May 2012, VOL 1, NO 1 by The Oncology Nurse

IER M E SUE R P IS

May 2012 Volume 1 • Number 1

PM O

PERSONALIZED MEDICINE IN ONCOLOGY TM

EDITORIAL Personalized Medicine in Oncology: The Landscape of the Next Generation of Cancer Care..........Page 12

BIOMARKERS Clinical Trial Designs for Biomarker Evaluation ....................................................Page 26 Precision Medicine: Applying Predictive and Prognostic Indices to Risk-Adapted Treatment Selection......................................................Page 50

INTERVIEW WITH THE INNOVATORS Accelerating Personalized Medicine Approaches in Multiple Myeloma: An Interview With Kathy Giusti and Deborah Dunsire, MD ............................Page 38

PHARMACOECONOMICS Cancer Care Grand Rounds ........................Page 58

IMPLEMENTING THE PROMISE OF PROGNOSTIC PRECISION INTO PERSONALIZED CANCER CARE

NOW APPROVED FOR SUBCUTANEOUS ADMINISTRATION

Subcutaneous VELCADE Demonstrated Efficacy Consistent With IV for the Primary Endpoint RESPONSE RATES† IN RELAPSED MULTIPLE MYELOMA (MM): SUBCUTANEOUS AND IV AT 12 WEEKS (AFTER 4 CYCLES) Single-agent VELCADE® (bortezomib)

AT 24 WEEKS (AFTER 8 CYCLES) VELCADE±dexamethasone

53% 51%

43% 42%

11% 12%

7% 8% ORR Primary Endpoint

SC (n=148) IV (n=74)

ORR

▼ The study met its primary non-inferiority objective that single-agent subcutaneous VELCADE retained at least 60% of the overall response rate after 4 cycles relative to single-agent IV VELCADE SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed MM. The primary endpoint was overall response rate at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival (OS), and safety. *INDICATIONS: VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. †

Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.1

VELCADE IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS ▼ Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Closely monitor patients with risk factors for, or existing heart disease ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

IN ALL INDICATIONS*

Difference in Incidence of Peripheral Neuropathy With Subcutaneous VELCADE PERIPHERAL NEUROPATHY (PN) IN RELAPSED MM: SUBCUTANEOUS AND IV GRADE ≥3

SC (n=147) IV (n=74)

16% ALL GRADES

38% 53% ▼ Starting VELCADE® (bortezomib) subcutaneously may be considered for patients with preexisting PN or patients at high risk for PN. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Treatment with VELCADE may cause PN that is predominantly sensory. However, cases of severe sensory and motor PN have been reported. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness ▼ Patients experiencing new or worsening PN during therapy with VELCADE may require a decrease in the dose, a less-dose-intense schedule, or discontinuation. Please see full Prescribing Information for dose modification guidelines for PN

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS CONTINUED ▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

Please see Brief Summary for VELCADE on next page. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com Reference: 1. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431-440.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/ postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been

isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. (continued)

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE (bortezomib). Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/ prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs

were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE (bortezomib) is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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labyrinth is an ancient symbol representing a journey. It combines the imagery of a circle and a spiral into a meandering but purposeful path. The ultimate goal of this symbolic journey is to reach a broader understanding or enlightenment.

PM O

May 2012 Volume 1 • Number 1

PERSONALIZED MEDICINE IN ONCOLOGY ™

EDITORIAL Personalized Medicine in Oncology: The Landscape PAGE 12 of the Next Generation of Cancer Care Robert E. Henry

CONFERENCE NEWS Join us on our journey to realize the tremendous possibilities of improving cancer prevention, diagnosis, and treatment through a new medical model of personalized care.

Global Biomarkers Consortium – Implementing the Promise of Personalized Cancer Care

PAGE 16

Immunotherapy for Advanced Prostate Cancer May PAGE 18 Be Underutilized New Agents Prove Potent Against HER2-Positive PAGE 19 Breast Cancer

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. OUR VISION Our vision is to transform the old medical model of stratified medicine 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.

Volume 1 • No 1

What Oncologists Need to Know About 7 New Agents

PAGE 22

BIOMARKERS Clinical Trial Designs for Biomarker Evaluation

PAGE 26

Sumithra J. Mandrekar, PhD; Daniel J. Sargent, PhD

Precision Medicine: Applying Predictive and Prognostic Indices to Risk-Adapted Treatment Selection

PAGE 50

Sandra Kurtin, RN, MS, AOCN, ANP-C

PERSONALIZED MEDICINE

ONCOLOGY

May 2012

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PUBLISHING STAFF EDITORIAL DIRECTOR Kristin Siyahian kristin@greenhillhc.com STRATEGIC EDITOR Robert E. Henry SENIOR COPY EDITOR BJ Hansen PRODUCTION MANAGER Marie RS Borrelli QUALITY CONTROL DIRECTOR Barbara Marino

Accelerating Personalized Medicine Approaches in Multiple Myeloma: An Interview With Kathy Giusti PAGE 38 and Deborah Dunsire, MD

CIRCULATION DEPARTMENT circulation@greenhillhc.com MANAGING DIRECTOR Pam Rattananont Ferris PUBLISHERS John W. Hennessy john@greenhillhc.com

PHARMACOECONOMICS Cancer Care Grand Rounds

Russell Hennessy russell@greenhillhc.com

A new study suggests higher U.S. oncology spending is ‘worth it.’ PAGE 58

DIRECTOR, CLIENT SERVICES Eric Iannaccone eric@greenhillhc.com Personalized Medicine in Oncology, ISSN applied for; (online) is published 6 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications, LLC. All rights reserved. Personalized Medicine in Oncology logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Personalized Medicine in Oncology (PMO), 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $50.00; institutions, $90.00; single issues, $5.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in PMO do not necessarily reflect those of the editorial board, the editorial director, or the publishers. Publication of an advertisement or other product mention in PMO should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the editorial board nor the publishers assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the editorial director.

Volume 1 • No 1

PERSONALIZED MEDICINE IN ONCOLOGY ™

INTERVIEW WITH THE INNOVATORS

BUSINESS MANAGER Blanche Marchitto

PM O

INTERVIEW WITH THE INNOVATORS An exclusive PMO series Personalized Medicine in Oncology™ is pleased to offer insightful interviews with leaders in oncology about their approach to personalized medicine. To watch our interviews, visit www.PersonalizedMedOnc.com/videolibrary

PERSONALIZED MEDICINE

ONCOLOGY

May 2012

Pancreatic Cancer: Progress and Challenges June 18-21, 2012 Lake Tahoe, NV An AACR Special Conference on: Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations June 27-30, 2012 Marriott Copley Place Boston, MA Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research October 16-19, 2012 Anaheim, CA Fifth Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved October 27-30, 2012 San Diego, CA EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 6-9, 2012 Dublin, Ireland

An AACR Special Conference on: Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment November 11-14, 2012 Hollywood, FL An AACR Special Conference on: Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances December 2-5, 2012 Miami, FL CTRC-AACR San Antonio Breast Cancer Symposium December 4-8, 2012 San Antonio, TX An AACR Special Conference on: Tumor Invasion and Metastasis January 20-23, 2013 San Diego, CA Ninth AACR-Japanese Cancer Association Joint Conference: Breakthroughs in Basic and Translational Cancer Research February 21-25, 2013 Maui, HI AACR-Society of Nuclear Medicine Joint Conference on State-of-the-art Molecular Imaging in Cancer Biology and Therapy February 27-March 2, 2013 San Diego, CA

Please visit www.aacr.org/meetingscalendar for the complete calendar, as conferences are added and updated on a regular basis

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 Pathology DAVID L. RIMM, MD, PHD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut

Lung Cancer VINCENT A. MILLER, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, New York

Gastrointestinal Cancer EUNICE KWAK, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts 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

SANJIV S. AGARWALA, MD St. Luke’s Hospital Bethlehem, Pennsylvania

STEPHEN GATELY, MD TGen Drug Development (TD2) Scottsdale, Arizona

DAVID A. PROIA, PHD Synta Pharmaceuticals Lexington, Massachusetts

TONY ALBINO, PHD Signal Genetics LLC New York, New York

STEVEN D. GORE, MD The Johns Hopkins University School of Medicine Baltimore, Maryland

RAFAEL ROSELL, MD, PHD Catalan Institute of Oncology Barcelona, Spain

EDITORIAL BOARD

GREGORY D. AYERS, MS Vanderbilt University School of Medicine Nashville, Tennessee LYUDMILA BAZHENOVA, MD University of California, San Diego San Diego, California LEIF BERGSAGEL, MD Mayo Clinic Scottsdale, Arizona

STEVEN T. ROSEN, MD, FACP Northwestern University Chicago, Illinois

K. PETER HIRTH, PHD Plexxikon, Inc. Berkeley, California

HOPE S. RUGO, MD University of California, San Francisco San Francisco, California

HOWARD KAUFMAN, MD Rush University Chicago, Illinois

DANIELLE SCELFO, MHSA Genomic Health Redwood City, California

KATIE KELLEY, MD UCSF School of Medicine San Francisco, California

KENNETH BLOOM, MD Clarient Inc. Aliso Viejo, California

LEE SCHWARTZBERG, MD The West Clinic Memphis, Tennessee

MINETTA LIU, MD Georgetown University Hospital Washington, DC

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 BETH FAIMAN, PHD(C), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio

KIM MARGOLIN, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington GENE MORSE, MD University of Rochester Rochester, New York AFSANEH MOTAMED-KHORASANI, PHD Radient Pharmaceuticals Tustin, California NIKHIL C. MUNSHI, MD Dana-Farber Cancer Institute Boston, Massachusetts

Volume 1 • No 1

PERSONALIZED MEDICINE

LAWRENCE N. SHULMAN, MD Dana-Farber Cancer Institute Boston, Massachusetts DARREN SIGAL, MD Scripps Clinic Medical Group San Diego, California MOSHE TALPAZ, MD University of Michigan Medical Center Ann Arbor, Michigan ANAS YOUNES, MD The University of Texas MD Anderson Cancer Center Houston, Texas

STEVEN O’DAY, MD John Wayne Cancer Institute Santa Monica, California

JOHN SHAUGHNESSY, PHD University of Arkansas for Medical Sciences Little Rock, Arkansas

ONCOLOGY

May 2012

Letter From the Editor in Chief

Welcome to Personalized Medicine in Oncology ™ Dear Colleague, Today’s oncologist faces a field both informed and blurred by the isolated successes of the phenomenon that is personalized medicine (PM). Breakthroughs in diagnosis and drug treatments are transforming some cancers from deadly, acute disease states into chronic ones. But the applause that accompanied the initial PM breakthroughs also distracts from the immense body of hard work still required by researchers and clinicians alike. Both are eager to apply PM principles to a needy patient population, but we are continually reminded that there is much work to be done before we are truly treating in a personalized way. The good news is that Al B. Benson III, MD PM is clearly on the march and is destined to have a predominant place in the treatment of cancer. This requires continual readjustment of the clinician’s approach to risk assessment, diagnosis, treatment, supportive care, and follow-up and engagement of stakeholders contiguous with the clinical oncologist on three fronts: patients and their caregivers, payers, and the increasingly complex laboratory infrastructure that is constructing the PM edifice. It is our intent to provide the forum where the latest, most impactful information about personalized care is exchanged, with the ultimate goal of helping clinicians to provide the best care to patients. Best regards,

Al B. Benson III, MD Editor in Chief

Volume 1 • No 1

WWW.PERSONALIZEDMEDONC.COM

May 2012

Editorial

Personalized Medicine in Oncology: The Landscape of the Next Generation of Cancer Care Robert E. Henry Strategic Editor Personalized Medicine in Oncology

ersonalized medicine. Innovation’s 21st-cenPM technology is helping fulfill that promise, making it tury poster child … and bastion of medical unthe centerpiece of healthcare policy, clinical practice, certainty, wishful thinking, and unfulfilled and financial management. Indeed, its first successes aspirations striking terror into the ledger sheets have caused healthcare system professionals to question of payers unable to cope with conventional (empirical) whether they have traded the problem of incurable medicine. Mastering personalized medacute diseases for the responsibility of icine (PM) requires an awareness of its long-term maintenance therapy at ungoverning dynamics, understanding sustainable cost levels. This would that it exists in many forms on multipresent healthcare with a dilemma inple planes. It possesses components stead of a solution, since healthcare opas diverse as individual biomarkers erates under the fundamental “Iron (KRAS mutations and HER2 expresTriangle” of value: the balance of cost, sion), broader prognostic nomograms, quality, and access. Therefore, for PM multivariate models (Oncotype DX), to be regarded as progress in cancer systems biology approaches utilizing care, it must demonstrate value rather patterns of genes, proteins or metabothan just quality. lites, and individualized strategies adThis consideration must precede the Robert E. Henry dressing subjective conditions of acceptance of PM. It caught the healthpatient lifestyle. Some PMs are treatcare community by surprise with what ments themselves: eg, tumor vaccines, image-guided appeared to be this good news/bad news scenario. Yet therapies based on fiducial markers, nanoparticles with upon closer examination, the bad news – higher drug targeted delivery, etc. But whatever its scope and form, cost of cancer treatment added to the transformation of PM has captured the mind of the medical community intrinsically acute fatal diseases into chronic ones requirand laity alike, who are determined to peel back its laying long-term treatment at higher costs than conveners and harness its immense power to defeat cancer. tional/empirical medicine – was not so bad, or at least it need not become so if all parties to the process work colPersonalized Medicine and Value laboratively to ensure that balance accompanies this PM is more goal than reality, yet it nonetheless repparadigm shift. At the heart of the matter is the resents the beginning of the fulfillment of a promise understanding of PM dynamics and conversely apprecimade throughout the 20th century to “lick cancer.” PM ating just how imprecise pre-PM healthcare intervention holds this elevated status for the simple reason – and often was. The implications abound for physician treatvery little concerning PM is simple – that it involves ment strategies, payer cost management strategies, paspecific, targeted eradication of cancer cells rather than tient prognostic expectations, research and development blunderbuss diagnostics and medicines too broadly instrategies, and policymaker legislation. vasive to heal the tumor at hand and ill-suited to tumor The central questions of PM in oncology are less about whether the new treatments will work than landscape particulars or the genetics driving the cancer.

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Editorial

whether we can afford them and what utilization efficiency measures are possible. Healthcare is reeling from excessive resource utilization, much of it wasteful, and most of it for outpatient treatment of patients with chronic diseases. What makes healthcare costs unsustainable is not simply the demographic increase in patients requiring treatment, but also their readiness to be treated and the reality that neither they nor physicians nor payers exercise sufficient vigilance to avoid resource misapplication. Healthcare disparities research is a growth industry, with every stakeholder, be they from the government, medical profession, private sector, or patient population, demonstrating a capacity to misapply or deny precious healthcare resources and wasting health and wealth in the process. Properly managed, PM can fill an efficiency gap in healthcare like nothing before it by satisfying the demand for certainty in resource allocation – targeting only the most likely candidates for treatment and, of equal importance, disqualifying from treatment attempts those many patients whose PM profile shows them to be incapable of responding favorably to a specific therapy.

Value: The Intersection of Science and Financial Viability PM is an extension of efficiency reform measures that include healthcare disparities reform, value-based medicine, patient-centered care, and wellness-based medicine (prevention, intervention, and innovation). Instead of fearing the empiric costs of care, PM elevates economics to a level of efficiencies heretofore impossible with empirical medicine. When PM testing identifies 85% of patients as ineligible for therapy and the remaining 15% as having a 90% chance of success with therapy, value sets in – and value is the ultimate goal of medicine…and the ultimate deliverable of PM. The value from identifying ineligible patients is immense, transforming actuarial models even as radically as the molecular imaging technology models are transforming medical textbooks. In the pre-PM era, pioneering cancer meta-analyst Sir Richard Peto stated, “Subgroup analysis kills people.”

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And in that era of the 1970s this was true – the science was not there to avoid unwarranted subgroup carve-outs done safely. PM not only allows subgroup analysis, it thrives on it. What PM does is avoid putting patients through unnecessary and often critically time-wasting therapy with no chance of success. Nor does PM torture the data with subgroup analysis that yields inaccurate projections of which patients are likely to succeed. Pharma has expended untold billions of dollars exploring unenriched patient populations at great cost. Thus, PM will help change the unsustainable research and development costs of new treatments, as well as saving money at the treatment level.

Instead of fearing the empiric costs of care, PM elevates economics to a level of efficiencies heretofore impossible with empirical medicine. The cost equation thus becomes viewed not in terms of the population as a whole but only in terms of the approachable population. The more oncologists understand a patient’s individual biology at the tumor level, the greater the likelihood of success with the therapy used. Value-based care thus replaces empiric trial-anderror treatment that not only burdens the healthcare system with wasted resources but also insinuates a culture of waste. This leads directly to the problem of healthcare disparities. A culture cannot rise above its own expectations for excellence. It will not take the High Road if it regards it as the stuff of foolhardy dreams. PM not only does its job effectively at its own site of activity, it also enriches the expectations of all participants to succeed and to get things right the first time! The path to efficient, successful resource allocation is being paved with PM building blocks.

Exploring the Personalized Medicine Frontier There are areas where understanding of PM principles is universal. For example, the status of KRAS bio-

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May 2012

Editorial

Biological Complexity: A Picture Is Worth a Thousand Words

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70. Used with permission, Elsevier Limited.

marker is a dichotomizing factor in colorectal cancer patients, and no oncologist would treat patients exhibiting KRAS-mutated tumors with anti-EGFR antibodies. Conversely, for patients with KRAS wild type, they would proceed with this treatment â&#x20AC;&#x201C; not with a guarantee of outcomes, but of patient eligibility for treatment. This is known universally. Other areas are much sketchier; the validation of PM hypotheses is uncertain, iterative. It becomes important that the clinician knows what it is that we do not know as he navigates clinical paths occasionally with no precedent, the only guide being a global knowledge of biological and genomic dynamics.

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Complexity Necessitates Specialization The simplicity of the PM premise and strategy belies the immense complexity of its execution, and so now that the premise of PM is largely accepted as praiseworthy, the order of the day for clinicians is to get on with understanding PM technologies and the new systems for informatics involved in the process of PM care: ie, what level of knowledge of which categories of PM technology must be understood in order to participate in this new type of medical care? The specifics of this informational challenge give focus to the unique PM mission: a quest to answer why some patients respond to therapies and others do not.

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Editorial

Dr Edward Benz of Dana-Farber Cancer Institute described the biological complexity as one element confronting the oncology community in a presentation delivered at the 2011 World Health Care Congress.1 This complexity has given rise to medical specialization needed to synchronize patient, tumor, diagnostics, and treatment. New technological disciplines are emerging. One such discipline is systems biology. In the course of explaining the role of systems biology in PM, researchers from MD Anderson Cancer Center point out how profoundly PM has changed the rules of engagement by subordinating the preeminence of randomized controlled trials, the gold standard of evidence, which “...are designed to determine the best approach for the average populations and not for specific individuals. The development of molecular profiling technologies to assess DNA, RNA, protein, and metabolites provides the potential to tailor medical care, both at tumor and patient levels. These approaches have the potential to fulfill the promise of delivering the right dose for the right indication to the right patient at the right time.”2

Tempering Enthusiasm: Coexistence of Personalized Medicine and Empirical Medicine The advance of PM can connote a false sense of the obsolescence of empirical science. Approximately 85% of patients do not have a personalized signature to make them eligible for PM treatment, and hyperbole regarding the current range of PM only hinders its actual implementation, which takes place alongside empirical medicine in a form of peaceful coexistence. They are not one another’s arch enemies, but complements. Physicians will not be abandoning empirical medicine anytime soon, and it will continue to play a role for that part of the cancer population that still requires it. Examples of limitation to PM include situations where access to tissue is limited, where heterogeneity within the patient’s tumor burden

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exists, and situations where mechanisms of resistance are not yet known (especially with novel agents). Clinicians recognize the realities of adding PM to empirical medicine one step at a time.

Conclusion The tactical execution of optimizing PM application at the oncology clinical level entails organizing and showcasing the vast, highly complex body of scientific research on personalized medical treatment of hematological and oncological diseases, translating innovation into clinical progress that delivers value – the balance of cost, quality, and access. Clinicians must understand the basic tenets of PM diagnosis, treatment, and informatics technologies in order to maintain a working grasp of PM that is realistic and grounded in current scientific updates. This will permit clinicians to include their patients in a dialogue on how to capitalize on the ability of PM to tailor cancer treatment according to their personal life goals – something that this targeted technology is only now beginning to make feasible, for PM is still more a promise than a reality. Currently we are witnessing a translational exposition of important new technologies in PM treatment of cancers. What remains to be seen is how skillfully and creatively this translational process is executed, what new avenues for PM open up before the ceaseless efforts of researchers, and how clinicians and their patients adapt to a culture of extraordinary change. Cultivating practitioner and patient clinical acumen in PM diagnosis and treatment will yield the long-awaited condition of healthcare value and triumphant outcomes that PM holds for cancer patients. u

References 1. Benz EJ Jr. Cancer research and care in the genomic age: toward personalized medicine. Presented at the 8th Annual World Health Care Congress; April 4-6, 2011; Washington, DC. 2. Gonzalez-Angulo AM, Hennessy BT, Mills GB. Future of personalized medicine in oncology: a systems biology approach. J Clin Oncol. 2010;28:2777-2783.

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May 2012

Conference News

Global Biomarkers Consortium — Implementing the Promise of Personalized Cancer Care

Edith Perez, MD, and Beth Faiman, PhD(c), MSN, APRN-BC, AOCN, lead a panel question-and-answer session with Gautam Borthakur, MD, and Sanjiv Agarwala, MD, (left to right) about incorporating personalized medicine into practice.

Sanjiv Agarwala, MD, presents a case study at the Global Biomarkers Consortium conference.

he inaugural conference of the Global Biomarkers Consortium brought together an international panel of oncology experts to explore the rapidly evolving field of biomarker research. Cochairs of the event were Hope S. Rugo, MD, director of Breast Oncology and Clinical Trials Education at the University of California San Francisco, and Rüdiger Hehlmann, MD, PhD, professor of medicine at the University of Heidelberg. Michael Kat-

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tan, PhD, Vincent Miller, MD, Edith Perez, MD, and Charles Bennett, MD, PhD, served as session chairs. At the conference, held March 9-11, 2012, in Orlando, Florida, a diverse field of experts addressed oncologists, hematologists, oncology nurses, pharmacists, and other healthcare professionals on a wide range of topics related to the clinical application of biomarkers in the treatment of solid tumors and hematologic malignancies. Conference attendees had numerous opportunities to ask questions. In addition, an audience response system provided opportunities for interactive learning experiences. Hehlmann opened the conference with a valuable historical overview of genetic profiling and oncologic biomarkers. In discussing development of new technologies, Miller reported, “There are an unprecedented number of targeted therapies in clinical trials – about 500 targeted therapies looking at about 140 genomic alterations.” In looking forward to next-generation sequencing, Miller concluded, “So I’m really excited about these broader technologies that may allow us to help more patients and more rationally approach treating patients in the near future.” Case studies of several types of cancer were presented by panel members. Perez presented “Evidence-Based Medicine to Translational Medicine to Personalized Medicine: A Natural Evolution,” and Beth Faiman, PhD(c), MSN, APRN-BC, AOCN, discussed “Roles and Responsibilities of the Interprofessional Team.” Perez and Faiman led a group composed of several doctors who had presented case studies in a panel questionand-answer session on “Incorporating Personalized Medicine Into Practice.” Personalized medicine based on an understanding of predictive molecular biomarkers holds great promise. Conferences such as this one help clinicians and other healthcare professionals keep up to date on developments in this challenging field. u

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Image: Colored scanning electron micrograph (SEM) of a lung cancer cell.

One focus: a shared commitment to improve the lives of cancer patients everywhere. Millennium: The Takeda Oncology Company is developing an extensive pipeline — among the top in oncology worldwide — with more than 17 compounds in development for a broad range of solid and hematological cancers. Our pipeline — rich in novel compounds — includes multiple candidates that target seven disease pathways: protein homeostasis, anti-angiogenesis, growth-signaling inhibition, cell-cycle inhibition, apoptosis, immunomodulators and hormone regulation. To make a dramatic impact on cancer therapeutics, we are dedicated to a strong partnership with the oncology community.

Conference News

Immunotherapy for Advanced Prostate Cancer May Be Underutilized Caroline Helwick

ipuleucel-T for metastatic castrate-resistant prostate cancer (mCRPC) offers a novel immunotherapy treatment option for a subset of patients, but the drug could be helping far more men than actually receive it, according to a speaker at the 37th Annual Congress of the Oncology Nursing Society. Sipuleucel-T, which activates T cells to stimulate an immune response to prostate cancer, is a first-line treatment option for men with symptomatic or minimally symptomatic mCRPC. “It is the only category 1 recommendation by the National Comprehensive Cancer Network for this group,” said Allison Tyler, RN, BSN, OCN, CCRP, clinical research nurse at the Cleveland Clinic, Cleveland, Ohio.

Even after responding to androgen deprivation therapy, nearly all men will develop CRPC; 80% will then develop metastatic disease, almost half of them within 2 years. In the pivotal IMPACT trial, men treated with the drug survived a median of 4 months longer than the control arm. Median overall survival was 25.8 versus 21.7 months, respectively, for a 22.5% reduction in risk (P=.032).1 Tyler noted that two-thirds of men treated with surgery or radiation are not cured of prostate cancer and will have a subsequent rise in the prostate-specific antigen (PSA) as an indicator of progression. Even after responding to androgen deprivation therapy, nearly all men will develop CRPC; 80% will then develop metastatic disease, almost half of them within 2 years. “These patients often go undiagnosed,” she said. In

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an analysis of a population (N=2516) screened for possible inclusion in a recent clinical trial, 30% of men thought to have nonmetastatic CRPC were found to have metastatic disease on imaging.2 “It is commonly said, ‘We don’t have patients fitting the profile for sipuleucel-T,’ but we know the patient population is out there, and we are not finding them early enough,” Tyler suggested, emphasizing that the presence of advanced symptoms eliminates sipuleucelT as a treatment option. In a review of over 1167 patient charts at 70 oncology practices, 61% of men with mCRPC had no symptoms or only minimal symptoms at diagnosis of metastatic disease. There was no pain or pain controlled by nonnarcotic medication.3

Identifying the Population “Regular monitoring can help identify disease progression in CRPC while patients are still asymptomatic or minimally symptomatic, but there are no definite guidelines for doing so,” she said. MRI effectively demonstrates extracapsular extension or seminal vesicle invasion. A CT scan is good for staging, however, early disease may be missed, and there is broad variation in sensitivity and specificity. Bone scans identify bone metastases, although negative results do not rule out disease. PET/CT scanning identifies tumors effectively and has high specificity for bone metastases. Once patients are being treated with immunotherapy, they need to understand that they may not manifest a clear-cut “response” to the drug, which acts in a manner much different from that of chemotherapy. “The main goal of the clinical study was not to lower PSA levels, but to prolong survival, which was shown in the trial,” she said. “The PSA may not plummet, as it did on earlier treatments, and patients may feel anxious about this,”

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she said. “They need to know that even if their PSA level does not decline, sipuleucel-T may help them live longer.” Tyler acknowledged that the treatment, which is completed in 1 month, is expensive but maintained that it is covered by most health plans, and most patients have minimal out-of-pocket costs. “For the ma-

jority of patients, this drug is a reasonably priced treatment option,” she said. u

References 1. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 2. Yu EY, Nathan E, Higano CS. Detection of metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC). J Clin Oncol. 2011;29(suppl). Abstract 4655. 3. Data on file. Dendreon Corporation.

New Agents Prove Potent Against HER2-Positive Breast Cancer Researchers seek to resolve outstanding issues regarding testing Caroline Helwick

rastuzumab changed the course of HER2positive breast cancer, and future anti-HER2 therapies may have an even greater impact, said Kristine Abueg, RN, MSN, OCN, clinical research nurse at Kaiser Permanente in Roseville, California, who discussed “What’s New in HER2?” at the 37th Annual Congress of the Oncology Nursing Society. In spite of a decade or so of established treatment with trastuzumab, questions still remain regarding the appropriate population to treat. In addition, many patients who respond to the drug eventually experience drug resistance and recurrence. Researchers are seeking to better understand resistance, and the pipeline is rife with agents that are effective upon trastuzumab failure, said Abueg. Four proteins make up the members of the HER family of cell surface receptors: HER1, HER2, HER3, and HER4. Trastuzumab targets HER2, the preferred partner for binding with the other members (heterodimerization) or itself (homodimerization) to create a signaling cascade. Trastuzumab’s dual-kill mechanism includes antibody-dependent cellular toxicity and the prevention of intracellular cell signaling, which induces apoptosis and

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prevents proliferation. Resistance that develops is associated with alternate signaling pathways, which are being targeted by new agents in development. “The key to understanding and ultimately mitigating this resistance lies in the HER2 signaling pathway,” she said.

The accuracy of immunohistochemical staining and scoring by fluorescence in situ hybridization has become questionable... HER2 Testing: Issues of Concern The accuracy of immunohistochemical (IHC) staining and scoring by fluorescence in situ hybridization (FISH) has become questionable, and provocative data are leading to a reexamination of current practice patterns, she said. In the pivotal studies, community pathology and central reference lab results have been discordant some 18% to 34% of the time. The implication is that a “fairly good number” of patients either receive trastuzumab unnecessarily or miss out on its benefits altogether, she said.

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The American Society of Clinical Oncology and the College of American Pathologists have issued revised guidelines for HER2 testing. The most recent recommendation is to prescribe anti-HER2 treatment when the FISH result is ≥2.0, and to retest when FISH is 1.8 to 2.2. This recommendation is now, however, compulsory.

The American Society of Clinical Oncology and the College of American Pathologists have issued revised guidelines for HER2 testing.

The other testing issue is the level of predictability of IHC and FISH, according to information from the pivotal trastuzumab studies. Consistent benefit from trastuzumab was observed in every subset (including patients who were actually HER2 negative), and FISH score strength was not predictive of this. Even some FISH-negative patients benefited from the drug. “The clinical implication is whether the HER2 ‘sensitive’ population can be expanded,” Abueg explained. Clinical trials are evaluating trastuzumab in the IHC 1+ and FISH-negative populations.

Overcoming Resistance With New Agents The powerful new agents under investigation are designed specifically to attack the proposed mechanisms of trastuzumab resistance. Lapatinib, of course, is already established for use after progression with trastuzumab. The ALTTO study is evaluating whether the adjuvant use of lapatinib in combination with trastuzumab, prior to the development of resistance, will be more effective than either agent alone. In the neoadjuvant NeoALLTO trial, the combination produced a 51% pathologic complete response rate,1 and the hope is that this type of activ-

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ity will be observed in the adjuvant setting, she said. Even more promising could be 4 investigational agents: • Neratinib, which works similarly to lapatinib, blocks HER2, HER1, and HER4, and inhibits intracellular cell signaling • Everolimus, an mTOR inhibitor proven in other cancers • Pertuzumab, a monoclonal antibody that blocks HER2/HER1 and HER2/HER3 dimerization and binds at a different site than trastuzumab • T-DM1 (trastuzumab emtansine), an antibody-drug conjugate with highly targeted delivery Each is backed by very encouraging data, but T-DM1 has elicited the most excitement, and for good reason, she noted. In a phase 2 open-label study, T-DM1 resulted in a median progression-free survival of 14 months versus 9 months with trastuzumab and docetaxel, reducing the risk of disease progression by 41% and proving to be very well tolerated.2 In 2010, the FDA declined to grant accelerated approval and called for phase 3 trials to be completed. Additional studies (EMILIA, MARIANNE, THERESA) are under way. “I have a patient on one of these trials who had an 11-cm liver metastasis and pulmonary nodules after multiple lines of treatment. Last week, she received her 47th cycle of T-DM1. Her tumor is now 1.1 cm and has been stable for two and a half years,” Abueg reported. While thrombocytopenia can be problematic, it has remained grade 1 for this patient. “I think this is a stunning result,” she commented. u

References 1. Baselga J, Bradbury I, Eidtmann H, et al; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633-640. 2. Hurvitz S, Dirix L, Kocsis J, et al. Trastuzumab emtansine (T-DM1) vs trastuzumab plus docetaxel (H+T) in previously untreated HER2-positive metastatic breast cancer (MBC): primary results of a randomized, multicenter, open-label phase II study (TDM4450g/BO21976). Presented at the 2011 European Multidisciplinary Cancer Conference. Stockholm, Sweden. September 23-27, 2011. Abstract 5001.

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May 2012

PMPM O C

ERSONALIZED EDICINE IN ONCOLOGY

ALL FOR PAPERS

Personalized Medicine in Oncology’s mission is to deliver practice-changing information to clinicians about customizing healthcare based on molecular profiling technologies and each patient’s unique genetic blueprint. 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

•

Presentation of emerging clinical data

Genetic Profiling Technologies •

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

In Practice Predictive Models and Diagnostics •

Genetics and Biomarkers •

•

A practical guide for community-based oncologists discussing clinical applications and strategies for incorporating personalized medicine techniques into practice

•

Development of treatment algorithms

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

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

The Cost of Personalized Medicine •

Personalized medicine policy drivers

•

Payer coverage of diagnostics and biologics

N=1 •

Case studies, patient-reported outcomes, defining treatment goals, partnering with patients and caregivers

Submit the entire manuscript and a cover letter stating the objectives of the article to PMO@greenhillhc.com. Manuscripts should follow the Author Guidelines available at www.PersonalizedMedOnc.com. "

Conference News

What Oncologists Need to Know About 7 New Agents Caroline Helwick

ncologists should understand the characteristics of 7 emerging drugs and biologics that should improve patient care. At the 2012 Pharmacy Program held during the 17th Annual Conference of the National Comprehensive Cancer Network (NCCN) in Hollywood, Florida, Van Anh Trinh, PharmD, of the University of Texas MD Anderson Cancer Center, Houston, and Robert Ignoffo, PharmD, of the University of California San Francisco and the Touro University College of Pharmacy, Vallejo, California, described the appropriate use of axitinib, crizotinib, ipilimumab, and vemurafenib and previewed carfilzomib, regorafenib, and vosaroxin.

New Tyrosine Kinase Inhibitors Axitinib was recently approved for, and carries an NCCN category 1 recommendation for, advanced renal cell carcinoma after failure of 1 prior systemic therapy, joining everolimus and sorafenib in this setting. “It’s hard to say which to use first. Selection can be guided by the toxicity profile,” Trinh suggested. In the pivotal

Axitinib was recently approved for advanced renal cell carcinoma after failure of 1 prior systemic therapy, joining everolimus and sorafenib... phase 3 trial comparing axitinib with sorafenib, the most potency was seen in cytokine-refractory patients, while in patients with prior sunitinib treatment the delay in progression was a modest 1.4 months, she noted. The approved dosing schedule is 5 mg orally twice a day (PO BID), with titration (after 2 weeks) to 7 mg BID, then (after 2 more weeks) to 10 mg BID. Axitinib should not be used concurrently with CYP3A4/5 inducers. Crizotinib is indicated for, and carries an NCCN category 1 recommendation for, locally advanced or

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metastatic non–small cell lung cancer with the ALK translocation. Off-label use is anticipated for anaplastic large cell lymphoma, Trinh said. The approved dose is 250 mg PO BID, with adjustments recommended for patients with hepatic impairment or severe renal insufficiency, but not for creatinine clearance ≥30 mL/min. Drug interactions can occur with potent CYP3A inducers or CYP3A substrates with a narrow therapeutic index. Complete blood count, liver function tests, and EKG are recommended for monitoring.

Novel Melanoma Agents “Ipilimumab and vemurafenib are long-awaited treatments for melanoma,” Trinh said. “Ipilimumab was the first drug to provide a survival improvement in a randomized phase 3 trial in melanoma.” The approved dosing schedule for ipilimumab is 3 mg/kg IV over 90 minutes every 3 weeks for 4 doses. Premedication and prophylactic antiemetics are not needed, nor are adjustments necessary for patients with hepatic or renal dysfunction. It is unclear whether “reinduction” is effective upon progression, but ipilimumab has been shown to restore disease control in two-thirds of patients and is an option in the NCCN Guidelines. Whether it will be reimbursed beyond 4 doses is an open question, according to Trinh. Since the drug works via the immune system, the unique clinical features of ipilimumab are a delayed onset of response and immune-related adverse effects. Inflammatory T-cell infiltrates can produce tissue necrosis within 12 weeks, which is mostly mild to moderate and reversible but can be life threatening. The skin, gastrointestinal tract, liver, and endocrine system can be affected (Table). Patients should be instructed to report side effects promptly; clinicians should monitor for these closely and treat them immediately with steroids (1-2 mg/kg prednisone or equivalent, then tapered). Ipilimumab

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Table. Ipilimumab Immune-Related Adverse Events Incidence (%) Any grade Median Onset (Grade 3+) (weeks)

Toxicity

Presentation

Dermatologic

Rash, pruritus, vitiligo, Stevens-Johnson syndrome, toxic epidermal necrolysis

Gastrointestinal

Management

40 (2)

3-4

Antihistamine, topical corticosteroid, high-dose corticosteroid

Diarrhea, colitis, toxic megacolon, bowel perforation

30 (7.6)

6-7

Antidiarrheal, budesonide, high-dose corticosteroid, infliximab

Hepatic

Right upper quadrant pain, transaminitis, hepatic failure

4 (<2)

6-7

High-dose corticosteroid, mycophenolate, other immunosuppressants

Endocrine

Fatigue, headache, visual changes, altered mental status, hypotension, decreased libido

7 (2)

9-11

High-dose corticosteroid and hormone replacement

can be restarted when grade 1 or 2 toxicity resolves but should be stopped in the case of grade 3+ toxicity. Vemurafenib is a kinase inhibitor of mutant BRAF (with activity against several other mutations) and is approved, with an NCCN category 1 recommendation, for unresectable or metastatic melanoma with the BRAFV600E mutation. Vemurafenib led to a 67% reduction in risk of death in the landmark phase 3 trial. The approved dosing schedule is 960 mg PO BID; adjustments are not needed for patients with mild to moderate liver or kidney dysfunction, although vemurafenib should be used with caution in patients with severe impairment. Drug interactions are possible when used along with CYP3A4 inducers and with CYP1A2, CYP2D6, and CYP3A4 substrates with a narrow therapeutic index. Adverse events are largely dermatologic, and more than one-third of patients may need dose modifications because of them. Clinicians should also watch for changes in liver function tests and for QT prolongation. “There is no consensus yet about how to integrate these agents into the treatment schema for advanced melanoma,” Trinh said. A reasonable approach is to use vemurafenib first in patients with mutant BRAF and rapidly growing disease or a need for immediate relief of

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symptoms, since patients respond rapidly, although drug resistance also emerges soon. Ipilimumab may be a good first choice for patients with limited tumor burden who “can afford to wait 3 or 4 months for clinical benefit.”

Emerging Drugs Ignoffo described 3 agents on the horizon that could also be game changers. Carfilzomib is a novel irreversible proteasome inhibitor that is mechanistically distinct from, more potent than, and a more selective inhibitor of the proteasome and immunoproteasome than bortezomib.

Ipilimumab may be a good first choice for patients with limited tumor burden who “can afford to wait 3 or 4 months for clinical benefit.” In the PX-171-004 study, in bortezomib-naive patients with relapsed/refractory disease, median progression-free survival (PFS) was 8 months, and median overall survival (OS) was not reached in myeloma patients receiving carfilzomib.1

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Carfilzomib is dosed on 2 consecutive days, 1 week apart, in 28-day cycles. Its rapid plasma clearance is not affected by renal dysfunction. Proteasome inhibition occurs after 1 dose and is prolonged due to inhibition of proteasome recovery between doses. In striking contrast to bortezomib, peripheral neuropathy grade 2/3 occurs in <1% of patients. Fatigue is the dose-limiting toxicity. Approval by the FDA is “highly probable,” he predicted.

Trinh concluded the session, saying “These are new and exciting drugs with efficacious and unique safety profiles.”

Conclusion

Regorafenib is an oral multikinase inhibitor against several endothelial receptor tyrosine kinases that is active in colorectal cancer. In the phase 3 CORRECT trial, median OS was significantly improved, although the difference was only 1.4 months (P=.005).2 Median PFS was improved by 1.2 months, a 51% reduction in risk (P<.000001). “Clinically, it’s an exciting drug based on the PFS curve,” Ignoffo said. “It seems regorafenib does not so much produce tumor shrinkage as prevent progression, leading to a high disease control rate.”

We’re just a

Vosaroxin is a first-in-class anticancer quinolone derivative that induces site-selective DNA damage by intercalating DNA and inhibiting topoisomerase II, leading to apoptosis. Vosaroxin combined with cytarabine showed favorable clinical activity and tolerability in patients with relapsed or refractory acute myeloid leukemia, with a median OS of 7.1 months, a 29% complete remission rate, and a median leukemia-free survival of 14.4 months.3

Trinh concluded the session, saying “These are new and exciting drugs with efficacious and unique safety profiles. Pharmacists and oncologists need to ensure their appropriate use, educate patients, monitor for and manage adverse events, guide patients to drug assistance programs, and stay updated with emerging information.” u

References 1. Vij R, Wang M, Kaufman JL, et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naïve patients with relapsed and/or refractory multiple myeloma [published online ahead of print May 3, 2012]. Blood. 2. Grothey A, Sobrero AF, Siena S, et al. Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. J Clin Oncol. 2012;30(suppl 4). Abstract LBA385. 3. Stuart RK. Vosaroxin in AML. Presented at Chemotherapy Foundation Symposium XXVIII, New York, November 10, 2010. http://www.sunesis. com/data-pdf/595/sunesis-vosaroxin-20101110-Stuart.pdf.

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Clinical Trial Designs for Biomarker Evaluation Sumithra J. Mandrekar, PhD; Daniel J. Sargent, PhD Division of Biomedical Statistics and Informatics, Mayo Clinic Rochester, Minnesota

Key Points • Lack of molecular profiling can often lead to incomplete and, in some cases, incorrect conclusions • For a marker or markers to be useful in clinical practice, the assay results must be accurate and reproducible • The gold standard for any predictive marker validation is a prospective randomized controlled trial • An optimal design can help to validate biomarkers designed to predict which patient is likely to benefit from a treatment and/or require intensive treatment

Sumithra J. Mandrekar, PhD

Daniel J. Sargent, PhD

he translation of clinical research to practice in the field of oncology has been slow despite a growing understanding of the genetic and molecular basis of this disease.1 While a myriad of factors impact this slow pace of progress, issues relating to clinical trial design play a significant role, including patient selection, choice of end points, choice

of control arm, and assay-related issues.2 Through a series of simulation studies, Stewart and colleagues3 studied the impact of subpopulation characteristics on overall study outcomes and concluded that a lack of molecular profiling can often lead to incomplete and incorrect conclusions. Consider the case of the Oncotype DX breast cancer assay that analyzes the expression of 21 genes to provide a recurrence score (RS) unique to each patient.4-6 The RS provides information about the likelihood of cancer recurrence and the likelihood of chemotherapy benefit in women with early-stage, estrogen receptor–positive breast cancer. It has recently been demonstrated, based on a meta-analysis of decision impact data from 912 patients from 7 independent studies, that physicians who used Oncotype DX changed their treatment decisions for more than one-third of patients.7 Specifically, 33% of the overall population switched from the combination of chemotherapy and hormonal therapy to hormonal therapy alone based on a low RS, and 4% of the overall population switched from hormonal therapy alone to the combination of chemother-

Dr Mandrekar’s primary research interest is in the design and analysis of phase 1, phase 2, and phase 3 clinical trials in cancer. Areas of active research include adaptive dose-finding trial design, designs for biomarker validation, meta-analyses, and general statistical inference. Dr Sargent’s primary research interest is in the area of the conduct and the methodology of clinical trials in cancer. Areas of active research include clinical trial design, design and analysis of studies involving tumor markers, meta-analyses, and survival analysis.

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apy and hormonal therapy based on a high RS. From the individual patient perspective, the impact of this is dramatic – reduced chemotherapy use spares the patients the negative effect on health and quality of life from unnecessary chemotherapy. These changes also result in reduced costs to society and the healthcare system. From a trial design perspective, if a biomarker can identify a group of patients more (or less) likely to respond, it can fundamentally help with the efficient demonstration of a treatment benefit. Prognostic marker validation can be established using the marker and outcome data from a cohort of uniformly treated patients with adequate follow-up.8 Designs for predictive marker validation, on the other hand, are inherently complex and involve the following key steps: 1) developmental study (phase 2 trial or previously conducted phase 3 trial with archived samples) with analysis focused on predicting response or treatment benefit (split-sample or cross-validation for assessing prediction accuracy); 2) data used to develop the marker or classifier should be distinct from the data used to test hypotheses about marker treatment effects; and 3) prospective randomized controlled trial (RCT) comparing new treatment to control using a biomarkerbased trial design and/or prospective-retrospective analysis of biomarker outcome data from multiple previously conducted RCTs. The use of an RCT, as opposed to a cohort or single-arm study, is fundamentally essential for initial as well as definitive predictive marker validation. The RCT assures that the patients who are treated with the therapy for whom the marker is purported to be predictive are comparable to those who are not, as changes in patient population based on biologic subsetting and/or evolution in imaging technologies can make comparisons against historical controls inaccurate. In the absence of an RCT, it is difficult if not impossible to isolate any causal effect of the marker on therapeutic efficacy from the multitude of other factors that may influence the decision to treat or not to treat a patient. For example, in 1 paper examining the predictive utility of tumor microsatellite instability (MSI) for the efficacy of 5-fluorouracil–based chemotherapy in colon cancer,

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a cohort of nonrandomized patients was used in whom the median age of the treated patients was 13 years younger than that of the nontreated patients.9 This made it difficult to separate the predictive ability of tumor MSI from factors such as age that may have influenced the decision to treat or not to treat the patient with chemotherapy.9 RCTs are also essential for making the distinction between a prognostic and predictive marker and provide the opportunity to assess and validate multiple promising markers for a given disease simultaneously.

In the absence of an RCT, it is difficult if not impossible to isolate any causal effect of the marker on therapeutic efficacy... The term “biomarker” in oncology refers to a broad range of markers, including biochemical markers, cellular markers, cytokine markers, genetic markers, physiological results, radiological measurements, physical signs, and pathological assessment. Furthermore, a single marker can refer to a “single” trait or a composite score from a signature. Given the current landscape of targeted therapeutics in oncology, which impact multiple downstream pathways, the focus is shifting from targeting a single marker to a composite score or multiple markers. For a marker or markers to be useful in clinical practice, the assay results must be accurate and reproducible (analytically valid), and the status of the marker or markers be associated with the outcome of interest (clinically valid). Finally, there must be a specific clinical question, proposed alteration in clinical management, and improved clinical outcomes (clinical utility). In this review article, we focus on trial designs for assessing and validating a single marker (or a composite score) for a targeted therapeutic (alone or in combination with chemotherapy) as well as designs for validating multiple markers for a single targeted therapeutic or a combination of multiple therapeutics. We will assume that the issues surrounding technical feasibility, assay

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performance metrics, and the logistics of specimen collection are resolved and that initial results demonstrate promise with regard to the predictive ability of the marker(s). Examples of real clinical trials, where available, will be used to illustrate the design concepts.

Designs for the Evaluation and Validation of a Single Biomarker Retrospective Evaluation As stated earlier, the term single biomarker can refer to either a “single” trait or a composite score from a signature. While the gold standard for any predictive marker validation continues to be a prospective RCT, retrospective validation may be acceptable in certain circumstances. The terms “retrospective” and “prospective” refer to both the data collection (using existing vs collecting new data) as well as the data analysis (prior to vs after seeing the data). While the literature is replete with several examples of a “successful” initial assessment of the predictive utility of a marker, most of these results are not replicable or validated in a prospec-

An example of a marker that was successfully validated retrospectively is KRAS as predictive of efficacy of panitumumab and cetuximab. tive trial. A recent study found that the quality of the preclinical data that were utilized to perform clinical research was a major contributing factor to the high failure rate of oncology clinical trials.10 Notably, only findings from 6 of 53 landmark studies (11%) could be replicated in an independent study. The following guidelines need to be met for a valid prospective-retrospective validation of a marker11: • Adequate amounts of archived tissue available from a large majority of the patients from a prospective RCT to avoid bias (ie, representative of the patients in the trial) and have adequate statistical power • Test is analytically validated for use with archived tissue

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• Prospective specification of the biomarker evaluation focusing on the evaluation of a single completely defined signature • Results from archived specimens are validated/replicated using specimens from multiple independent studies An example of a marker that was successfully validated retrospectively is KRAS as predictive of efficacy of panitumumab and cetuximab in advanced colon cancer. This marker was first identified in single-arm trials after nontargeted phase 3 RCTs had been completed.12-14 A prospective KRAS analysis plan was specified and implemented using the data from the multiple retrospective RCTs. The percentage of study populations for which KRAS status was assessed in these trials ranged from as low as 23% to as high as 92%. The results consistently demonstrated that the benefit from panitumumab and cetuximab is restricted to patients with wild-type KRAS status, with mutant KRAS patients deriving no clinical benefit. An example of a well-conducted initial assessment of a predictive marker is epidermal growth factor receptor (EGFR) expression as a predictive tumor biomarker of survival benefit from the addition of cetuximab to firstline chemotherapy in patients with advanced non–small cell lung cancer (NSCLC).15 Samples were available from 99.6% of the patients enrolled in the FLEX trial, and the hypothesis was prospectively specified. Patients with high EGFR expression based on immunohistochemistry (≥200) had significantly longer overall survival (OS) with cetuximab plus chemotherapy, thus warranting further validation of the predictive utility of this marker. Prospective Evaluation Prospective designs for the evaluation (ie, initial validation) and the definitive validation of a single predictive marker (or a score from a marker panel) for a targeted agent (alone or in combination with chemotherapy) can be categorized as follows: A) Enrichment Designs B) All-Comers Designs, which can be further classified into:

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B1) Hybrid Designs B2) Marker by Treatment Interaction Designs B3) Marker-Based Strategy Designs C) Adaptive Signature Designs Trials can also utilize a combination of the above designs; for example, the in-development phase 3 marker validation trial Z41102 (A081105), a double-blind placebo-controlled trial of personalized adjuvant treatment in completely resected NSCLC with EGFR mutation (Figure 1). In this trial, completely resected NSCLC stage I-III (excluding N3 disease and T1aN0M0) patients with EGFR mutation (following an enrichment strategy) are randomized to erlotinib versus standard of care within group 1 (T2bN0, T3N0, T4N0; any T1N1, N2) and group 2 (T1aN0, T1bN0, T2aN0). Here, groups 1 and 2 can be considered as the â&#x20AC;&#x153;marker subgroups.â&#x20AC;? The primary comparison will be OS for patients receiving personalized adjuvant treatment with erlotinib versus standard of care. The null hypothesis of interest is that personalized adjuvant treatment with erlotinib is not superior to standard of care. The target sample size is set so that there will be at least 85% power to reject this null hypothesis if the truth is that personalized adjuvant treatment with erlotinib is superior to standard of care with a hazard ratio (HR) of at least 0.67 in favor of erlotinib (50% improvement, or 7.5 years vs 5.0 years in median OS). Secondary within-group comparisons will also be undertaken to determine if further studies are warranted within that group. Enrichment Designs An enrichment design screens patients for the presence or absence of a biomarker profile, and then only includes patients who either have or do not have the profile in the clinical trial.16 The goal of these designs is to understand the safety, tolerability, and clinical benefit of the treatment within the patient subgroup determined by a specific marker status. This design is based on the paradigm that not all patients will benefit from the study treatment under consideration, but rather that the benefit will be restricted to a biomarker-defined subgroup of patients. N0923 is an example of an ongoing phase 2 trial following an enrichment design strategy for

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Figure 1. Z41102 Trial Design

Group 1: T2bN0, T3N0, T4N0; any T1N1, N2 Completely resected NSCLC EGFR mutant Group 2: T1aN0, T1bN0, T2aN0

R A N D O M I Z E

Arm A: Platinum-based chemo followed by erlotinib 150 mg/day Arm B: Platinum-based chemo followed by placebo 150 mg/day Arm C: Erlotinib 150 mg/day

Arm D: Placebo 150 mg/day

assessing the predictive utility of the presence of more than 1 neuroendocrine marker (synaptophysin, chromogranin, CD56) to NTX-010, a replication-competent picornavirus. This double-blind phase 2 study randomizes patients with extensive-stage small cell lung cancer with the presence of the marker (described above) to the experimental agent versus placebo after standard platinumcontaining cytoreductive induction chemotherapy. An example of a phase 3 trial that utilized an enrichment design strategy for definitive marker validation is N9831 (and NSABP B-31), in which only patients who were positive for HER2 were enrolled (based on a local assessment).17 This trial demonstrated that trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide significantly improved disease-free survival among women with surgically removed HER2-positive breast cancer. However, subsequent analyses raised questions regarding the assay reproducibility based on local versus central testing for HER2 status.18,19 Since only patients deemed HER2 positive based on the local assessment were enrolled, and tissue from patients deemed HER2 negative was not collected, the question of whether trastuzumab therapy benefits a potentially larger group than the approximately 20% of patients defined as HER2 positive in these 2 trials is the subject of an ongoing trial.20 Clearly, this example reiterates that enrichment designs are to be used for marker validation if, and only if, there is compelling evidence

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Figure 2. TAILORx Trial Design Preregistration (tumor block submission)

Oncotype DX Recurrence Score (RS)

Intermediate risk (RS: 11-25)

Low risk (RS <11)

High risk (RS >25)

Randomization (1:1)

Hormonal therapy

Chemotherapy + hormonal therapy

Hormonal therapy

Chemotherapy + hormonal therapy

to suggest benefit only in a marker-defined subgroup(s), and when the assay performance is well established with short turnaround times for marker assessment. All-Comers Designs In this design, all patients meeting the eligibility criteria, which does not include the biomarker status in question, are entered.16 The ability to provide adequate tissue may be an eligibility criterion for these designs, but not the specific biomarker result or the status of a biomarker characteristic. These designs are further categorized into hybrid designs, marker-based strategy designs, and marker by treatment interaction designs. Hybrid Designs In the case of a hybrid all-comers design, only a certain subgroup of patients based on their marker status are randomized between treatments, whereas patients in the other marker-defined subgroups are assigned the standard of care treatment(s).16 This design is an appropriate choice for validating a predictive marker when there is compelling evidence demonstrating the efficacy of a certain treatment(s) for a marker-defined subgroup, thereby making it unethical to randomize patients with that particular marker status to other treatment options. However, unlike the enrichment design strategy, all patients

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regardless of the marker status are enrolled and followed. This provides the possibility for future testing for other potential prognostic markers. An example of a marker validation trial (to validate a composite score) that utilized the hybrid design strategy is the TAILORx (Trial Assigning Individualized Options for Treatment [Rx]) trial to validate Oncotype DX, a 21-gene RS in tamoxifen-treated breast cancer patients (Figure 2).4 A noninferiority design (null hypothesis of no difference) was utilized to determine whether patients with an RS between 11 and 25 derive benefit from adjuvant chemotherapy.4 A decrease in the 5-year disease-free survival rate from 90% with chemotherapy to 87% or lower on hormonal therapy alone would be considered unacceptable. A key aspect of this trial is that all patients will provide tissue samples for banking and future research. Marker-Based Strategy Designs This design randomizes patients to have their treatment either based on or independent of the marker status.16 A disadvantage of this design is that it fundamentally includes patients treated with the same regimen on both the marker-based and the nonmarkerbased arms, resulting in a significant overlap (driven by the prevalence of the marker) in the number of patients receiving the same treatment regimen in both arms. As a consequence, the overall detectable difference in outcomes between the 2 arms is reduced (depending on the marker prevalence), thus resulting in a comparatively larger trial. An example of a marker-based strategy design in the phase 2 setting is the comparison of adenosine triphosphate (ATP)-based tumor chemosensitivity assay (ATPTCA)-directed chemotherapy versus clinicianâ&#x20AC;&#x2122;s best choice of treatment in recurrent platinum-resistant ovarian cancer patients.21 The primary end point of the trial was comparison of response rates and progressionfree survival (PFS) between the ATP-TCA arm and the clinicianâ&#x20AC;&#x2122;s choice arm. A total of 180 patients were randomized. There were no significant differences in outcomes, although a trend toward improved response rates and PFS in the ATP-TCA arm was noted. A notable

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observation was that within the clinician’s choice arm, oncologists switched to the use of chemotherapy combinations similar to those in the ATP-TCA–directed arm over time (~70% overlap in the treatment choices between the arms). As a consequence, patients randomized to the clinician’s choice arm after the first year had significantly better PFS compared with patients randomized to that arm within the first year! Two limitations of this design are: 1) significant overlap of patients receiving the same regimen in both arms (depending on the marker prevalence), thus diluting the detectable treatment effect (and lowering the power); and 2) true interaction between a treatment regimen and the ATPTCA marker status cannot be assessed, as not all marker subgroups (as classified by the ATP-TCA score) receive all treatments in the nonmarker-based (ie, the clinician’s choice) arm. However, the latter can be overcome by implementing a second randomization in the clinician’s choice arm to the possible treatment regimens. Admittedly though, this will require a large number of randomized patients. Marker by Treatment Interaction Designs The marker by treatment interaction design uses the marker status as a stratification factor and randomizes patients to treatment choices within each marker-based subgroup.16 While this is similar to conducting 2 independent RCTs under 1 large RCT umbrella, it differs from a single large RCT in 2 essential characteristics: 1) only patients with a valid marker result are randomized, and 2) there is a prospective sample size specification for each marker-based subgroup.16 A separate evaluation of the treatment effect can be tested in the 2 markerdefined subgroups, or a test of interaction can be carried out first. An example of the marker by treatment interaction design with separate evaluation within 2 marker-defined subgroups is the biomarker validation study (MARVEL: Marker Validation of Erlotinib in Lung Cancer) of secondline therapy in patients with advanced NSCLC randomized to receive pemetrexed or erlotinib (N0723) to validate the predictive utility of EGFR as a marker for erlotinib.

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Adaptive Signature Designs These are a class of sequential testing strategy designs that have a single primary hypothesis that is tested either in the overall population first and then in a prospectively planned subset (if the overall test is not significant), or in the marker-defined subgroup first and then in the entire population if the subgroup analysis is significant.16 The former approach is recommended in cases where the experimental treatment is hypothesized to be broadly effective, and the subset analysis is ancillary. The latter (also known as the closed testing procedure) is recommended when there are strong preliminary data to support that the treatment effect is strongest in the marker-defined subgroup, and that the marker has sufficient prevalence that the power for testing the treatment effect in the subgroup is adequate. Sample size considerations for these strategies are largely driven by 3 statistical parameters: 1) α, the type I error

The adaptive signature designs are a class of sequential testing strategy designs used when the marker and the threshold are both unknown… or probability of a false-positive result; 2) β, the type II error or probability of a false-negative result; and 3) δ, the targeted difference or targeted effect size. These designs differ in the choice of the values for these statistical parameters, which is dictated by the inference framework of the design, and appropriately control for the type I error rates associated with multiple testing. A modification to this approach, taking into account potential correlation arising from testing the overall treatment effect and the treatment effect within the marker-defined subgroup, has also been proposed.22 The adaptive signature designs (ASDs) are a class of sequential testing strategy designs used when the marker and the threshold are both unknown at the start of the trial.23,24 The ASD allows for the “discovery and validation” process of the marker within the realm of the single

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phase 3 trial, using either a cross-validation approach or the split-alpha approach. In the ASD approach, the new treatment is compared with the control arm in all patients at a prespecified significance level. If this overall comparison is significant, then it is taken that the treatment is broadly effective. However, if the overall comparison is not significant, a second-stage analysis is undertaken for the development and use of a biomarker signature, using a split-sample or a cross-validated approach.23,24 In the cross-validated ASD, the algorithm for developing a predictive classifier is prospectively defined. At the end of

Appropriate caution needs to be exercised against model overfitting to prevent classifiers from making poor predictions. the process, an indication classifier for future patients is obtained by applying the algorithm to the full set of patients treated in the clinical trial, whereas a conservative estimate of the treatment effect for future classifier-positive patients is obtained by employing a K-fold cross-validation procedure. The effectiveness of the indication classifier, however, depends on the algorithm used and the data set (ie, the unknown truth about how treatment effect varies among patient subsets). Appropriate caution needs to be exercised against model overfitting to prevent classifiers from making poor predictions. The predictive ability of the classifier will be reflected in the cross-validated estimate of the treatment effect for classifier-positive patients. The cross-validation approach, unlike an exploratory exercise that is conducted on the full data set without any cross-validation, which is fraught with many issues, likely produces an unbiased estimate of the performance of a defined algorithm for developing a predictive classifier using the data set of a clinical trial itself.

Designs for the Evaluation and Validation of Multiple Markers In the previous section, we discussed possible trial designs for the case of a single marker (or a composite score

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derived from multiple genes) hypothesized to have predictive ability. However, in reality, there may be multiple markers that can predict a clinical outcome. For example, let us suppose that markers M1 and M2 jointly predict a clinical outcome. One straightforward approach to testing the value of the markers in this situation would be to perform a sequential testing for M1 and M2 and then eliminate/randomize patients based on the combined marker status. A second option could be to use a composite score approach (as outlined in the examples in the previous section) developed using information from both M1 and M2 and then randomizing patients based on the composite score. Here, we discuss the use of designs outlined in the previous section for the multiple markers scenario. We also introduce the concept of adaptive trial designs, where multiple therapeutics/multiple markers can be evaluated in the same trial. Hybrid Designs The all-comers hybrid design strategy can be utilized to validate multiple markers. The MINDACT (Microarray in Node-Negative Disease May Avoid Chemotherapy) trial for node-negative breast cancer patients was designed to evaluate MammaPrint, the 70gene expression profile discovered at the Netherlands Cancer Institute.25 This trial utilized composite risk scores from 2 markers: clinic-pathological factors as well as the 70-gene expression profile. Another example of a hybrid design for validating multiple markers is ECOG 5202, in which patients are stratified by disease stage (IIA vs IIB), microsatellite stability (MSS; stable vs MSI, where MSI is further classified into MSI-Low, MSI-High), and 18q loss of heterozygosity (LOH). Patients deemed to be at a high risk (MSS/18q LOH or MSI-Low/18q LOH) for recurrence after surgery (estimated 5-year survival rate of 60%) are randomized to 1 of 2 treatment arms, whereas patients deemed to be at a low risk (MSS or MSI-Low with retention of 18q alleles) for recurrence after surgery (5-year survival rate estimate of 90%) will not receive any adjuvant therapy.16 One limitation of this design is that it does not allow for a determination of the benefit

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of bevacizumab in the low-risk strata; however, if the outcomes in the absence of treatment are as favorable as predicted in that group, no postsurgical therapy would generally be recommended. Combination Designs An example of a phase 3 trial utilizing an enrichment followed by a marker by treatment interaction design is the Tailor trial in second-line NSCLC (Figure 3).26 The aim of this study is to validate the predictive value of the KRAS mutation, EGFR protein expression, and EGFR gene copy number, as well as smoking and histotype in patients who do not have EGFR mutations. The primary hypotheses, based on a 2-sided interaction test with 95% power, is that docetaxel is better than erlotinib in group A (30% improvement in OS, for an HR of 1.43 in favor of docetaxel), and erlotinib is better than docetaxel in group B (21% improvement in OS, for an HR of 0.79 in favor of erlotinib). A limitation of this trial is that the secondary within-group comparisons are not adequately powered to detect clinically relevant differences in outcomes. Another example of a combination design of an enrichment strategy followed by a marker-based strategy design is trial 0601, coordinated by the Spanish Lung Cancer Group. This is also a phase 3 trial comparing erlotinib with chemotherapy in stage IV NSCLC patients with EGFR mutations (Figure 4).27 Adaptive Designs Adaptive design strategies are a class of randomized designs by which a variety of marker signatures and drugs can be tested under 1 umbrella protocol.16,28 In these designs, the success of the drug-biomarker subgroup is assessed in an ongoing manner that allows either the randomization ratio to be altered to place more patients on the most promising arm(s) and/or the underperforming drugs and/or the biomarker subgroups to be eliminated midway through the trial. Key requirements for adaptive designs include: 1) a rapid and reliable end point, which can be somewhat challenging in the oncology setting where time to event end points or

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Figure 3. Combination Design Strategy (Tailor): Enrichment Followed by a Marker by Treatment Interaction Design

Marker testing

Preregistration

EGFR 19 or 21 mutant (~10%)

Erlotinib

EGFR Wild Type (~90%)

KRAS mutation; EGFR expression; EGFR gene copy number

Group A: KRAS+, or KRAS- & FISH-, IHC-

Erlotinib

Stratified RANDOMIZATION

Group B: KRASand FISH+ or IHC+

Docetaxel

end points that involve following a patientâ&#x20AC;&#x2122;s status for a predetermined time period (such as the progression status at 2 years) are typically used; and 2) real-time access to all clinical and biologic data, which can be a daunting task in multicenter trials at the current time. Examples of phase 2 trials that have utilized or are utilizing an adaptive design strategy are the I-SPY 2 (investigation of serial studies to predict therapeutic response with imaging and molecular analysis 2) and BATTLE (Biomarker-integrated Approaches of Targeted Therapy of Lung Cancer Elimination) trials.29,30 I-SPY 2 is an ongoing neoadjuvant trial in breast cancer that is designed to compare the efficacy of standard therapy with the efficacy of novel drugs in combination with chemotherapy. All drugs will be evaluated within the biomarker-defined signature groups. Regimens that have a high predicted probability of being successful in a phase 3 trial are moved forward to phase 3 testing within subpopulations corresponding to the most promising biomarker signature(s). Regimens that have a low probability of efficacy for all biomarker signature subgroups will be dropped from further development.29 The BATTLE trial used an outcome-based adaptive design for randomizing patients to treatment choices

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Figure 4. Combination Design Strategy (0601): Enrichment Followed by a Marker-Based Strategy Design

Assess: EGFR 19 or 21 mutation; 14-3-3σ methylation

EGFR Wild Type

14-3-3σ methylated EGFR mutant

Gemcitabine + cisplatin

Marker-based strategy arm 14-3-3σ unmethylated

Randomize Docetaxel + cisplatin Nonmarker– based strategy arm

Off study

Erlotinib

based on multiple biomarker profiles in NSCLC. Patients had their tumors tested for 11 different biomarkers, were subsequently categorized into 1 of 5 biomarker subgroups, and were then randomized to 1 of 4 treatment choices.30 The first 97 patients were assigned equally using a balanced randomization to 1 of the 4 treatments. Subsequent patients were adaptively randomized, where the randomization rate was proportional to the ratio of the estimated 8-week disease control rates. The results from the BATTLE trial showed, as hypothesized, that each drug works best for patients with a specific molecular profile.31 Two successor trials, BATTLE 2 and BATTLE 3, are currently in development, both following an adaptive design strategy. The integrated phase 2/3 designs (also known as the multiarm multistage [MAMS] designs) also fall under the class of adaptive design strategies, as they enable the simultaneous assessment of multiple markers/experimental agents against the standard of care in the phase 2 portion using an intermediate (or surrogate) end point.32,33 The phase 3 portion subsequently continues with the promising marker subgroups/experimental arms from the phase 2 portion, comparing them with the standard of care. GOG-182 is an example of a cooperative group trial funded by the National Cancer Institute

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that utilized the MAMS design. This was a 5-arm trial in advanced-stage ovarian cancer or primary peritoneal carcinoma.34 Finally, the adaptive signature designs, introduced earlier, can also be used to develop and validate multiple markers.24

Summary An optimal design can help to validate biomarkers designed to predict which patient is likely to benefit from a treatment and/or require intensive treatment. This will help improve the success rate of clinical drug development, bring down trial costs in terms of patients and resources, and prevent patients from being exposed to toxic treatments that may not benefit them. A welldesigned prospective RCT based on biomarkers that are analytically and clinically valid is a key step in translating basic science to clinically useful markers that improve clinical practice. In addition, to fully realize clinical utility, it is imperative that there be 1) a strong biological basis for the target of therapy; 2) a clearly defined subgroup that will benefit from therapy, and a practical method that can identify them from the general patient population; and 3) further studies demonstrating that the biomarker results truly influence clinical decisions and are cost-effective. u

Acknowledgments Supported in part by the National Cancer Institute grants: Mayo Clinic Cancer Center (CA-15083) and the North Central Cancer Treatment Group (CA25224). Disclosures: DJS: Consultant for Genomic Health and Amgen; SJM: no potential conflicts.

References 1. Hutchinson L, Kirk R. High drug attrition rates – where are we going wrong? Nat Rev Clin Oncol. 2011;8:189-190. 2. Rubin EH, Gilliland DG. Drug development and clinical trials – the path to an approved cancer drug. Nat Rev Clin Oncol. 2012;9:215-222. 3. Stewart DJ, Whitney SN, Kurzrock R. Equipoise lost: ethics, costs, and the regulation of cancer clinical research. J Clin Oncol. 2010;28:2925-2935. 4. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26:721-728. 5. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor–positive breast cancer. J Clin Oncol. 2006;24:3726-3734. 6. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence

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of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817-2826. 7. Hornberger J, Chien R. Meta-analysis of the decision impact of the 21gene breast cancer Recurrence Score® in clinical practice. Presented at 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX. Poster P2-09-06. 8. Mandrekar SJ, Sargent DJ. Genomic advances and their impact on clinical trial design. Genome Med. 2009;1:69. 9. Elsaleh H, Joseph D, Grieu F, et al. Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet. 2000;355:1745-1750. 10. Begley CG, Ellis LM. Drug development: raise standards for preclinical cancer research. Nature. 2012;483:531-533. 11. Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst. 2009;101:14461452. 12. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040-2048. 13. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757-1765. 14. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408-1417. 15. Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012;13:33-42. 16. Mandrekar SJ, Sargent DJ. Clinical trial designs for predictive biomarker validation: theoretical considerations and practical challenges. J Clin Oncol. 2009;27:4027-4034. 17. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684. 18. Perez EA, Suman VJ, Davidson NE, et al. HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. J Clin Oncol. 2006;24:3032-3038. 19. Paik S, Kim C, Wolmark N. HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med. 2008;358:1409-1411. 20. Hayes DF. Steady progress against HER2-positive breast cancer. N Engl J Med. 2011;365:1336-1338. 21. Cree IA, Kurbacher CM, Lamont A, et al; TCA Ovarian Cancer Trial

Group. A prospective randomized controlled trial of tumour chemosensitivity assay directed chemotherapy versus physician’s choice in patients with recurrent platinum-resistant ovarian cancer. Anticancer Drugs. 2007;18:1093-1101. 22. Song Y, Chi GY. A method for testing a prespecified subgroup in clinical trials. Stat Med. 2007;26:3535-3549. 23. Freidlin B, Simon R. Adaptive signature design: an adaptive clinical trial design for generating and prospectively testing a gene expression signature for sensitive patients. Clin Cancer Res. 2005;11:7872-7878. 24. Freidlin B, Jiang W, Simon R. The cross-validated adaptive signature design. Clin Cancer Res. 2010;16:691-698. 25. Bogaerts J, Cardoso F, Buyse M, et al. TRANSBIG consortium. Gene signature evaluation as a prognostic tool: challenges in the design of the MINDACT trial. Nat Clin Pract Oncol. 2006;3:540-551. 26. Farina G, Longo F, Martelli O, et al. Rationale for treatment and study design of tailor: a randomized phase III trial of second-line erlotinib versus docetaxel in the treatment of patients affected by advanced non-small-cell lung cancer with the absence of epidermal growth factor receptor mutations. Clin Lung Cancer. 2011;12:138-141. 27. Rosell R, Taron M, Sanchez JJ, et al. Setting the benchmark for tailoring treatment with EGFR tyrosine kinase inhibitors. Future Oncol. 2007;3:277-283. 28. Mandrekar SJ, Sargent DJ. Design of clinical trials for biomarker research in oncology. Clin Investig (Lond). 2011;1:1629-1636. 29. Barker AD, Sigman CC, Kelloff GJ, et al. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther. 2009;86:97-100. 30. Zhou X, Liu S, Kim ES, et al. Bayesian adaptive design for targeted therapy development in lung cancer – a step toward personalized medicine. Clin Trials. 2008;5:181-193. 31. Kim ES, Herbst RS, Lee JJ, et al. The BATTLE trial (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination): personalizing therapy for lung cancer. Presented at the 101st Annual Meeting of the American Association of Cancer Research; April 17-21, 2010; Washington, DC. Abstract LB-1. 32. Hunsberger S, Zhao Y, Simon R. A comparison of phase II study strategies. Clin Cancer Res. 2009;15:5950-5955. 33. Parmar MK, Barthel FM, Sydes M, et al. Speeding up the evaluation of new agents in cancer. J Natl Cancer Inst. 2008;100:1204-1214. 34. Copeland LJ, Bookman M, Trimble E. Gynecologic Oncology Group Protocol GOG 182-ICON5. Clinical trials of newer regimens for treating ovarian cancer: the rationale for Gynecologic Oncology Group Protocol GOG 182-ICON5. Gynecol Oncol. 2003;90(2 Pt 2):S1-S7.

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At diagnosis of metastatic colorectal cancer (mCRC)

Are you getting the full picture? Name: Age: Cancer: Specialty: Biomarker Status:

George 58 mCRC Storyteller

Not an actual patient.

At diagnosis of mCRC, testing a patient’s tumors for biomarkers can help determine predictive and/or prognostic information1 Colorectal cancer is the 3rd leading cause of cancer death in men and women in the U.S.2 Understanding the patient’s biomarker profile helps define the characteristics of the patient’s disease and their overall prognosis.1 Knowing a patient’s biomarker status at diagnosis may help guide clinical decisions.3,4 Understanding the biomarker pathways involved in mCRC tumorigenesis can help inform appropriate treatment planning.3,5,6

KRAS and BRAF signaling are involved with colorectal tumorigenesis and tumor progression3 The KRAS gene may be mutated or wild-type. When KRAS is mutated, it is permanently switched on, whereas wild-type KRAS protein is activated when the EGFR is stimulated.3,5 Increased BRAF signaling may occur due to mutations in the BRAF gene.5 BRAF mutations are limited to those tumors that do not have KRAS exon 2 mutations.7

Provides information on a patient’s likelihood of response or non-response to biomarker-directed treatment1

Approximately 2 out of every 3 patients are KRAS wild-type vs mutant5,7

May help define the patient’s overall prognosis irrespective of therapy1

Approximately 5%-9% of colorectal cancers are characterized by a specific mutation in the BRAF gene7

Testing of biomarkers at diagnosis of mCRC is important for treatment planning3,7*

Strongly recommends KRAS genotyping of CRC tumor tissue (either primary tumor or metastases) in all patients with mCRC at the time of stage IV disease diagnosis. Early establishment of KRAS status is appropriate in order to plan for the treatment continuum.7

T E S T

BRAF genotyping can be considered for patients with tumors characterized by the wild-type KRAS gene. Such testing is currently optional and not a necessary part of decision making.7

T O

P L A N

EGFR = epidermal growth factor receptor. *In a CLIA-certified laboratory. References: 1. Tejpar S, Bertagnolli M, Bosman F, et al. Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. Oncologist. 2010;15:390-404. 2. American Cancer Society. Cancer Facts & Figures: 2011. http://www.cancer.org/acs/groups/content/@epidemiologysurveillance/ documents/document/acspc-029771.pdf. Accessed March 1, 2012. 3. Monzon FA, Ogino S, Hammond EH, et al. The role of KRAS mutation testing in the management of patients with metastatic colorectal cancer. Arch Pathol Lab Med. 2009;133(10):1600-1606. 4. Grossman AH, Samowitz WS. Epidermal growth factor receptor pathway mutations and colorectal cancer therapy. Arch Pathol Lab Med. 2011;135:1278-1282. 5. Krasinskas AM. EGFR signaling in colorectal carcinoma. Pathol Res Int. 2011;2011:1-6. http://www.hindawi.com/journals/ pri/2011/932932/cta. Accessed January 6, 2012. 6. Linardou H, Briasoulis E, Dahabreh IJ, et al. All about KRAS for clinical oncology practice: gene profile, clinical implications and laboratory recommendations for somatic mutational testing in colorectal cancer. Cancer Treat Rev. 2011;37(3):221-233. 7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. Accessed March 15, 2012.

Interview With the Innovators

Accelerating Personalized Medicine Approaches in Multiple Myeloma: An Interview With Kathy Giusti and Deborah Dunsire, MD Deborah Dunsire, MD President and Chief Executive Officer Millennium: The Takeda Oncology Company Kathy Giusti Founder and Chief Executive Officer Multiple Myeloma Research Foundation Multiple Myeloma Research Consortium

In the attempt to bring personalized treatment to multiple myeloma patients, the Multiple Myeloma Research Foundation (MMRF) began its CoMMpassSM (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile) study – a landmark study designed to uncover the molecular segments and variations in multiple myeloma. The most ambitious study of its kind in multiple myeloma and the cornerstone of the MMRF’s larger Personalized Medicine Initiative, the study will collect and Kathy Giusti Deborah Dunsire, MD analyze tissue samples and genetic information from approximately 1000 multiple myeloma patients over the next 5 years. Companies such as Millennium: The Takeda Oncology Company and Onyx Pharmaceuticals have entered into collaboration with the MMRF to support this initiative. Personalized Medicine in Oncology had the pleasure of sitting down with Kathy Giusti, Founder and CEO of the MMRF, and Dr Deborah Dunsire, President and CEO of Millennium, to talk about the definition of personalized medicine, improving patient care, and the current and predicted future landscape of personalized medicine in multiple myeloma.

ince 2005, Dr Dunsire has led Millennium and the efforts around its advancing oncology pipeline that consists of over 20 compounds in various stages of development and the further development of the company’s flagship cancer drug, Velcade (bortezomib), which is approved for the IV treatment of patients with multiple myeloma. Velcade is also approved for the treatment of patients with mantle cell lym-

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phoma who have already received at least 1 prior treatment, and most recently (January 2012) for subcutaneous administration of the drug in all approved indications. Ms Giusti is the Founder and Chief Executive Officer of the Multiple Myeloma Research Foundation (MMRF) and the Multiple Myeloma Research Consortium (MMRC). Together, the two organizations have developed innovative models that serve to rapidly

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break down barriers slowing multiple myeloma research and accelerate the development of next-generation treatments. Chief among these are an integrated clinical network of leading centers that collaboratively conduct early-stage clinical trials, as well as a stateof-the-art tissue bank that has advanced the science of biobanking and genomic studies and provides a foundation for the organizations’ pursuit of personalized medicine. PMO Thank you for taking the time to talk with us. We’d like to start by asking each of you how you define personalized medicine in oncology. Ms Giusti When we’re talking with patients, we try to keep the definition as simple as we can and say that it’s about finding the right drug for their type of disease at the right time in their disease. We also know that in myeloma it can be complicated because the disease is so heterogeneous and uncommon. Dr Dunsire One person’s multiple myeloma might be driven by a different genetic mutation than another person’s, and it might make sense then to try and identify what combination of medicine is the most effective for a given genetic driver. That’s the foundation of personalized medicine – really understanding the biology of a particular patient’s disease versus calling it one large disease entity, multiple myeloma, for instance, and then targeting the therapy to the drivers. PMO Unfortunately, personalized medicine in oncology remains sporadic and occurs mainly at wellfunded academic centers or is driven by physicians who understand the molecular biology behind multiple myeloma. How do we bring the research and the science to the community oncologists so that we can affect the largest numbers of patients? Ms Giusti One thing we have found is that if you are going to understand personalized medicine, you have to be able to reach out to the community doctors, because they’re the ones seeing those patients right when they’re diagnosed, before their treatment even begins, and it’s that early biopsy, that early tissue sample that we so desperately need. So you have to bring the community oncologists in so that you get access to the patients and

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access to that early tissue. And then you want to follow those patients longitudinally over time. Although academic scientists also see patients, they also play a critical role in their ability to look at the science translationally and help us to understand what we’re seeing in the data. And what’s so special about the MMRF initiative is that we’re also working with industry, because the more teams we have looking at our data across patients longitudinally, the more likely we are to get to a cure faster. Many great minds are better than fewer. Dr Dunsire As we gather data on newly diagnosed myeloma patients followed longitudinally, we’ll be able to target groups of patients that have similar genetic drivers if we find a new therapy that’s specific to those. So we might be able to speed up the clinical research over time. It is going to take time to build the databases. But patients, community physicians, academics, organizations like the Multiple Myeloma Research Foundation, and industry need to be engaged together.

How do we bring the research and the science to the community oncologists so that we can affect the largest numbers of patients? PMO It sounds like both of you are talking about the CoMMpass trial, which I know is very near and dear to your hearts. Perhaps you can share with us your perspectives on how you think the CoMMpass trial is going to impact the development of new treatments for multiple myeloma. Ms Giusti The joy of the CoMMpass trial is that over time it looks at 1000 patients and studies them from that very first bone marrow biopsy through 5 years, looking at their data longitudinally. We’re banking the tissue, we’re looking at all the molecular data, and we’re looking at all the clinical data. And what’s critically important is to see how a patient’s myeloma changes over time. That’s really important, because the disease gets more and more heterogeneous.

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The objective of the study is to look at the myeloma world and start segmenting those patients. Myeloma is not 1 disease, it’s more like 10, 15 – we don’t know how many – and over time begin to understand what hypotheses we are starting to see in terms of the treatments that might be appropriate for patients at low, medium, and high risk. And hopefully over time, as we accumulate more and more data, we’ll be able to look at those data and understand more about biomarkers and new targets in the disease. So the MMRF, being a trusted third party, could bring everybody together. I think it was critically important to us, and we were thrilled to work with companies like Millennium to get it started.

In most cases the current evidence base doesn’t allow matching a unique cytogenetic profile with a specific therapeutic regimen.

Dr Dunsire I think the trial is a great initiative, and it appears to be alone in its class right now. Many times when we test new medicines, they’re tested in patients who have relapsed and gone through all of the standard tested therapies, and that’s appropriate, but it means we’re testing new therapies in patients whose disease has many more mutations than perhaps the disease in a newly diagnosed patient might have. If we get these longitudinal data sets, we’ll be able to understand how patients’ disease evolves over time and potentially how to bring effective therapies earlier in the disease than the traditional therapeutic development might allow. Everybody can benefit. Patients benefit by potentially getting new therapies sooner and by getting a therapy that’s most likely to benefit their particular disease. And if their disease is not likely to benefit, they’re not exposed to an ineffective therapy and all its side effects. So that’s really the goal, to increase that benefit-to-risk ratio. PMO As you’ve both pointed out, multiple myeloma is a very heterogeneous disease. Does that produce any

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special challenges with respect to the CoMMpass trial? Ms Giusti Absolutely. I think when you have a disease that is heterogeneous and uncommon, that’s when you have to build collaborative models like this one, because you’re not seeing enough patients at any one center to get a database of 1000 patients to study over time. So if you’re trying to look at segmentation, you have to have that critical mass. PMO And as new molecular biomarkers are discovered and developed that have an impact on multiple myeloma, how is that going to impact the CoMMpass trial? Ms Giusti It’s so interesting in myeloma right now because we don’t have validated targets or validated biomarkers, and the truth is when you look at proteasome inhibitors like Velcade or drugs like Revlimid, they are so effective in myeloma patients that almost every patient is likely going to be on a Velcade-based drug or on an IMiD [immunomodulatory drug]. So what you’re really looking at over time is what else is changing in these patients. And what we’re finding are mutations like BRAF – and what that means for the combinations of drugs. I think our hunch is that you’ll often have myeloma patients who will be on a proteasome inhibitor and IMiD, and what are we adding? What are we adding over time that’s really going to help them? So I think as we move to that world, we really have to understand how we’ll begin to work with diagnostic companies and how we’ll start to build out the field of myeloma. Dr Dunsire You can think of it at both ends of the disease. So if you can bring the right combination at the time of the patient’s diagnosis, that’s your highest chance of ultimately curing disease, and at Millennium that’s our aspiration. But, as Kathy mentioned, new mutations emerge that you might not have expected or perhaps wouldn’t have seen a decade ago. We can bring new combinations of therapy because now we have in our arsenal a growing number of molecularly targeted therapies, for instance, against BRAF.

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Science is moving as fast as it can to get ahead of the ingenuity of the cancer cell. PMO FISH [fluorescence in situ hybridization] testing today is certainly an important tool in establishing prognosis in patients with multiple myeloma, and it may in turn drive therapy. But in most cases the current evidence base doesn’t allow matching a unique cytogenetic profile with a specific therapeutic regimen. Do you see that changing as a result of the CoMMpass trial or some of the other research that’s going on? How is that going to change over time? Dr Dunsire Our sincere hope is to better understand from a population database what the real trends are and which trends matter, because sometimes you see changes that don’t necessarily have a driving capability. So you have to discern which ones are drivers and which aren’t, and the only way you can do that is with a large amount of data. Under these circumstances, we may ultimately have the ability to specifically target groups of patients. I doubt it’ll ever be for only 1 patient because patients share some commonality. Ms Giusti Yes, absolutely. You’re going much deeper than just FISH. The greatest challenge we have in CoMMpass is not only getting great tissue samples and keeping track of all these patients but taking all of those data and making them publicly available on IT systems where everybody can use them and study them. So as we started developing the IT system, the challenge has been: are we developing this for bioinformatics individuals, are we developing it for translational individuals, or are we developing it for the community oncologist or even the educated patient? And the truth is we have to develop it for everybody. And that has been at least an 18-month process for us to start to build that system out. It is not available today. And we look at these systems and ask: “Can you make a system that’s as easy to follow as Amazon, so that when people go in they can start really looking at the information?” PMO Personalized medicine for multiple myeloma depends to a large extent on laboratory testing and identifying and characterizing these molecular biomarkers.

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There have been a lot of data published talking about some of the drawbacks and talking about some of the issues associated with laboratory testing. For example, FISH testing for deletion 17p where it may be at a different level at different times in the patient’s disease. Are Millennium and the MMRF doing anything to work with the diagnostic end of things to begin to standardize it and improve testing for some of these molecular biomarkers? Dr Dunsire I think we’re in the infancy of doing that in this particular disease. That has certainly happened in other diseases, lung cancer being one of them with the EGFR mutation and ALK mutation, both of which have specific therapies. So I think in some ways there’s a feedback loop between the emerging science and emerging therapies that drives the need for much more standardization, for availability of companion diagnostic kits, for instance.

So you have to discern which ones are drivers and which aren’t, and the only way you can do that is with a large amount of data. I think we’re at the beginning of that in multiple myeloma, and I can’t say that it’s an initiative that’s very far advanced right now. At Millennium, we recognize the importance of diagnostics within the realm of personalized medicine and continue to explore opportunities that might fit into our overall strategy. Ms Giusti Yes, we even offer funding for diagnostic awards at our foundation to make sure that anybody interested in the diagnostic world can apply. There’s still a lot of work to be done. I think it comes back to having the data and really understanding what’s going on before you move to the diagnostic piece. Dr Dunsire A good therapeutic will drive the need and the innovation behind the diagnostic as well. So, they kind of partner hand in hand. PMO Multiple myeloma is a very diverse disease that not only affects plasma cells but also causes secondary

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Dr Dunsire and Ms Giusti share a laugh during the interview with Personalized Medicine in Oncology.

effects. And of course, there are the adverse effects of therapy. Are the efforts here with the CoMMpass trial and with other research going to be impacting some of these other issues, for example, the management of bone disease in multiple myeloma, anemia, infections, thrombotic events, and of course, the adverse events of therapy? Ms Giusti Yes, in the CoMMpass trial we are collecting all of these clinical data that we can go back and look at and generate hypotheses. What are we seeing in terms of how patients are tolerating treatments? What are we seeing in their genetic makeup that makes them better able to tolerate certain drugs? I think the beauty of CoMMpass is that it will generate a lot of hypotheses, and clinically what’s important to us is to work with companies like Millennium to determine which hypotheses we want to test. And then we can move to our clinical network, the MMRC, to build out clinical trials that will allow us to again have critical mass and have really good innovative clinical trials. So I think that’s been the joy of developing collaborative models since 1998 – you keep generating hypotheses, and you have the systems and the models in which to test them.

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Dr Dunsire When you think about the potential for reduction in side effects, it’s not only knowing who to treat, whose disease is most likely to be responsive, but the data might actually show who is at the highest risk of a given side effect for a given drug. There is another thing we can do about that. When we bring together rational combinations of therapy, sometimes somewhat lower doses can be used, therefore exposing the patient to fewer side effects. PMO Dr Dunsire, you mentioned earlier the interplay between pharmaceutical industry and diagnostics kits as being important. In fact, some of the great success stories in personalized medicine and oncology are examples of collaborative efforts between a diagnostics company and a pharmaceutical company, and the FDA seems to be receptive. Do you envision such a collaborative relationship in the agents that you’re researching and developing? Dr Dunsire We certainly look for that. One that’s very early for colorectal cancer comes to mind in which we are in parallel developing the test right from the inception of the clinical trials. That’s the ideal circumstance when you have an agent that you know is targeting a specific receptor in a specific cancer. Often, we have drugs like Velcade that are much broader in their action, so they’re not specifically targeted, but wherever we find efficacy, it’s still very important. So we would prefer to be targeted from the very beginning, but if an agent’s great, we will work post hoc to understand how to manage it better, how to target data, and how to better select the patients. But Millennium has a very large investment in translational medicine. What that means is investing in finding the patient selection markers for a given therapy. We know the chemistry, we know the target, and we know how to assess whether the drug is interacting with the target, but figuring out how to select patients who are going to respond to that is next in the evolution of the science. PMO It sounds like to really get personalized medicine in oncology to be a reality, there’s a lot of education that needs to happen – educating physicians, nurses,

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pharmacists, and patients. Are your organizations working together or individually to achieve that? Ms Giusti I think the most important element is making sure that the patients are educated. I think one of the hardest parts about personalized medicine is that as a patient, you need to understand your genomics. But sometimes in myeloma, knowing your genomics puts you at high risk, and that can be challenging news to hear. Just as an anecdote from myself as a myeloma patient – I was a translocation 4;14, high-risk patient, and that was really hard for me to know, but high-risk can sometimes be a good thing, because later on I was very lucky. I was on Velcade. Later, researchers retrospectively looked at the data and realized patients with that translocation do very well on proteasome inhibitors. And now you want to make sure all of the patients know this kind of information, but it’s hard because now patients are hearing that maybe they’re high-risk, but they may not know the whole story. We have had many conversations about always having the patient at the middle. I really believe the patient is at the middle now because we are looking at the patient and saying, “It’s your tissue, it’s your data, it’s your doctor, it’s your life. You have to be educated on this and know that even if you’re high-risk today, it may not mean you’re high-risk tomorrow. So just know what has to happen in terms of new clinical trials.” And that comes back to working with the community oncologists, who are seeing 70% of these patients, and making sure they’re educated on what we are seeing genomically. So we’re constantly partnering with Millennium in terms of investing in consumer- and patientbased programs as well as CME programs for our doctors. Dr Dunsire I think one of the most concerning things is to encounter patients who just listen to their doctors, because doctors may be coming up the learning curve too. It’s so important for patients or their loved ones to engage in finding out about their disease, because nobody can advocate for them like they can. The patient really is the person whose life is at stake. Getting accessible information to patients is so critical; that’s why we partner with organizations such as

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the Multiple Myeloma Research Foundation, because it enables us to get data to very learned third parties who can get it to patients in a way that’s distanced from the company, so the patient can trust that the source is not biased, but they can still get access to the information. To me, that’s so critical, because the patients are the people who are going to sign up to have the biopsies, for instance, and to release their tissue to the tissue bank. The fact that they understand that this is not only important to them, but important for the understanding of the entire scope of the disease is so critical, and the faster we can build those databases with patients’ consent, the faster we get to outcomes.

One of the most concerning things is to encounter patients who just listen to their doctors, because doctors may be coming up the learning curve too.

PMO Our ability to accumulate data far outstrips the medical community’s ability to understand it and act on it appropriately. There has to be a parallel track for physicians as well to be able to understand this. Dr Dunsire Yes, and I think we have seen that even with data that are absolutely clear and incontrovertible. For example, with the KRAS mutations and the use of EGFR inhibitors in colorectal cancer, it is a relatively simple message, but it still takes time for physicians to hear it, understand it, and act upon it across the spectrum. Academic centers act very quickly. Community doctors are faced with a much broader variety in everything they see, so it’s harder to accumulate all that new knowledge in every field at the same time. I think pharmaceutical sales reps can be an integral component of the education, bringing that information to doctors. The partnerships that we engage in around major medical meetings, as well as the small community physician meetings throughout the year at different venues, help to get that message out, and then, of course, there are the various clinical milestones that are published in

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Dr Deborah Dunsire explains the approach of Millennium Pharmaceuticals to personalized medicine.

peer-reviewed journals and publications. So there are a number of different forums to get that information out, but what’s most important is having a really crystal clear message – when you see a particular constellation of symptoms, this is what it means, and here’s what you do about it. It’s my belief that we’re not there yet in multiple myeloma.

Everything will move faster when we can get more data. Of course, the informatics to manage all of that and make sense of it all is critical. PMO So we’re not there yet in terms of the data, or we’re not there yet in terms of the educational initiatives, or both? Ms Giusti As Deborah said, there’s not anything they can specifically act on right now, but that doesn’t mean that you don’t need to be learning in terms of what we’re seeing. Especially when you start to segment myeloma, they need to start understanding what might be high-risk, medium-risk, low-risk, and how we start to handle those things.

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Dr Dunsire You have to really think about the explosion of knowledge in the biology of cancer. Cancer is a group in excess of 100 different diseases, for example, lung, colorectal, breast, or myeloma! Then when you start dividing each one up according to the genetic drivers, it’s an exponential function. And so oncologists today are having to take in so much more data faster than ever before, so we really have a responsibility to keep that information flowing, make it clear and understandable and actionable. Ms Giusti It’s nice to have been a third party that’s been collecting the names of all the patients and the community oncologists who have joined our community since we started in 1998, because as new findings come out, it does make it easier for us that we have everybody in our database, and we can literally put together simple materials, do CME programs, and educate people very, very quickly. One of the things that helps us is our expanded access program. We’re really starting to understand which community oncologists are seeing the bulk of patients, which community centers might be able to do good tissue banking, and which can be involved in phase 2 clinical trials. So we need to start keeping those data systems together so that we can reach out to them right away and get to the centers that are seeing the highest volume of patients. PMO I’m going to ask both of you to look into the future. What do you foresee as the future of personalized medicine in oncology when sequencing the entire human genome will cost less than $1000? Dr Dunsire Everything will move faster when we can get more data. Of course, as Kathy pointed out, the informatics to manage all of that and make sense of it all is critical, and we certainly are building that kind of infrastructure. So our job is to help patients understand why it could be extremely valuable to not only have the data but also be able to share the data, anonymized, but within a much broader database, because that’s the only place that we can truly get power in the data. Ms Giusti I think there are 2 elements that are

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changing healthcare dramatically. One is that it’s becoming much more efficient to acquire genomics from these patients. The second is the social networking phenomenon. I have patients who literally go on Facebook and say: “Hi, I’m a fellow t(4;14)” or “I’m a fellow syngeneic transplant,” not a fellow myeloma patient. I think the greatest roadblock is going to be how quickly we can build the IT systems, and how many people are going to be able to understand all of these data and really be able to help us do something with them quickly. It takes a certain skillset to be able to look at all of that and understand where we go clinically from that information, and how we design new and innovative trials that will show that there’s an unmet medical need in a certain area where we need to move the trial and get FDA support faster. The whole world is changing overnight. PMO So what do you say to patients who sort of fall into a gray area, who don’t carry a molecular marker that’s been associated with a specific therapy? What do you offer those patients? Dr Dunsire I’d say they don’t carry a molecular marker…yet. Eventually, they will. Cancer is a disease of cells growing and dividing abnormally. We might not yet know how to recognize that, but through the acquisition of more and more data, we’ll start to say, “That very unusual myeloma patient who doesn’t have any of the known abnormalities shares this mutation with 20 other people.” Maybe that’s a new target that’s worth looking at. So I would say that just because we’ve only categorized a few doesn’t mean we’re at the end; it means we’re at the beginning, and they should still seek deep sequencing information and contribute to the databases, because that’s the only way we’ll find the rest of those markers. Ms Giusti Absolutely. We didn’t expect to see patients with BRAF mutations when we started our genomic initiative. That’s why you have to keep building on that database; you want to be sure that what you saw is true, and you want to see new things as you have more and more tissue and more access to patients.

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PMO So let’s talk a minute about the economics of personalized medicine for oncology, because many people have questioned whether we can afford personalized medicine in oncology, whether this is the answer to the American health system. Would it make sense, for example, not for Millennium necessarily, but would it make sense for a pharmaceutical company to develop a drug that diagnostics show is going to be effective for only 5% of the patients? Dr Dunsire I think a lot depends on the tumor type – how many people does 5% represent? It also depends on the magnitude of benefit. Nonetheless, I think about personalized medicine as the only way forward because of the current paradigm – treating 100 people to get a response in 30 or 35. A company may have to question the economics of that course of action. In addition to that, the impact of 65 of the 100 patients not gaining benefit but experiencing side effects may also impose a negative economic impact.

What do you say to patients who sort of fall into a gray area, who don’t carry a molecular marker that’s been associated with a specific therapy? To really treat these diseases, personalized medicine, I think, is actually what makes the economics viable. Ms Giusti It’s frustrating. When patients call us now and they’ve relapsed, many times the first question we’re asking them is what they have already been on and what trial might we be able to get them into. And that’s just somewhat serendipity, because the questions we really want to ask are: what does your disease look like from a molecular standpoint, what have other patients who have a disease that looks like yours done, and what do we think has worked for them so we don’t subject you to things that are going to have high side effects or things that just don’t work? It’s hugely challenging for patients, and expensive. PMO When erlotinib was developed – and although it was only going to affect 3% to 5% of the patients with

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Dr Deborah Dunsire and Ms Kathy Giusti – partners in the fight against multiple myeloma.

non–small cell lung cancer – everyone applauded that effort. In multiple myeloma specifically, if you found there was an agent that only affected 5% of myeloma patients, would that make sense from a resource allocation perspective? Dr Dunsire I think it could. Again, it comes down to the potential benefits seen.

One of the other critical parties that need to be on board for personalized medicine in oncology to work is the regulators. And I go back to the example of Gleevec for chronic myelogenous leukemia, where it was felt that this was a very small patient population, but it’s a transforming agent that is potentially curative and has totally changed the face of that disease, so that made perfect sense in hindsight. Prospectively, it was done because the company believed in taking forward an agent with that type of efficacy, even if it was for a small population. At

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Millennium, we are about curing cancer, and if we find an agent that has the potential to do that, even if it’s in a very small patient population, if we know who they are, it could make very good economic sense for them and for us, for regulators, and for payers. PMO We talked about all of the shareholders in treating myeloma patients. We haven’t talked about payers yet. They need to be educated too. What are we doing for them? Dr Dunsire We have a field force that reaches out specifically to educate payers. Obviously, the biggest payer and the hardest to reach is Medicare. But in the private payer market, the insurance companies, we find a very receptive audience wanting to understand the data and the impact on patients. I’ve personally found that the payers are very much part of the constellation of people who are caring for patients and that they’re very receptive and thirsty to hear the data. They’re also very critical thinkers about the data, so you can’t pass something by them that’s modest or not better than another therapy, because they’re extremely well educated. Ms Giusti What we have found is that myeloma is not necessarily big on their radar right now because it’s not one of the most expensive cancers that they’re dealing with, but they are watching our model and what we’re doing because they like the way that we educate our patients. So, for example, if a patient goes to our Web site and joins the MMRF, they immediately get a welcome, they get a PDF of information on the disease and information on the treatments, and we’re in touch with them all the way through their journey. Payer groups look at that and see that is a very economical and a great way to work with patients. We’re seeing the same thing with a lot of the community oncologist networks who are saying: “You already have CME materials; can we just co-market with you and provide those materials to all of our doctors?” And that’s a great idea, to be honest with you. As long as we’re developing these materials, why not make sure the dissemination of the information is as broad as it possibly can be.

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Clinical Sites for the MMRF CoMMpass Study Institute/Principal Investigator

Study Coordinator Contact Information

Baylor Cancer Center, Dallas, TX / Joseph Fay, MD Washington University School of Medicine, St. Louis, MO / Ravi Vij, MD Winship Cancer Institute of Emory University, Atlanta, GA / Sagar Lonial, MD University of Chicago Cancer Center, Chicago, IL / Todd Zimmerman, MD Virginia Cancer Specialists PC, Fairfax, VA / Gregory Orloff, MD Hackensack University Medical Center, Hackensack, NJ / David Siegel, PhD, MD Mount Sinai Medical Center, New York, NY / Sundar Jagannath, MD Waverly Hematology Oncology, Cary, NC / Suzanne Kirby, MD Billings Clinic, Billings, MT / Brock Whittenberger, MD Bay Area Cancer Research Group, Pleasant Hill, CA / Robert Robles, MD Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN / Jesus Berdeja, MD Barbara Ann Karmanos Cancer Institute, Detroit, MI / Jeffrey Zonder, MD New Bern Cancer Care, New Bern, NC / John Cho, MD Atlanta Cancer Care, Alpharetta, GA / Ronald Steis, MD Hematology Oncology, Baton Rouge Clinic, Baton Rouge, LA / Michael Castine, MD Bennett Cancer Center, Stamford, CT / Michael Bar, MD University of Nebraska Medical Center, Omaha, NE / Edward Faber, MD University of Southern California, Los Angeles, CA / Silkander Ailawahdi, MD Sharp Memorial Hospital, San Diego, CA / Rajesh Belani, MD Dartmouth-Hitchcock Medical Center, Lebanon, NH / Kenneth Meehan, MD Medical Associates of Brevard, Melbourne, FL / Sumeet Chandra, MD Maimonides Cancer Center, Brooklyn, NY / William Solomon, MD

Debra Kee (214) 370-1500 debra.kee@baylorhealth.edu Mark Fiala (314) 454-8302 mfiala@dom.wustl.edu Alaina Mitchell (404) 778-5747 alaina.r.mitchell@emory.edu Kathryn McDonnell (773) 702-1835 kmcdonnell@medicine.bsd.uchicago.edu Stacey Banks (703) 208-3148 stacey.banks@usoncology.com Laura McBride (201) 336-8704 lmcbride@humed.com Lauren Schulman (212) 241-2592 lauren.schulman@mssm.edu Gena Boyd (919) 233-8585 gboyd@waverlyhemeonc.com Linda Allen (406) 435-7484 lallen@billingsclinic.org Denise Dunco (925) 676-3200 ddunco@bacrg.com Meredith Zimlich (615) 329-7245 meredith.zimlich@scresearch.net Christiane Houde (313) 576-9381 houdec@karmanos.org Sara Thorsby (252) 636-5135 sthorsby@cchealthcare.com Julie Carney (770) 777-1315 jcarney@atlantacancercare.com Evie Key (225) 767-0822 ekey@brclinic.com Sue Murdock (203) 964-9578 smurdock@stamhealth.org Marge Moragues (402) 559-2471 mamoragues@unmc.edu Nancy Berman (323) 865-3928 nancy.berman@med.usc.edu Cathy Wood (858) 939-5062 cathy.wood@sharp.com Darcie Findley (603) 650-4595 darcie.l.findley@hitchcock.org Melissa Studebaker (321) 254-4776 mstudebaker@mabmd.com Rolinda McIntosh (718) 765-2693 rmcintosh@maimonidesmed.org

List of sites at press time. For an updated list, please visit www.themmrf.org/research-programs/commpass-study/.

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PMO One of the other critical parties that need to be on board for personalized medicine in oncology to work is the regulators. What has been your experience with the FDA and the regulatory bodies? Dr Dunsire We have had outstanding interactions with the FDA on this score. Dr Hamburg has been very clear that she is most excited about finding transforming therapies across all diseases. They also want to be sure that any biomarkers are robustly validated so that they predict overall outcomes. So there is a dialogue, and it’s a very open, robust, and engaged dialogue. Ms Giusti We have a great relationship with the FDA. I have to say they’ve been phenomenal. We go down at least once, often twice a year, and just give them a full update on what’s happening in the field of myeloma. And I have to say, they have been incredibly welcoming. We remind them all the time that even though we’ve made tremendous progress, there still is a certain element of unmet medical need. We did talk with them about the CoMMpass trial. They were ecstatic that we were doing it, because I think they too want to know that the data are coming in, and we’re all going to start looking at them together. I think what people are applauding is the fact that we now have this whole collaboration where you’re looking at a group like ours reaching out, getting to 1000 patients. We’re doing it with the community centers and academic centers looking at the data, and then

we have companies like Millennium coming in, helping to fund the trial and looking at the data that will eventually go out into the public domain. And the FDA is listening to this and saying hooray, thank goodness. May you find great information and may you find biomarkers, and please come back and talk to us about it and design the right kind of clinical trial that we can help you. I think we both feel very fortunate in our relationships with the FDA. PMO Twenty years ago FDA was willing to fast-track in the HIV/AIDS arena. Dr Dunsire And that made a huge difference to patients. PMO Are they willing to do that now for personalized medicine? Ms Giusti Yes. Dr Dunsire They certainly have demonstrated that a couple of times in the past year. I think of the Pfizer compound for ALK-positive lung cancer, which came together with a diagnostic. Here a pharmaceutical company and a diagnostic company collaborated. The FDA was a great partner all the way through that, and the drug was brought to market incredibly quickly, with very fast passage through the regulators. So I think like any relationship, when it’s open, transparent, factual, and collaborative, great things can result. PMO Thank you both for being with us today and for this very insightful discussion and your perspectives. u

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Biomarkers

Precision Medicine: Applying Predictive and Prognostic Indices to Risk-Adapted Treatment Selection Sandra Kurtin, RN, MS, AOCN, ANP-C The University of Arizona Cancer Center, Tucson, Arizona

Key Points â&#x20AC;˘ Predictive and prognostic biomarkers and consideration of patient attributes should be applied when selecting a personalized, life-span approach to therapy â&#x20AC;˘ Risk-adapted treatment selection challenges the oncology professional to maintain a working knowledge of tissue diagnoses and specific pathology techniques

he shift from dose-intense standard chemoongoing integration of advances in molecular biology, therapy to therapies targeting specific signaldiagnostic imaging, and risk-adapted treatment selecing pathways, molecular targets, or elements tion. Scientific practicality (knowing how to adapt these of the tumor microenvironment presents a key elements and clinical trials data for the individual number of challenges to the oncology patient based on the goals of therapy) professional and the patient. Cancer diis essential to the best possible outagnosis and treatment requires precicome. This paper describes the key elsion in the diagnostic evaluation ements of precision medicine with (asking all the critical diagnostic quesclinical insights gained over 27 years tions at the time of diagnosis), compreof oncology practice, including 22 hensive assessment of the individual years as an advanced practitioner in patient (personal attributes that place oncology. a patient at risk), and consideration of a life-span approach (the concept of a Advances in Molecular marathon as opposed to a sprint). PreBiology: The Foundation for Effective Treatment cision medicine allows for the best evidence-based approach to treatment for Precision medicine is the applicaSandra Kurtin, RN, MS, AOCN, ANP-C tion of predictive biomarkers, together each individual patient, while limiting with consideration of prognostic biounnecessary exposure to potentially markers and patient attributes, in the selection of thertoxic and costly therapies in order to preserve future apy using a personalized life-span approach (Table 1).1,2 treatment options for patients unlikely to respond. ImPrognostic biomarkers reflect the likely natural history plementing the principles of precision medicine requires

Ms Kurtin is a nurse practitioner at the University of Arizona Cancer Center and a clinical assistant professor of medicine at the University of Arizona colleges of medicine and nursing. Her practice focuses on patients with hematologic and gastrointestinal malignancies and those participating in phase 1 clinical trials. She serves as an educator for oncology fellows, residents, nurses and nursing students, and she has mentored many in research, evidence-based practice, and publishing. She also teaches regionally, nationally, and internationally at conferences. She serves on a number of international boards including the Myelodysplastic Syndromes Foundation and the International Myeloma Foundation.

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of a given disease in untreated patients3 and may influence the approach to treatment based on high-risk or low-risk disease. For example, a patient with multiple myeloma with the 17p cytogenetic abnormality is known to have an inferior disease trajectory independent of other disease attributes and will be considered for autologous stem cell transplant earlier in the phase of treatment.4 Similarly, a patient with triple-negative breast cancer (negative estrogen, progesterone, and HER2) is felt to have high-risk disease, which with no option for hormonal therapy will require combination therapy with drugs thought to be effective in this setting.5 Predictive biomarkers, on the other hand, are attributes of the tumor thought to identify patients who may benefit from a given therapy.3 These biomarkers are used to guide treatment selection. For example, a patient with metastatic colorectal cancer who is found to have wild-type KRAS is more likely to benefit from epidermal growth factor receptor inhibitor (EGFR-I) therapy, whereas a patient who has mutated KRAS is not likely to benefit.6 A single biomarker can have both predictive and prognostic value, but each has different clinical utility. For example, HER2 testing in patients with breast cancer serves as a negative prognostic indicator (considered higher risk) but also has positive predictive value (patients are likely to respond to HER2-directed therapies).5,7 Thus, biomarker-driven treatment selection may limit exposure of potentially toxic treatments in patients not likely to benefit and is therefore more cost-effective and offers the best option for therapy in patients with positive predictive biomarkers. Optimally, all subpopulations of patients with predictive and prognostic biomarkers enrolled in clinical trials will be enrolled in tandem trials for tissue banking and longitudinal analysis to further characterize these attributes and clinical outcomes. Selected predictive and prognostic indices for common solid tumors are included in Table 2.5-12 Examples of high-risk features for common hematologic malignancies are provided in Table 3.1 The growing trend in risk-adapted treatment selection – based on specific attributes of the tumor, extent of disease, and the individual patient – challenges the

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Table 1. Key Elements of Precision Medicine1 Definition • Application of predictive biomarkers together with consideration of prognostic biomarkers and patient attributes in the selection of therapy, using a personalized life-span approach • Effective diagnostics • Characteristics of the individual patient • Comorbidities • Performance status • Lifestyle • Finances • Quality of life Risk-adapted treatment selection • Characteristics of the disease • Prognostic biomarkers • Predictive biomarkers • Tissue type • Staging • Currently available treatment options • Shift from safety and efficacy alone to biomarker-driven therapy • Optimal sequencing and duration of therapy • Understanding and application of response criteria Partnership with the patient and family • Selection based on risk analysis and patient choice Adapted from Kurtin S. J Adv Pract Oncol. 2010;1:19-29.

oncology professional to maintain a working knowledge of tissue diagnoses and specific pathology techniques. This is necessary to facilitate accurate diagnoses and consider all necessary testing at the time of the original biopsy or resection. Selecting treatment based on the global diagnosis for both solid and liquid tumors is no longer adequate, and several technologies are now available for obtaining molecular biomarkers, including interphase cytogenetics, fluorescence in situ hybridization, polymerase chain reaction, and gene expression profiling. Individual testing may be performed on tissue or blood, and diagnostic packages such as the Oncotype Continued on page 53

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Table 2. Application of Predictive and Prognostic Indices in Selected Solid Tumors5-12 Biomarker Breast Cancer (BC)

Technique for Evaluation

Clinical Significance

Hormone receptors (ER, PR)

Tissue analysis (IHC)

Recommended for all patients with newly diagnosed invasive or recurrent BC. ER status has significant predictive value for tumor response to HT in metastatic disease. Significance of PR status less clear. ER+, PR+ tumors may respond better to HT. ER/PR status may change over the course of disease.

HER2

Tissue analysis (IHC, FISH, HERmark)

Recommended for all newly diagnosed BC patients. TK that is overexpressed in 15%-30% of BC. 3+ HER2 expression associated with poor prognosis. HER2+ patients may benefit from trastuzumab and anthracyclines. Measurement of activated form of HER2 may be useful in evaluating disease progression.

BRCA1 BRCA2

Tissue analysis (IHC, serum)

Tumor suppressor genes. Mutation linked to increased lifetime risk of breast, ovarian, and pancreatic cancer. Patients with presence of mutations may benefit from increased surveillance.

uPA PAI-1

Tissue analysis (IHC)

Plays a role in degradation of the extracellular matrix, tissue remodeling, cell adhesion, and migration. Elevated levels associated with negative outcomes in node-negative BC. Recommended in risk assessment for N0 BC.

CTC

Serum

High CTC count at diagnosis is associated with poor prognosis (â&#x2030;Ľ5 CTC at baseline). If the number of CTC does not decrease during therapy, patient is likely to progress on current therapy.

CEA

Serum

Used as a measure of tumor activity. Not elevated in all patients, even with bulky disease. Not specific to CC; elevated in smokers.

UGT1A1

Serum

Enzyme critical to inactivation of SN-38 (irinotecan metabolism). Polymorphism associated with hyperbilirubinemia. UGT1A1*28 allele may have increased toxicity to irinotecan.

DPD deficiency

Serum

DPD deficiency is important for 5-FU metabolism. Deficiency associated with severe toxicity to 5-FU.

MSI

Tissue (IHC)

Mutations (microsatellites) in the mismatch repair gene. Testing recommended for all patients <50 years. Stage II patients with MSI high-frequency tumors have a good prognosis and may not benefit from adjuvant chemotherapy using 5-FU.

KRAS

Tissue

KRAS mutations are a biomarker predictive of

Colorectal Cancer (CC)

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Table 2. Application of Predictive…(continued) Biomarker KRAS (continued)

Technique for Evaluation

Clinical Significance negative response to anti-EGFR monoclonal antibodies (EGFR-I). Mutations in codon 12 and 13 of exon 2 most common. KRAS13 p. G13D mutation may have response to EGFR-I; being investigated in clinical trials. WT-KRAS with low-level expression of amphiregulin and epiregulin (ligands for EGFR) also have inferior response to EGFR.

BRAF

Tissue (PCR)

BRAF mutation is an indicator of poor prognosis. BRAF V600E mutations predictive of negative response to EGFR-I. May have limited benefit in the first-line metastatic setting with chemo.

PI3KCA

Tissue

Mutated PI3KCA stimulates the AKT pathways, increasing tumor cell growth in CC.

PTEN

Tissue

Negative regulator of PI3KCA. PTEN+ tumors may have more favorable outcomes. PTEN− tumors may not respond to EGFR-I.

Non–Small Cell Lung Cancer (NSCLC) EGFR

Tissue (IHC, FISH, or PCR)

EGFR (HER1) commonly overexpressed in NSCLC; indicates proliferative advantage and ↑ metastatic potential. More common in adenocarcinoma, never-smokers, Asian descent. EGFR mutation predictive of response to EGFR-I. Most common EGFR mutation: exon 19 (60%), associated with ↑ OS. Rare EGFR mutation: exon 20 insertion, associated with resistance to EGFR-I.

KRAS

Tissue (IHC)

One of the most common mutations associated with NSCLC (20%-30%). Regulates activation of ≥10 downstream effector pathways. Clinical utility not yet established for NSCLC. KRAS-mutant patients may have higher risk of recurrence postoperatively.

ERCC1

Tissue

Low ERCC1 predictive of response to platinum compounds.

RRM1

Tissue

Low RRM1 predictive of response to gemcitabine.

EML4-ALK

Tissue

EML4-ALK+ predictive of response to crizotinib.

5-FU indicates 5-fluorouracil; BRCA, breast cancer susceptibility protein; CEA, carcinoembryonic antigen; CTC, circulating tumor cell; DPD, dihydropyrimidine dehydrogenase; EGFR, epidermal growth factor receptor; EML4-ALK, echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase; ER, estrogen receptor; ERCC1, excision repair cross-complementation group 1; FISH, fluorescence in situ hybridization; HT, hormone therapy; IHC, immunohistochemistry; MSI, microsatellite instability; OS, overall survival; PAI-1, plasminogen activator inhibitor type-1; PCR, polymerase chain reaction; PR, progesterone receptor; PTEN, phosphatase and tensin homolog; RRM1, ribonucleotide reductase M1; TK, tyrosine kinase; uPA, urokinase plasminogen activator.

DX, a 21-gene assay estimating a recurrence score in breast cancer with both prognostic and predictive value, have become more common.

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Risk-Adapted Treatment Selection: What You See Is What You Get Applying the concepts of predictive and prognostic

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Table 3. High-Risk Features of Common Hematologic Malignancies1 Disease

High-Risk Features

ALL

BCR-ABL+ disease Undifferentiated leukemia Age >35 years WBC >30 × 109/L at diagnosis

Null ALL. CD10+ (CALLA) mature B-cell ALL. >4-5 weeks to achieve a CR (>0.1% residual disease by PCR).

AML

High-risk cytogenetics: Complex cytogenetics (>5 abnormalities) Abnormalities of chromosome 5 or 7 17p abnormality, t(6;9), t(3;21), 11q23 deletion (common in MDR AML)

Intermediate cytogenetic risk: +8, +6, +21, −Y, 12p−. NPM1 mutation with FLT3-ITD. CEBPα mutation. Increasing blasts. Antecedent hematologic malignancies.

CLL

High-risk cytogenetics: del(11q) and del(17p) Intermediate-risk cytogenetics: 14q, 12+ Unmutated (germline) IgVH gene CD38 expression in >30% of lymphocytes ZAP-70 expression in >20% of lymphocytes

Elevated serum thymidine kinase. Presence of large-cell transformation. Elevated β2-microglobulin. Doubling time of lymphocyte count <12 months. Rai stage III or IV, Binet stage C.

MDS

High-risk cytogenetics: Complex (>3 abnormalities) Chromosome 7 abnormalities: 7q, −7, del(7p); t(5q) Inv16, t(8;12) – implies diagnosis of AML

Thrombocytopenia at presentation. High transfusion burden. IPSS intermediate 2/high-risk disease.

High-risk cytogenetics: t(4;14), t(14;16), −17p13 Intermediate-risk cytogenetics: −13q Serum albumin <3 g/dL Plasma cell labeling index >3% Hypodiploidy ISS stage III-IV

Bone marrow plasma cells >50%. β2-microglobulin >4 mg/L. Creatinine >2 mg/dL. Platelet count <150,000/mm3. Relapse <12 months from HCT or first-line therapy.

NHL

Elevated lactose dehydrogenase IPI stage III-IV disease High Ki-67 rate Elevated β2-microglobulin

Elevated HLA-DR. Elevated c-Myc (>80%). Bcl-2 overexpression.

Adapted from Kurtin S. J Adv Pract Oncol. 2010;1:19-29. Reprinted with permission. ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CR, complete response; HCT, hematocrit; HLA-DR, human leukocyte antigen–DR; IPI, International Prognostic Index; IPSS, International Prognostic Scoring System; ISS, International Staging System; MDR, multidrug resistance; MDS, myelodysplastic syndromes; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; PCR, polymerase chain reaction; WBC, white blood cell.

indices in risk-adapted treatment selection is expected, based on recent scientific discoveries. However, selecting therapies based on the diagnostic evaluation adds an element of complexity to the treatment of each patient. The selection of primary therapies in some tumors, the sequencing of therapies, and the choice of therapies in metastatic disease or in the instance of disease progression are driven by these principles. For effective treatment planning, a comprehensive disease-specific

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diagnostic evaluation is essential, as each disease requires specific testing. Asking key questions at the time of the initial tissue diagnosis is perhaps the most critical step in the diagnostic process. For example, it is well established that a fine-needle aspirate is inadequate for the diagnosis of lymphoma, that obtaining fewer than 12 regional lymph nodes with primary colorectal surgery is suboptimal, and that an adequate bone marrow analysis requires an aspirate with spicules, a core biopsy, and analysis of

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Table 4. Disease-Specific Diagnostic Imaging10-18 Cancer Type

Recommended Baseline Imaging

ALL

• CXR • Other imaging based on symptoms or clinical findings only

AML

• CXR • Other imaging based on symptoms or clinical findings only

Breast

• Diagnostic bilateral mammography, ultrasound, or MRI as indicated • Additional testing determined by stage of disease and symptoms – Stage III – bone scan, CT of abdomen and pelvis, chest imaging – Bone scan for localized bone pain or elevated alkaline phosphatase – CT of abdomen and pelvis for elevated LFTs, abnormal PE – FDG PET/CT only in selected instances of locally advanced or metastatic disease

CML

• CXR PA and lateral • Abdominal ultrasound or CT of abdomen with clinical evidence of splenomegaly

Colorectal

• Contrast-enhanced diagnostic CT of chest, abdomen, and pelvis • PET/CT not routinely indicated

MDS

• CXR • Other imaging based on symptoms or clinical findings only

Myeloma

• Skeletal survey (plain films) • CXR PA and lateral • MRI of spine if findings on plain films or clinical signs/symptoms

NHL – DLBCL, • CT of chest, abdomen, and pelvis FL, MCL, • MUGA scan or echocardiogram CLL/SLL • PET/CT only indicated for initial diagnosis of MCL or DLBCL – recommended only in selected cases for diagnosis or treatment evaluation for indolent lymphomas (FL, CLL/SLL) • MRI or CT of brain for selected high-risk cases or with symptoms Non–small cell lung

• CT of chest to adrenals • PET/CT – findings require pathological confirmation • MRI of brain • Endoscopic ultrasound and biopsy

ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML; chronic myelogenous leukemia; CXR, chest x-ray; DLBCL, diffuse large B-cell lymphoma; FDG, fluorodeoxyglucose; FL, follicular lymphoma; LFT, liver function test; MCL, mantle cell lymphoma; MDS, myelodysplastic syndromes; MUGA, multigated acquisition; NHL, non-Hodgkin lymphoma; PA, posteroanterior; PE, physical examination; SLL, small lymphocytic leukemia.

cytogenetics to provide adequate diagnostic and prognostic information. In all cases, a complete diagnostic evaluation prior to implementing any antineoplastic therapy is essential, because once treatment has been administered, the tissue will be altered and testing will not provide similar prognostic or predictive information. Most tumor types require baseline diagnostic imaging. Because appropriate baseline imaging for each tumor type will vary, however, it is critical to understand

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the best approach to diagnosing each tumor type in order to adequately plan the diagnostic process and prepare the patient and family. For example, bone involvement is common in a patient with multiple myeloma; however, a bone scan is of limited diagnostic value. Similarly, whereas obtaining a PET/CT scan for staging a patient with follicular non-Hodgkin lymphoma (NHL) is not useful, it may provide diagnostic benefit in a patient with more aggressive diffuse large B-cell NHL. Ap-

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patients with metastatic or incurable disease. Many tumor types have limited treatment options. Perhaps the NSCLC stage III or IV best example is the patient with metastatic colorectal cancer, with EML4-ALK– EML4-ALK– EGFR– FDA-approved therapies limited to 6 EML4-ALK+ EGFR+ EGFR– nonsquamous histology squamous agents; patients with mutated KRAS histology are limited to 4 FDA-approved therapies. Thus, each agent must be used VEGF-I ineligible VEGF-I eligible to its fullest potential over the longest period of time. The goals of therapy and the degree of flexibility with Cisplatin-pemetrexed CarboplatinCisplatin-vinorelbine treatment must be adapted to the inOR paclitaxel + ± cetuximab OR cisplatin-vinorelbine bevacizumab cisplatin OR dividual patient. For example, in the ± cetuximab OR OR cisplatincarboplatin with cisplatin OR pemetrexed setting of metastatic disease, achievdocetaxel OR carboplatin with gemcitabine OR ing stable disease is an acceptable outdocetaxel OR Erlotinib paclitaxel gemcitabine OR Crizotinib or come. In patients with potentially paclitaxel gefitinib curable disease, however, a more aggressive approach to treatment is preNSCLC indicates non–small cell lung cancer. ferred, with application of the propriate diagnostic imaging at baseline and at defined principles of precision medicine and an attempt to emuintervals can also provide the most accurate analysis of late the clinical trial protocol associated with the most response to treatment, but the timing for evaluation favorable outcomes. Nevertheless, the patient’s tolerance varies for each tumor type. For example, a patient with of therapy must also be considered, including reversible Hodgkin lymphoma will typically have undergone a versus potentially irreversible adverse events and the PET/CT scan after 2 months of treatment, and negative severity of symptoms despite optimal management. results from the scan in this setting are considered a posRisk-adapted treatment selection for non–small cell itive predictor of long-term survival. A patient with follung cancer is illustrated in the Figure. This algorithm licular lymphoma, on the other hand, generally receives illustrates the variability in approach to treatment based 3 to 4 months of treatment prior to undergoing repeat on the application of principles of precision medicine. imaging, unless a physical exam and analysis of laboraSimilar algorithms and guidelines are available online tory measures such as serum lactate dehydrogenase show through the National Cancer Institute, the National no evidence of improvement. It should be noted that Comprehensive Cancer Network, the American Society of Clinical Oncology, and the American Society of PET/CT evaluation is only recommended in selected Hematology. To remain effective as members of the oncases of follicular lymphoma. Common approaches to cology team, advanced practice clinicians in oncology diagnostic imaging are reviewed in Table 4.10-18 Scientific practicality is perhaps the most important and oncology nurses must maintain a current working component of precision medicine. This is a term I use to knowledge of all of these concepts. describe the application of clinical trials data to the popMade-to-Order Clinical Trials: ulation at large in a way that allows effective control of The Way Forward the disease for as long as possible with an acceptable level Predictive and prognostic indices and the notion of of toxicity. This concept is of particular importance in

Figure. Application of Biomarkers in NSCLC

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Biomarkers

precision medicine have evolved as a result of ongoing clinical trials in oncology. The integration of functional imaging, sequential tissue analysis, and use of biomarker assays has developed as a result of these trials. The shift from a one-size-fits-all model of drug development, where a new agent is tested in a wide variety of tumor types to determine the maximum tolerated dose and sensitivity to individual diseases, is now being replaced by trials with a specific patient prototype in mind. These made-to-order clinical trials are designed based on a predetermined biomarker profile generated by laboratory disease models, with inclusion criteria specific to the biomarker and disease prototype.2 This approach will require a shift in the definition of clinical efficacy and clinical trial end points as well as development of new technologies to obtain these measures. Because these trials will be costly, with the potential benefit focused on only a small population of patients, it will be necessary to address hard questions, such as who will spend the time and money discovering, designing, and developing novel drugs for newly discovered targets. The current environment of skepticism toward pharmaceutical corporations, despite their significant contributions to clinical research in oncology and limited funding sources outside of these corporate entities, will make this new drug development process more difficult, particularly for orphan diseases.

Cancer Happens in Humans – Most Often the Older Adult We must always remember that beyond the tissue diagnosis, diagnostic imaging results, and laboratory values, there is a patient with all of the unique characteristics of age, comorbidities, lifestyle, treatment goals, and available resources. These are what I consider the personalized aspects of oncology care. The goal of personalized medicine is to apply the principles of precision medicine in a way that provides the greatest benefit with the least amount of risk to the individual patient. Consideration of the effect of comorbidities, the cost of treatment, self-care capabilities, available care-

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giver support, proximity to the clinical setting, and quality of life must be central to the treatment plan. The patients and their primary caregivers should be provided with adequate information to make an informed choice. As clinicians, we must find ways to educate ourselves and our patients about these complex concepts. Continued enrollment of patients in clinical trials that include tissue banking and biomarker assays will promote refinement of risk-adapted treatment selection based on predictive and prognostic indices. u

References 1. Kurtin S. Risk analysis in the treatment of hematologic malignancies in the elderly. J Adv Pract Oncol. 2010;1:19-29. 2. Yap A, Sandhu SK, Workman P, et al. Envisioning the future of early anticancer drug development. Nat Rev Cancer. 2010;10:514-523. 3. Chu E. An update on the current and emerging targeted agents in metastatic colorectal cancer. Clin Colorectal Cancer. 2011;11:1-13. 4. Richardson PG, Lauback J, Mitsiades C, et al. Tailoring treatment for multiple myeloma patients with relapsed and refractory disease. Oncology (Williston Park). 2010;24(suppl 2):22-29. 5. Bishop C. Biomarkers in breast cancer. J Adv Pract Oncol. 2011;2:101-111. 6. Grande C, Viale PH, Yamamoto D. Biomarkers in colorectal cancer: implications for nursing practice. J Adv Pract Oncol. 2010;1:245-255. 7. Aggarwal C, Somiah N, Simon GR. Biomarkers with predictive and prognostic function in non-small cell lung cancer: ready for prime time? J Natl Compr Canc Netw. 2010;8:822-832. 8. National Cancer Institute. Breast cancer treatment (PDQ®): triple-negative breast cancer. NCI Web site. www.cancer.gov/cancertopics/pdq/treat ment/breast/healthprofessional/page8. Updated November 21, 2011. Accessed March 14, 2012. 9. National Cancer Institute. General information about non-small cell lung cancer (NSCLC). NCI Web site. www.cancer.gov/cancertopics/pdq/ treatment/non-small-cell-lung/healthprofessional#Section_48499. Updated February 10, 2012. Accessed March 14, 2012. 10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Breast Cancer. V.1.2012. www.nccn.org. Published January 20, 2012. Accessed March 16, 2012. 11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Non-Small Cell Lung Cancer. V.2.2012. www.nccn.org. Published October 4, 2011. Accessed March 16, 2012. 12. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Colon Cancer. V.3.2012. www.nccn.org. Published January 17, 2012. Accessed March 16, 2012. 13. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. V.1.2012. www.nccn.org. Published July 26, 2011. Accessed March 16, 2012. 14. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Acute Myeloid Leukemia. V.2.2011. www.nccn.org. Published December 21, 2011. Accessed March 16, 2012. 15. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Acute Lymphoblastic Leukemia. V.1.2012. www.nccn.org. Published March 12, 2012. Accessed March 16, 2012. 16. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Myelodysplastic Syndromes. V.1.2012. www.nccn.org. Published December 6, 2011. Accessed March 16, 2012. 17. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Non-Hodgkin’s Lymphomas. V.2.2012. www.nccn.org. Published February 23, 2012. Accessed March 16, 2012. 18. Kurtin S. Leukemia and myelodysplastic syndromes. In: Yarbro CH, Wujcik D, Gobel BH, eds. Cancer Nursing: Principles and Practice. 7th ed. Sudbury, MA: Jones & Bartlett LLC; 2010:1369-1398.

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Pharmacoeconomics

Cancer Care Grand Rounds A new study suggests higher U.S. oncology spending is ‘worth it.’

persistent health-care myth is that the U.S. system is uniquely wasteful versus the European countries that spend far less per patient as a result of tight government control. Only the establishment experts who spread this myth will be surprised, but new research shows American patients are often getting more value – better outcomes and longer lives – in return for those extra dollars. More remarkable still, the news arrives via the policy journal Health Affairs, in a symposium on the cost and quality of U.S. cancer care. This is like the Vatican saying go ahead, worship the graven images and false idols.

While U.S. health care could obviously be far more efficient, most of its dysfunctions are the result of government’s perverse incentives. Tomas Philipson of the University of Chicago and colleagues compare U.S. oncology spending over the period from 1983 to 1999 (the last year for which data are available) with that in 10 European Union countries. Costs were lower overall overseas and grew by 16%, while they grew by 49% in the U.S. Yet U.S. cancer mor-

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tality rates are lower, despite higher cancer rates, and “We found that the value of survival gains greatly outweighed the costs, which suggests that the costs of cancer care were indeed ‘worth it,’” Mr. Philipson et al. write. Throughout the entire period, U.S. cancer survival gains were larger, reaching 11.1 years over 1995 to 1999 against 9.3 years in the EU. The researchers then compared the U.S. and EU gains using conservative, commonly accepted measures for the value of a statistical life, less the cost of the care. The U.S. comes out ahead by $598 billion. In other words, though the U.S. spends more, patients and society benefit far more. Over 1995-1999, each $100 increase in per capita cancer spending – approximately $20,000 per cancer patient – was associated with another 2.3 years of life for the average patient. The authors are also careful to show that these results reflect real patient outcomes. Another myth is that U.S. survival rates are an artifact of the time of diagnosis, a “lead-time bias” that comes from more screening and earlier cancer detection, but without any improvement in life expectancy. Mr. Philipson’s method controls for such bias. The U.S. system is relatively more expensive because diagnosis and treatment are much more intensive, and doctors tend to leverage the latest therapies and drugs against one of the world’s leading killers. While U.S. health care could obviously be far more efficient, most of its dysfunctions are the result of government’s perverse incentives. The sophisticates who pine for the allegedly more enlightened forms of European rationing and price controls – for more perverse incentives – would do well to peruse the Health Affairs symposium. Mr. Philipson’s paper suggests those are good ways to stop anticancer progress in its tracks, or reverse it altogether. Reprinted with permission of The Wall Street Journal © 2012. Dow Jones & Company. All rights reserved.

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