing costs by closely managing what they do. When integrated delivery networks succeed, they are rarely led by a hospital. ObamaCare seeks to replicate these institutions nationwide, even though their successes had more to do with local traditions and superior management. That’s hard to engineer through legislation. u © Scott Gottlieb, MD. Reprinted with permission.

Personalized Medicine in Oncology ™ offers reprints of individual articles in printed or electronic form to increase awareness of your product or company.

ORDER TODAY! Russell Hennessy • 732.992.1888 • russell@greenhillhc.com

Volume 2 • No 2

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April 2013

97

The Last Word

The Affordable Care Act and Oncology Personalized Medicine: Compatibility and the Governing Dynamics of Healthcare

O

ur last column examined the tripartite nation through the lenses of value, sectors, and wellness. ture of healthcare: a clinical/business/policy The ACA is pure Policy designed to expand insurentity with each of the 3 sectors influencing ance coverage. But this is all so vague…coverage of the net condition of healthcare. While what? For whom? Paid for by whom? the healthcare entity should act in balWho are the winners and losers? Can ance, in reality each sector periodically PM continue to progress, or will the springs forward with powerful initiaACA stifle this? tives and “takes charge” of healthcare Nothing makes healthcare as inuntil another sector responds with its vigorating as the collision of these initiative to redress the balance. core dynamics. The ACA did not Significantly, insurance does not glide into the healthcare system – translate directly into care. The second it dropped into it with a thump to principle on which healthcare rests is broaden the access to insurance to value: the balance of cost, quality, and 25 million more people. It does so by access – which again instinctively gravcost-shifting from one class of Ameriitates toward a balance of forces, since cans to another. It is neither ideologRobert E. Henry healthcare cannot exist as a simple ically pure nor financially sound, but matter of pure medical quality, pure it will certainly impact. cost-effectiveness, or perfect access, but a Lagrangian Rather than rattle off projections as to how it will balance of the three. impact PM, it may be more instructive to pose questions The third 3-part principle of healthcare is wellness: based on the interaction of the aforementioned forces a cycle of prevention, intervention, and innovation emanating from the dynamics of healthcare sectors, working together. No surprise here…making it work value, and wellness. Does the ACA help the uninsured requires a balance of these forces to keep healthcare while hurting others, reducing access to PM biologicals, viable, humane, and progressive. imaging, and laboratory diagnostics by “dumbing down” Personalized medicine (PM) is clearly a Clinical healthcare into a tepid, egalitarian bowl of porridge? initiative, relying heavily on innovation and individHow much money can the Federal Reserve dare print to ualized care, biomarkers, and biologics essential to its fund what critics call an inherently unaffordable initiaimplementation. It has begun to “drive” healthcare tive? Will the level of care be commensurate with true away from the old, imprecise blockbuster drug model.

PM? Will the aging American population be receiving But because healthcare is not a unilateral entity, angrade A care, or will healthcare quality suffer under the other sector – Policy – is making itself felt in the form financial pressures involved in increasing the insured? of the Affordable Care Act (ACA). The practicing onThe ACA imposes obligations on other people to cologist must now navigate new waters where Policy add 25 million insured lives, with a paradoxical efcollides with Clinical. The operative question is, how fect. About 8 million people will lose private health compatible are PM and the ACA? The answers will be insurance, and 3 to 4 million will drop their coverage. slow in coming, but it may help to examine this quesSome will go over to the government insurance, which

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does not have enough money to pay for all the newly insured patients. Will hospitals start restricting levels of care to patients? Will there be differences in care for government versus privately insured patients? How many of the newly added patients will need cancer care?

Will there be an improvement in preventive screening to catch cancer early? Insurers won’t be able to charge newly insured people with cancer more than healthy people – so how will the insurers remain solvent under these conditions, and will they devise elaborate eligibility measures for patients to receive PM care for cancer?

One highly significant characteristic of the ACA is how it differs fundamentally from PM: it is not about individuals. It is about populations and obligations to pay for other people’s “rights” as defined by law (which brings up the feisty question, is healthcare a right?). PM is based on crafting a solution based on an individual’s needs, whereas the ACA does not regard patients in that way. If there isn’t enough money, can we expect standardization of care, thereby causing long-term access denial to certain PM treatments because of the cost-shifting the ACA entails? The ACA looks at patients in large chunks/buckets. Rather than fostering innovation, will it tend to place a financial “governor” on it? The ACA is a social class entitlement initiative.

So how will it affect the uptake of PM and the continuation of the immense research into biomarkers and new biologics?

The fact that someone has health insurance does not mean that he can afford a biologic. Cost-sharing and annual or lifetime limits only fail to apply to Medicaid patients – giving these patients an advantage in getting access to expensive care, based on cost-shifting from the newly insured patient to the existing insurance market. Who will pay for that? Private companies. Will these companies be able to fund this level of coverage required for PM-styled care?

Is there sufficient evidence to convince payers to cover PM innovations? Given the fact that government lacks the money to fund the ACA, will PM run into a collectivist view of healthcare, stemming from the philosophy behind the ACA (ie, it is “unfair” for some people to get

Volume 2 • No 2

access to PM while others get conventional chemotherapy)? As biologics keep mainstream cancer patients alive for a long time, can we pay for it? What lambda will our society designate for the improvements that PM brings to cancer care? Will treatment be based on one’s “value to society”? Will the ACA create a 2-tiered or 3-tiered system of care? Will the ACA result in more people having access to PM oncology care, or fewer? More access to quality biologics care, or less? A more equitable access to oncology care…that excludes PM? Because it is necessary to increase the cost of insurance to everyone else to fund it for the indigent, will everyone get less of the whole? Can we afford to keep oncologists and oncology nurses reimbursed sufficiently to maintain a sufficient workforce? Has solid epidemiological study been done to dovetail this workforce to our aging population and the number of cancer patients who will require treatment? How much will premiums change? How will insurers’ demands for guarantees of effectiveness and safety rise to qualify for coverage of PM screening, diagnostics, and treatment? If you think your fight is with the payer, keep in mind that insurers, under the ACA, are becoming regulated utilities – and so are limited by the government.

The questions raised by the ACA are legion…and not going to go away on their own. They will require all to come to grips with what real forces govern healthcare and end the pretense that any healthcare sector can dictate the course of healthcare, or legislate in opposition to the true governing dynamics. So be prepared, fair oncologist, for encounters with your insurer and your government regarding attempts to place limits on PM. As Bette Davis uttered in All About Eve, “Fasten your seatbelts, it’s going to be a bumpy night.” As to answers to the above questions, I assure you in full confidence…I’m sure I don’t know! u Robert E. Henry

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April 2013

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biotheranostics.com REFERENCE: Kim B, Schroeder BE, Schnabel CA, et al. Physician-Reported Clinical Utility of the 92-Gene Molecular Classifier in Tumors With Uncertain Diagnosis Following Standard Clinicopathologic Evaluation. Personalized Medicine in Oncology. 2013;2:68-76.

CancerTYPE ID Indications for Use and Limitations CancerTYPE ID is indicated for use in tumor specimens from patients diagnosed with malignant disease and is intended to aid in the classification of the tissue of origin and tumor subtype in conjunction with standard clinical and pathological assessment by a qualified physician. CancerTYPE ID is not intended to predict patient survival benefit, treatment efficacy or to distinguish between benign versus malignant lesions. Tumor types not included in the CancerTYPE ID reference database may exhibit RNA expression patterns that are similar to RNA expression patterns within the reference database. This test was developed and performance characteristics have been determined by bioTheranostics, Inc. It has not been cleared or approved by the U.S. Food and Drug Administration. This test is used for clinical purposes. It should not be regarded as investigational or for research. How this information is used to guide patient care is the responsibility of the physician. bioTheranostics is certified under the Clinical Laboratory Improvement Amendments of 1988 as qualified to perform high complexity clinical laboratory testing.

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testimonials The Global Biomarkers Consortium Inaugural Meeting held this past year in Orlando was a wonderful opportunity to think about myeloma and other cancers from a different perspective. Typically we focus on treatment and outcomes from a purely drug-specific approach, but this meeting offered each of the diseases discussed a chance to segment the disease, and then think about treatment and outcomes. These types of presentations bring new clarity to how we treat and diagnose cancer, and really help to focus on the future of oncology.

– Sagar Lonial, MD Emory University

I think the main differentiating factor of this meeting is its multidisciplinary, multicancer format which brings together groups of people that don’t usually talk to each other. Also the topics are very unique and the whole concept of biomarkers in cancer is a “hot” topic.

– Sanjiv Agarwala, MD St. Luke’s Cancer Center

who attends GBC Primary site of practice

Profession 10.3%

13%

10.3%

45%

Academic clinical practice

29% 16.1% MD/DO

24.1%

PhD

Community hospital

RN/APN

Private practice

RPh/PharmD

6.4%

Pharmaceutical industry Other

New patients seen per week

Professional experience

26.7%

12.9%

22.6%

Other

10.3%

Academic research only

33.3%

56.7%

20%

1-3years years 1-3 3-5years years 3-5

6.7% 3.2% 6.7%

5-10years years 5-10

1-5 1-5 5-10 5-10

26.7%

10-20years years 10-20 >20years years >20

www.globalbiomarkersconsortium.com

20%

10-15 10-15 >15 >15