PMO February 2014

A Peer-Reviewed Journal

February 2014 • Volume 3 • Number 1

PM O

BIOMARKERS • IMMUNOTHERAPY • TARGETED THERAPIES • DIAGNOSTICS

Personalized Medicine in Oncology TM

TRANSFORMING CANCER RESEARCH PROGRESS REPORT: Implementation of ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research ......................Page 14

INTERVIEW WITH THE INNOVATORS Partners HealthCare Center for Personalized Genetic Medicine: Utilizing Genetics and Genomics to Improve Care of Patients.

An Interview With Scott T. Weiss, MD, MS, and Heidi L. Rehm, PhD.................................Page 18

MULTIPLE MYELOMA CME Considerations in Multiple Myeloma. Ask the Experts: Beyond Complete Responses ..........................Page 24

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies: Highlights From the Second Annual Conference of the Global Biomarkers Consortium..................Page 32

VALUE-BASED CANCER CARE Need for Innovative Strategies for Quality Care Will Continue to Grow......................................Page 44

CASE STUDY

BIOMARKERS Use of GLOBAL Biomarkers in Multiple Myeloma…......Page 50 CONSORTIUM Clinical Approaches to Targeted Technologies ™

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

WORLD CUTANEOUS MALIGNANCIES CONGRESS

© 2014 Green Hill Healthcare Communications, LLC An affiliation of The Lynx Group

WORLD CUTANEOUS

™

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ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

RECHARGE THE POSSIBILITIES

• Efficacy and safety evaluated in the largest prospective single-arm PTCL study (Study 3, N=131)1 • Studied in a pretreated, histologically diverse PTCL population1 • Patients could be treated until disease progression at their discretion and that of the investigator1

Important Safety Information WARNINGS AND PRECAUTIONS • Treatment with ISTODAX® (romidepsin) has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX. The risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Ensure that potassium and magnesium are within the normal range before administration of ISTODAX • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D)

ADVERSE REACTIONS Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (N=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (N=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).

ISTODAX® is a registered trademark of Celgene Corporation. © 2013 Celgene Corporation 07/13 US-IST130001a

www.istodax.com

Demonstrated efficacy in PTCL after at least 1 prior therapy in Study 3a1

15% ~60% 25%

(19/130) Complete Response Rate (CR+CRu) by independent central review (95% CI: 9.0, 21.9) • Similar complete response rates in the 3 major PTCL subtypes (NOS, AITL, ALCL)

9.2 months

(11/19) of Complete Responses (CR+CRu) exceeded • Follow-up was discontinued in the remaining 8 patients prior to 9.2 months (33/130) Objective Response Rate (CR+CRu+PR) by independent central review (95% CI: 18.2, 33.8)

1.8 months a

(~2 cycles) median time to Objective Response

Efficacy based on 130 patients with histological confirmation by independent central review.1

Infections were the most common type of serious adverse event reported in Study 3 (N=131) and Study 4 (N=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.

The most common adverse reactions regardless of causality in Study 3 (N=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (N=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

DRUG INTERACTIONS • Monitor prothrombin time and International Normalized Ratio in patients concurrently administered ISTODAX (romidepsin) and warfarin sodium derivatives • Romidepsin is metabolized by CYP3A4 Monitor patients for toxicity related to increased romidepsin exposure and follow dose modifications for toxicity when ISTODAX is initially co-administered with strong CYP3A4 inhibitors Avoid co-administration of ISTODAX with rifampin and other potent inducers of CYP3A4 • Exercise caution with concomitant use of ISTODAX and P-glycoprotein (P-gp, ABCB1) inhibitors

USE IN SPECIFIC POPULATIONS • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution Please see Brief Summary of Full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS, on the following pages.

Reference: 1. ISTODAX [package insert]. Summit, NJ: Celgene Corp; 2013.

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monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate.

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a Brief Summary of the Prescribing Information for the peripheral T-cell lymphoma indication only; see Full Prescribing Information for complete product information.

5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman.

In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)].

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

Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2.

The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles.

Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥10%) as adverse reactions are included in Table 2.

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

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1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle.

Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug.

2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.

• Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.

• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.

Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.

• Grade 4 febrile (≥38.5° C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.

2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)].

5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)].

5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)].

In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.

Potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)].

5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden should be closely

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Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).

In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus.

Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification.

8.3 Nursing Mothers It is not known whether romidepsin 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 ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.

8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were >65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted.

Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)].

8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted.

Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)].

10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required.

There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 or Baxter Oncology GmbH Halle/Westfalen, Germany ISTODAX® is a registered trademark of Celgene Corporation © 2010-2013 Celgene Corporation. All Rights Reserved.

U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBSPTCL.005 06/13

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Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).

7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)].

7.2 Drugs that Inhibit Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic drug interaction trial the strong CYP3A4 inhibitor ketoconazole increased romidepsin (AUC0-∞) by approximately 25% [See Clinical Pharmacology (12.3)]. Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity [see Dosage and Administration (2.2)] when romidepsin is initially co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).

7.3 Drugs that Induce Cytochrome P450 3A4 Enzymes Avoid co-administration of ISTODAX with rifampin. In a pharmacokinetic drug interaction trial with co-administered rifampin (a strong CYP3A4 inducer), romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively [See Clinical Pharmacology (12.3)].

Typically, co-administration of CYP3A4 inducers decrease concentrations of drugs metabolized by CYP3A4. The increase in exposure seen after co-administration with rifampin is likely due to rifampin’s inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of ISTODAX. It is unknown if other potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) would alter the exposure of ISTODAX. Therefore, the use of other potent CYP3A4 inducers should be avoided when possible.

7.4 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)].

There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman.

8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established.

FEBRUARY 2014

VOLUME 3, NUMBER 1

TABLE OF CONTENTS TRANSFORMING CANCER RESEARCH

14

PROGRESS REPORT: Implementation of ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research

An update on ASCO’s vision for a cancer research system that fully capitalizes on scientific and technological advances to deliver more effective and personalized cancer therapies faster.

INTERVIEW WITH THE INNOVATORS

18

Partners HealthCare Center for Personalized Genetic Medicine (PCPGM): Utilizing Genetics and Genomics to Improve Care of Patients. An Interview With Scott T. Weiss, MD, MS, and Heidi L. Rehm, PhD

PMO speaks with Drs Weiss and Rehm about the impact of the PCPGM on improving healthcare through the promotion and implementation of personalized medicine.

MULTIPLE MYELOMA CME

24 Considerations in Multiple Myeloma. Ask the Experts: Beyond Complete Responses

Jeffrey Wolf, MD; Amy Marsala, NP; Rebecca Young, PharmD, BCOP

In this edition of Considerations in Multiple Myeloma, experts from the University of

California San Francisco answer questions related to the management of patients with multiple myeloma who achieve complete responses.

GLOBAL BIOMARKERS CONSORTIUM

32

Clinical Approaches to Targeted Technologies: Highlights From the Second Annual Conference of the Global Biomarkers Consortium Professor Rob Coleman, FRCP; Jorge E. Cortes, MD The faculty presents an in-depth review of strategies for the clinical application of biomarkers toward optimal personalized care for patients with cancer, including the validation of biomarkers and their incorporation into clinical trials.

OUR MISSION Personalized Medicine in Oncology provides the bridge between academic research and practicing clinicians by demonstrating the immediate implications of precision medicine – including advancements in molecular sequencing, targeted therapies, and new diagnostic modalities – to the management of patients with cancer, offering oncologists, oncology nurses, payers, researchers, drug developers, policymakers, and all oncology stakeholders the relevant practical information they need to improve cancer outcomes. This journal translates the new understanding of the biology of cancer into the day-to-day management of the individual patient with cancer, using a patient’s unique genetic makeup to select the best available therapy.

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

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PUBLISHING STAFF Senior Vice President/Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Group Director, Sales & Marketing John W. Hennessy jhennessy2@the-lynx-group.com Publisher Russell Hennessy rhennessy@the-lynx-group.com Editorial Director Kristin Siyahian ksiyahian@the-lynx-group.com Strategic Editor Robert E. Henry Senior Copy Editor BJ Hansen Copy Editor Rosemary Hansen Production Manager Marie RS Borrelli The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Jackie Luma Deanna Martinez IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Green Hill Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-656-7935 fax: 732-656-7938

February 2014

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Vol 3, No 1

The Personalized Medicine Coalition presents the 10th Annual Luncheon Address on

THE STATE OF PERSONALIZED MEDICINE The annual PMC luncheon address at the National Press Club serves as a forum to discuss key issues facing personalized medicine with leaders in health care.

Featuring a keynote address by

Patrick Conway, M.D. Chief Medical Officer Centers for Medicare & Medicaid Services

Thursday March 13, 2014 • Noon – 2:00 p.m. ET The National Press Club • Washington, DC

To learn more and register, visit: www.personalizedmedicinecoalition.org

The Personalized Medicine Coalition (PMC), representing innovators, scientists, patients, providers and payers, promotes the understanding and adoption of personalized medicine concepts, services and products to benefit patients and the health system. The Coalition’s mission is to educate policymakers and the public about the power and potential of individualized health care and raise the profile of personalized medicine so that both patients and the health system will benefit from improved clinical care and increased overall value.

202-589-1770 · pmc@PersonalizedMedicineCoalition.org

FEBRUARY 2014

VOLUME 3, NUMBER 1

T

TABLE OF CONTENTS

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

(Continued)

Global biomarkers Consortium Clinical Approaches

VALUE-BASED CANCER CARE

44

Need for Innovative Strategies for Quality Care Will Continue to Grow

TM

In his address at the ASCO Quality Care Symposium, Dr Lee N. Newcomer recommends new approaches for oncology reimbursement.

to Targeted Technologies

TM

SAN ANTONIO BREAST CANCER SYMPOSIUM

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Important information in personalizing medicine from the San Antonio Breast Cancer Symposium

CASE STUDY

50

Use of Biomarkers in Multiple Myeloma A case presented by David G. Roodman, MD, PhD, Indiana University School of Medicine, at the recent GBC annual conference.

Save the date for the Third Annual Conference, October 29-November 1, 2014 Visit www.globalbiomarkersconsortium. com to register

AMERICAN SOCIETY OF HEMATOLOGY ANNUAL MEETING

52

I mportant information in personalizing medicine from the American Society of Hematology annual meeting

THE LAST WORD

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New Technology Diffusion Essential to Personalized Medicine PMO interviews Dr Gary Owens about the adoption of scientific knowledge to daily medical practice.

Professional Experience of GBC Attendees 26.7%

Personalized Medicine in Oncology is included in the following indexing and database services: Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases

Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copy­right ©2014 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), 1249 South River Road, Suite 202A, Cranbury, NJ 08512. 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, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. 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.

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1-3 years 3-5 years 5-10 years 10-20 years >20 years February 2014

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Vol 3, No 1

EDITORIAL BOARD

EDITORS IN CHIEF Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania Al B. Benson III, MD Northwestern University Chicago, Illinois SECTION EDITORS Breast Cancer Edith Perez, MD Mayo Clinic Jacksonville, Florida 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 Drug Development Igor Puzanov, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee Lung Cancer Vincent A. Miller, MD Foundation Medicine Cambridge, Massachusetts Predictive Modeling Michael Kattan, PhD Case Western Reserve University Cleveland, Ohio 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

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

Nikhil C. Munshi, MD Dana-Farber Cancer Institute Boston, Massachusetts

Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona

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

Kenneth Bloom, MD Clarient Inc. Aliso Viejo, California

David A. Proia, PhD Synta Pharmaceuticals Lexington, Massachusetts

Mark S. Boguski, MD, PhD Harvard Medical School Boston, Massachusetts

Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain

Gilberto Castro, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil

Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois

Madeleine Duvic, MD The University of Texas MD Anderson Cancer Center Houston, Texas

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

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio Stephen Gately, MD TGen Drug Development (TD2) Scottsdale, Arizona Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland K. Peter Hirth, PhD Plexxikon, Inc. Berkeley, California Gregory Kalemkerian, MD University of Michigan Ann Arbor, Michigan Howard L. Kaufman, MD Rush University Chicago, Illinois Katie Kelley, MD UCSF School of Medicine San Francisco, California Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota

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

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

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

Gene Morse, PharmD University at Buffalo Buffalo, New York

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Afsaneh Motamed-Khorasani, PhD Radient Pharmaceuticals Tustin, California

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Danielle Scelfo, MHSA Genomic Health Redwood City, California Lee Schwartzberg, MD The West Clinic Memphis, Tennessee John Shaughnessy, PhD University of Arkansas for Medical Sciences Little Rock, Arkansas Lillie D. Shockney, RN, BS, MAS Johns Hopkins University Baltimore, Maryland Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida Darren Sigal, MD Scripps Clinic Medical Group San Diego, California David Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee Moshe Talpaz, MD University of Michigan Medical Center Ann Arbor, Michigan Sheila D. Walcoff, JD Goldbug Strategies, LLC Rockville, Maryland Anas Younes, MD The University of Texas MD Anderson Cancer Center Houston, Texas

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Faculty Perspectives

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LETTER TO OUR READERS

The Importance of the Multidisciplinary Team in Personalizing Care Dear Colleague,

O

ne of the things that sets oncology care apart from the care of other illnesses is the necessity for the patient to be under the care of a multidisciplinary team. A patient with a cardiac issue may be managed just fine by a cardiologist. A patient diagnosed with cancer, however, requires a multidisciplinary team working together to provide the necessary diagnostic tests, treatment planning, and coordination of care in keeping with specific standards of care in order for the patient to receive Lillie D. Shockney, the right care, in the right setting, by the right providers.

RN, BS, MAS The first team members to come to mind are the surgical oncologist, medical oncologist, radiation oncologist, radiologist, cancer rehabilitation therapist, and pathologist. However, there are other important team members: the nurse navigator, the social worker, oncology nurses, technicians, the chaplain, the palliative care team, and others who help to further address the patient’s personal needs, which include physical, emotional, financial, cultural, educational, psychosocial, as well as spiritual needs. This means that at any given time, any one of these professionals referenced above is the most important person to the patient in that moment.

Each of us has a pivotal role to carry out on behalf of the patient. Collectively, however, we have the opportunity to truly provide personalized care that goes well beyond the patient’s pathology and staging workup results. We are treating a person who is 35 years old, is an elementary school teacher who has a 9-year-old son with autism, is scraping by financially because her husband has been laid off, and she has just been diagnosed with stage 2a Each of us has a pivotal breast cancer. All of these considerations need to be factored into the parole to carry out on behalf tient’s treatment planning, including her future life goals. For example, she and her husband hope to have another child once he gains employment. of the patient.

One of her greatest joys is playing the piano. Having the multidisciplinary team know these additional things about her helps the team collectively plan her treatment, beginning with fertility preservation, cancer prehabilitation to prevent deconditioning instead of having to recondition her later, and to be cautious when considering what therapies to use so that a side effect like peripheral neuropathy can be avoided.

How does this all come together? That is one of the challenges I want us all to take on, beginning now – really knowing our patients, keeping them on track for their life goals, and maintaining joy in their lives, so that personalized care really is personalized. We should include in tumor board discussions all of this information referenced above as well as revisit the patient’s status after her treatment is done so the team can hear that this patient is back teaching school, pregnant, and playing the piano.

So join me in ensuring that personalized medicine and personalized care unite. Our patients deserve it, and our professional (and personal) lives are all the more enriched as a result.

Sincerely,

Lillie D. Shockney, RN, BS, MAS Johns Hopkins Medicine PMO Board Member

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

In this sixth annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this second issue, experts from Dana-Farber Cancer Institute answer questions related to the management of patients in the maintenance setting.

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Fourth Annual Navigation and Survivorship Conference November 15-17, 2013 The Peabody Memphis • Memphis, Tennessee CONFERENCE CO-CHAIRS Program Director: Lillie D. Shockney, RN, BS, MAS University Distinguished Service Associate Professor of Breast Cancer Departments of Surgery and Oncology Administrative Director, The Johns Hopkins Breast Center Administrative Director, Johns Hopkins Cancer Survivorship Programs Associate Professor, JHU School of Medicine Departments of Surgery, Oncology & Gynecology and Obstetrics Associate Professor, JHU School of Nursing Baltimore, Maryland

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TRANSFORMING CANCER RESEARCH

Exclusive to PMO : The following report was prepared by the American Society of Clinical Oncology

PROGRESS REPORT: Implementation of ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research

I

n November 2011, ASCO issued a prescription for transforming clinical cancer research in the United States and speeding the creation of effective new therapies for patients. In its report, Accelerating Progress Against Cancer: ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research, ASCO laid out a vision for a cancer research system that fully capitalizes on scientific and technological advances to deliver more effective and personalized cancer therapies faster.

Since issuing the report, ASCO has worked with partners to drive the report’s recommendations forward.

Many other major stakeholders, including the National Cancer Institute (NCI) and the US Food and Drug Administration (FDA) – have also launched initiatives that will contribute to achieving the vision of the Blueprint.

Together, these steps represent significant new momentum toward a research system that realizes the potential of precision medicine.

ASCO’s Blueprint: Cancer Research for the Molecular Era In its 2011 report, ASCO made the case that the US cancer research system was not fully equipped to deliver on the potential of new scientific advances – in particular, our rapidly growing understanding of the biology of cancer, the increasing classification of cancers by their molecular characteristics rather than only their location in the body, and advances in “big data” and information technology.

To bring the clinical cancer research system fully into the “molecular era” and speed the search for new therapies, ASCO made recommendations to policymakers and the cancer community in 3 key major areas: • Establish a new approach to therapeutic development, driven by our more thorough understanding of cancer biology and the advent of new technologies • Design smarter, faster clinical trials to provide evidence for effective treatments targeted to patients most likely to benefit • Harness advances in health information technology to seamlessly integrate clinical research and patient care

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Progress is occurring despite growing threats to cancer research funding. Accounting for recent cuts due to the federal sequester, the budget of the National Institutes of Health is at its lowest level since 2000 when adjusted for inflation – a drastic reduction in America’s historical commitment to biomedical research. Continued budget cutting in Congress could soon reduce the nation’s investment even further, risking our scientific leadership at the very moment of greatest potential for new advances.

In response, ASCO has called on the nation’s leaders to sustain the search for cures and better treatments against a group of diseases that affects or touches nearly every American.

New Approaches to Therapeutic Development The Blueprint described a vision in which development of new therapies is driven primarily by the molecular characteristics of each patient’s cancer rather than only its location in the body. Since 2011, this vision has moved closer to reality. Recently, for example, researchers reported the discovery that endometrial cancers share many of the same molecular characteristics as hard-totreat breast and ovarian cancers,1 creating the potential for therapies that would benefit women with a range of seemingly different diseases.

ASCO also called for therapeutic development to be driven by clearer priorities, increased collaboration, and new approaches to development of diagnostics and biomarkers. Examples of progress include: • ASCO developing recommendations on clinically meaningful outcomes for trials: ASCO is currently nearing completion of consensus recommendations to help ensure that new cancer therapies provide meaningful improvements in patient survival and quality of life. The recommendations will identify specific, clinically meaningful goals that should refocus clinical trials of new therapies for breast, colon, lung, and pancreatic cancers on outcomes that would have the most impact on patients in the clinic. Outcomes were proposed by ASCO-convened working groups of researchers and patient advocates and then shared with medical professionals, patients, advocates, and trial sponsors during a recent public comment period.

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Once completed in the coming months, ASCO intends for the recommendations to improve the prioritization of therapeutic candidates based on their potential to meet these outcomes in clinical trials, and to help shape the design of trials themselves. The current draft of the recommendations is available on ASCO.org.

• FDA prioritizes breakthrough cancer therapies: Through legislation passed by Congress in July 2012, the FDA created a program to speed development of “breakthrough therapies” for life-threatening diseases, including cancer. To receive this designation, a drug must show potential to offer substantial improvement over available therapies in preclinical or phase 1 research. The FDA then provides intensive guidance on trial design and ongoing coordination with the manufacturer to create the most efficient path to review. To date, the agency has granted the breakthrough designation to 30 therapies, of which at least 9 are for cancers, including lung and breast cancers, melanoma, and certain hard-to-treat lymphomas and blood cancers.2 ASCO and the FDA held a seminar on the regulatory path of the breakthrough therapies on May 30, 2013.

Faster, Smarter Clinical Trials The Blueprint promotes a more flexible, nimble, and efficient clinical cancer research system in which trial design and participation are driven primarily by the molecular characteristics of a patient’s cancer. Key progress in this area includes: • Progress in revitalizing federally funded clinical cancer research: In April 2010, the Institute of Medicine (IOM) released a landmark report calling for actions to modernize and strengthen the NCI Clinical Trials Cooperative Group Program, which has contributed many of the most important advances against cancer in recent decades. ASCO supports full implementation of the IOM report and has worked with IOM, NCI, and others to achieve this goal. Progress in the last 2 years includes: −−Strengthening of the Cooperative Group Program: NCI has issued funding opportunity announcements for the new National Clinical Trials Network, which results from the strategic consolidation of the Cooperative Group Program. Under this consolidation, 9 previous adult research groups have reorganized to form 4 groups with a shared goal of conducting state-of-the-art cancer trials.

The Network will also include a pediatric component. This streamlined approach promises more uniformity, greater collaboration, and faster completion of important trials. The first round of research grants under the new structure will be issued

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Success Rates Climbing for New Cancer Therapies A recent analysis by the Tufts Center for the Study of Drug Development showed that the number of cancer drug candidates entering trials and gaining FDA approval has increased in recent years. The proportion of cancer drugs that ultimately received approval (as a percentage of those entering trials) rose from 9.9% in the mid 1990s to 19.8% in the early 2000s.

This analysis offers encouraging evidence that new research approaches may be taking hold and leading to improved results. However, much more can be achieved through full implementation of ASCO’s Blueprint, together with sustained US investment in cancer research. in March 2014. ASCO worked with the IOM to host workshops in March 2011 and February 2013 to ensure accountability, transparency, and open discussion concerning these changes. −−Reorganization of NCI’s community-based research programs: NCI has also announced that it will consolidate 3 different programs that support clinical research in community-based oncology practices, where most US cancer patients receive their care. As part of the change, NCI will promote trials that incorporate emerging science and novel trial designs. ASCO supports the overall approach, while expressing concern that growing limits on funding for clinical trials will reduce the capacity of participating practices to address new requirements that they conduct research on cancer care delivery in addition to their clinical research.

ASCO intends for the recommendations to improve the prioritization of therapeutic candidates based on their potential to meet these outcomes in clinical trials...

• ASCO is developing recommendations to avoid unnecessary exclusion of patients from trials: ASCO is in the midst of an effort to help modernize and streamline eligibility criteria for molecularly driven clinical trials. The primary objective is to ensure that patients are selected for trials primarily based on their molecular characteristics, while avoiding exclusion from trials based on criteria that are less meaningful in the context of precision medicine – for example, because of prior cancers or brain metastases. An ASCO working group is currently collecting data and survey-

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primary purpose of the system is quality improvement of cancer care, there are many secondary ties to advance learning. For clinical and TRANSFORMING translational researchers, CancerLinQ will unlock an CANCER RESEARCH ented wealth of anonymous data on cancer patients’ characteristics, treatments and outcomes. Instead of olely on the 3 percent of patients who participate in clinical trials, researchers will learn from every patient’s ce and draw hypotheses for clinical research from the vast “real world” of cancer care. ASCO is developing ta governance policies and protocols to assure ethical stewardship of this resource.

• Innovative lung cancer trial breaks new ground toward precision medicine: NCI, together with Friends of Cancer Research, has developed an innovative trial for advanced lung cancer in which all patients are analyzed for molecular mutations and then directed to different arms, testing different therapies, based on their mutations. This biomarker-driven trial embodies many of the recommendations made in ASCO’s Blueprint.

• FDA is working to streamline data collection for new uses of existing therapies: In 2012, the FDA released draft guidance that would eliminate the need for research sites to collect and companies to submit data on already known, low-grade safety risks associatunderway to improve sharing, analysis of cancer care data: ASCO is leading an initiative to develop ed with expanded uses of als for cancer care data and overcome the and widespread limit secure ing experts in the field plans to inconsistencies complete draft that currently ready approved drugs.sharing ASCO of is sharing its feedback on between providers, patients andthis researchers. late 2012 to identify recommendations winter. ASCO hosted a summit inwith the FDA as thepotential agency works to finalize the and aims to issue new standards breasttocancer information • ASCO and FDAon partner advance surrogate later end this year. document, which would help accelerate approvals of points: ASCO, other specialty societies, and the FDA additional indications for marketed drugs, a common cosponsored a series of public meetings in 2012 and feature of the oncology landscape. early 2013 to discuss the use of surrogate end points for efficacy in cancer clinical trials. Such end points Harnessing Health Information Technology – including various alternatives to overall or progresWhen the Blueprint was issued in 2011, the potential sion-free survival – are critical to new trial designs of health information technology (HIT) to inform cancer research and care was only beginning 4 to be realized.

While major work remains to be done, ASCO and othWhile the primary purpose of the system is ers have made significant strides in this area: • ASCO’s Quality Institute completes prototype of quality improvement of cancer care, there CancerLinQ: This groundbreaking HIT initiative are many secondary opportunities to will fulfill ASCO’s commitment to develop a “rapid learning system” to achieve higher-quality, higheradvance learning. value cancer care with better outcomes for patients.

The CancerLinQ prototype, completed in March that can provide meaningful data on patient benefits 2013, includes de-identified data on more than in a shorter amount of time. The recent meetings 150,000 patients with breast cancer and clearly addressed minimal residual disease end points for cerdemonstrates the feasibility of building the system. tain blood cancers and pathologic complete response Lessons from the prototype will guide the develop(pCR) in breast cancer. In the breast cancer workment of CancerLinQ over the next several years. shop, experts discussed draft FDA guidance to encourWhile the primary purpose of the system is quality age use of pCR in trials of neoadjuvant therapy. improvement of cancer care, there are many secondary ASCO is looking to the FDA to finalize this docuopportunities to advance learning. For clinical and ment for breast cancer and to promote similar aptranslational researchers, CancerLinQ will unlock an proaches in other areas. unprecedented wealth of anonymous data on cancer

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patient characteristics, treatments, and outcomes. Instead of relying solely on the 3% of patients who participate in clinical trials, researchers will learn from every patient’s experience and draw hypotheses for clinical research from the vast “real world” of cancer care.

ASCO is developing strong data governance policies and protocols to assure ethical stewardship of this resource.

• Efforts are under way to improve sharing, analysis of cancer care data: ASCO is leading an initiative to develop standards for cancer care data and overcome the widespread inconsistencies that currently limit secure sharing of information between providers, patients, and researchers. ASCO hosted a summit in late 2012 to identify potential solutions and aims to issue new standards on breast cancer information later this year.

ASCO Pledges to Continue Working to Advance All of the Blueprint’s Recommendations in Partnership With Others in the Cancer Research Community Looking to the future, ASCO has outlined the following as priorities for the next 1 to 2 years: • Address federal research funding threats: Recent progress toward a 21st-century clinical research system will fall short of its potential unless investments in cancer research are sustained. Since the federal sequester went into effect April 1, NCI has already been forced to slash its 2013 budget by nearly 6%, reducing the number of new research grants and straining existing research efforts. Congress and the Obama administration must work to restore the nation’s historical, lifesaving commitment to cancer research.

• Develop CancerLinQ and establish responsible pathways for research: ASCO’s Institute for Clinical Excellence plans to move ahead with a phased development of the quality improvement system. ASCO is consulting with many stakeholders, including those in the research and regulatory communities, to under-

stand the potential for the resulting observational data sets to inform the discovery and use of new cancer therapies.

• Continue to establish consensus on new research end points: ASCO is currently discussing topics for future workshops that will bring the research community together to identify and agree on surrogate end points for clinical trials.

Congress and the Obama administration must work to restore the nation’s historical, lifesaving commitment to cancer research.

• Implement ASCO’s upcoming recommendations for clinically meaningful outcomes and eligibility criteria: ASCO will work with stakeholder organizations to promote the use of these consensus recommendations to shape the design and speed the completion of clinical trials.

• Regulation of cancer diagnostics: ASCO will continue to work with the FDA to modernize oversight of molecular diagnostics that are vitally important for clinical decision making in the era of precision oncology therapeutics. u

References

1. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67-73.

2. Breakthrough therapies. Information is drawn in part from the following industry announcements (as of May 28, 2013): LDK378 for ALK+ non-small cell lung cancer; Novartis press release, March 15, 2013. Ibrutinib for relapsed or refractory mantle cell lymphoma, Waldenstrom’s macroglobulinemia, and chronic lymphocytic leukemia; Pharmacyclics press release, April 8, 2013. Palbociclib (PD-0332991) for breast cancer; Pfizer press release, April 10, 2013. Lambrolizumab for advanced melanoma; Merck press release, April 24, 2013. Daratumumab for double refractory multiple myeloma; Janssen Research & Development press release, May 1, 2013. Obinutuzumab (GA101) for chronic lymphocytic leukemia; Roche press release, May 16, 2013.

See also from the FDA: www.fda.gov/RegulatoryInformation/Legislation/Federal FoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDA SIA/ucm341027.htm.

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INTERVIEW WITH THE INNOVATORS

Partners HealthCare Center for Personalized Genetic Medicine: Utilizing Genetics and Genomics to Improve Care of Patients An Interview With Scott T. Weiss, MD, MS, and Heidi L. Rehm, PhD

H

arvard Medical School and Partners HealthCare System established the Harvard-Partners Center for Genetics and Genomics (HPCGG) in 2001. The center was launched in recognition of the excitement of the Human Genome Project and as an early commitment to the importance of genetic and genomic knowledge in human health. HPCGG offered a framework for aiding genetic discovery, stimulating research that would lead to the integration of genetic knowledge into patient care, developing an information infrastructure that would facilitate the application of genetic and genomic data in research and clinical settings, applying genetic discoveries and technological advances in the development of molecular diagnostic tests that could be used in

everyday medical practice, and building an education program that would expand the number of clinicians and investigators trained in genetics and genomics.

In late 2008, the name of the center was changed to Partners HealthCare Center for Personalized Genetic Medicine (PCPGM) to reflect a heightened focus on translational issues related to moving genetics and genomics into clinical practice. Previous direct discovery components were moved out of the center and into affiliated academic medical centers. The name change also affirms Partners HealthCare’s emphasis on personalized medicine.

The publisher of Personalized Medicine in Oncology (PMO) had the pleasure of interviewing the Scientific Director of PCPGM, Dr Scott T. Weiss, as well as clinical molecular geneticist, Dr Heidi L. Rehm of PCPGM at the recent meeting of the Personalized Medicine Coalition, where Drs Weiss and Rehm were presenters.

PMO Dr Weiss, as the scientific director of the Partners HealthCare Center for Personalized Genetic Medicine, and Dr Rehm, as a clinical molecular geneticist, how do you define the term “personalized medicine”?

Dr Weiss Personalized medicine is providing the right care for the right patient at the right time. It’s about knowing the patients’ genetic and genomic background and how they’re going to respond to a particular drug. It’s

understanding the particular molecular makeup of their disease and tailoring therapy to that molecular makeup.

Dr Rehm In my mind, personalized medicine is what physicians have always practiced. You take the patient’s symptoms and the information from the tests that you run and then figure out the best plan for the individual.

In a way, the approaches we’ve taken to treat an individual have always been personalized based on the context of the data available. We’re in a different era now because we can add genetics to that.

I sometimes like to talk about personalized genetic medicine, because I think that’s what most people are really talking about – the use of genetics in stratifying populations and deciding what the best treatments are for those individuals.

PMO Harvard Medical School and Partners HealthCare System launched the Harvard-Partners Center for Genetics and Genomics in 2001 in recognition of the excitement for the Human Genome Project and to explore the importance and impact of genetic and genomic

Scott T. Weiss, MD, MS

Heidi L. Rehm, PhD

Scott T. Weiss, MD, MS, is the Scientific Director of Partners HealthCare Center for Personalized Genetic Medicine and Associate Director of the Channing Division of Network Medicine at Brigham and Women’s Hospital.

Heidi L. Rehm, PhD, is Chief Laboratory Director of the Laboratory for Molecular Medicine at PCPGM. She is a board-certified clinical molecular geneticist and Associate Professor of Pathology at Harvard Medical School, with appointments at Brigham and Women’s Hospital, Massachusetts General Hospital, and Boston Children’s Hospital.

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knowledge in health. The center later updated its name to Partners HealthCare Center for Personalized Genetic Medicine to emphasize the ability of genetic information to personalize treatment for patients. We’d like to ask you each to talk about the goals of the center and its impact on personalizing medicine.

Dr Weiss I think that the initial goal of the center was more along the lines of a traditional academic program focused on research. Since I’ve been the director over the past 5 years, the mission has been focused directly on more applied personalized medicine and actually improving personalized medicine for both the patients and the doctors who are part of the Partners HealthCare System. Enhancing research in medical diagnostics, prognostics, and therapeutics is part of the center’s mission.

Partners HealthCare encompasses 2 anchor academic medical centers: Massachusetts General Hospital and Brigham and Women’s Hospital. In addition, we have a large number of affiliated hospitals that extend from Faulkner Hospital in the south, Newton-Wellesley Hospital to the west, to North Shore Medical Center north of Boston.

The approach that the center is taking is really a 3-pronged approach that emphasizes different aspects of the delivery of personalized care to patients. The first is enhancing research across the Partners HealthCare System by a series of core laboratories and providing the huge investigative community of Partners HealthCare with resources in terms of the genomics capability, a large biorepository for samples, and consented samples from Partners’ patients. It’s directly linked to the electronic medical record.

The second piece of the center’s mission is the actual delivery of genetic and genomic tests to patients. We run the largest molecular laboratory across the system focused on providing approximately 5000 genetic tests per year to patients, both at Partners and throughout the world, focused on the germline, whereas the 2 molecular labs within the pathology department are focused on the cancer testing. Our focus is germline content delivery for patients.

The third area is an IT infrastructure that is focused on delivering genetic and genomic content to practitioners. Whether it’s cancer testing that’s been in the molecular pathology labs or germline testing that’s been in our lab, all of it is eventually going to filter and funnel through the GeneInsight suite of software, which will deliver content to practitioners.

It’s really those 3 prongs. An IT infrastructure for personalized medicine, a laboratory to deliver clinical test results and enhancing translational research in genetics and genomics in personalized medicine, which are

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the ways that the center is trying to drive this forward.

Dr Rehm I will add that our goals are about translating both discoveries and new technologies into medical practice in ways that are efficient and effective.

Within the center, one of the things we did early on was to position all of our core facilities that support research in genomics in the same space with our clinical lab so we could very quickly translate the technologies being used in research into clinical tests that could be used in medical practice.

We have really focused on bringing novel discoveries and developing tests that aren’t available elsewhere, and doing that as early and quickly as possible. We bring new technologies to improve existing tests and then work not just to launch them but also to integrate them into care and understand how they are used in the context of medicine.

We have really focused on bringing novel discoveries and developing tests that aren’t available elsewhere, and doing that as early and quickly as possible.

PMO In the advent of personalized medicine and companion diagnostics, biopharmaceutical companies face exciting and evolving scientific opportunities. Please comment on the ways in which your center is working to advance the scientific processes to meet patient needs.

Dr Weiss I’d just like to pick on 2 specific examples in the grant area where the center is working to advance personalized medicine. The first goes back to this issue of curation of the genome.

Part of the problem with the technology as it exists today is that the curation of these variants is not very accurate. We’re discovering tons of variants, and we’ve already looked at a subset of those variants, but we don’t really know what their relationship is to the disease. Is it really a causative variant? Is it something that’s an unknown variant and we really don’t know what it does? Is it noncausal?

Dr Rehm is one of the coprincipal investigators in the community of clinical geneticists across the country who are working to curate the variants more accurately so we can improve the interpretation of what’s going on with whole exome and whole genome sequencing, whether it’s for somatic variation or for germline. That’s one area.

I think the other area that the center is working in relates to another grant that we just got funded from the National Heart, Lung, and Blood Institute to try to improve the translation of genetic and genomic discoveries

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INTERVIEW WITH THE INNOVATORS

and move them into commercialization. In that grant, it’s a collaboration between research ventures and licensing of partners – a medical technology device group called CIMIT [Center for Integration of Medicine and Innovative Technology], Harvard Medical School, Massachusetts General Hospital, and Brigham and Women’s Hospital – all working together with venture capital to take discoveries like our panel test for pulmonary disease and try to figure out a way that we can commercialize these things and move them into the commercial environment in a more rapid fashion.

I think those 2 specific examples both come from grants that the center is involved in. One, better curation of the medical genome and, second, a more rapid path to commercialization for genomic discoveries are 2 of the many ways that the center is working to improve personalized medicine.

One of the challenges that we all face in the era of companion diagnostics is how to pair and appropriately decide on the right drug using these companion diagnostics.

PMO Thank you, Dr Weiss. Dr Rehm, can you speak to how the center is advancing science to meet patient needs?

Dr Rehm This is related to what I was talking about before. One of the dilemmas with companion diagnostics is that in order to decide to use a drug, you need to run a diagnostic. But the problem with the approaches that we want to take in genetics is that we don’t even have enough tumor tissue, for example, to run 25 different companion diagnostic tests to then decide which of the 25 treatments might be appropriate. And it also costs too much money to run them all individually.

I think one of the challenges that we all face in the era of companion diagnostics is how to pair and appropriately decide on the right drug using these companion diagnostics and balance that with large-scale approaches that allow us to accomplish our goal, which is to take a broad view and pick out the needle in the haystack.

This has been an evolving process over the past few years to decide how to logistically go about realizing the benefit of companion diagnostics, but also realizing the practicalities of how we test tumor specimens today.

PMO Yes, tumor sample size is an issue, and the ability to run 1 test to detect many genetic mutations could be of great value. What about heterogeneity of tumors?

Dr Rehm The other thing we’ve always appreciated in cancer is that the tumor evolves over time, and it acquires new mutations. Even if you found the right

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treatment at one point in time, eventually resistance will evolve.

So one of the questions is that if we look at a tumor and we test for just 1 factor, we may be missing a concurrent factor, or the next factor that may be evolving at a low level now but will grow into a prominent role in the tumor’s progression. So by using a multianalyte testing approach, you can pick out not only 1 factor but sometimes multiple factors and thereby predict how that tumor may progress and evolve over time by seeing an early glimpse of the next stage of that tumor. The tools that allow us to take broad views also enable us to possibly predict the multistep progression of tumors.

PMO Are the payers more inclined to reimburse 1 multianalyte diagnostic test?

Dr Rehm It is a delicate balance, and they certainly take the view that they don’t want to pay for more than is clinically indicated.

Now, if I say to them that these 5 different analytes are clinically indicated for this patient, and if I were to run each of them separately, it’s going to cost $1000. On the other hand, I could run them all as 1 test, and it’s going to cost $800. Hopefully they’d be okay with that.

So there’s a balance there. Yes, it’s okay to cast a broader net if you’re not incurring more costs than what is clinically indicated.

PMO So, for example, they have no problem with you testing for ALK in lung cancer or EGFR in lung cancer mutations, but if you want to test for BRAF and there’s no evidence behind that, they’re not going to pay for it?

Dr Rehm That’s exactly right. I think they’re probably going to take different views as to whether you should even be looking at those results. They may say, sure, run the technical platform any way you want, but you should only be looking at what’s clinically relevant versus another group that might be okay with you looking at everything as long as it doesn’t cost more.

PMO Dr Weiss mentioned a strong IT infrastructure at your center to facilitate personalized medicine. Dr Rehm, you’ve conducted research on the use of IT enabling personalized medicine. Can you discuss your findings from that research?

Dr Rehm One of the projects that we’ve worked closely on is a project called RISGIM (refining IT support for genetics in medicine), led by Dr David Bates.

This project centered on launching a genetics application for physicians where we would electronically deliver genetic test reports to the physicians so they can get access in real time to the results of their patients, and also receive updates when new knowledge is learned about their genetic test results, even if they were run years ago.

So every time new knowledge is learned on a variant, the physicians who have a patient with that variant get

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an e-mail alert with a hyperlink into their record: they can then click on that, go into the record, review what the new knowledge is and then decide whether to bring the patient back in and treat him or her differently based on that new knowledge.

The study was really about how this system can enable improved care of these patients. Is it a system that a physician can easily figure out how to use without any training, because physicians don’t want to take a course to learn how to use most medical applications? So it’s about whether we can make a system that’s so easy and straightforward that physicians can just jump on it the day it comes out, figure out how to use it, and make it useful in the clinic.

That was what the study was about, and the outcome of it was, yes, they loved this application. The alerts we sent, they clicked on them 98% of the time and learned that new information, and they found the tool very useful. There were subtle things that they gave us feedback on that we were able to then integrate into updated versions of the software to make it even easier for them to use. That was a really nice study showing that an application we developed was useful and could serve the needs of the physicians. And then we were able to show that the time it took for new knowledge to be given to patients and the physicians was dramatically decreased with the software compared with how we were doing it prior to that software. That software is called Gene­ Insight Clinic.

PMO In your tenure as a geneticist, can you describe the most significant advances that impacted your ability to provide better care for patients?

Dr Rehm Next-generation sequencing in my mind dramatically changed what we can offer patients from a diagnostic standpoint in genetics. With the previous cost of sequencing, we could only offer the most likely genes that might be involved. Because of that the physician could only test these most obvious genes. So when you confirmed that most likely assumption, you didn’t really change how the patients were treated.

When we launched next-generation sequencing, all of a sudden we had the ability to put everything under the sun into a test. That has some downside also, but the upside was that we started making diagnoses that the physicians never thought about and certainly weren’t treating their patients accordingly. For example, 2% of patients with left ventricular hypertrophy, a thickened heart, actually have Fabry disease instead of hypertrophic cardiomyopathy. So when we are able to run a broad test and include the GLA gene that no physician ever ordered, 2% of the patients are positive. That’s the only gene for that disease – and there’s a treatment. They can put them on enzyme replacement therapy.

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This is making a difference in the outcome of these patients. We can take a much broader view of the possible etiologies for a given patient’s disorder and find those things that they possibly hadn’t thought about. That’s certainly also true now with exome and genome approaches, where you can take the broadest of possible approaches to thinking about a question.

PMO Dr Weiss, your research has been predominantly in the field of asthma genetics, asthma pharmacogenomics, COPD [chronic obstructive pulmonary disease] genomics, and predictive medicine. Are there lessons from other specialties in the area of genetics and genomics that impact your research, and can you give an example?

It’s very clear that cancer is leading the translational aspects of personalized medicine, but that doesn’t mean that other complex traits are all that far behind.

Dr Weiss I can tell you that it’s very clear that cancer is leading the translational aspects of personalized medicine, but that doesn’t mean that other complex traits are all that far behind. I want to give a very clear example from my own research about how genetics and genomics are influencing healthcare. It’s a little bit different from cancer, but I think it’s very instructive.

In 1996 I became a professor at Harvard Medical School, and I realized that all of the research that had been done up until that time was really not going to carry me forward in terms of being competitive in the future. I started to work to develop my understanding of genetics and genomics and so by 2000, when the human genome was mapped, I was fully funded to do genetics and genomics research.

One of the grants I received was to fine-map a region on chromosome 12q. Fine-mapping involves using either microsatellite markers in the linked region that are linked to a phenotype and relating those markers to the phenotype, or more fine-mapping would be done with single nucleotide polymorphisms and relating them to the phenotype.

That work identified the vitamin D receptor as a potential asthma gene, and we published the genetic association study that showed this relationship. Another group, Tom Hudson’s group at the Montreal Genome Centre, confirmed it. But there were other genetic association studies that had negative results for this gene.

But then we did an interesting thing. We said, we know that asthma is an early life disease. Let’s look at the

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intake of vitamin D during pregnancy and see what the relationship of that is to asthma and asthma occurrence.

We did 2 studies where we looked at the mother’s intake of vitamin D and showed in both studies that the higher the intake of vitamin D, the less asthma in the offspring. In fact, both of these studies suggested that in the mothers who had the highest intake, we saw about a 50% reduction in asthma. We then wrote a grant to do a clinical trial where we give vitamin D to pregnant women. That trial is now in its fifth year, and we’re following the children up until age 3, and our results will be ready next year.

How will the introduction of companion diagnostics and the discovery of biomarkers in medicine impact clinical trial enrollment and design?

Here’s an example where we went from genetics and genetic association to a clinical trial to a potential preventive for asthma in less than 10 years.

So, do I believe that personalized medicine is going to extend beyond cancer? Absolutely. Is this going to happen for diseases like asthma and COPD? Absolutely. I think the problem is that most of what we’re doing now in personalized medicine is focused on the medical exome. The medical exome encompasses the simplest aspects of molecular biology, really protein coding function.

What we know from genome-wide association studies is that 80% of what we’re finding in those studies in complex traits, diseases like asthma or coronary disease, high blood pressure, preeclampsia, multiple sclerosis, rheumatoid arthritis, you name it, 80% of the variation in those disorders is in the regulatory portion of the genome, the noncoding portion of the genome.

You’ve got 2 different revolutions going on in personalized genetics and genomics. One, where we are right now, which is focused on the exome, and this coming wave that is going to be focused on regulatory variation, and I think that the vitamin D story is a great example of low-hanging fruit. Now there’s the opportunity to go back and look at more of the molecular mechanisms around how the vitamin D is protective. There’s a whole host of reasons for that.

But I think this is an example – if the trial is successful and we can actually prevent a portion of childhood asthma – where genetics and genomics are going to have a big impact in an area that people never thought about.

PMO How will the introduction of companion diag-

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nostics and the discovery of biomarkers in medicine impact clinical trial enrollment and design?

Dr Rehm It’s a great question. I have spoken to one pharmaceutical company about this. On the one hand you can make the argument that if you really could look at not just 1 marker but lots of markers or even the whole exome, you’d be able to do a better job stratifying your population and enhancing the likelihood that your drug works in a specified group.

On the other hand, there’s this added complexity to the questions you’re asking. There is this hesitation, even though the perspective is that the science is better, that it complicates the story so much when you’re going through the FDA approval process for your drug. If you add all the complexity of many targets to the process, it can make it more difficult to get your drug approved.

I think the pharmaceutical companies are struggling with what is the practical right approach, even though scientifically having the world at their hands is certainly the most scientifically valid approach. But just from a practical standpoint to get their drug through the FDA process and have a clean set of data, it is challenging to take these broader approaches. I don’t know what the right answer is.

Dr Weiss I think there are 2 ways that genomic discoveries are going to impact clinical trial design.

One is this whole issue of segmentation, where you’re going to be focusing clinical trials on specific subsets of the population.

I think the second way is actually influencing trial designs. People are going to use more adaptive trial designs in which they’re going to reshuffle and restratify patients on the basis of a genotype or a transcriptome or some other omics stratifier that will actually be built into the trial design.

One is preselection of patients, and the other is actually changing trial design based on these omics diagnostics or prognostics.

PMO Value is more than cost; it is the balance of cost, quality, and access. How long will it take for personalized medicine to begin paying dividends economically, when it already pays dividends clinically, and become attractive to payers by showing value? How would you articulate that value proposition?

Dr Rehm One example is tyrosine kinase inhibitors that had been approved as third-line therapy for patients.

Many patients with lung cancer eventually get to the need for a third-line therapy. So you’re essentially paying for it in a lot of people. On the other hand, if we run EGFR testing, only 20% of them are positive and therefore only 20% of them should be getting that drug, and 20% is a lot cheaper for the insurers than 100%.

So in my mind, by dictating who has the mutation and

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therefore has a reasonable likelihood of response, it’s not only optimizing outcomes for the patients who should get the drug, it’s even more from a value proposition, getting rid of 80% of the costs and not paying for those who aren’t going to respond because they don’t have the mutations.

That’s where the value proposition comes in, and it’s not just about improving quality of care in this arm, it’s about saving healthcare costs on that arm.

Dr Weiss If you look at what has happened over the past 5 years – the rapid increase in diagnostics, prognostics, the increase in the number of companies that are providing these, and the change in the way clinical practices are being performed – I think that it’s a mistake to think that there’s going to be kind of an abrupt time point that’s sort of pregenomics/postgenomics. I would say we’re in the continuum now. I think we’re still in the relatively flat phase of an accelerating curve that’s going to dramatically increase, but as these curation efforts improve, as our ability to translate these discoveries into commercialization improves, I think this is only going to become more and more and more a part of clinical practice.

I think there’s the issue of the value proposition, and in particular third-party payers. I think we can already see that for whole exome sequencing; it’s being adopted by third-party payers because the diagnostic odyssey, in which a small number of tests accumulate for a patient who doesn’t have a diagnosis, may be more costly than simply going directly to whole exome testing and getting the answer. I think it is a clear-cut, sort of simple costeffectiveness example.

We have issues of healthcare in this country, issues that go well beyond personalized medicine. But I think it’s a false dichotomy to set up that third-party payers are going to have to pay for all of this, no questions asked.

We’re going to have to show at every step of the way that these things are not just cost-effective, but that there really is value added to this, and that’s as it should be.

But I think we’re in this revolution now. It’s clearly happening now.

I think that everything we do in medicine has to be justified in some way in terms of showing that it’s costeffective. Let’s go back to the vitamin D example.

If it turns out that we can prevent half of all asthma by giving pregnant women vitamin D – and we know that 70% of all pregnant women in the United States are

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vitamin D deficient – you’re going to have an unbelievable impact. You don’t need to do a fancy cost-effectiveness analysis, because vitamin D costs a couple of dollars, and you can show pretty clearly on the back of an envelope that treating pregnant women with vitamin D to prevent asthma is hugely cost-effective.

I also don’t believe you have to do a randomized control trial of every technology or every novel therapy to show cost-effectiveness. But absolutely, I believe that we should be looking at these aspects of personalized medicine that are the most cost-effective, that are going to give us the greatest potential benefit, and close in on those as being the things that we implement most readily.

We’re going to have to show at every step of the way that these things are not just cost-effective, but that there really is value added to this, and that’s as it should be.

People tend to focus on the biggest things. You know, when will it be that whole genome sequencing will be standard of care? I don’t think that’s necessarily the way that the personalized medicine field ought to be thinking about this. I think we ought to be thinking about this as an incremental improvement and looking continuously at what we’re doing and saying, how do we benefit the patients as a result of these discoveries, and if we do that, I think we’ll see the implementation of a lot of things that have huge potential benefit to patients.

Just based on my own research experience, I think there’s going to be much more of this that’s nondrug related that could be unique in the area of preventive genomics, if you will, where you’re going to see benefits.

Again, that’s one of the reasons I like the vitamin D example, because it’s something that’s not cancer and not tied to a therapeutic, but just an example of something that went from a basic science discovery to a clinical trial in less than 10 years that could have huge public health impact and huge cost savings to society.

PMO Thank you both very much for your time today.

You’re insights are stimulating. We wish you both continued success. u

4TH ANNUAL CONFERENCE

May 8, 2014 Loews Hollywood Hotel • Los Angeles, CA

Michael A. Kolodziej, MD

Grant Lawless, RPh, MD, FACP Program Director Associate Professor University of Southern California

National Medical Director Oncology Solutions Aetna

CO-CHAIR

CO-CHAIR

www.regonline.com/AVBCC2014

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CONTINUING EDUCATION 6th Annual

DECEMBER 2013 • VOLUME 6 • NUMBER 5

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Beyond Complete Responses Publishing Staff Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto

LETTER

FROM THE

EDITOR-IN-CHIEF

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

In this 6th annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this fifth issue, experts from the University of California, San Francisco answer questions related to the management of patients with MM who achieve complete responses.

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

Associate Director, Content Strategy & Development John Welz Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen

FACULTY Jeffrey Wolf, MD Clinical Professor Department of Medicine Director, Myeloma Program University of California, San Francisco San Francisco, CA

Amy Marsala, NP Nurse Practitioner UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA

Rebecca Young, PharmD, BCOP Clinical Pharmacist UCSF Medical Center Assistant Clinical Professor UCSF School of Pharmacy San Francisco, CA

Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Jackie Luma Deanna Martinez

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

IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski

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

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

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

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

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

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

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-026-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss existing and emerging therapeutic options for patients with newly diagnosed or relapsed/refractory MM and how to tailor therapy for individual patients • Describe the pharmacokinetics and pharmacodynamics of nov-

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

Rebecca Young, PharmD, BCOP, has nothing to disclose. She does intend to discuss either non–FDA-approved or investigational use for the following products/devices: investigation of carfilzomib in newly diagnosed MM.

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

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

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

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

Planners’ and Managers’ Disclosures Dana Delibovi, Medical Writer, has nothing to disclose. She does not intend to discuss non–FDA-approved or investigational use for any products/devices.

William J. Wong, MD, MLI Reviewer, has nothing to disclose.

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

Shelly Chun, PharmD, MLI Reviewer, has nothing to disclose.

Faculty Disclosures Sagar Lonial, MD, is on the advisory board for and is a consultant to Bristol-Myers Squibb, Celgene Corporation, Millennium: The Takeda Oncology Company, Novartis, Onyx Pharmaceuticals, and sanofi-aventis. He does not intend to discuss any non–FDAapproved or investigational use of any products/devices.

Jeffrey Wolf, MD, is on the speaker’s bureau for Amgen, Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals. He does intend to discuss either non–FDAapproved or investigational use for the following products/devices: MLN9708 and frontline carfilzomib.

Amy Marsala, NP, has nothing to disclose. She does not intend to discuss non–FDA-approved or investigational use of any products/devices.

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13008E.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

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

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

Estimated time to complete activity: 1.0 hour Date of initial release: December 12, 2013 Valid for CME/CPE/CE credit through: December 12, 2014 SCAN HERE to Download the PDF or Apply for Credit.

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

The Significance of Achieving Complete Response in Multiple Myeloma Jeffrey Wolf, MD

Clinical Professor, Department of Medicine Director, Myeloma Program University of California, San Francisco

Introduction Complete response (CR) is an extremely important goal of therapy for patients with multiple myeloma (MM). In this article, Jeffrey Wolf, MD, discusses recent data and consensus on the role of newer combination regimens in achieving and maintaining this endpoint, as well as the strong association of CR with survival outcomes, and the individualization of therapy for promoting optimal patient outcomes.

Which regimens are showing the greatest promise in terms of CR for newly diagnosed patients with MM? Today, the consensus in academic oncology is that triplet therapies are optimal for induction therapy; this approach is being adopted by more and more community oncologists as well. Commonly used triplet regimens with a robust evidence base in the transplant-eligible population include lenalidomide/bortezomib/dexamethasone (RVD) and cyclophosphamide/bortezomib/dexamethasone (CyBorD).1-3 These regimens provide high rates of very good partial re-

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sponse or better (≥VGPR), including high rates of CR.2,3 In a phase 1/2 study by Richardson and colleagues, the CR/near-complete response (nCR) rate was 57% in newly diagnosed patients treated with RVD, in phase 2 and before proceeding to autologous stem cell transplantation (ASCT).2 In a phase 2 study by Reeder and colleagues, treatment with 4 cycles of CyBorD in newly diagnosed patients led to CR/nCR and VGPR rates of 46% and 71%, respectively.3 Two additional frontline 3-drug regimens are also showing promise, both of which include novel proteasome inhibitors. The first of these is carfilzomib/ lenalidomide/low-dose dexamethasone (CRd). In a phase 1/2 trial by Jakubowiak and colleagues, after a median of 22 cycles and a median follow-up of 25 months (during which only 7 of 53 patients underwent ASCT), 87% of those treated with CRd achieved ≥VGPR, including 64% who achieved CR.4 The second regimen is MLN9708 combined with lenalidomide and dexamethasone.

Richardson and colleagues recently reported early phase 1/2 trial results (after a median of 6 cycles in phase 1 and a single cycle in phase 2), which showed that treatment with this triplet produced ≥VGPR in 9 of 19 patients with newly diagnosed MM.5 Clinicians await more mature data from these studies as well as from randomized, controlled, phase 3 trials enrolling larger cohorts of patients. RVD is under investigation in phase 3 trials designed to compare its efficacy with or without transplant, to determine whether this regimen produces deep enough responses to warrant delay of ASCT to first progression.6,7 Results from these trials will attempt to address the following controversial question: Will regimens that include novel, targeted drugs be effective enough to shift the current paradigm from early transplantation (just after induction) to delayed transplantation (at first relapse)?

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CONTINUING EDUCATION

Figure. 12-year PFS and OS rates by depth of response after induction and ASCT (N=344).13

Table. Association Between Post-ASCT Response and Median EFS and OS (N=632)15 Survival

40 35

35

Patients (%)

30

28 22

OS

19

20

16

16

15 10

11 8

8

5 0

0 CR

nCR

VGPR

PR

SD

0

PD

Differences in median survival between CR versus nCR, CR versus VGPR, and CR versus PR were statistically significant in favor of CR (P≤.01).

ASCT indicates autologous stem cell transplantation; CR, complete response; nCR, near-complete response; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; VGPR, very good partial response.

For the population of patients not eligible for transplant, we are free to use melphalan as part of an induction regimen. Beyond that, there is no longer a marked difference in approach between transplant-eligible and -ineligible patients. The distinction between the groups has been blurred by the increasing use of the same regimens in both settings. However, we now tend to use melphalan less often in older, transplant-ineligible patients. We may tailor regimens a bit when treating elderly patients or those whose performance status renders them too vulnerable for transplant.8 For example, we have used a dose-adjusted regimen of RVD in which lenalidomide is given at 15 mg (instead of at the usual 25-mg dose), bortezomib is given weekly instead of twice weekly, and dexamethasone is reduced from 40 mg to 20 mg.

In frail or otherwise compromised older patients, clinicians in both academic and community settings may elect to use a doublet instead of a triplet regimen.

Lenalidomide plus low-dose dexamethasone is a 2-drug regimen with a strong evidence base in older patients.9 If a patient has a high-risk cytogenetic abnormality, such as translocation 4;14 or deletion 17p,10,11 we tend to use bortezomib plus dexamethasone, as long as there is no special concern regarding bortezomib-induced neurotoxicity.

As our therapies improve and we move closer to making myeloma a curable disease, we must absolutely strive for CR. Should CR always be the goal of antimyeloma therapy, or is ≥VGPR a sufficient goal?

There is no question that the goal of treatment should be CR. Granted, some data have suggested that achievement of ≥VGPR in transplant-eligible patients is a robust indicator of prognosis.12 However, the observation that VGPR is “sufficient” in many patients does not entail that VGPR is a “good enough” goal.

As our therapies improve and we move closer to making myeloma a curable disease, we must absolutely strive for CR. Right now, we have a small number of patients with MM who have achieved CR and are essentially cured. Some of the patients treated at our center who underwent ASCT in the 1990s have not relapsed. We are curing a small population, and we are going to cure more in time. To make this happen, the goal out of the gate must be CR. Major studies supply evidence for the value of CR. A retrospective, multicenter evaluation of 344 patients by Martinez-Lopez and colleagues assessed the long-term prognostic significance of response in MM after transplantation; pa-

l

nCR

PR

nCR vs PR,

nCR vs PR,

(months)

(months)

P value

P value

EFS

61

40

34

<.00001

.07

OS

NR

NR

61

.01

.04

ASCT indicates autologous stem cell transplantation; CR, complete response; EFS, event-free survival; nCR, near-complete response; NR, not reached; OS, overall survival; PR, partial response.

PFS

25

10

26

CR (months)

parameter

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tients were treated between 1989 and 1999.13 Both overall survival (OS) and progression-free survival were significantly prolonged in patients who attained CR after transplantation compared with those who attained nCR, VGPR, and partial response (PR). At 12 years of follow-up, the percentage of patients who survived was highest among the group that achieved CR (Figure).13 After 17 years, OS plateaued in all groups, but at a three-fold higher rate in patients who attained CR posttransplant versus those who achieved nCR/VGPR/PR at ASCT (35% vs 11%, respectively).

Similar results were observed in an analysis of data from the prospective Grupo Español de Mieloma 2000 trial.14 In patients who achieved CR after ASCT, both event-free survival (EFS) and OS were significantly longer than in patients achieving nCR. The nCR group, in turn, had significantly longer OS (but not EFS) than those who achieved only PR (Table).14 In this trial, posttransplantation response was markedly influenced by pretransplantation response, underscoring the importance of aiming for CR from the start of treatment.

Data from important trials of antimyeloma therapy—VISTA; Total Therapy 2, 3, and 5; and an older trial evaluating vincristine/doxorubicin/dexamethasone—showed a directly proportional relationship between CR and survival.15-18 For instance, in the phase 3 VISTA trial, which compared bortezomib/melphalan/prednisone versus melphalan plus prednisone alone in a nontransplant population, attaining CR was associated with a significantly longer time to progression and OS.15 These findings support the strategy of continuing therapy in transplant-ineligible patients until CR. Although there will always be concern regarding the tolerability of drug treatment, on the whole, current regimens are fairly tolerable. Specifically, we now have oral immunomodulators and can administer bortezomib by subcutaneous (SC) injection, which reduces the risk of peripheral neuropathy.19 The SC route is quickly becoming the standard of care in terms of bortezomib administration. We can also offer patients improved supportive care. Taken together, all of these factors enable us to offer highly effective therapies for longer periods of time.

Does a patient’s age have an impact on how aggressively you strive for CR? Achieving CR is especially important in younger patients with MM. If we fail to produce a cure or a very long remission in these individuals, they will die of the disease well before their time. Young patients in nCR, VGPR, or PR after several induction cycles are the ones we generally take to ASCT sooner rather than later. We feel that they need to be consolidated to try to get them to CR. In some cases, we may also switch the induction regimen (eg, from CyBorD to RVD or vice versa), add a drug to a doublet regimen, or use other strategies to improve reponse. The point is that we make every effort to produce CR, working to support patients through any toxicities associated with more aggressive treatments.

In many older patients, CR should also be the goal. The reality for this age group, however, is that frailty, comorbidities, and lower performance status may make it more difficult to push as hard.8 These patients may not tolerate the treatments or doses often required to attain CR. Sometimes, we must accept the fact that VGPR is the most that can be achieved without risking quality of life and severe cytopenias or infections.

We also must remember that every patient, regardless of age, is unique and complex. A few patients achieve CR and never need treatment again. Others achieve CR and sustain it with single-agent maintenance therapy. Still others, typically with high-risk cytogenetics, may achieve CR, but the remission is short-lived; these patients require skillful selection of second-line and salvage therapies to keep new clones from growing out and causing progression.

Continued on Continued on page page31 8

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CONSIDERATIONS IN MULTIPLE MYELOMA

Nursing Strategies for Improved Outcomes in Multiple Myeloma Amy Marsala, NP

Nurse Practitioner UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA

Introduction Although the benefits seen with newer multidrug regimens have significantly improved clinical outcomes, patients with multiple myeloma (MM) are often challenged by the development of adverse events (AEs) that may impact quality of life (QoL) and lead to delays or discontinuation of treatment. In this article, Amy Marsala, NP, discusses nursing strategies for preventing and managing these events in the era of novel agents, and how consideration of patient-related factors contributes to effective individualized care.

How do patient preferences and limitations affect the choice of agents or regimens used in the treatment of MM? Multiple factors can influence treatment selection for patients with MM. Two of the most important factors are high-risk cytogenetics and prior response to treatment, including length of progression-free survival, how well therapy was tolerated, and whether the patient is still experiencing lingering toxicites.1,2 From a patient perspective, choice of treatment may also be influenced by mode of administration and toxicity profiles of various therapies and the type of maintenance follow-up that is required.2,3 In patients who are older or who have complex comorbidities, treatment tolerability is often an issue. For such individuals, dosing and schedule adjustments may be necessary to reduce the likelihood of exacerbating existing conditions such as peripheral neuropathy (PN), myelosuppression, or thromboembolic complications.3 For many of our patients, travel time to the clinic, access to transportation, and degree of caregiver dependence may impact medication adherence and influence treatment decisions. Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, as well as alkylating agents, such as melphalan and cyclophosphamide, have the advantage of being administered orally. In the outpatient setting, oral regimens offer greater convenience and consequently reduce certain barriers to adherence compared with regimens requiring attendance at the clinic for injections or infusions. Both lenalidomide and pomalidomide are typically dosed once daily on days 1 to 21 of repeated 28-day cycles.4,5 Melphalan and cyclophosphamide can be dosed weekly, which reduces daily pill burden.6,7 While daily dosing of agents can also lead to compliance issues, especially if complicated medication schedules or high pill burdens are involved, most patients still prefer oral administration over more invasive and lengthy intravenous (IV) administration.

The first-in-class proteasome inhibitor bortezomib is available as either an IV infusion or a subcutaneous (SC) injection.8 SC bortezomib has become the preferred route at our center and requires less maintenance than IV bortezomib or the next-generation proteasome inhibitor, carfilzomib, which is typically administered as an IV infusion on 2 consecutive days for 3 weeks of a 4-week schedule.8,9 While total time of carfilzomib infusion is 2 to 10 minutes,9 medication preparation involving vein access and pre- and post-hydration results in a longer amount of chair time than IV bortezomib. The extra time and energy needed for IV treatments may be a deterrent for some patients, especially those who have remained in the workforce, are caring for young children, or must rely heavily on caregivers for transportation and support.

Treatment-related toxicities impact the frequency and duration of clinical follow-up. Complete blood counts and chemistry panels are routinely drawn

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once weekly for patients receiving SC or IV medications, and less frequently for those receiving oral therapies.10 For patients with more aggressive MM or those with therapy-related hemodynamic instability, additional follow-up, including laboratory tests and possible blood or platelet transfusions, are often required if dose adjustments cannot be made without compromising disease control.10 Patients with relapsed/refractory MM are typically treated with combination regimens that include IMiDs, proteasome inhibitors, and/or alkylators plus dexamethasone.3 In this setting, the potential for cumulative toxicities must take precedence over patient preferences related to time commitments and routes of administration. To the best of their ability, clinicians should balance their efforts to minimize toxicities that are particularly distressing or which compromise QoL with maintaining control of the disease.

How can chemotherapy-induced nausea and vomiting (CINV) be managed in patients receiving combination therapy?

In the outpatient setting, the routine use of antiemetics has been reasonably effective in the management of CINV. Fortunately, novel antimyeloma agents are typically associated with lower rates of nausea and vomiting than older chemotherapeutic drugs used several decades ago. For example, bortezomib and lenalidomide are classified as having minimal emetogenic potential (<10% of patients experience emesis when antiemetics are not given).11 In fact, a recent cross-sectional cohort study reported that patients who had been treated for the previous 12 months with bortezomib, lenalidomide, and lower-dose alkylating agents reported symptoms of CINV as the least of all therapy-related toxicities.2 Similarly, carfilzomib and pomalidomide have demonstrated low to minimal emetogenic risk, especially when administered with dexamethasone.5,9 Some patients may be at increased risk for experiencing CINV. Female patients, those of younger age (<50 years), patients who are low regular alcohol users (<1 ounce per day), and those with a history of prior CINV all have elevated risk.11 Management of CINV should be approached similarly to management of pain, with an emphasis on prevention prior to onset of symptoms.10,11 It is important for clinicians to be mindful not only of acute CINV, which occurs 0 to 24 hours postchemotherapy, but delayed and breakthrough CINV as well, which may occur several days after chemotherapy, necessitating further antiemetic intervention.11 In accordance with antiemesis guidelines from the National Comprehensive Cancer Network, patients receiving chemotherapy with low risk of emetogenic potential should be treated prior to therapy with 1 or more antiemetic agents (Table).12 For patients who are at higher risk for CINV, 2 agents can be used. The concomitant use of dexamethasone to treat MM has also been effective as prophylaxis and treatment of nausea, although steroid use has its own toxicity profile that requires additional considerations.10 For patients with recurrent or unremitting CINV, or for patients receiving high-dose myeloablative therapies, including cy-

Table. Antiemetics for Patients Receiving IV Chemotherapy with Low Emetogenic Potential12 Metoclopramide 10-40 mg PO or IV (and then either every 4 or 6 hours as needed) or Dexamethasone 12 mg PO or IV daily or Prochlorperazine 10 mg PO or IV (and then every 6 hours as needed [maximum 40 mg/day]) Âą lorazepam, 0.5-2 mg PO or IV every 4 or 6 hours as needed Âą H2 blocker or proton pump inhibitor IV indicates intravenous; PO, by mouth.

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Figure. Treatable contributing factors for cancer-related fatigue.14 Activity level

Malnutrition

Sleep disorders

Pain

Cancer-related fatigue

Emotional distress

• Depression • Anxiety

Noncancer comorbidities

• Endocrine dysfunction (hypothyroidism) • Infection • Cardiac dysfunction • Pulmonary dysfunction • Renal dysfunction • Hepatic dysfunction • Neurologic dysfunction

Anemia

Reprinted with permission.

clophosphamide >1500 mg or IV melphalan 200 mg/m2 while undergoing transplantation, more potent medications may be necessary. Palonosetron, a nextgeneration serotonin subtype-3 receptor antagonist, aprepitant, a neurokinin-1 receptor antagonist, and olanzapine, an antipsychotic, can be given prophylactically and during treatment, but may require more complex management.12 Clinical implications of CINV include an increased risk for malnutrition, dehydration (and subsequent electrolyte imbalances), and weakness, which can ultimately affect organ function.13 The social health impact of chronic CINV hinders patient participation in social and public events, decreases energy and mood, and may worsen overall performance status. Patients should be assessed during every follow-up visit for the presence and severity of CINV and its interference with QoL. They should be encouraged to eat foods that offer the greatest appeal and to prepare smaller, more frequent meals or snacks to minimize weight loss. Treatment of underlying gastrointestinal disturbances, such as gastrointestinal reflux, abdominal bloating and cramping, or bowel movement irregularities is also important. In addition, adjusting the dose of current antiemetics, switching to antiemetics of a different class, and adding additional therapies are viable approaches to ameliorate symptoms.

What can be done to address chronic fatigue?

Chronic fatigue continues to pose a great challenge for most patients undergoing active antimyeloma therapy.14 The multifactorial and complex nature of fatigue demands comprehensive management of chronic anemia and pain, physical deconditioning, emotional stress, depression, and sleep disturbances.15 Nurses play a critical role in screening patients to identify modifiable causes of fatigue and implementing interventions to improve health outcomes (Figure).14 Chronic fatigue is often compounded by chronic anemia, which can be secondary to therapy or may be due to the disease itself or comorbid conditions.

Treatment-induced myelosuppression may require dose adjustments or even discontinuation of therapy if anemia is severe (hemoglobin <8 g/dL).16 Cautionary supplemental use of injectable erythropoiesis-stimulating agents, such as epoetin alfa weekly or darbepoetin alfa weekly or every 3 weeks, has been recommended for those with chemotherapy-related severe anemia, with the goal of raising hemoglobin to 10 mg/dL.16 For anemia and/or fatigue related to iron deficiency or general malnutrition, counseling patients on diet modifications may also improve overall energy.

Another cause of fatigue is the likelihood for decreased activity due to chron-

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ic pain in patients with myeloma-related bone disease. Approximately 85% of patients with MM have or will develop lytic bone lesions or fractures, which inhibit daily activities and decrease functional status.2,17 Therefore, effective pain management through adequate disease control and the use of pain medications prescribed at the lowest effective doses is imperative. Procedural kyphoplasty for eligible patients and adjunctive use of bisphosphonates to manage bone pain and prevent new fracture and lesions are also recommended.17 Localized radiation therapy may also be implemented to palliate specific bone sites and soft tissue pains with the goal of alleviating pain and enabling increased physical activity.17 Fatigue is also compounded by generalized muscle atrophy and physical deconditioning, which occurs in approximately 50% of patients during active treatment.15 Considerable research has demonstrated that patients who participate in low to moderate physical activities on a routine basis of 3 to 4 times per week can decrease their overall fatigue as well as improve their sleep quality, mood, and functional status.15 Coordinating care with cancer exercise specialists or assisting patients to create modified exercise programs and resistance activities should be explored. Engaging in as much physical activity as patients can comfortably tolerate is critical to enhancing energy and improving QoL. In our clinic, we routinely monitor patients for their ability and motivation to be active and make recommendations accordingly.

Facilitating periodic discussions with patients about their mood and perception of functional status as it corresponds with the ability to enjoy life should be practiced. Antidepressants such as paroxetine, bupropion, or fluoxetine can be given to augment mood, although for some patients these agents may increase sedation and alter sleep patterns.14 Research on the use of psycho-stimulants including methylphenidate and modafinil are inconclusive, but these agents have been shown to provide enhanced mood and energy for select patients, although they may cause other undesirable AEs.14 Medications such as lorazepam or clonazepam may reduce anxiety and promote sleep; these agents may also alleviate CINV.12 We also encourage patients to seek out formal support groups, spiritual resources, pet therapy, and the help of family and friends as valuable resources during and after treatment. ♦ References

1. Munshi NC, Anderson KC, Bergsagel L, et al; on behalf of the International Myeloma

Workshop Consensus Panel 2. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood.

2011;117:4696-4700.

2. Jordan K, Proskorovsky I, Lewis P, et al. Effect of general symptom level, specific adverse events, treatment patterns, and patient characteristics on health-related quality of life in patients with multiple myeloma: results of a European, multicenter cohort study. Support Care Cancer. 2013 Oct 13. [Epub ahead of print].

3. Castelli R, Gualtierotti R, Orofino N, et al. Current and emerging treatment options for patients with relapsed myeloma. Clinical Medicine Insights: Oncology. 2013;7:209-219.

4. Revlimid [package insert]. Summit, NJ: Celgene Corporation. November 2013.

5. Pomalyst [package insert]. Summit, NJ: Celgene Corporation. February 2013.

6. Alkeran Tablet [package insert]. Rockville, MD: ApoPharma USA, Inc. June 2011.

7. Cytoxan Tablets [package insert]. Princeton, NJ: Bristol-Myers Squibb. September 2005.

8. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc. 2012.

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

10. Polovich M, Whitford JM, Olsen M (eds). Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, PA: Oncology Nursing Society, 2009.

11. Navari RM. Management of chemotherapy-induced nausea and vomiting: focus on newer agents and new uses for older agents. Drugs. 2013;73:249-262.

12. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Antiemesis. Version 1.2013. http://www.nccn.org/ professionals/physician_gls/PDF/antiemesis.pdf. Accessed November 25, 2013.

13. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358:2482-2494.

14. Carroll JK, Kohli S, Mustian KM, et al. Pharmacologic treatment of cancer-related fatigue.

Oncologist. 2007;12(suppl 1):43-51.

15. Coleman EA, Goodwin JA, Coon SK, et al. Fatigue, sleep, pain, mood and performance status in patients with multiple myeloma. Cancer Nurs. 2011;34:219-227.

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

17. Terpos E, Moulopoulos LA, Dimopoulos MA. Advances in imaging and the management of myeloma bone disease. J Clin Oncol. 2011;29:1907-1915.

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CONSIDERATIONS IN MULTIPLE MYELOMA

Pharmacologic Perspectives on Novel Therapies in Multiple Myeloma Rebecca Young, PharmD, BCOP

Clinical Pharmacist, UCSF Medical Center Assistant Clinical Professor, UCSF School of Pharmacy San Francisco, CA

Introduction The development and approval of more effective drugs have led to better complete response (CR) rates and prolonged survival in multiple myeloma (MM). When choosing among these novel therapies, it is essential to consider factors such as pharmacologic profiles and dosing requirements to promote individualized care. In this article, Rebecca Young, PharmD, BCOP, discusses recent advances in the management of myeloma, including novel agents being incorporated into combination regimens and the role of bisphosphonates for improving patient outcomes.

How are newer frontline regimens improving outcomes in patients with MM? Survival of patients with MM has dramatically improved in recent years, as initial treatment has shifted from conventional chemotherapy to incorporation of novel therapies such as immunomodulatory drugs (IMiDs) and proteasome inhibitors. Thalidomide was the first novel IMiD to demonstrate clinical benefit in MM. A phase 3 randomized trial demonstrated significantly higher response rates in newly diagnosed patients who received thalidomide plus dexamethasone, compared with dexamethasone alone (63% vs 41%, respectively; P=.0017).1 Lenalidomide, a potent analogue of thalidomide with an improved toxicity profile—including lower rates of neurotoxicity—exerts a unique dual mechanism of action comprising both tumoricidal and immunomodulatory effects.2 Lenalidomide plus low-dose dexamethasone (Rd) has been associated with improved short-term overall survival (OS) with less toxicity compared with the historical standard of lenalidomide plus high-dose dexamethasone (RD). Newly diagnosed patients with MM were studied in an open-label noninferiority trial of lenalidomide 25 mg on days 1 to 21, plus either high-dose dexamethasone (40 mg on days 1-4, 9-12, and 17-20), or low-dose dexamethasone (40 mg on days 1, 8, 15, and 22). Interim analysis at 1 year showed that OS was higher with Rd than with RD (96% vs 87%; P=.0002). Low-dose dexamethasone was also better tolerated than high-dose dexamethasone, with less incidence of grade 3/4 toxicities within the first 4 months of treatment (35% vs 52%, respectively; P=.0001).3 Bortezomib, the first-in-class reversible proteasome inhibitor, has also transformed outcomes for patients with MM. Bortezomib-based therapy has been shown to improve survival in patients with translocation 4;14, a high-risk cytogenetic feature that typically confers poorer prognosis.4 Combination therapy with melphalan and prednisone plus either thalidomide or bortezomib has been shown to be effective in patients not eligible for transplant, producing significantly improved CR rates, time to progression, and OS.5,6 In the phase 3 randomized IFM 2005-01 trial, the combination of bortezomib plus dexamethasone (VD) demonstrated significantly higher rates of postinduction CR/near-complete response (nCR) (14.8% vs 6.4%), very good partial response ([VGPR] 37.7% vs 15.1%), and overall response rate ([ORR] 78.5% vs 62.8%) compared with vincristine/doxorubicin/dexamethasone (VAD) in transplant-eligible patients with MM. After a median follow-up of 32.2 months, progression-free survival (PFS) was slightly higher, though not statistically significant, with the VD regimen compared with the VAD regimen (36 months vs 29.7 months; P=.064).7 In a phase 2 clinical trial, cyclophosphamide/bortezomib/dexamethasone

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(CyBorD) as frontline therapy in 33 newly diagnosed patients with MM produced an ORR of 88% by intention-to-treat analysis. Patients received oral cyclophosphamide 300 mg/m2 (days 1, 8, 15, and 22), intravenous (IV) bortezomib 1.3 mg/m2 (twice weekly; days 1, 4, 8, and 11), and oral dexamethasone 40 mg (days 1-4, 9-12, and 17-20) every 28 days for 4 cycles. For those completing all 4 cycles of treatment (n=28), the ORR was 98% (including 71% in ≥VGPR and 46% CR/nCR).8 Despite the high response rates noted above, the investigators modified the treatment schedule for an additional 30 patients in an effort to decrease toxicity and treatment delays. Additional patients received the same weekly dose of cyclophosphamide, but were given once-weekly bortezomib 1.5 mg/m2 (days 1, 8, 15, and 22), and weekly dexamethasone in cycles 3 and 4.

Although patients who received twice-weekly bortezomib had higher baseline advanced-stage disease, weekly bortezomib produced similar responses with less grade 3/4 toxicity. Fewer dose reductions of bortezomib and dexamethasone were required with once-weekly bortezomib, and rates of peripheral neuropathy (PN) were the same despite higher total bortezomib dose per cycle in the once-weekly versus the twice-weekly schedule (6.0 mg/m2 vs 5.2 mg/m2).9 A phase 1/2, multicenter trial by Richardson and colleagues was the first prospective study of lenalidomide/bortezomib/dexamethasone as treatment for patients with newly diagnosed MM (N=66).10 The phase 2 study portion established a maximum planned treatment dose of lenalidomide 25 mg (days 1-14), bortezomib 1.3 mg/m2 (days 1, 4, 8, and 11), and dexamethasone 20 mg (days 1, 2, 4, 5, 8, 9, 11, and 12) given every 3 weeks. In the phase 2 population, the partial response rate was 100%, with 74% of patients achieving ≥VGPR. Primary toxicities included PN (80%) and fatigue (64%), with only 27%/2% and 32%/3% grade 2/3. No treatment-related mortality was observed.

What do pharmacists need to know about carfilzomib and pomalidomide?

Carfilzomib, a next-generation epoxyketone-based proteasome inhibitor, is approved by the US Food and Drug Administration (FDA) for the treatment of patients with MM who have received at least 2 prior therapies, including bortezomib and an IMiD, and have demonstrated disease progression on or within 60 days of the completion of their last therapy.11 Two advantages that carfilzomib has over bortezomib are its ability to provide a more durable, irreversible inhibition of the proteasome, and its association with a lower incidence of PN. These characteristics and others are highlighted in the comparison of bortezomib and carfilzomib found in Table 1.12,13 Initial dose of carfilzomib is 20 mg/m2 on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) of a 28-day cycle. The dose should be increased on cycle 2 and subsequent cycles to 27 mg/m2.12 Doses should be capped at a body surface area of 2.2 m2. Higher doses and alternative infusion strategies are currently under investigation. Carfilzomib is a substrate of P-glycoprotein, and weakly inhibits cytochrome (CYP) 3A4 and P-glycoprotein.12,13 Carfilzomib received accelerated approval by the FDA in July 2012 based on Table 1. Comparison of Proteasome Inhibitors Approved for MM12,13 Chemical structure Inhibition type Administration route Cytochrome metabolism Half-life (minutes)

Bortezomib

Carfilzomib

Boronic acid

Epoxyketone

Reversible

Irreversible

IV/SC

IV

3A4, 2C19

Minimal

110

<30

IV indicates intravenous; MM, multiple myeloma; SC, subcutaneous.

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Table 2. Recommended Dosing of Bisphosphonates for Prevention of SREs27,28 Clearance Creatinine

Zoledronic Acid

Pamidronate

(mL/min)

(mg)a

(mg)

>60

4

90

50-60

3.5

IV over at least 2 hours

40-49

3.3

30-39

3

<30

Avoid use

30-90b IV over 4-6 hours

a

All doses infused IV over 15 minutes. b In absence of formal guidelines, clinicians may consider reduced doses given over an extended interval of 4-6 hours based on individual patient risk assessment.

IV indicates intravenous; SREs, skeletal-related events.

results of a phase 2, open-label, single-arm trial that enrolled 266 heavily pretreated patients (≥2 prior therapies) with relapsed and/or refractory MM. Among the efficacy population (n=257), median duration of treatment was 3 months, and ORR was 23.7%.11,14 The efficacy of carfilzomib in frontline regimens for newly diagnosed patients with MM is the focus of ongoing investigation. Carfilzomib in combination with lenalidomide and dexamethasone as initial therapy has been evaluated in 2 phase 1/2 single-arm trials.15,16 Results from these studies have led to this combination being listed as a category 2A treatment option in the National Comprehensive Cancer Network guidelines for myeloma.17 Similar to bortezomib, no significant changes in pharmacokinetics in renally impaired patients have been observed with carfilzomib.14-16 In patients with high tumor burden, clinicians should monitor for signs/symptoms of tumor lysis syndrome. Prehydration with a minimum of 250 to 500 mL during cycle 1 of carfilzomib is recommended, and should be continued on subsequent cycles if necessary. Infusion reactions may occur immediately or within 24 hours of carfilzomib administration. Premedication with dexamethasone 4 mg to reduce the incidence and severity of infusion reactions is recommended during cycle 1, during escalation cycles, and as needed with subsequent cycles. Bone marrow suppression, especially thrombocytopenia, is a toxicity frequently observed with carfilzomib use. Other rare, but serious toxicities associated with this agent include cardiovascular complications (development or worsening of congestive heart failure, pulmonary edema, decreased left ventricular ejection fraction), pulmonary complications, and hepatotoxicity.18

Currently, it is unclear if patients will continue to benefit from bisphosphonate therapy after they achieve a CR. Pomalidomide, a next-generation oral immunomodulatory agent, is also approved by the FDA for the treatment of patients who have received at least 2 prior therapies, including bortezomib and an IMiD, and who have demonstrated disease progression on or within 60 days of therapy completion.19 In general, IMiDs suppress production of various cytokines that support tumor cell growth, alter bone marrow microenvironment, as well as inhibit angiogenesis. Pomalidomide is 10fold more potent than lenalidomide and up to 15,000 times more potent than thalidomide in inhibiting tumor necrosis factor-α.20 The recommended starting dose of pomalidomide is 4 mg once daily orally on days 1 to 21 of repeated 28-day cycles until disease progression.21 This agent is primarily metabolized by CYP3A4 and CYP1A2, and is a substrate for P-glycoprotein. Pomalidomide and its metabolites are excreted renally.21 Use of this agent should be avoided in patients with serum creatinine >3 mg/dL due to lack of safety data.

A multicenter, randomized, open-label, phase 3 trial compared the efficacy and safety of pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone in patients with MM who were refractory to both lenalidomide and bortezomib (N=455).22 At interim analysis (median follow-up, 4.2 months), PFS was significantly longer in patients who received pomalidomide and low-dose dexamethasone (3.6 months vs 1.9 months; P<.0001) compared

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with high-dose dexamethasone. Regimens containing pomalidomide and carfilzomib are promising. For example, interim results of a phase 1/2 trial evaluating a combination of carfilzomib/pomalidomide/low-dose dexamethasone in 32 heavily pretreated patients with relapsed and/or refractory MM suggest that this regimen is well tolerated with high response rates, even in patients with poorrisk cytogenetics such as deletion 17p.23 Pomalidomide is associated with a relatively low risk of PN compared with other IMiDs.13 Common grade 3/4 toxicities associated with the use of this agent include myelosuppression, fatigue, and infections.21 Pomalidomide should be administered on an empty stomach, and is only available through the Celgene Risk Evaluation and Mitigation Strategy program to prevent its administration during pregnancy, due to the risk of embryo-fetal toxicity. As with other IMiDs, the risk of thromboembolism is increased with administration of pomalidomide, requiring the need for thromboprophylaxis.21 What is the role of bisphosphonates in managing myeloma-related bone disease?

Osteolytic bone disease, a common complication of myeloma, affects approximately 85% of patients at diagnosis.17 Bisphosphonates exert their effects by inhibiting osteoclast recruitment and maturation, and inducing osteoclast apoptosis. IV zoledronic acid and pamidronate, as well as oral clodronate (available outside of the United States) are the only agents approved for the treatment of myeloma-related bone disease.17 All patients with myeloma-related bone lesions at the time of diagnosis should be started on bisphosphonate therapy, repeated every 3 to 4 weeks, concurrently with induction chemotherapy. Use of bisphosphonates in asymptomatic (smoldering) or stage I disease is debatable. A recent Cochrane meta-analysis of 20 randomized controlled trials concluded that adding bisphosphonates to the treatment of MM reduced vertebral fractures and pain; the duration of therapy was typically 2 years.24 Subset data for patients receiving zoledronic acid for longer than 2 years demonstrated a continued reduction in skeletal-related events (SREs) and prolonged OS. Currently, it is unclear if patients will continue to benefit from bisphosphonate therapy after they achieve a CR. Use beyond 2 years is dependent on the patient’s response to therapy, as well as the physician's discretion. If bisphosphonate therapy is stopped after 2 years, it should be resumed at disease progression.25 Whether zoledronic acid is superior to pamidronate in preventing myeloma-related bone disease remains to be determined. The Cochrane meta-analysis reported that zoledronic acid is the only bisphosphonate to demonstrate superior OS compared with placebo in a randomized study.24 In a randomized, doubleblind, multicenter trial, zoledronic acid was found to be as effective as pamidronate in reducing pain, incidence of SREs, and delaying time to first SRE.26 Overall, zoledronic acid and pamidronate are equally well tolerated.27,28 Possible toxicities include bone pain, gastrointestinal disturbances, fatigue, fever, renal impairment, and hypocalcemia. Providers should monitor for renal dysfunction, and adjust doses appropriately. Standard and recommended dose adjustments are shown in Table 2.27,28 Osteonecrosis of the jaw (ONJ) is a rare but serious complication associated with prolonged bisphosphonate therapy.

This event occurs more often with zoledronic acid than with pamidronate therapy.29 Preventive measures such as completing dental work-up prior to the start of bisphosphonates, waiting 6 to 8 weeks after invasive dental procedures prior to starting bisphosphonates, and maintaining good oral hygiene have been shown to decrease the incidence of ONJ.30 ♦ References

1. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24:431-436.

2. Dimopoulos MA, Terpos E. Lenalidomide: an update on evidence from clinical trials. Blood Rev. 2010;24(suppl 1):S21-S26).

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

4. Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010;28:4630-4634.

5. Kapoor P, Rajkumar SV, Dispenzieri A, et al. Melphalana and prednisone versus melphalan, prednisone and thalidomide for elderly and/or transplant ineligible patients with multiple myeloma: a meta-analysis. Leukemia. 2011;25:689-696.

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6. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol.

2010;28:2259-2266.

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

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

9. Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115:3416-3417.

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

11. US Food and Drug Administration. Announcements. FDA approves Kyprolis for some patients with multiple myeloma. July 20, 2012. www.fda.gov/newsevents/newsroom/pressannouncements/ucm312920.htm. Accessed December 1, 2013.

12. Jain S, Diefenbach C, Zain J, et al. Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma. Core Evid. 2011;6:43-57.

13. El-Amm J, Tabbara IA. Emerging therapies in multiple myeloma. Am J Clin Oncol. 2013 Aug 7. [Epub ahead of print].

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

15. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma.

Blood. 2012;120:1801-1809.

16. Korde N, Zingone A, Kwok M, et al. Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexamethasone (CRd) in newly diagnosed multiple myeloma (MM) patients. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 732.

17. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in

Oncology (NCCN Guidelines®). Multiple Myeloma, V2. 2014. www.nccn.org. Accessed November 24, 2013.

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

19. US Food and Drug Administration. Announcements. FDA approves Pomalyst for advanced multiple myeloma. February 8, 2013. www.fda.gov/newsevents/newsroom/pressannouncements/ ucm338895.htm. Accessed December 5, 2013.

20. Corral LG, Haslett PA, Muller GW, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha.

J Immunol. 1999;163:380-386.

21. Pomalyst [package insert]. Summit, NJ: Celgene Corporation. February 2013.

22. Dimopoulos MA, Lacy MQ, Moreau P, et al. Pomalidomide in combination with low-dose dexamethasone: demonstrates a significant progression free survival and overall survival advantage, in relapsed/refractory MM: a phase 3, multicenter, randomized, open-label study. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 6.

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

24. Mhaskar R, Redzepovic J, Wheatley K, et al. Bisphosphonates in multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev. 2012;5:CD003188.

25. Terpos E, Roodman GD, Dimopoulos MA. Optimal use of bisphosphonates in patients with multiple myeloma. Blood. 2013;121:3325-3328.

26. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer. 2003; 98:1735-1744.

27. Aredia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp. May 2012.

28. Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp. September 2013.

29. Zervas K, Verrou E, Teleioudis Z, et al. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients. Br J Haematol. 2006;134:620-623.

30. Dimopoulos MA, Kastritis E, Bamia C, et al. Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventative measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol. 2009;20:117-120.

The Significance of Achieving Complete Response in Multiple Myeloma

Continued from Continued frompage page263

Newer technologies, notably genomic sequencing and testing after CR for minimal residual disease, hold the promise of enhancing our predictions of each patient’s clinical course. These technologies may also improve our ability to choose drugs and to determine when maintenance is warranted. The result will be greater personalization of care and a better chance at CR for more patients with MM. ♦ References

1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. Version 2.2013. http://www.nccn.org. Accessed June 2, 2013.

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

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

4. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up. J Clin Oncol (ASCO Annual Meeting Abstracts).

2013;31(15 suppl):Abstract 8543.

5. Richardson PGG, Berdeja JG, Niesvizky R, et al. Oral weekly MLN9708, an investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): a phase I/II study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(15 suppl):Abstract 8033.

6. Randomized trial of lenalidomide, bortezomib, dexamethasone vs high-dose treatment with SCT in MM patients up to age 65 (DFCI 10-106). NCT01208662. http://www.clinicaltrials. gov/ct2/show/NCT01208662?term=RVD&rank=9. Accessed November 22, 2013.

7. Study comparing conventional dose combination RVD to high-dose treatment with ASCT in the initial myeloma up to 65 years (IFM/DFCI2009). NCT01191060. http://www.clinicaltrials. gov/ct2/show/NCT01191060?term=RVD&rank=2. Accessed November 22, 2013.

8. Palumbo A, Bringhen S, Ludwig H, et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood. 2011; 118:4519-4529.

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

10. Cavo M, Tacchetti P, Patriarca F, et al; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085.

11. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119:940-948.

12. Harousseau J-L, Avet-Loiseau H, Attal M, et al. Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol. 2009; 27:5720-5726.

13. Martinez-Lopez J, Blade J, Mateos M-V, et al. Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood. 2011;118:529-534.

14. Laheurta JJ, Mateos MV, Martinez-López J, et al. Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: sequential improvement of response and achievement of complete response are associated with longer survival. J Clin Oncol. 2008; 26:5775-5782.

15. Harousseau J-L, Palumbo A, Richardson P, et al. Superior outcomes associated with complete response: analysis of the phase III VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone. Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 2778.

16. Barlogie B, Anaissie E, Haessler J, et al. Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma. Cancer. 2008;113: 355-359.

17. Usmani SZ, Waheed S, Van Rhee F, et al. Total Therapy 5 (TT5) for newly diagnosed highrisk multiple myeloma (HRMM): comparison with predecessor trials Total Therapy 3a and 3b (TT3 a/b). J Clin Oncol (ASCO Annual Meeting Abstracts). 2013;31(15 suppl):Abstract 8539.

18. Alexanian R, Weber D, Giralt S, et al. Impact of complete remission with intensive therapy in patients with responsive multiple myeloma. Bone Marrow Transplant. 2001;27:1037-1043.

19. 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;12:431-440.

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Clinical Approaches to Targeted Technologies:

Highlights from the Second Annual Conference of the Global Biomarkers Consortium

Professor Rob Coleman, FRCP Director of the Sheffield Cancer Research Center Sheffield, United Kingdom

Jorge E. Cortes, MD Chair of the CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, The University of Texas MD Anderson Cancer Center Houston, Texas

CME/CPE/CE Information Sponsors This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC. Commercial Support Acknowledgment This activity is supported by an educational grant from Novartis.

Target Audience This activity was developed for medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of solid tumors or hematologic malignancies.

Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing

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Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.25 contact hours.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.25 contact hours (0.125 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-027-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies • Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies • Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

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ersonalized medicine is the future of oncology.

Treatments targeted to each patient’s genomic and molecular profile hold the promise of streamlined regimens with improved outcomes. The pace of discovery for targeted technologies continues to accelerate, raising expectations for more accurate personalization of care. The excitement of advances, however, must not blind us to the challenges. Progress in personalized medicine is often a slow, upward climb, and the journey from bench to bedside depends in part upon the painstaking development of clinically useful biomarkers.

The Global Biomarkers Consortium (GBC) is a community of world-renowned health professionals, coming together to provide a forum for strategies in the clinical application of biomarkers toward optimal personalized care for patients with cancer. The validation of biomarkers and their incorporation into clinical trials were a key

focus of the second annual conference of the GBC, held October 4-6, 2013, in Boston, Massachusetts. This monograph will highlight key topics and insights from that meeting.

Evolution of Personalized Medicine in Oncology The age of personalized medicine in oncology has dawned and new opportunities appear on the horizon.

This was the theme of a presentation by Razelle Kurzrock, MD, Professor of Medicine at the University of California, San Diego. She pointed out that oncology began with nonspecific cytotoxic therapies, yielding small, incremental improvements in survival and significant toxicities. Now, the paradigm is shifting toward therapy targeted to a patient’s tumor-specific genomic and molecular profile. The 5-year relative survival rate for all cancers combined has increased only from 49%

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

by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

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

Planners’ and Managers’ Disclosures John Fox, MD, MLI Reviewer, has nothing to disclose.

Patricia Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose.

Dana Delibovi, Medical Writer, has nothing to disclose. She does not intend to discuss any non–FDA-approved or investigational use of any products/devices.

Faculty Disclosures Professor Rob Coleman, FRCP, has given expert testimony for Novartis.

He does not intend to discuss any non−FDA-approved or investigational use of any products/devices.

Jorge E. Cortes, MD, has received research support from Ariad, Bristol-Myers Squibb, Novartis, Pfizer, and Teva and is a consultant for Ariad, Bristol-Myers Squibb, Pfizer, and Teva. He does not intend to discuss any non−FDA-approved or investigational use of any products/devices.

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

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/ CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13002E.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org.

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

Estimated time to complete activity: 1.25 hours Date of initial release: January 17, 2014 Valid for CME/CPE/CE credit through: January 17, 2015

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To obtain a digital version, download a free QR code app on your SmartPhone and then scan this code.

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Meta-analysis of Single-Agent Phase 2 Lung Cancer Trials Table 1 by Populations Selected and Unselected for Molecular Targets (2000-2009)5 Enriched for Molecular Targets

Unselected

P Value

Progression-free survival

6.0 mo

2.8 mo

.005

Overall survival

11.3 mo

7.5 mo

.05

Response rate

48.8%

9.7%

.005

(1975-1977) to 67% (2001-2007),1 a statistically significant improvement, but one that is nonetheless disappointing. Our newfound ability to sequence the human genome quickly and at declining cost portends not only better diagnosis, risk stratification, and treatment selection, but, ultimately, better treatment outcomes.

For example, although we once viewed lung cancer as a handful of histopathologically determined diseases genomic sequencing shows us that lung cancer may actually be comprised of 100 or more different diseases.2,3 As a result, we now understand that various therapies, when given to unselected patients with lung cancer, show minimal activity, with responses in only a small subset of patients. However, patients defined by a specific genomic profile may respond very well to certain therapies.

Selecting therapy by molecular profile can significantly improve our treatment success and reduce treatmentrelated adverse events, but whether this principle can be applied to routine clinical practice is a key question researchers are now seeking to answer.

Clinicians have always tried to find commonalities to guide care, but that paradigm is fast becoming outdated.

An affirmative answer is emerging. For example, the small-molecule kinase inhibitor cabozantinib has been shown to be effective in the treatment of medullary thyroid cancer, a disease in which the majority of patients have tumors that display a RET mutation.4 Furthermore, a meta-analysis of phase 2, single-agent lung cancer trials showed markedly better outcomes when patient selection was enriched to recognize molecular targets (Table 1).5 Evidence is accumulating that such enrichment improves patient care. Clinical trials conducted at the MD Anderson Cancer Center (MDACC) evaluated cancer not by organ of origin but by molecular pathway. One such pathway is the phosphoinositide 3-kinase (PI3K)/ Akt/mammalian target of rapamycin pathway, which is a

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driver in many tumor types. In a phase 1 study at MDACC, the partial response (PR) rate to targeted therapy was 30% in patients with heavily pretreated, metastatic tumors, compared with a background historic PR rate of just 10% in the same setting when no specific targeted approach was used.6 Subsequent investigation refined the data set and revealed that patients harboring the H1047R mutation of the PIK3CA gene were more amenable to targeted treatments than were those with other mutations within the pathway.7 Studies such as these teach us not to think simplistically about personalized medicine. It is not enough to consider only the pathway involved; the specific mutations—both where they occur and what type they are— make a significant difference. Multiple mutations also complicate the picture. For instance, the presence of a mutation in PTEN, a “driver” mutation that activates PIK3CA/Akt, appears to increase the likelihood that a patient will have a mitogen-activated protein kinase (MAPK)-expressing mutation that confers resistance to therapies, such as KRAS, MRAS, or BRAF gene mutations.7 In these types of cases, treatment needs to be targeted to both PIK3CA/Akt activation and MAPKtype resistance. In heavily pretreated patients with various cancers and a KRAS gene mutation along with a PTEN aberration, data show that the rate of response to treatment is only 4%.8 In contrast, the response rate in patients with various cancers and PIK3CA or PTEN aberrations without KRAS mutations is 22%.8 Genomics is a disruptive technology, and a key disruption is that we can no longer look at patients as broadly defined “types.” Clinicians have always tried to find commonalities to guide care, but that paradigm is fast becoming outdated. The problem, however, is that truly personalized medicine requires a specially tailored regimen for each patient. Hypothetically, if there are 300 anticancer agents, there are 45,000 possible 2-drug combinations and 4.5 million possible 3-drug combinations.

Managing this complexity requires a metamorphosis in clinical trial design and in patient care.

The classic design—a randomized trial in unselected patients—supplies evidence only in support of those therapies that hit the most common genomic/molecular targets of a location-defined tumor. The design misses the fact that, in a small subset of patients with a less common genomic profile, another therapy can be very effective. Thus, trial design must change from large studies in unselected populations to smaller studies in selected, biomarker-denoted populations. Future trials may also become patient-centric rather than drug-centric or primary tumor-centric. For example, instead of taking a group of patients and testing a drug across a group with tumors of similar anatomic origin, we might move to-

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ward looking at patients as individuals, using multiple biomarkers to classify their cancers by molecular characteristics irrespective of the primary site, and then validate specific drug combinations in single patients or small groups with comparable actionable mutations.

However, even this approach may be overly simplistic.

For example, treating melanoma harboring the BRAF V600E mutation with vemurafenib improves clinical outcomes, while treating colorectal cancer with BRAF V600E mutations can result in worse outcomes.

Our ability to profile cancers genomically is a major breakthrough. However, it demands radical changes in the way we study and ultimately treat patients with cancer.

Bioinformatics Today In his conference presentation, Ulrich Mansmann, Prof Dr, Director at the Munich Institute, stated that biomarkers—identified and developed via bioinformatics—must answer 5 key questions: 1. How likely is it that a particular cancer will develop in a patient? For example, mutation in the BRCA1 or BRCA2 gene is a biomarker used in screening for elevated risk of breast or ovarian cancer.

2. What is the type/genomic profile of the cancer? We now profile and risk-stratify many cancers via biomarkers, such as HER2-positive breast cancer or multiple myeloma positive for deletion 17p.

3. What is the optimal choice of therapy for this cancer?

The selection of imatinib for Philadelphia chromosome–positive (Ph+) leukemias is one example of drug choice based on a specific biomarker.

4. What is the optimal dosage of therapy for the patient?

Biomarkers—such as genetic polymorphisms that reduce hepatic metabolism via cytochrome P450 pathways—may signal the need for dose adjustment.

5. Will the cancer recur? Novel biomarker assays, such as Oncotype DX, can predict the likelihood of distant recurrence and other aspects of disease progression.

To answer these questions effectively, bioinformatics— the field of computer science that stores, organizes, and analyzes biologic data—must process and make accessible mountains of data. This is a tall order, and there is as yet no standard computational approach to this challenge.

Bioinformatics does a good job of gathering the data, which include genomic sequences as well as the genemediated cellular, molecular, and biologic functions that make up “gene ontology.” However, we still have no recipe for software programs that can accept such tremendous data inputs and render the kind of easy-to-use outputs needed to guide everyday clinical practice. The ultimate but unrealized goal of bioinformatics is to first craft a computer model that integrates complex information, then validate the model and use it to draw sensible

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and practical clinical conclusions. Fundamentally, bioinformatics confronts a problem facing many fields today: Is the human mind equipped to analyze the “big data” our computers can amass?

It is encouraging to note that many good data sets are available. Some have been analyzed to the point where patterns have emerged. Patterns allow the recognition of “molecular hubs”—genes that link extracellular signals to the control of such events as tumor cell proliferation or suppression of apoptosis. In such cases, it is possible to map gene ontology into treelike structures that organize cellular, molecular, and biologic events resulting from a particular normal or mutated gene.9 Published compendia, such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) database,10,11 and published data from next-generation sequencing (NGS) aid statisticians in their work.

However, we still have no recipe for software programs that can accept such tremendous data inputs and render the kind of easy-to-use outputs needed to guide everyday clinical practice.

In addition, there are analytical tools, such as the R-project and Bioconductor, that offer algorithms for eliciting meaningful end points from large data sets. Bioinformatics teams can sometimes use or adapt these tools; in other situations, teams must design their own analytical tools specific to the data they need to analyze.

Bioinformatics has developed techniques to mine data for clinically useful information. One method is transcription fold-change analysis.12 When a cell undergoes a modification (eg, from normal to cancerous), there is a corresponding change in the activity of RNA (transcription activity) linked to specific genes in that cell, which is expressed as change by n-fold. The fold change is tested over multiple cells and then evaluated for evidence and probability of a systematic difference between one state (eg, normal) and the other state (eg, cancerous). Transcription fold-change analysis can show that cells with specific genes or mutations may undergo different degrees of fold-change when switching from healthy to cancerous. Fold-change analysis was part of a recent study that identified genomic “hot spots” in breast cancer cells; hot spots are genes that show high transcriptional activity in the malignant cell but not in the cells of normal breast tissue.13 Another approach, used to find potential molecular targets of therapy, uses gene-set enrichment analysis software, which analyzes groups of genes that share biologic function, and chromosomal location or regulation,

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Table 2 Solid Tumor Biomarkers in Routine Clinical Use • Estimating risk of developing cancer

– BRCA1 germ-line mutation

• Screening

– PSA test • Differential diagnosis – Tissue immunohistochemistry • Determining prognosis – Gene expression signatures (eg, Oncotype DX) • Predicting response – ER, HER2, KRAS, and EGFR mutations; ALK translocations • Monitoring for disease recurrence – Tumor markers • Monitoring for response or progression in metastatic disease – Circulating tumor cells PSA indicates prostate-specific antigen.

with the goal of identifying multiple determinants of cancers.12 A related method, called TARGETgene,14 is a computer tool that searches a database of the interactions of candidate genes and maps them to a gene network. TARGETgene can rapidly extract genetic interactions from a precompiled database stored as a MATLAB MAT-file without the need to interrogate remote SQL databases. Millions of interactions involving thousands of candidate genes can be mapped to the genetic network within minutes. The TARGETgene

Validation—the proof that a biomarker can reliably guide clinical risk stratification and treatment—is an essential step in moving from what is possible to what is practical. software scores the value of potential targets by 2 criteria: (1) Is the gene in a molecular hub or is it in the periphery? (hub genes have more value as a target), and (2) What is the extent of the gene’s distortion? (distortion is the degree of variation between the expression of RNA and the subsequently generated proteins; the more distortion, the less value as a target). Once the TARGETgene software has identified potential targets, it can link them with current and investigational drugs with activity against those targets. TARGETgene has been developed by the Biomedical Simulations Resource (BMSR) at the University of Southern California, under support from the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health (P41-

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EB001978). It is distributed by the BMSR at no charge to the user, under the terms of a Release Agreement.

Finally, a model called Virtual Patient uses a database such as KEGG to generate the molecular features of a cell in a certain setting.15,16 Once a Virtual Patient is created, it functions as an avatar for interventions. For example, researchers can test the predicted effects of a particular drug on a patient with a specific genomic profile. This kind of approach is a promising way to handle the vastness and complexity of genomic and molecular features; it has resulted in some useful generalizations with clinical significance, such as the well-known “Hallmarks of Cancer.”16 There is cause for optimism that “big data” can be harnessed to help patients with cancer. We believe that bioinformatics can and will untangle the web of cancer genomics.

Validating Biomarkers: Solid Tumors According to Rob Coleman, FRCP, Director of the Sheffield Cancer Research Center, United Kingdom, we are clearly moving away from nontargeted, organ-directed cancer treatments and toward treatments targeted to molecular pathways. This simple statement, however, masks the complexity of finding valid biomarkers. Validation—the proof that a biomarker can reliably guide clinical risk stratification and treatment—is an essential step in moving from what is possible to what is practical.

There are several barriers to validation. One barrier is the sheer volume of biomarker data that must be analyzed. Other barriers are misaligned trial designs and the difficulties of procuring funding. Moreover, the validity of a biomarker also depends upon its utility in clinical practice—ie, does knowledge of the biomarker status change treatment and ultimately patient outcomes? Barriers to acceptance include regulatory environments designed for traditional drugs and traditional diagnostics rather than biomarkers used for treatment planning; poor or uncertain reimbursement of biomarker testing; and a publication environment skewed toward publishing positive results, when, for biomarkers, disproving an hypothesis may be equally important.

Currently, there are only a small number of biomarkers in routine use for solid tumors (Table 2). Some biomarkers are tested at a central laboratory, to help clinicians select a treatment or stratify risk (eg, the Oncotype DX assay). Others are more patient-centric biomarkers, such as prostate-specific antigen, which are tested at numerous healthcare venues.

Attaining rapid validation for more biomarkers will require better strategies. The first of these strategies is to provide strong evidence of clinical, biological, and analytic validity of a biomarker. Too often, the discovery of

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a potentially predictive biomarker—clinical and biological validity—prompts investigators to leap straight to the development phase, without thinking through the analytic validity of the assays or sequencing proposed.

Dr Coleman discussed the following scenario: Researchers identify a molecular trait or profile that can reliably discriminate between 2 or more clinical groups.

They then verify the finding in an independent second or third group, using a prespecified hypothesis and a proper statistical plan that minimizes post hoc analyses.

This approach aims for clinical and biological validity, and it is usually performed well. The researchers, however, do less well in determining analytic validity. They incompletely answer questions such as “Is the biomarker testing result sensitive to how the sample is collected, processed, stored, and shipped?” and “What are the characteristics of the assay in terms of its usual metric sensitivity, specificity, false-positive and false-negative results, and reproducibility?” Detailed responses to these questions are essential if a biomarker is actually going to be applicable for routine clinical use.

The second strategy concerns the need to improve clinical acceptance of a biomarker. It is important to remind ourselves that while clinical, biological, and analytic validation of biomarkers is necessary, it is not sufficient for their acceptance in clinical practice. Acceptance requires proof of utility: Is the biomarker meaningful, relevant, and valuable across real-world practice settings?

Answering that question in the affirmative demands 2 things: (1) evidence of an effect-size large enough to make treatment decisions, and (2) a favorable benefit-toharm ratio. To be accepted as clinically useful, a biomarker needs support from prospective clinical trial testing or a meta-analysis of prospective/retrospective biomarker studies that demonstrate improved patientrelevant outcomes.17 Very few biomarkers have achieved these benchmarks.

Fortunately, with the growing understanding of the need to prove biomarker utility, there is a push to accrue data by running prospective randomized trials. Ongoing trials with Oncotype DX (eg, the TAILORx trial) and with MammaPrint sequencing (eg, the MINDACT trial) are examining the utility of these tests to aid in selecting effective therapies. Biomarker validation is now supported by initiatives such as REporting recommendations for tumor MARKer prognostic studies (REMARK) criteria, Biospecimen Reporting for Improved Study Quality (BRISQ) criteria, and several others. Biomarker trial design is improving, and there are proposals for overcoming regulatory, reimbursement, funding, and publication hurdles.

Even with all of these efforts, the path to clinical use of biomarkers remains a challenge because of their com-

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Table 3 FLT3 Inhibitors Currently in Development Preclinical

Phase 1

Phase 2

Phase 3

VX-322

IMC-EB10

Sorafenib

PKC-412

VX-398

KW-2449

MLN-518

CEP-701

MC-2002

AP-24534

AC220

MC-2006

CHIR-258

Crenolanib

PLX3397

plexity. A recent example is the proteomic research to identify candidate proteins predictive of bone metastases. The initial inspiration for this research came from observations of differential risk of metastases among patients with breast cancer as a function of menopausal status.18 Approximately 5 years have since elapsed between the discovery of a candidate protein and the beginning of evaluation of its presence in tissue samples from clinical trials. Even if tissue-sample investigation proves useful, the requisite studies to confirm clinical utility will still take at least another 4 to 5 years.

Fortunately, with the growing understanding of the need to prove biomarker utility, there is a push to accrue data by running prospective randomized trials.

Biomarker development can be a virtuous or vicious cycle. When virtuous, all parts of validation align: trial design, measures of clinical/biological/analytic validity, prospective evaluation, funding, regulatory review, reimbursement, and publications. When vicious, barriers to some or all of these factors hinder or even stop the development process. We must implement strategies that ensure a virtuous cycle in most cases.

Validating Biomarkers: Hematologic Malignancies Currently, there are no protein biomarkers cleared by the US Food and Drug Administration (FDA) in hematologic malignancies. Getting clearance through better validation was the theme of a presentation by Jorge E. Cortes, MD, Chair of the CML and AML Sections and D.B. Lane Cancer Research Distinguished Professor for Leukemia Research in the Department of Leukemia, at The University of Texas MD Anderson Cancer Center in Houston.

Dr Cortes presented an anecdote that illustrates the problem. Evidence overwhelmingly shows that treatment with imatinib, nilotinib, or another tyrosine kinase inhibitor (TKI) significantly improves outcomes in patients

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with Ph+ chronic myeloid leukemia (CML).19,20 Use of TKIs in this population has produced a marked overall increase in survival compared with survival rates in the pre-TKI era.21 Testing to determine Ph+/Ph− status is widely available in many institutions and laboratories.

Approval of the first agent in the class, imatinib, was granted based on the chromosomal biomarker that identifies this disease, but the assessment of this chromosomal abnormality has not been validated with the standards requested today.

Now that TKIs are available, clinicians would like to monitor the progress of treatment with a molecular biomarker, measuring the BCR-ABL gene fusion that results from the Ph.22 This molecular biomarker enables us to measure molecular response, which helps to determine treatment efficacy and select the next sequence of treatment. The biomarker may also carry additional mutations that reduce or increase sensitivity to TKIs.23,24 Yet this protein biomarker has not been validated sufficiently to be cleared by the FDA for clinical use. One problem is that the testing has been difficult to standardize across laboratories. Therefore, we have tests that are widely available and used for diagnostic, prognostic, and therapeutic decision-making, but are not considered validated to direct approval of targeted therapies.

Suboptimal survival with conventional cancer treatment has been a powerful motivation to study targeted therapies in biomarker-selected populations.

For most hematologic malignancies, data are available to show that many expressed proteins and their genomic triggers can help answer the 5 key questions we ask of biomarkers (see “Bioinformatics Today” section above).

Yet these biomarkers are not validated to the degree needed for FDA clearance.

In acute myeloid leukemia (AML), for example, research has identified a number of different mutations with a significant impact on prognosis. One meaningful type of genomic biomarker is the FLT3 gene mutation, which occurs in approximately 30% of patients with AML and predicts shorter durations of remission and overall survival.25 One mutation, FLT3-ITD, is linked to particularly poor outcomes.25 A number of drugs inhibit the molecular products of FLT3 mutations (Table 3), some of which are currently in clinical use. These drugs, however, do not exclusively target FLT3. Validated protein biomarkers would enable clinicians to determine how well a drug is targeting FLT3 mutations versus unmutated FLT3; such biomarkers could

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also help to characterize resistance early in AML. Other important genomic biomarkers in AML are RAS-type gene mutations. Mutations affecting Ras proteins occur in approximately one-third of patients with AML,26,27 and Ras is activated in many others. Targeting oncogenic Ras-protein pathways appears to be a potential strategy for treating AML. Drugs that inhibit farnesyltransferase, an enzyme that ensures the cellular signaling functions of Ras proteins, were proposed as promising treatments for patients with RAS-mutated leukemia.28,29 When these drugs were used in patients not selected by any biomarkers, the response rate was very low and the drugs were not able to obtain regulatory approval. A genetic predictor of response to the farnesyltransferase inhibitor tipifarnib, the RASGRP1:APTX gene expression ratio, has been identified.28 Selection of patients with this biomarker may increase the success rate in a well-defined population. The MAPK called MEK, a kinase activated downstream from Ras, also appears to be a useful target of therapy. These biomarkers could be valuable if they are validated, demonstrate clinical utility, and are cleared for clinical use.

Recently, research has elucidated the role of STAT gene activation associated with Janus kinase 2 (JAK2) mutations in patients with myeloproliferative neoplasms.

Although JAK2 mutations are not commonly expressed in acute leukemia, a small subset of patients with AML do harbor these mutations, including patients with myeloproliferative neoplasms that evolve into AML. When patients with these mutations are treated with ruxolitinib, a JAK1/2 inhibitor, they respond. In a study of 38 patients with refractory leukemias treated with this agent, there were 3 complete responders. All 3 of these responders had AML that evolved from a myeloproliferative neoplasm, and 2 of the 3 had JAK2 gene mutations.30 These data illustrate the value of personalized therapy. They also demonstrate the need to validate the biomarkers that can enable true personalization—down to the level of each individual patient—a clinical reality.

The hematology/oncology community must embrace the fact that just identifying a protein molecule or gene mutation is not enough; we need to systematize how we assess, interpret, and apply those biomarkers in the clinic, and how we analyze, interpret, and implement the complexity that results from the multiple possible combinations of mutations at different levels.

Challenges in Biomarker-Based Clinical Trials Suboptimal survival with conventional cancer treatment has been a powerful motivation to study targeted therapies in biomarker-selected populations. As presented by Roy S. Herbst, MD, PhD, Ensign Professor of Medicine and Professor of Pharmacology at Yale School of Medicine, New Haven, Connecticut, such studies re-

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quire innovative designs. In other words, there must be a paradigm shift in how we design and implement our research programs. The need for this shift became apparent in the clinical literature approximately a decade ago.

One influential 2002 study reported similar poor survival rates of 4 platinum-based, doublet chemotherapies in patients with advanced non–small-cell lung cancer (NSCLC); median survival was 7.9 months, with a 2-year survival rate of 11%.31 Fortunately, research has uncovered numerous molecular and genomic biomarkers in NSCLC. Where formerly this disease was merely bifurcated into adenocarcinoma and squamous cell carcinoma, we can now classify each of these 2 diagnostic categories by biomarker. The result is that clinicians can evaluate tumor cells obtained on initial lung biopsy for 70 or more mutations and rebiopsy and evaluate for molecular/genetic anomalies at the time of tumor progression.

While the technology exists for developing detailed biomarker profiles in NSCLC and other cancers, one unmet need is for more efficient discovery trials to match biomarkers to targeted drugs. For example, an important area of NSCLC research involves the binding of programmed cell death-1 ligand 1 (PD-L1), which is expressed on the tumor-cell surface, to proteins PD-1 and B7.1 on the surface of T lymphocytes. Binding initiates inhibition of the immune system via the T-cell, allowing tumor growth.32 The major histocompatibility complex appears to mediate the process, but it is not yet known what genetic mutations are the ultimate drivers. There are a number of potential therapeutic approaches for blocking PD-L1, among them the use of anti–PD-L1 antibodies.32 In situations like these, it would be ideal if, early on in drug development, we could also develop biomarker strategies. This way, testing for the relevant biomarker would be validated and refined in tandem with the targeted drug. To this end, translational research in lung cancer is adopting the BATTLE approach—The MDACC’s Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination. BATTLE is a potentially useful model for research in other cancers as well.

A key feature of the BATTLE design is that it matches targeted agents with abnormal, biomarker-denoted pathways early in the process. As shown in Figure 1, the first iteration of BATTLE (BATTLE-1) mandates biopsy and biomarker analysis of the tumor immediately upon registration into the clinical program, then selects patients for randomization into accruing studies of different drugs on the basis of their molecular/genomic profiles.

The purpose of the study is to determine whether matching a specific biomarker to targeted therapy indeed produces a better clinical outcome. The hope is that patients will be assigned to more effective therapies because

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Figure 1 BATTLE-1 Patient Evaluation Schema

Registration Biopsy

1 week

Randomize to Trial

Consent

2 weeks Biomarker analyses

Molecular Pathology Lab

8 weeks

Primary End Point: 8-Week DC

BATTLE indicates Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination; DC, disease control.

they have been selected based on their predicted sensitivity to a drug. This approach will hopefully yield better clinical outcomes than assignment of all patients to a drug that may benefit only a subset of patients. BATTLE-2 builds on the knowledge gained from BATTLE-1, refining the process of randomization to trials of more specifically targeted drugs and drug combinations. BATTLE-2 also selects and validates biomarkers in real time, as the trial progresses.

There is also an unmet need to streamline and reconfigure both the phase 3 trials that support drug approval and the randomized trials that evaluate drugs in combination therapy. A recent report of the Institute of Medicine (IOM) has called for the modernization of clinical trials to improve speed and efficacy, incorporate innovative science, improve prioritization, and incentivize participants.33 The National Cancer Institute (NCI) is implementing a comprehensive approach in order to encompass rapid changes in our understanding of cancer biology.34 On the basis of a review of the available published literature, along with input from experts in the field and interested individuals, the NCI’s recommendations focused on 4 broad goals to enhance the value of national Cooperative Group clinical trials in cancer going forward: 1. Consolidation and Efficiency. Improve the efficiency and reduce the average time for the design and launch of innovative clinical trials by consolidating functions, committees, and Cooperative Groups; streamlining oversight processes; facilitating collaboration; and streamlining and standardizing data collection and analysis.

2. Science. Incorporate innovation in science and trial

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Figure 2 Drug Development: The Big Picture Preclinical Research

Clinical Studies

E Synthesis and Purification

NDA Review

Phase 1 E

Phase 2 Phase 3

Accelerated Development Review Animal Testing

Short-Term

E

Treatment IND Parallel Track

Long-Term Institutional Review Boards Industry Time FDA Time IND Submitted Sponsor/FDA Meetings Encouraged Advisory Committees

NDA Submitted Review Decision Sponsor Answers Early Access: Any Questions E Subpart E From Review

FDA indicates US Food and Drug Administration; IND, investigational new drug; NDA, new drug application.

design (eg, in studies identifying biomarkers that can predict therapeutic response).

3. Funding and Support. Adequately support those clinical trials that have the greatest possibility of improving survival and quality of life for patients with cancer, and increase the rate of clinical trial completion and publication.

4. Participation. Incentivize the participation of patients and physicians in clinical trials by providing adequate funds to cover the costs of research and by reimbursing the costs of standard patient care during the trial.

Research teams are making parallel efforts to respond to the IOM’s call by developing modernized “master protocols” for larger randomized clinical trials. The aim of these protocols is to treat many patients based on biomarker groups, to support drug approval. A key strategy of master protocols is to be certain that all enrolled patients have biomarker profiling via NGS; results of sequencing are then used in randomization. One trial with a modernized, master protocol design is ALChEMIST— the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial—which will enroll large numbers of patients with early-stage disease who harbor EGFR gene mutations.35 Another modernized trial is a planned study in refractory squamous NSCLC. In this trial, biomarker profiling

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will be followed by placement into 5 groups: 4 groups selected on the basis of biomarkers and 1 nonmatched group. Patients within each of the 4 profiled groups will be randomized into 2 treatment arms: (1) standard chemotherapy or (2) a targeted agent appropriate for the group’s biomarker. All patients in the single nonmatched group will receive standard chemotherapy. This study will begin as a phase 2/3 trial for 60 to 80 patients; if drug activity is observed, the goal will then be to enroll 500 to 1000 patients per year, with a possible increase from 4 to 6 targeted arms.36 The trial design, with 4 to 6 biomarker-specific groups, is estimated to achieve an approximately 70% “hit rate” of matching patients with drugs that prove effective for them. This innovative model represents today’s paradigm shift away from nonselected study populations and toward the investigation of treatment personalized by biomarkers.

These and other novel strategies will be required if we are to take advantage of our current knowledge in the biology of cancer and be able to better select therapies for smaller subsets of patients.

Regulatory Perspectives In the simplest terms, personalized medicine identifies actionable genomic and molecular targets and matches treatment aimed at those targets. Offering a personalized approach to more patients in the United States will likely require accelerated FDA approvals once validated clinical evidence is obtained, as described in a presentation by Mikkael Aaron Sekeres, MD, MS, Professor of Medicine and Director of the Leukemia Program at Cleveland Clinic Taussig Cancer Institute in Cleveland, Ohio, and Chairperson of the FDA’s Oncologic Drugs Advisory Committee.

Basic research has discovered many genomic and molecular targets, but the sheer number and complexity of targets can actually pose problems. For example, recent work has identified TET2 mutations, and possibly IDH1/2 and DNMT3A mutations, as underlying causes of epigenetic instability and aberrant DNA methylation in myeloid malignancies.37 In principle, patients with these mutations would be particularly susceptible to therapies with hypomethylating agents. Indeed, new evidence shows that patients with these abnormalities who have been treated with hypomethylating agents are twice as likely to achieve a complete response to this group of drugs as are those patients who do not have the target mutations. This is exciting—a molecular lesion that predicts a higher response rate to a drug. The problem, however, is that we have neither the ability to sort out actionable specific mutations from the vast number of candidates nor the optimal drugs to target most of the abnormalities with precision.

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The sophistication of the drugs we now have available has not kept up with the sophistication of the molecular targets we can identify. When a clinician has only 1 or 2 drugs available, true personalization is not possible, because he or she is compelled to treat patients with the same agents that can be prescribed regardless of molecular/genomic profile. Another problem is that all mutations are not associated with the same predictive or prognostic significance. For example, there are numerous specific TET2 gene mutations, but it is not known which ones are truly actionable as biomarkers.

Given this situation, 2 goals emerge: (1) making more drugs available, and (2) identifying actionable biomarkers more skillfully. To be able to translate this into standard-of-care practice, both of these goals depend upon the regulatory environment. Meeting the first goal requires getting more targeted drugs approved by the FDA. Meeting the second goal requires the development, validation, and clearance of specific biomarker testing.

Increasingly, when a targeted drug comes before the FDA’s Oncologic Drugs Advisory Committee, the question asked is, “Should a companion test that is accurate in measuring the target mutation be required for a drug that is specific for that abnormality?” It is no longer sufficient to have a drug proven to work in patients whose tumor is associated with a specific molecular abnormality; development teams must also make sure that the test that will measure that abnormality is accurate, valid, reliable, and accessible by centers around the country. This is a challenge—it requires research to pin down exactly which mutation or abnormality in a group of patients are the true targets, then produce and refine a testing method to identify such changes.

How can investigators and manufacturers accelerate drug approvals and biomarker test clearances? They can start by understanding the FDA and its culture. Ensuring the safety of drugs was the agency’s original mission in 1938; it is still true today that its first focus is safety. The FDA has a philosophy of deliberateness and caution that affects all stakeholders (Figure 2). It takes, on average, 8.5 years to study and test a new drug to a level sufficient to gain approval for use in the United States. Significant changes in science can happen during that time, which then influence the approval process.

Another aspect of the FDA’s process is the option for standard or accelerated approval. Accelerated approval is likely to be the mechanism by which many targeted drugs will receive approval through the agency, especially if they fill a significant unmet clinical need. For indications in which a new product appears to provide benefit over existing therapy, accelerated approval may be granted on the basis of a surrogate end point that is reasonably likely to predict clinical benefit. An example of

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a surrogate marker is tumor shrinkage; the surrogate stands in for overall or progression-free survival advantages that are the classic end points for standard oncologic drug approval. Getting accelerated approval demands that there be a follow-up study confirming clinical benefit. Several drugs have been removed from the market when confirmatory studies failed to show benefit.

Finally, the FDA—an organization fundamentally charged, as mentioned earlier, with patient protection— cares deeply about symptomatology, comorbidity, and other patient-centered aspects of treatment. Ruxolitinib, for instance, was approved largely on its ability to improve symptoms in patients with myelofibrosis (MF).

The bone marrow in patients with this disease accumulate fibrosis and bone marrow stem cells migrate to the spleen, which may become so enlarged that it compresses the stomach and can prevent adequate nutrition.

Ruxolitinib, which targets JAK1/2, has a very favorable effect on several of the debilitating symptoms of MF, including splenomegaly.38

Symptom patterns, chronic disease, and other broad clinical features are the original metric of personalization, and they still matter today.

A thorough understanding of the regulatory climate suggests several steps be taken to hasten biomarker clearance and the approval of targeted drugs. First, make biomarker testing and drug development a tandem process; this reassures the FDA that clinicians will be able to identify the best candidates for the approved drug. Second, pay close attention to adverse events, by incorporating toxicity measures in both single-arm and randomized pivotal studies, and in any trial used to confirm an accelerated approval. Third, amid all the excitement about the molecular and genomic targets, do not forget the importance of symptom control, patient age, and comorbidities. Symptom patterns, chronic disease, and other broad clinical features are the original metric of personalization, and they still matter today. Molecular and genomic targeting is not about attacking a tumor, but about healing the patient.

Conclusion The second annual conference of the GBC represented a unique opportunity for a diverse, world-renowned faculty to discuss the challenge of making biomarkers actionable for clinical use with the ultimate goal of improving patient outcomes. Meeting this challenge is essential, for without clinical validation of biomarkers, and

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without innovative clinical trials that fully integrate genomic and molecular targets, the promise of personalized medicine in oncology will not be fully realized. Thus, refined biomarker validation strategies, novel designs for clinical trials of targeted therapy, and improved bioinformatics are just some of the areas that must rapidly evolve for us to progress in oncology and achieve a significant impact on the mortality associated with the majority of cancers. u Dana Delibovi contributed to the development of this article.

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18. Coleman RE, Marshall H, Cameron D, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011;365:1396-1405.

19. Kantarjian HM, Talpaz M, O’Brien S, et al. Imatinib mesylate for Philadelphia chromosome-positive chronic-phase myeloid leukemia after failure of interferon-α: follow-up results. Clin Cancer Res. 2002;8:2177-2187.

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ersonalized edicine in Oncology

BIOMARKERS • IMMUNOTHERAPY • TARGETED THERAPIES • DIAGNOSTICS

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VALUE-BASED CANCER CARE

Need for Innovative Strategies for Quality Care Will Continue to Grow Oncology Reimbursement Requires New Approaches, Says Lee Newcomer

C

urrent economic trends mandate the development of innovative strategies to effect quality and efficiency in cancer care, applying the same rigor as used in clinical trials, according to Lee N. Newcomer, MD, MHA, Senior Vice President, UnitedHealthcare, who addressed cost issues and barriers in provider reimbursement at the 2013 ASCO Quality Care Symposium.

Less Money for Patient Care Within 2 to 3 years, consumers’ out-of-pocket costs will consume half of the average household income, Newcomer said. Another 10 or 15 years down the road, healthcare costs will require the entire household income, according to a study published in 2012 (Young RA, DeVoe JE. Ann Fam Med. 2012;10:156-162).

Such an impossible situation will mean that providers at every level will have to get by with less. “No one will be exempt from having less money available to take care of even more patients,” said Newcomer. “It won’t matter whether you’re a social worker or a nurse or a physician, a hospital, a pharmacy institute, or a payer. We will all have less money to work with,” he emphasized.

The funding of clinical trials is complicated because everyone wants a share of the savings that result from improved care efficiency and lower costs.

“One of the things we have to learn to do is to eliminate all of the waste. The things that don’t make as much difference to us as quality-of-life money. We have to figure out how to deliver the best outcome with the limited resources we have available.”

Currently, approximately 22% of every UnitedHealthcare oncology dollar goes to pharmaceuticals, the cost of which is increasing by 10% to 15% annually.

Hospital costs account for 54% and are also increasing at a rate of approximately 10% annually. Physicians – all physicians, not just oncologists – account for the remain-

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ing 24% of the cost, and their costs are in a negativeinflation status, said Newcomer.

Innovation in Reimbursement Innovation in payment strategies focuses on 3 basic models: the pay-for-performance model, bundling or episodic payment, and capitation. Pay-for-performance is by far the most popular strategy and is usually tied to clinical pathway adherence. At UnitedHealthcare, currently 80% of the patients with cancer are treated based on predetermined pathways, according to Newcomer.

Measuring the performance and outcome of various payment strategies faces several barriers, he says. The first relates to enrollment of a sufficient number of patients to conduct quality-of-care studies. The majority of patients do not qualify as “typical” patients that would be needed for a study of different reimbursement models. Related to study enrollment is the time required to conduct studies, which require several years to complete.

Identifying an appropriate control or comparison group can also be problematic, including the decision to compare outcomes and costs on a year-to-year basis, or to use a control group followed over the same duration of time as the study group.

Finally, the funding of clinical trials is complicated because everyone wants a share of the savings that result from improved care efficiency and lower costs. Moreover, most healthcare organizations already have relatively slim margins from which to trim additional costs.

“It’s very difficult to find a lot of money to fund pay-for-performance programs,” said Newcomer.

As another example of the difficulties involved in finding reward money for pay-for-performance initiatives, he described an oncology practice that performed better than the national average for virtually all types of cancer; however, that practice already received a 33% premium on payments as a result of a higher fee schedule, and the group’s performance was only slightly better than the national average.

“For pay-for-performance to work, we not only need to get good results, but we need to get results that are proportionate to the payment,” said Newcomer.

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EDITORIAL VALUE-BASED CANCER CARE

Measuring Quality and Cost-Effectiveness The difficult realities associated with the payfor-performance approach have led Newcomer, and possibly others, to reconsider the approach to measuring quality and cost-effectiveness. Specifically, he questions whether payers have had the wrong focus in their efforts to achieve cost-efficiency and good outcomes.

Payers can easily compare chemotherapy regimens, he continued. As part of preauthorization, detailed clinical information can be obtained, and then a payer can initiate an intend-to-treat study, specifying the regimen during preauthorization. Within a couple of years, a large organization can accrue hundreds, if not thousands, of patients using various chemotherapy regimens for different types of cancer.

“This would give us a very good start toward comparative effectiveness studies, comparing regimens against each other,” said Newcomer.

Such studies could help fill the void that has resulted from the disappearance of phase 3 cooperative group

trials that compared chemotherapy regimens in various types of cancer.

Quality Care Research To reduce costs, payers need to know which regimens provide the best results at the lowest cost and lowest toxicity. “That is something payers can do and can do effectively, and with a large enough volume that we could start parsing out those regimens that are ineffective, and lowering cost in the process,” Newcomer said.

Moving forward, he concluded, quality care researchers must continue to test solutions, because the need for better quality and efficiency will always be relevant. At the same time, payers, clinicians, researchers, and other interested parties must be realistic about the financial results that can be expected from improvements in quality and efficiency.

Finally, quality care researchers must apply the same rigor as clinical researchers use in clinical trials. “The scientific method applies to business applications as well,” said Newcomer. u

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2013 SAN ANTONIO BREAST CANCER SYMPOSIUM

Adjuvant Bisphosphonates: Winner in Postmenopausal Breast Cancer

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djuvant bisphosphonates reduce the risk of bone metastases by about one-third and improve breast cancer–related survival by 17% in postmenopausal women with early breast cancer, according to a large meta-analysis reported here. Bisphosphonates had no effect on premenopausal women in the adjuvant setting.

“Adjuvant bisphosphonates had no significant effect on distant recurrences outside the bone, but the risk reductions in bone recurrence and breast cancer death were similar regardless of estrogen receptor status, node

No significant effect of bisphosphonates was found for local recurrence (6.3% and 5.5%, respectively) or contralateral breast cancer (2.5% and 2.4%, respectively). status, and use/nonuse of chemotherapy,” stated Robert E. Coleman, MD, University of Sheffield, UK, who presented the meta-analysis results on behalf of the Early Breast Cancer Trialists’ Collaborative Group. He emphasized that results were similar with clodronate and the aminobisphosphonates (65% of patients taking bisphosphonates were taking zoledronic acid).

Bisphosphonates are thought to work by embedding in bone and interrupting the vicious cycle leading to bone breakdown, Coleman told listeners.

The meta-analysis was based on 36 randomized trials comparing adjuvant bisphosphonates with placebo or no bisphosphonate conducted over the past 15 years. Seven of the trials were of oral clodronate and 29 of zoledronic acid.

The meta-analysis was based on individual patient

data for 22,982 patients (17,791 of all patients received clodronate or an aminobisphosphonate); a total of 11,036 women were postmenopausal.

With 10 years of follow-up, in the overall analysis, adjuvant bisphosphonates had no significant effect on all recurrences (26.5% with no bisphosphonate, 25.4% with bisphosphonate), distant recurrence (22.3% and 20.9%, respectively), bone recurrence (8.4% and 6.9%, respectively), or non-bone recurrence (15.1% and 15%, respectively).

Similarly, no significant effect of bisphosphonates was found for local recurrence (6.3% and 5.5%, respectively) or contralateral breast cancer (2.5% and 2.4%, respectively).

Among postmenopausal women, adjuvant bisphosphonates significantly reduced the risk of distant recurrence versus no bisphosphonate: 21.9% versus 18.4% at 10 years (P=.0003, an absolute gain of 3.5%). This difference was mainly driven by the 10-year reduction in bone recurrence: 8.8% versus 5.9% (P<.0001, an absolute gain of 2.9%).

Adjuvant bisphosphonates had no effect on mortality due to breast cancer or other causes in the overall analysis; however, among postmenopausal women, at 10 years there was an absolute gain of 3.1% for breast cancer mortality (18.3% for no bisphosphonate vs 15.2% for bisphosphonate; P=.004); and an absolute gain of 2.3% for all-cause mortality (23.8% for no bisphosphonate vs 21.5% for bisphosphonate; P=.007).

Peter Ravdin, MD, PhD, Cancer Therapy and Research Center, San Antonio, TX, called these results “practice changing.” He said that the impact of bisphosphonates in the adjuvant setting is comparable to that of chemotherapy and trastuzumab in HER2-positive women. Ravdin was not involved in any of the trials included in the meta-analysis. u

Breast Cancer Agents in the Pipeline

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elow are summaries of some of the newer agents on the horizon the for treatment of patients with breast cancer selected from presentations at the San Antonio Breast Cancer Symposium.

Veliparib, a PARP inhibitor, showed promise in the I-SPY 2 trial for the neoadjuvant treatment of triple-negative breast cancer (TNBC) in combination with carbo-

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platin. This combination will move to phase 3 testing in TNBC. Veliparib is also being studied in advanced breast cancer, cervical cancer, and ovarian cancer. (For further details of I-SPY 2, see article on page 47.)

Ridaforolimus (RIDA), an mTOR inhibitor, is a non-prodrug analogue of rapamycin. Dalotuzumab (DALO) is a monoclonal antibody targeted to insu-

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lin-like growth factor 1; the scientific rationale for the combination of RIDA/DALO is upstream and downstream inhibition of molecular targets on the PIK3 pathway. In one phase 2 trial of RIDA/DALO in metastatic estrogen receptor–positive (ER+) breast cancer that progressed on previous treatments, median progression-free survival (PFS) was similar to that of exemestane, but no survival advantage was shown for the combination. The trial was stopped due to the toxicity experienced at the doses used, but the investigators concluded that further study is warranted. Lower doses of RIDA will be studied in the new phase 2 trial for high-proliferation ER+ breast cancer progressing on prior hormonal therapies. The study will compare RIDA/ DALO versus RIDA/DALO/exemestane in this group of patients.

Ganetespib, a heat shock protein 90 (Hsp90) inhib­ itor, is now in phase 2 testing as frontline therapy in women with metastatic HER2-positive (HER2+) or TNBC in the ENCHANT-1 trial. Hsp90 inhibitors block multiple oncogenic pathways that play key roles in different breast cancer subtypes. ENCHANT-1 showed that treatment with ganetespib was well tolerated with an acceptable safety profile; diarrhea is the most common side effect. Ganetespib demonstrated promising antitumor activity in both the HER2+ and TNBC subgroups, with durable responses. Enrollment is continuing in the phase 2 trial. Future strategies that will be studied include combinations with other treatments in early and advanced-stage breast cancer, and biomarker studies will be conducted to try to determine which patients benefit from this treatment.

Palbociclib, an oral selective cyclin-dependent kinase 4/6 inhibitor, passed the phase 2 hurdle and has been given breakthrough status by the FDA. In the phase 2

trial, palbociclib plus letrozole improved PFS versus letrozole alone in advanced/metastatic ER+, HER2+ breast cancer; median PFS was 26.1 months versus 7.5 months with letrozole alone.

Palbociclib is now in phase 3 testing in the PENELOPE trial as adjuvant therapy for patients with hormone receptor–positive, HER2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy.

Following neoadjuvant chemotherapy and surgery with or without radiation therapy, about 800 patients will be randomized to once-daily oral palbociclib versus placebo for 13 cycles. Patients will receive concomitant endocrine therapy according to local standards. They will be followed until progression, secondary malignancy, unacceptable toxicity, or withdrawal of consent.

Ramucirumab, a novel monoclonal angiogenesis inhibitor targeted to VEGFR-2, failed to meet its primary end point of PFS in the ROSE/TRIO-12 trial when added to docetaxel chemotherapy in metastatic breast cancer. These findings are disappointing and would appear to spell the end of antiangiogenesis agents in breast cancer. However, investigators say that they will search for a biomarker to identify subgroups that could benefit from this strategy. Ramucirumab is moving ahead as second-line therapy for gastric cancer; the FDA has granted ramucirumab priority review in this setting.

Entinostat, a novel oral small molecule inhibitor of benzamide histone deacetylase, was shown to extend PFS when added to exemestane versus exemestane alone in postmenopausal women with advanced ER+ breast cancer progressing on a nonsteroidal aromatase inhibitor in the phase 2 ENCORE 301 study; median PFS was 4.28 months for the combination versus 2.27 months for exe­ mestane alone. Entinostat is now being evaluated in phase 3 trials. u

I-SPY 2: First Results Based on Biomarkers/ Genetic Signatures in Breast Cancer

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eliparip/carboplatin was identified as a worthy combination to move forward in trials of triplenegative breast cancer (TNBC), a subtype of breast cancer with a very poor prognosis.

This combination was a “winner” in the phase 2 I-SPY 2 trial, a series of studies of novel agents/combinations of therapies in biomarker-identified subsets of pa-

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tients. The trial has a unique adaptive design that allows screening of a series of novel agents in combination with standard neoadjuvant therapy for high-risk breast cancer in small numbers of patients with a particular biomarker/ signature.

These first efficacy results of I-SPY 2 showing that veliparip/carboplatin “graduated” in TNBC were pre-

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2013 SAN ANTONIO BREAST CANCER SYMPOSIUM EDITORIAL

sented by Hope Rugo, MD, University of California at San Francisco. I-SPY 2 has also identified neratinib as a “graduate,” but those data aren’t yet available.

“Our goal is to accelerate the process of identifying drugs that are effective for specific breast cancer subtypes and reduce the cost, time, and numbers of patients needed to get effective drugs to market. Today’s report is on 1 of 7 current experimental arms of I-SPY 2,” Rugo told listeners.

The ultimate plan for drugs that “graduate” in I-SPY 2 is a 300-patient phase 3 trial that includes the subset of patients that will benefit from that drug.

The study compares 12 weekly cycles of standard pac­ litaxel versus 12 weekly cycles of paclitaxel plus novel agent A versus 12 weekly cycles of paclitaxel plus novel agent B. This treatment is followed by doxorubicin-based chemotherapy. Response is determined by pathologic complete response (pCR), defined as no residual invasive cancers in the breast and lymph nodes, and MRI assessment after definitive surgery.

“Adaptive randomization based on the performance of regimens within biomarker subtypes/MammaPrint

genetic signatures is the key for enrolling patients.

Random probabilities are updated as the study proceeds according to MammaPrint signature, and the threshold for success is based on response for each patient’s tumor based on MRI and pCR assessment over time,” she explained.

The response of each patient informs the randomization assignment for the next patient on study, she continued. Each new patient benefits from the information obtained from the prior patient [with that same signature]. “This allows us to drop an agent that isn’t working,” Rugo explained.

Randomization is assigned based on performance of the experimental regimens within 8 biomarker subtypes (based on HR, HER2, and MammaPrint He-1 and Hi-2).

The results reported here included 71 evaluable patients; 44 had TNBC. The estimated probabilities of pCR showed that the probability of success with veliparip/carboplatin is 99%, mainly due to the success of this regimen in TNBC. By contrast, veliparip/carboplatin had little probability of succeeding in the HER2-positive/hormone receptor–positive subset.

The ultimate plan for drugs that “graduate” in I-SPY 2 is a 300-patient phase 3 trial that includes the subset of patients that will benefit from that drug. “The phase 3 trial will incorporate outcome data to correspond with pCR. We hope this will be a mechanism for accelerated approval,” Rugo said. u

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CONFERENCE CO-CHAIR Global Biomarkers Consortium Jorge E. Cortes, MD

CONFERENCE CO-CHAIR Global Biomarkers Consortium Roy S. Herbst, MD, PhD

Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

Ensign Professor of Medicine Professor of Pharmacology Chief of Medical Oncology Director, Thoracic Oncology Research Program Associate Director for Translational Research Yale Cancer Center New Haven, CT 2014WCMC/GBC_Asize_111113

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MM CASE STUDY

Case Study: Use of Biomarkers in Multiple Myeloma At the 2013 conference of the Global Biomarkers Consortium, which took place October 4-6, 2013, in Boston, Massachusetts, David G. Roodman, MD, PhD, director, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, discussed the use of personalizing therapy in the management of multiple myeloma.

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utcomes associated with multiple myeloma (MM) have improved dramatically in recent years with the development of the serum free light chain (sFLC) assay, the advent of gene expression profiles that predict cytogenetic abnormalities, and the introduction of novel agents for treatment.

Case: Lower Lumbar Pain Increasing in Intensity A 65-year-old female presents with low lumbar back pain that has increased in intensity over the past 6 months despite conservative therapy. Otherwise, she has been in her usual state of health. Her Eastern Cooperative Oncology Group performance status is 1.

Due to their short half-life (approximately 6 hours in serum), light chain assays can rapidly determine response to therapy as well as early relapse.

Other diagnoses besides lumbosacral strain are considered.

The diagnostic evaluation includes a blood workup that reveals anemia (hemoglobin 11.5 g/dL) and renal dysfunction (serum creatinine 2.5 mg/dL) on routine screening, whereas these values were normal 1 year earlier. Her total serum protein is elevated.

The laboratory values prompted her physician to order urine electrophoresis, with the suspicion of a plasma cell proliferative process.

Table 1

International Staging System for Symptomatic Myeloma

Stage

Criteria

1

Serum β2-microglobulin <3.5 mg/L and serum albumin ≥3.5 g/dL

2

Not stage 1 or 3

3

Serum β2-microglobulin ≥5.5 mg/L

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KEY POINTS Therapy for patients with MM should be tailored according to: ➤ The biology of the disease (cytogenetics, FISH, gene expression profile signature, microRNA profiles, and proliferation can all be assessed, but their utility in selecting among different therapies is still under investigation) ➤ Comorbidities and toxicities (age, renal failure, neuropathy, cytopenias, risk of thrombosis) ➤ Quality of life for patient ➤ Previous therapy and response

Serum protein electrophoresis reveals no monoclonal protein, but the free kappa light chain level is 7600 mg/L (normal up to 19.4 mg/L); lambda light chain is 3.22 mg/L. Kappa/ lambda ratio = 4520. Her albumin is 3.5 g/dL, and her β2-microglobulin is 3.5 mg/dL. “One of the major advances in following patients with MM is the development of the sFLC assay,” said Roodman. “Immunoglobulins are made of light chains and heavy chains, and there are hidden epitopes when the light chains and heavy chains are combined. Once they break apart, these epitopes are exposed. Kappalambda light chain epitopes that are exposed when taken apart can be used to follow the patient and determine their risk.”

Because of their short half-life (approximately 6 hours in serum), light chain assays can rapidly determine response to therapy as well as early relapse.

Serum albumin and β2-microglobulin are important markers in MM; β2-microglobulin reflects tumor burden. An International Staging System (ISS) for symptomatic MM, developed in 2005 (Table 1), uses serum albumin and β2-microglobulin. At the time the ISS was developed, patients who met the criteria for stage 1 disease had a median survival of about 5.5 years, and those who met stage 3 criteria – indicating a high tumor burden – had a median survival of about 2.5 years. Median survival has changed over time since the introduction of novel therapies, said Roodman.

A skeletal survey should be performed when MM is suspected, as MM is the most frequent cancer to involve the skeleton, he said.

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MM CASE STUDY

High-Risk Features Table 2 Diagnostic Criteria for Myeloma Her bone marrow aspirate reveals 30% kappa-restricted plasma cells, and Patient Criteria MGUS1,2 Smoldering Myeloma1 Active Myeloma her cytogenetics and fluorescence in situ M protein <3 g/dL spike ≥3 g/dL spike and/or In serum and/or urine2 hybridization (FISH) studies are consisMonoclonal <10 ≥10 ≥102 tent with high-risk MM. A bone survey plasma cells in reveals lytic lesions at T8, T9, and T10. bone marrow, % Cytogenetics and FISH of the plasma cells should be part of the End-organ damage None None ≥1 CRAB feature3 evaluation, said Roodman.

C: Calcium elevation (>11.5 mg/L or ULN) MM is an extremely heterogeR: Renal dysfunction (serum creatinine >2 mg/dL) neous disease in terms of its genetA: Anemia (Hb <10 g/dL or 2 g <normal) ics. “Ninety-eight percent of MM B: Bone disease (lytic lesions or osteoporosis) patients have some abnormal genetOnly patients with symptomatic MM should be treated. ic subtype,” he said. “About half are Hb indicates hemoglobin; MGUS, monoclonal gammopathy of undetermined signifihyperdiploid in terms of the karyocance; ULN, upper limit of normal. type and half are hypodiploid.”

Molecular characterization of the 1. International Myeloma Working Group. Br J Haematol. 2003;121:749-757.

2. Kyle RA, et al. N Engl J Med. 2002;346:564-569. tumor cells, along with β2-micro3. Durie BG, et al. Hematol J. 2003;4:379-398. globulin level, gene expression profiles, proliferative index, and the type of monoclonal protein, can help differentiate between high-risk and low-risk myeloma. MM Bortezomib-containing regimens may improve outrisk categories on the basis of these risk factors are shown comes in patients with poor prognostic characteristics in Table 2. based on age, renal impairment, and high-risk cytogenetPatients with t(11;14), (6;14), (4;14), or (14;16) and ics. The addition of bortezomib to thalidomide and hyperdiploidy or low β2-microglobulin have “good-risk” dexamethasone improves progression-free survival (PFS) MM, with a median survival of about 8 years. Those in poor prognosis subgroups, including those with t(4;14) patients with deletion 17p have a much worse prognoand deletion 17p. sis, with a median survival of only 2.5 years. “Usually Short induction with weekly bortezomib followed by patients with 4;14 translocation have deletion 13p by maintenance resulted in similar response rates but shortcytogenetics, which is a high-risk feature,” he said. “If er PFS and overall survival in high-risk versus stanthey don’t have the deletion, they’re intermediate risk.” dard-risk cytogenetic groups.

Diagnosis: MM ISS Stage 2 This woman was diagnosed with active MM ISS stage 2 with high-risk features due to adverse cytogenetics and FISH studies. The patient is a transplant candidate. Her initial therapy is bortezomib, lenalidomide, and dexamethasone, with monthly zoledronic acid. She achieves a complete response 3 months later.

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After 15 months, her kappa light chain is found to be 7400 mg/L, and multiple new lesions are found on her skeletal survey. She is entered into a clinical trial to receive carfilzomib, lenalidomide, and dexamethasone.

Multiple novel treatment options are already available for MM, and more than 40 new targets are being pursued in clinical trials. u

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Conference Co-Chairs

Program Director Lillie D. Shockney, RN, BS, MAS Sharon Gentry, RN, MSN, AOCN, CBCN

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ASH 2013

Hematologists Question Panel About Guidelines and Performance Measures At a special symposium on quality and clinical practice guidelines during ASH, guideline developers fielded questions from hematologists. Panelists included Holger Schünemann, MD, PhD, of McMaster University in Hamilton, Canada, an expert in guideline development; and Lee H. Schwamm, MD, executive vice chair of neurology at Massachusetts General Hospital, Boston, MA, who chairs the Get With The Guidelines – Stroke clinical work group.

Following are some of those exchanges.

Holger Schünemann, MD, PhD

How do you keep guidelines up to date?

Dr Schwamm This is a tremendous challenge. We need to be with the guidelines, not ahead of them. Randomized controlled trials need to be digested and reviewed, and systematic processes applied. This means a professional commitment by members of our societies to engage in guideline updates and review and to shorten the cycle it takes to produce quality guidelines.

With changes in the US healthcare system, and with constrained resources, how do we incorporate cost-effectiveness into guidelines?

Dr Schwamm We often think of resources as being about the cost of drugs. But societal costs are also significant, and the patient is bearing an increasing proportion of the burden. Shifting care from inpatient to outpaLee H. Schwamm, MD tient settings may save hospitals money, but it increases the patient burden dramatically.

The conversation ultimately occurs with the patient at the bedside, and this conversation should include understanding what the therapy will cost the patient.

Adherence will be greater when treatment is presented in the context of what the patient can afford.

Dr Schünemann The answer is that resources need to be invested in order to determine which resources need to be expended. We must have adequately trained individuals supporting the guideline development process.

Recent studies point to the failure of electronic medical records (EMRs) to provide benefits and suggest that EMRs are huge decrements to physician productivity. It has been reported that physicians spend 12% of their time with patients and 50% on documentation to meet meaningful use requirements. Much of this information is likely

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to be specious. How will this affect guideline development?

Dr Schwamm EMR is the promise of the future and also the disruption of our practices. We have a 10-year journey ahead of us to make documentation a seamless part of what we do and not the bane of our existence.

Regarding quality of the information obtained, it is important to distinguish registry-based quality assurance programs from EMR-derived information. Human intervention is still needed to cull accurate information from physician records and to reconcile information found in 5 different places. We must emphasize to the regulatory bodies the necessity of having registries that do require some human intervention.

Once you move away from safety or emergency interventions, you have guidelines based on a wide distribution of expert biases and patient values – which is the reality of trying to come up with uniform guidelines. The problem is that these guidelines are linked by private and government insurers to pay-for-performance measures and the publication of “report cards.” It seems the fundamental core of the guidelines has been subverted into a means of standardizing practice that ignores disagreement among experts and ignores patient choice.

Dr Schünemann The pay-for-performance issue requires careful choice of the right recommendations. We must look for indicators that reward performance and better patient outcomes. Weak recommendations and suggestions rarely lend themselves for use as performance measures, but they can still be useful – for example, not in documenting whether an intervention was applied but whether shared decision making occurred in an informed way. Weak recommendations also lay out in a transparent way the disagreement among people who interpret the evidence. New guidelines should display this disagreement so that the physician can reflect on this with the patient and weigh the options.

Dr Schwamm It is incumbent upon professional societies to make good measures that are a compromise between the ease of collection and the value of the information. Ideally, we want every physician to know what the guidelines are and to be able to articulate why they are or are not adhering to them. It is important that the next physician to see that patient does not simply correct the first physician’s “mistake” by initiating the recommendation, but that he or she also understands the dialogue. u

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Lenalidomide as Maintenance in Transplant Myeloma Population Still Debated

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hile the FIRST trial in transplant-ineligible patients demonstrated the benefit of continuous lenalidomide, studies in younger transplant patients yielded conflicting results for maintenance lenalidomide, especially with regard to an overall survival (OS) advantage.

Mayo Clinic investigators performed a systematic review and meta-analysis of existing outcome data – updated with data from ASH – to evaluate the role of lenalidomide as maintenance therapy.

They identified 4 randomized controlled trials (IFM 2005-02, CALGB 100104, MM-015, and RV-MMPI209) that met the inclusion criteria, involving 1935 patients who received lenalidomide 10 mg daily after induction or transplant, continued until progression.

mide maintenance after transplantation in 614 myeloma patients younger than 65 years who had not progressed after first-line autologous stem cell transplant. Patients were randomized to maintenance with lenalidomide (1015 mg/day) or placebo until disease progression.

The initial analysis found an improvement in PFS but not OS. To evaluate why no OS benefit was found, the investigators conducted a follow-up analysis.

In the new analysis, median PFS from randomization was 46 months with lenalidomide and 24 months with placebo (P<.001), but despite the longer 77-month follow-up, median OS was still not significantly improved with maintenance lenalidomide, being approximately 80 months in each arm (P=.80).

Meta-Analysis Shows PFS but Not OS Benefit “All 4 studies showed an improvement in PFS [progression-free survival], with an overall 51% reduction in risk of progression (P<.001),” reported Preet Paul Singh, MD. “There was modest [but nonsignificant] improvement in OS with lenalidomide maintenance, with 2 studies showing a benefit and 2 not showing any, resulting in a modest 23% reduction in risk (P=.071).”

But the use of lenalidomide maintenance was also associated with a 62% increase in the risk of second primary malignancies (P=.006), as well as a 4.9-fold increased risk of neutropenia (P<.001), a 2.7-fold increase in thrombocytopenia (P<.001), a 2.3-fold risk in fatigue (P=.01), and a 3.2-fold increase in venous thromboembolism (P=.02).

“The subset of patients benefitting the most from lenalidomide maintenance is not yet defined, and the risks and benefits should be discussed with all patients,” Singh said.

“All 4 studies showed an improvement in progression-free survival, with an overall 51% reduction in risk of progression.”

– Preet Paul Singh, MD

Lenalidomide Maintenance in Updated IFM 2005-02 Analysis Similarly, a new analysis of the multiple myeloma IFM 2005-02 trial showed that lenalidomide maintenance prolongs PFS after stem cell transplantation but does not improve OS. The results are contradictory to those of the CALGB 100104 trial, which found an OS benefit and therefore established the lenalidomide maintenance paradigm.

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“The discrepancy between PFS and OS was still present,” said Michel Attal, MD, of the Centre Hospitalier Regional Universitaire Hôpital Purpan in Toulouse, France. “This is possibly attributed to the shorter survival time after first disease progression in the maintenance arm than is observed in patients receiving placebo.”

Attal called attention to the median second PFS, which was the time from the first progression to the second progression. In this scenario, the placebo arm was superior, with a median second PFS of 24 months versus 13 months with lenalidomide (P=.001). He suggested that the reduced second PFS with maintenance may be the result of resistance clones that emerge after extended treatment with lenalidomide.

Second primary malignancies were also almost twice as high in the lenalidomide arm, and rates of severe neutropenia were 3 times higher.

The meaning of these findings, according to Attal, is that “the benefit of lenalidomide maintenance is an early benefit, occurring in the first 2 years,” after which resistance emerges and creates “a late negative impact of maintenance.” u

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Idelalisib Improves Outcomes in Heavily Pretreated CLL Patients

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planned interim analysis of a phase 3 study shows that idelalisib, a first-in-class selective oral kinase inhibitor, when combined with rituximab is superior to rituximab alone on the end point of progression-free survival (PFS) in patients with heavily pretreated chronic lymphocytic leukemia (CLL).

The 24-week data from the randomized, placebo-controlled trial were presented by Richard Furman, MD, assistant professor of hematology and oncology, Weill Cornell Medical College, New York City.

Idelalisib plus rituximab “provided effective, durable disease control and improved overall survival for patients with relapsed CLL who were not suitable for cytotoxic chemotherapy, including high-risk patients,” said Furman.

Idelalisib plus rituximab “provided effective, durable disease control and improved overall survival for patients with relapsed CLL who were not suitable for cytotoxic chemotherapy, including high-risk patients.”

– Richard Furman, MD The study provides the first phase 3 randomized data available for idelalisib, which has been granted breakthrough status by the FDA. Idelalisib targets the delta isoform of the phosphatidyl­ inositol-3-kinase (PI3K-δ) enzyme, which is critical for the activation and survival of CLL cells and other lowgrade B-cell lymphomas. It inhibits homing and retention of malignant B cells in lymphoid tissues, reducing B-cell survival, and it restrains proliferation and induces apoptosis in CLL cells.

In the study, 220 adult patients with relapsed CLL who were deemed unfit for further cytotoxic chemotherapy because of comorbidities and who had measurable lymphadenopathy that had progressed following completion of previous therapy were randomized to receive a combination of either idelalisib twice daily and rituximab or placebo twice daily and rituximab continuously

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until disease progression or death. Patients were eligible for the trial if they had received at least 1 anti-CD20 antibody-containing therapy or at least 2 cytotoxic therapies. Patients had a median of 3 prior therapies before enrollment, with 90% having received prior rituximab.

The median patient age was 71 years.

After 24 weeks, the PFS for the combination idelalisib/rituximab group was 93%, compared with 46% for those treated with rituximab alone (P<.0001). The median PFS has not yet been reached in the idelalisib/ rituximab arm; it was 5.5 months in the rituximab/placebo arm. Patients in the idelalisib/rituximab arm had a significantly better overall response rate relative to the patients treated with rituximab alone (81% vs 13%, respectively; P<.0001) in addition to a higher lymph node response rate (93% vs 4%, respectively).

Patients randomized to idelalisib/rituximab also experienced a 72% improvement in overall survival compared with the control group (P=.018).

The combination of idelalisib plus rituximab had an acceptable adverse event profile, said Furman.

Grade ≥3 adverse events were reported in 56.4% of patients in the idelalisib/rituximab arm compared with 47.7% in the rituximab/placebo arm. The most common adverse events included transaminitis, pyrexia, fatigue, nausea, chills, diarrhea, and infusionrelated reactions.

Most study discontinuations were due to disease progression, though 9 patients in the combination arm and 11 in the control arm discontinued due to adverse events.

With several new agents on the horizon for the treatment of CLL, the optimal sequence of therapies will be ripe for exploration. Said Jennifer Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute, “That’s going to depend to some extent on emerging patterns of resistance and whether some agents may work better than others based on those emerging patterns of resistance. Certainly, combinations of these agents will be of great interest, and I think that’s what we’ll be evaluating over the next 5 years or so.”

Furman said that he sees idelalisib being used beyond the heavily pretreated CLL patient population. “Given the efficacy and low risk for long-term toxicities demonstrated, we believe this treatment could be applicable to all CLL patients because it eliminates the need for chemotherapy,” he said. u

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Novel Anti-CD20 Antibody Superior to Rituximab on Progression-Free Survival in Unfit CLL Patients

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binutuzumab, a novel, glycoengineered, type II CD20 antibody, in combination with chlorambucil was superior to rituximab plus chlorambucil in prolonging progression-free survival (PFS) in previously untreated patients with chronic lymphocytic leukemia (CLL) with comorbidities.

Treatment with obinutuzumab also led to a significantly higher objective response rate, and more patients treated with obinutuzumab were negative for minimal residual disease (MRD) in the bone marrow and blood, announced Valentin Goede, MD, hematologist/oncologist at the Center for Integrated Oncology, University Hospital Cologne, Germany.

On November 1, 2013, the FDA approved obinutuz­ umab for use in combination with chlorambucil for the treatment of patients with previously untreated CLL. The findings “mean a significant and potentially practice-changing treatment advance for this large patient population,” said Goede. “What we currently know is if we combine obinutuzumab or rituximab with a weaker chemotherapy backbone, obinutuzumab is obviously superior to rituximab, so in this setting I would say that it will substitute for rituximab...at least in the population of elderly patients.”

In CLL11, 781 patients with CLL complicated by comorbidities were randomized to 1 of 3 first-line regimens: chlorambucil alone, chlorambucil plus rituximab, or chlorambucil plus obinutuzumab. To be eligible for the trial, patients had to have a total Cumulative Illness Rating Scale score >6 and/or creatinine clearance <70 mL/min.

Results from the first stage of the trial were reported previously and showed that obinutuzumab/chlorambucil and rituximab/chlorambucil were each associated with significantly better PFS compared with chlorambucil alone.

Updated results from stage I were reported here.

Compared with chlorambucil alone, the risk of disease progression or death was improved by 82% with obinutuzumab (P<.0001). The median PFS was 26.7 months with the combination. Rituximab plus chlorambucil

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produced a 66% reduction in the risk of progression or death, and a 16.3-month median PFS. Overall survival was also superior with obinutuz­umab, with a hazard ratio for death of 0.41 (P=.0022).

In the second-stage analysis, a head-tohead comparison of the 2 combination regimens was conducted. In this comparison, the Valentin Goede, median PFS with obinutuzumab plus chlor­ MD ambucil was 11.5 months greater than with rituximab plus chlorambucil (26.7 vs 15.2 months), corresponding to a 61% reduction in risk by adding obinutuzumab instead of rituximab (P<.0001).

The median PFS with obinutuzumab plus chlorambucil was 11.5 months greater than with rituximab plus chlorambucil (26.7 vs 15.2 months).

Complete responses were achieved in 21% of the obinutuzumab arm versus 7% of the rituximab arm. The overall response rates were 78% with obinutuzumab and 65% with rituximab (P<.0001).

Some 19.5% of patients in the obinutuzumab arm were MRD negative for bone marrow versus 2.6% in the rituximab group (P<.0001). MRD was negative in blood in 37.7% of the obinutuzumab arm versus 3.3% in the rituximab arm.

After a median follow-up of approximately 19 months, survival favors obinutuzumab in the head-tohead comparison with rituximab (P=.0849), although the data for survival remain immature, with fewer than 15% of events included in the analysis, Goede said.

There were more grade ≥3 adverse events with obinutuzumab/chlorambucil than with rituximab/ chlor­ambucil (70% vs 55%). Infusion-related reactions (20% vs 4%) and thrombocytopenia (10% vs 3%) were more frequent in the obinutuzumab arm. u

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ALL: Genetics Providing New Insights Into Signaling Pathways and Treatment Targets

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hose frustrated with low long-term remission rates in adult acute lymphocytic leukemia (ALL) can find hope in the superior outcomes associated with treatment for pediatric ALL. Overall survival with therapy reaches 85% in children but lags at 45% in adults. Targeting specific pathways and adding novel agents to standard therapy should improve outcomes in adult ALL. “To achieve the goal of curing all patients with ALL and reducing toxicity, there is a need for new therapies to target underlying molecular pathology of the disease, which forms the crux of leukemia research at this time,” said Christine Harrison, PhD, professor of childhood cancer cytogenetics, Newcastle University Leukaemia Research Cytogenetics Group, UK.

“There is a need for new therapies to target underlying molecular pathology of the disease.”

– Christine Harrison, PhD

Advances in sequencing technology will identify genes and pathways that are consistently altered in highrisk ALL, which should yield novel targets, she said.

Although virtually all chromosomal abnormalities occur in both adult and childhood ALL, there is a significant difference in the incidence of most cytogenetic subgroups according to age, she said. For example, the good-risk cytogenetic subgroups characterized by ETV6RUNX1 and high hyperdiploidy are seen almost exclusively in young children, whereas the incidence of BCRABL1 increases dramatically with age.

Gene expression profiling has identified a subgroup of BCR-ABL1–like ALL that accounts for 10% to 15% of childhood and 25% of adult precursor B-cell ALL, “and there is evidence for sensitivity to tyrosine kinase inhibitors when incorporated into therapy,” she said.

A recently identified abnormality is intrachromosomal amplification of chromosome 21 (iAMP21). It defines a distinct cytogenetic subgroup of older children (median age 9 years) with precursor B-cell ALL and is “associated with a dismal outcome” and a high risk of early and late relapse. When standard therapy is used, prognosis is

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poor, but modified treatment with high-risk regimens significantly improves outcomes.

Looking Into Pharmacogenomics Relapse of childhood ALL is unacceptably high for some subgroups. Inherited genomic variation contributes to the risk of relapse and to adverse effects of therapy, said Mary Relling, PharmD, chair, Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN. Her laboratory is using candidate gene interrogation and is applying genome-wide approaches such as gene expression profiling, genome-wide single nucleotide polymorphism (SNP) analyses, and whole exome/genome sequencing of patients undergoing uniform treatment to identify genes and genome variations that determine the disposition and effects of antileukemic agents.

The goal is to elucidate the genomic determinants of toxicity and efficacy of antileukemic agents.

In scanning the genomes of children with ALL and controls, 6 of 18 SNPs that differed in frequency between the 2 groups were associated with 1 of the 4 main subtypes of ALL. Two SNPs were linked to the ARID5B gene.

Polymorphisms in ARID5B are highest among Hispanics and lowest in blacks, “which mimics the frequency of childhood ALL in these racial groups,” she said.

They could account for some of the racial disparities in outcome of ALL therapy due to the higher frequency of variants associated with relapse in Hispanics, she said.

Inherited variations in ARID5B were found to influence the response to methotrexate and to be associated with enhanced accumulation in leukemia cells, allowing for lower doses.

They have also found evidence that ALL subtypes differ in their responsiveness to asparaginase. Using a genome-wide approach, they discovered that both inherited and acquired genomic interindividual variation in the aspartate metabolic pathway contribute to resistance to asparaginase in ALL. At present, genetic testing of thiopurine methyltransferase (TPMT) is being conducted before initiation of thiopurines to minimize acute myelosuppression, said Relling. Acute myelosuppression can be prevented by adjusting doses of thiopurines based on TPMT phenotype or genotype without compromising these agents’ effectiveness.

Antibody-Based Therapies New antibody therapies that target cell surface anti-

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gens were reviewed by Anjali Advani, MD, staff physician, Hematologic Oncology and Blood Disorders, Cleveland Clinic, Cleveland, OH. Rituximab, a naked antibody, targets CD20. Although only half of precursor B-cell ALL cases express CD20 on 20% or more lymphoblasts, CD20 expression is associated with a shorter duration of remission and worse overall survival in adult ALL, making CD20 an attractive target to combine with chemotherapy.

Epratuzumab is a humanized monoclonal antibody that targets CD22, a regulator of B-cell activation and the interaction of B cells with T cells, said Advani. In a phase 1 study, surface CD22 was not detected on flow cytometry on peripheral blood leukemic blasts within 24 hours of epratuzumab administration. Later-phase clinical trials showed a higher rate of complete molecular remission (CMR) when epratuzumab was combined

with backbone chemotherapy compared with chemotherapy alone.

Bispecific single-chain T-cell engaging (BiTE) antibodies retarget cytotoxic T-cell lymphocytes at preselected surface antigens on tumor cells. Blinatumomab is the first member of the class of BiTE antibodies; it combines a CD3 binding site for T cells and a CD19 binding site for B cells, thereby creating the opportunity for T cells to destroy B cells. In a small 4-week study, infusions of blinatumomab led to B-cell depletion, an 80% CMR, and a relapse-free survival rate of 61% at 3 months of follow-up.

Inotuzumab ozogamicin is a promising monoclonal antibody against CD22 bound to calicheamicin for the treatment of relapsed/refractory ALL. A response rate of 57% was obtained in a phase 1/2 trial of heavily pretreated adults with refractory CD22-positive ALL. u

Anti-CD20 Agent Improves Outcomes in Elderly/ Unfit Patients With Chronic Lymphocytic Leukemia

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lderly and unfit patients constitute the majority of patients with chronic lymphocytic leukemia (CLL), but unfortunately these groups have limited treatment options. A second-generation fully humanized monoclonal antibody against the CD20 protein, ofatumumab, added to chlorambucil improves clinical outcomes and is tolerable irrespective of age and fitness in patients with previously untreated CLL who are considered inappropriate for fludarabine, according to the results of a phase 3 study.

In older CLL patients who are unfit for the gold standard therapy of fludarabine-cyclophosphamide-rituximab, chlorambucil using various dosing schedules remains a treatment option, said Peter Hillmen, MD, PhD, lead investigator of the study and consultant hematologist, Leeds Teaching Hospitals NHS Trust, St. James University Hospital, Leeds, UK. Ofatumumab has a discrete epitope that targets both the small and large extracellular loops of CD20. In vitro, it displays more activity through complement and through antibody-dependent cellular cytotoxicity than rituximab.

In the phase 3 study, known as COMPLEMENT 1, 447 patients with previously untreated CLL who were considered inappropriate for fludarabine-based therapy

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based on advanced age and/or comorbidities were randomized to chlorambucil or ofatumumab plus chlorambucil until best response.

Ofatumumab was given as an intravenous infusion for a maximum 12 cycles. Chlorambucil was dosed orally at 10 mg/m2 on days 1 through 7 of each 28-day cycle.

About one-fourth of the patients were older Peter Hillmen, than 75 years; 87% in each group were either MD, PhD ≥65 years or had ≥2 comorbidities or a creatinine clearance <70 mL/min and thus ineligible for flu­ dar­abine, said Hillmen.

Nineteen percent of patients in each arm required chlorambucil dose reduction as a result of experiencing neutropenia. After a median follow-up of 28.9 months, progression-free survival, as assessed by an Independent Review Committee, was 22.4 months in the ofatumu­ mab-chlorambucil arm compared with 13.1 months in the chlorambucil alone arm, corresponding to a 43% improvement with ofatumumab (P=.001). Overall survival (OS) was also significantly superior in the ofatumumab arm (82% vs 69%; P<.001), as was the rate of complete response (14% vs 1%). The median OS was not reached in either arm.

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Twelve percent in the ofatumumab-chlorambucil arm were negative for minimal residual disease compared with 4% in the chlorambucil alone arm.

There was a trend toward a shorter time to response in the ofatumumab-chlorambucil arm versus the chlorambucil alone arm (median: 1.1 vs 1.9 month; P=.084). The median duration of response was longer in the ofatumu­ mab-chlorambucil arm at 22.1 versus 13.1 months (P<.001) in the chlorambucil alone arm. The time to next treatment was also significantly longer in the ofatumu­ mab-chlorambucil arm versus chlorambucil alone, with a median 39.8 versus 24.7 months (P<.001).

More than 80% of patients completed at least 6 cycles. Combination treatment was well tolerated. The rate of withdrawal from treatment due to adverse events was 13% in each arm. The rate of grade ≥3 adverse events was 50% with ofatumumab-chlorambucil versus 43% with chlorambucil alone; 10% in the ofatumu­mabchlorambucil arm had grade ≥3 infusion reactions. There was a higher rate of grade ≥3 neutropenia in patients assigned to ofatumumab-chlorambucil compared with chlorambucil alone (26% vs 14%), but this difference did not translate into a higher risk of infection, said Hillmen. u

More Transplants Made Possible Through Haploidentical Donors

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or the treatment of leukemia and other hematologic malignancies, the pool of donors for hematopoietic stem cell transplant can be greatly expanded through the use of haploidentical, or half-matched, donors, according to research groups who reported studies with good outcomes at ASH. With allogeneic bone marrow transplant (BMT), finding a suitable donor can be a challenge. Only one-quarter of siblings will be a human leukocyte antigen (HLA) match, and HLA matches among the pool of unrelated donors are rare. Time is also a factor in coordinating a transplant from an unrelated donor. When a fully HLA-matched donor is not available, transplants of haploidentical hematopoietic stem cells can be effective, the studies suggest.

“Almost every patient has at least 1 haploidentical relative, but until recently, haploBMT carried excessive risks.”

– Yvette L. Kasamon, MD

“Almost every patient has at least 1 haploidentical relative, but until recently, haploBMT carried excessive risks,” said Yvette L. Kasamon, MD, of Johns Hopkins University, Baltimore, MD, one of the pioneering centers for haploidentical transplants.

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The primary risks include disease recurrence and the development of graft-versus-host disease (GVHD), but the studies reported at ASH found these risks to be minimal.

Laurence Cooper, MD, PhD, of MD Anderson Cancer Center, Houston, TX, who moderated the press conference where the studies were described, said these approaches “move the technology forward,” which promises to expand the number of patients who can receive transplants.

Haploidentical transplant, he said, “shortens the time to finding the donor. We don’t have to pull potential donors from a massive registry. We will often find a donor in the same room as the patient.”

Posttransplant Cyclophosphamide Is Safe and Effective in the Elderly Kasamon and colleagues demonstrated that advanced age need not be a prohibiting factor in haploidentical transplantation when patients are otherwise transplant eligible, at least when using a reduced-intensity regimen and posttransplant cyclophosphamide, which can be delivered in the outpatient setting.

“We found no apparent decrement in overall outcomes in patients aged 60 and older, or even 70 to 75, compared to those in their 50s,” Kasamon said. “Since many elderly patients may lack a suitable matched sib donor, the haplo option becomes even more attractive.”

She said at a press briefing that, in most cases, Hopkins no longer searches for a matched unrelated donor for patients with a relative who is a potential haploid donor.

The study was a retrospective review of 273 patients

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aged 50 to 75 years who received a nonmyeloablative regimen and haploBMT with posttransplant high-dose cyclophosphamide plus drugs for GVHD prophylaxis.

This resulted in a low rate of acute GVHD (32% for all grades and 3% for grades 3/4), a low rate of chronic GVHD (12% at 1 year), a 1-year relapse rate of 37%, and a 6-month nonrelapse mortality rate of 11%. By age, outcomes were comparable, and nonrelapse mortality was similar, she reported.

“These results underscore that a reduced-intensity, related haploidentical transplant should be considered a very reasonable treatment option for suitable patients, up to at least age 75, who require a transplant,” Kasamon said.

Improvements in Outcomes Through Graft Manipulation European investigators described a means of making haploidentical transplants safer and more effective through the removal of cells that are most likely to trigger donor cells to attack recipient cells, leading to GVHD, while retaining cells that will be protective.

“We recently developed a new method of graft manipulation based on the physical removal of alpha/ beta-positive T cells and CD19-positive B cells, which permits us to leave mature natural killer cells and gamma/delta-positive T cells in the graft, which help prevent relapse and protect against infection,” said Alice Bertaina, MD, of the Bambino Gesu Children’s Hospital in Rome, Italy.

“The selective graft manipulation results in effective prevention of both acute and chronic GVHD, rapid recovery of neutrophil and platelet counts, and low transplant-related mortality,” she said. “Although the median observation time is still limited, the cumulative incidence of disease recurrence is encouraging.”

Their study included 50 children with acute lymphoblastic or acute myeloid leukemia with a parent serving as the haploidentical donor. The donor’s blood was filtered through a column where magnetic microbeads captured and separated the T cells to be retained from those slated for elimination. Patients underwent a myeloablative regimen, with or without total body irradiation, and received antithymocyte globulin and rituximab.

Over 36 months, the cumulative incidence of transplant-related mortality was only 4%, the relapse rate was just 19%, and the leukemia-free survival rate was 77% and rising to 80% in the subset with acute lymphoblastic leukemia. The incidence of acute GVHD was 26%, and no child developed gut or liver acute disease.

Bertaina predicted that using this approach, more patients will receive transplants and fewer will die during the procurement of an unrelated donor.

“Until now, we have searched for unrelated volunteer donors, but it is difficult to propose to the parents that we must wait for this search before we treat,” she said. “These results open another avenue and show that it can actually be advantageous to choose a haploidentical relative.” u

Ph+ CML: Deep Molecular Response Achieved and Sustained More Often With Nilotinib

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hree large randomized phase 3 trials demonstrated superiority of nilotinib over imatinib in achieving molecular response (MR) and complete cytogenetic response (CyR) across various populations of patients with Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML), including those who had a suboptimal response to frontline imatinib.

LASOR: Frontline Imatinib Failures In patients who do not achieve a complete CyR with frontline imatinib, higher rates of MR are achieved by switching to nilotinib compared with escalating the dose of imatinib to 600 mg daily, reported Jorge E. Cortes, MD, chair, CML and AML

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sections, MD Anderson Cancer Center, Houston, TX. “Patients with suboptimal CyR to imatinib represent a significant unmet need in the treatment of CML chronic phase,” said Cortes. “This important study is the only randomized evaluation of imatinib dose escalation versus switching to the more potent BCR-ABL tyrosine kinase inhibitor nilotinib in this population.”

The study included 191 adults with suboptimal CyR to frontline treatment with imatinib 400 mg once daily who were randomized to nilotinib 400 mg twice daily or imatinib 600 mg once daily. The primary end point, complete CyR at 6 months, was observed in 49.0% and 42.1% of patients in the nilotinib and imatinib arms, respectively, but this difference failed to achieve signifi-

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cance (P=.3844). The high rate of crossover from imatinib to nilotinib confounded the results, said Cortes. Fifteen patients in the imatinib arm crossed over, compared with 6 in the nilotinib arm.

“None of the nilotinib patients who crossed over to imatinib versus 6 of the 15 imatinib patients who crossed over to nilotinib achieved complete CyR at the primary analysis time point 6 months after randomization,” he noted.

“This important study is the only randomized evaluation of imatinib dose escalation versus switching to the more potent BCR-ABL tyrosine kinase inhibitor nilotinib in this population.”

– Jorge E. Cortes, MD The clinical benefit of nilotinib is therefore best evaluated when considering crossover patients as nonresponders, he said. In this type of analysis, 47 of 86 patients (54.7%) in the nilotinib arm and 34 of 88 (38.6%) in the imatinib arm achieved complete CyR at 6 months.

ENESTnd: Newly Diagnosed Patients Updated 5-year data from the open-label, randomized multicenter ENESTnd trial support nilotinib as first-line therapy in adults with newly diagnosed Ph+ CML in chronic phase, said Giuseppe Saglio, MD, director of the department of molecular medicine and targeted therapy, University of Turin, Italy. Some 846 patients were randomized to nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, or imatinib 400 mg once daily.

REPRINTS

The rates of early and deeper sustained MR, including MR4.5, were higher with nilotinib at either dosage compared with imatinib. At 1 year, the rate of MR4.5 was 6% to 19% greater with nilotinib compared with imatinib, and by 5 years, this difference reached 21% to 23%, said Saglio.

Further, fewer patients on nilotinib progressed to accelerated phase/blast crisis (AP/BC). The estimated rates of patients whose disease did not progress to AP/BC at 5 years were 99.3% and 98.7% in the nilotinib arms (300 mg and 400 mg twice daily, respectively) versus 95.2% in the imatinib arm.

Fifteen patients treated with imatinib had CML-related deaths, compared with 10 patients in the nilotinib arms.

Estimated overall survival at 5 years was 93.6% and 96.0% in the nilotinib 300-mg and 400-mg twice-daily arms, respectively, compared with 91.6% in the imatinib arm.

ENESTcmr: Patients With Residual Disease Three-year data from ENESTcmr, an open-label, randomized phase 3 study, demonstrate that Ph+ CML patients with detectable BCR-ABL following longterm treatment with imatinib achieved deeper molecular responses after switching to nilotinib, reported Brian Leber, MD, associate professor of pathology and molecular medicine, McMaster University, Hamilton, Canada.

In ENESTcmr, 207 patients were randomized to nilotinib 400 mg twice daily or imatinib 400 mg or 600 mg once daily. Seven of 32 responders in the imatinib arm achieved MR4.5 after switching to nilotinib.

Among patients without documented MR4.5 at baseline, the cumulative incidence of MR4.5 was higher in patients randomized to nilotinib versus imatinib (46.9% vs 33.3%; P=.0453). MR4.5 was achieved faster, with a median time to response of 24.0 months in the nilotinib arm, and was not reached in the imatinib arm (P=.0011). By 36 months, no patients in either arm had progressed to AP/BC. u

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FIRST Trial Shows Value of Continued Use of Lenalidomide in Newly Diagnosed Myeloma Patients

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he value of the continued use of lenalidomide in patients with newly diagnosed multiple myeloma was front and center among more than 800 abstracts on multiple myeloma presented at ASH. Featured in a Plenary Session were results from the phase 3 FIRST trial (Frontline Investigation of Revli­ mid + Dexamethasone Versus Standard Thalidomide) in newly diagnosed multiple myeloma patients ineligible for stem cell transplantation. FIRST is the largest trial ever conducted in multiple myeloma.

The key finding of FIRST was that lenalidomide given continuously to newly diagnosed, transplant-ineligible patients prolongs both progression-free survival (PFS) and overall survival (OS). The hazard ratio (HR) of 0.72 for PFS, the study’s primary end point, was highly statistically significant, thus establishing continuous lenalidomide “as a new standard of care,” according to Thierry Facon, MD, of the Hôpital Claude Huriez and CHRU Lille in Lille, France.

Discussing the study was Jesús F. San Miguel, MD, PhD, professor of medicine and head of hematology at the Hospital Universitario de Salamanca, Salamanca, Spain, who agreed with the investigators.

“Continuous lenalidomide plus low-dose dexamethasone demonstrates a significant PFS and OS advantage,” San Miguel noted. While suggesting that some questions remain to be answered – such as the role of alkylators (ie, melphalan) in light of these findings, and the identification of the population most likely to benefit from this approach – he commented, “Overall, we have a new standard of care that is active, convenient, and has excellent tolerability.”

Study Details The study enrolled 1623 patients, aged ≥65 years (median age 73) or otherwise ineligible for stem cell transplant. Unlike many other trials, patients with renal insufficiency were allowed, making this essentially a “real-life patient population,” Facon noted.

Patients were randomly assigned to receive continuous lenalidomide (Rd), lenalidomide for 72 weeks (Rd18), or melphalan/prednisone/thalidomide (MPT) for 72 weeks.

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Among the study’s main findings were: • Median PFS, the primary end point, was 25.5 months with Rd, 20.7 months with Rd18, and 21.2 months with MPT. The HR for the primary comparison (Rd vs MPT) was 0.72 (P=.00006). For Rd versus Rd18, the HR was 0.70 (P=.00001) • 3-year PFS was 42% with Rd and 23% in the other arms; the 2 lenalidomide arms were equivalent until month 18, when the curves markedly separated • A consistent benefit was seen across most subgroups • Rd was superior to MPT across all secondary efficacy end points • There were no unexpected toxicities

“We have a new standard of care that is active, convenient, and has excellent tolerability.”

– Jesús F. San Miguel, MD, PhD

The interim analysis for OS, with 35% of the intentto-treat arms having died, was significantly improved with continuous lenalidomide treatment. At 4 years, 59.4% of Rd patients were alive, compared with 51.4% on the MPT arm (HR 0.78; P=.0168) and 55.7% on the Rd18 arm (P=.307). The time to progression and time to second antimyeloma therapy were also significantly prolonged with Rd (P=.00001 for both).

The rate of secondary hematologic malignancies was low overall but was actually higher in the MPT arm, with 12 patients (2.2%) developing hematologic malignancies compared with 2 patients (0.4%) in each lenalidomide arm. Solid tumors developed in 2.8% of both the MPT and Rd arms and in 5.4% of the Rd18 arm.

“In the relapse setting, len/low-dose dex has been shown very safe in terms of second malignancies, and this trial confirms it is also safe in the first-line setting,” Facon said. u

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Novel CAR-T Therapy Topped the News at ASH

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xcitement was palpable at ASH this year over a novel approach to treating subtypes of leukemia and lymphoma. Although still limited to pilot studies in small numbers of patients, the findings for engineered T cells – so called CAR-T therapy – are very impressive. Patients with highly aggressive and refractory disease have had dramatic responses to therapy, achieving complete remissions and no longer demonstrating signs of tumor on CT scans. Some remissions are ongoing for up to 3 years.

“It looks like the disease has disappeared after a single infusion of these engineered T cells,” said James Kochenderfer, MD, from the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI).

“We are tremendously excited about these results. About half of our CLL patients responded to this therapy, with most of them having several pounds of tumors eradicated by the genetically modified T cells.”

– David Porter, MD The pace of research is rapid, with several pharmaceutical companies now working in partnership with the NCI and the University of Pennsylvania. Other studies are ongoing at MD Anderson Cancer Center. Researchers estimate the therapy could become available as early as 2016.

The approach takes advantage of the fact that the CD19 protein is expressed almost universally on B cells. The process involves extracting T cells from the patient, subjecting the cells to chimeric antigen receptor (CAR) cell engineering, and then infusing the engineered T cells back into the patient. The engineering takes about 10 days and alters the T cell through 1) the addition of a receptor that targets the CD19 antigen on leukemic cells, and 2) the insertion of a viral vector into the cells that triggers the T cells to expand, proliferate, and seek out and destroy all remaining cancer cells.

Michael Kalos, PhD, from the University of Pennsyl-

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vania, maintained that engineered T cells are “poised to replace bone marrow transplants with a therapy that is less expensive and is more widely available.”

NCI Study Results in Lymphoma Kochenderfer presented results from the NCI’s study of 15 adult patients with advanced B-cell lymphomas, including 9 patients with chemotherapy-refractory disease (some with up to 10 prior lines of treatment). Patients received reduced-intensity conditioning and then an infusion of their own T cells that had been CAR engineered. Of 13 evaluable patients, 12 responded: 7 patients had complete remissions, 5 had partial remissions, and 1 had stable disease.

“Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable,” Kochenderfer said at a press briefing.“We are particularly encouraged by the partial and complete responses that we observed in a number of patients with diffuse large B-cell lymphomas who had exhausted all other treatment options...and who are not generally thought to be good candidates for hematopoietic stem cell transplantation,” he added.

Lymphoma patients are also being treated at MD Anderson Cancer Center, with a nonviral gene transfer approach that expresses “second-generation” CD19-specific T cells. Four patients with non-Hodgkin lymphoma treated with a high T-cell dose are in remission after 3 months, according to Partow Kebriaei, MD. Summary of Trial Data in CLL and ALL Kalos summarized the clinical results to date for adult patients with advanced relapsed or treatment-refractory chronic lymphocytic leukemia (CLL) and both adult and pediatric patients with treatment-refractory acute lymphocytic leukemia (ALL).

In 2 studies, 32 adult patients with CLL have been treated, of whom 15 achieved partial responses and 7 achieved complete responses. All of these complete responses are ongoing, Kalos reported.

Coinvestigator at the University of Pennsylvania, David Porter, MD, added, “We are tremendously excited about these results. About half of our CLL patients responded to this therapy, with most of them having several pounds of tumors eradicated by the genetically modified T cells.”

“We’ve now seen remissions lasting for more than 3 years, and there are clues that the T cells continue to kill leukemia cells in the body for months after treatment.

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Even in patients who had only a partial response, we often found that all cancer cells disappeared from their blood and bone marrow, and their lymph nodes continued to shrink over time. In some cases, we have seen partial responses convert to complete remissions over several months,” Porter said.

Also at the University of Pennsylvania, 22 children with ALL have been treated, of whom 19 (86%) achieved a complete response, which is ongoing in 14 patients. Five adults with ALL have been treated, all achieving a complete response and 4 of which are ongoing, some out to 18 months.

“Our results demonstrate the potential of this treatment for patients who truly have no other therapeutic option,” said Stephan Grupp, MD, a coinvestigator. “In the relatively short time that we’ve observed these pa-

tients, we have reason to believe that this treatment could become a viable therapy for their relapsed, treatment-resistant disease.”

Toxicity Profile The treatment is not without toxicity. Most patients have developed cytokine release syndrome, which produces high fever, hypotension, respiratory problems, delirium, and other concerning symptoms that usually require a stay in the intensive care unit. However, most patients recover within 2 days, and symptoms resolve within 3 weeks.

Grupp said the symptoms associated with delayed cytokine release can be severe but can be managed with the monoclonal antibody tocilizumab, which he called a “game changer” for controlling these toxicities. u

Hematologists Often Ignore Treatment and Monitoring Recommendations

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ost hematologists and oncologists do not follow evidence-based recommendations for managing acute or chronic myeloid leukemia (AML, CML) or B-cell lymphomas, according to survey results compiled by inPractice Resources LLC, a company that develops interactive educational resources for oncologists.

Among the deficiencies: approximately 40% of clinicians were not appropriately monitoring treatment response in CML, and 20% were inappropriately using cytogenetic testing.

While acknowledging that advances in understanding CML, AML, and B-cell lymphomas and the emergence of new treatments have increased the complexity of decision making in patient care, Kevin Obholz, PhD, editorial director for inPractice Resources, noted, “a significant proportion of US hematology/ oncology specialists are not applying optimal care” for these malignancies.

The investigators aimed to identify and quantify professional practice gaps and barriers to optimal care for patients treated at both academic and community centers. To do so, they recruited 250 physicians and interviewed 27 for the initial qualitative exploratory phase of the study. The focus was on the personal, contextual, and behavioral factors that influence a provider’s clinical reasoning process in diagnosis and treatment.

These interviews were analyzed using thematic anal-

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ysis, and the findings shaped the subsequent quantitative phase of the study. For this, 121 physicians completed an online survey of multiple-choice questions, differential rating scales, and case vignettes. A group of expert hematologists provided evidence-based responses for comparison.

“A group of 9 core practice gaps were identified through combined analysis of data from the online surveys and in-depth interviews,” the authors reported.

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Treatment Recommendations Often Not Followed The current treatment guidelines recommend the tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, and nilotinib as first-line therapy; dasatinib and nilotinib are second-generation agents that have shown superior efficacy and safety over imatinib. Experts suggest these are preferred over imatinib, since they are superior in achieving early responses and major molecular remissions.

Study participants did not adequately recognize that early molecular response to TKI therapy is significantly associated with long-term survival outcomes.

Only 33% of participants agreed with evidence-based expert opinion that early molecular responses to TKIs correlate with long-term clinical outcomes for patients with chronic phase CML. Similarly, only 38% agreed with expert opinion that achieving a major molecular response to TKIs substantially decreases the patient’s risk of disease progression.

The less experienced the clinician, the more likely he or she was to disregard the superiority of the second-generation TKIs in achieving these landmarks, the study found.

“Notably, study participants did not adequately recognize that early molecular response to TKI therapy is significantly associated with long-term survival outcomes, which could impact clinical decisions for patients with chronic phase CML,” Obholz said.

Ignorance of Monitoring and Switching Recommendations There was also a knowledge gap with regard to the appropriate monitoring of response to TKIs. Quantitative polymerase chain reaction (PCR) on peripheral blood is

now the recommended approach, while bone marrow cytogenetics is no longer recommended for monitoring.

The guidelines support cytogenetics at 3 months and 12 months if a major molecular response is not achieved, but 1 in 5 clinicians order these expensive, invasive procedures as often as every 2 to 6 months. PCR should be used every 3 months to monitor response, but only 40% agreed with the guidelines and expert opinion on this issue. Similarly, only 22% of the clinicians agreed with expert opinion regarding timing and frequency of cytogenetic analysis by bone marrow biopsy to assess responses to first-line TKI treatment for chronic phase CML. Therefore, there is overuse of bone marrow cytogenetic analysis by community oncologists and underuse and inappropriate use of PCR, the survey indicated.

In addition, current guidelines suggest that 3-month response on PCR correlates with outcomes, and that if patients do not achieve a good response by this time point they should probably be switched to a new drug, yet 40% of respondents were unsure or would not change therapy at that threshold.

Ignorance of Novel Agents Fewer than 30% knew the mechanisms of action for agents in phase 2 trials, including inotuzumab ozogamicin (27%), blinatumomab (26%), idelalisib (22%), obinutuzumab (20%), and fostamatinib (18%).

Furthermore, when asked to match 9 targeted agents approved for B-cell lymphomas and B-cell acute lymphoblastic leukemia to their molecular target, only 20% of respondents were able to do so.

“This potentially represents missed opportunities to enroll eligible patients on clinical trials,” Obholz said.

“There is a clear need for better education of community physicians. Those with more experience and those in academic centers are more likely to agree with expert recommendations. With these relatively rare hematologic diseases, clinicians need expert-led education targeted to them and tools that will help them learn how to make better decisions.” u

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PM O

Interview With the Innovators A PMO Exclusive Series The world of personalized medicine is a rapidly changing, ever-evolving state involving many stakeholders on the front lines of its creation: physicians, industry, researchers, patient advocates, and payers.

PMO seeks out the leaders in these sectors and brings you their game-changing strategies, missions, and impact on personalizing oncology care.

To view Interview With the Innovators, or to nominate an interviewee, visit us at

www.personalizedmedonc.com

PMO Interviewees include:

Lawrence M. Weiss MD, Clarient Diagnostic Services, Inc. Inno111313

Edith Perez, MD Mayo Clinic

Kimberly Popovits Genomic Health

Edward Abrahams, PhD Personalized Medicine Coalition

THE LAST WORD

New Technology Diffusion Essential to Personalized Medicine An Interview With Dr Gary Owens

D

oes the following statement ring a bell?

“Scientific knowledge about best care is not applied systematically or expeditiously to clinical practice. It now takes an average of 17 years for new knowledge generated by randomized controlled trials to be incorporated into practice, and even then apDr Gary Owens plication is highly uneven.”

It should. Published in the March 2001 Institute of Medicine report, Crossing the Quality Chasm: A New Health System for the 21st Century, and faithfully quoted ever since, this statement would hold a high place if we were to compile a compendium of “Medical Platitudes We Love and Never Implement.” This mantra has a special significance to oncology personalized medicine, which cannot abide a glacial movement of innovation from bench to bedside. Correcting the situation requires vigilance by all stakeholders, from pharma to oncologist, payer to large employer, who must work together to ensure the timely uptake of new treatment options. Lives literally depend on it.

Word needs to get out immediately to the practicing physician and the payer, and pharma should lead the momentumgenerating activity.

So went our conversation with Dr Gary Owens, president of Gary Owens Associates and a renowned authority on payer acceptance of oncology innovation.

He identified diffusion as the essential companion to innovation in driving the success of personalized medicine. As former pharmacy and therapeutics committee chairman at a large Blue Cross plan, Dr Owens’ stance holds a special irony as he urges the fast uptake of expensive new cancer technologies – provided the evidence of value is there, of course. His payer’s keenly honed skills to avoid costly new technologies that lack meaningful improvement make his admonition to step up the pace of diffusion compelling. He points out that researchers have refined cancer innovation so adeptly, living up to its premise of drilling down to disease spe-

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cifics, that other healthcare stakeholders have been caught unprepared to respond and implement many discoveries, hurting patient interests. He maintains that pharma should take the lead in stepping up awareness of new products and their value propositions.

He points up the difference between the incremental improvements of recent conventional drug innovation versus the brilliant, highly targeted therapies that work in small cancer populations. The very core of personalized medicine in oncology demands a lightning response, not years between approval and utilization, he says. Cancer demands a change in the rate of diffusion of its special new technologies, if personalized medicine is to meet its goals in cancer treatment.

Dr Owens pointed out the specific dynamics in play.

Cancer drug/biologics innovation targets increasingly narrow patient subsets. The cost of treatment is high, and the window of opportunity to employ these agents is correspondingly smaller than ever. Consequently, word needs to get out immediately to the practicing physician and the payer, and pharma should lead the momentum-generating activity. He describes a typical scenario and its implications for the patient and indeed the entire healthcare stakeholder community.

“Instead of a drug being developed to target non– small cell lung cancer (NSCLC),” he stated, “it might target nonsquamous NSCLC, then be refined a step further for patients with ALK mutations. When you do that, it comes with a price tag for the agent that is sometimes 6 figures for a year’s therapy, or larger. When you think about that, if these drugs are being misused because the diagnostics are not being applied properly, the waste factor multiplies rather rapidly, doesn’t it?

The value proposition goes out the window if the test isn’t used properly.”

But diffusion doesn’t end there, he cautions. “Not only does the technology have to diffuse into the community and be used,” he observed, “it has to become part of the guidelines itself. These have to turn around quickly enough to help guide therapy. We can’t take the scenario where it takes the guidelines 2 years to catch up with the innovation, then another year or 2 after that for people to actually be using it routinely without failing in clinical practice. Pharma is going to have to help drive that. If they are going to base their pricing and their

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value propositions off these limited populations, then they have to drive the application of the technology that will help us identify these populations.”

Here is a realist, totally familiar with manufacturers, clinicians, researchers, and patients, calling for the manufacturer to pitch in with the rest of the healthcare community. He knows this curious community of healthcare stakeholders, their historical mutual distrust, and their need to pool their resources and redefine responsibilities in the rapidly changing, research-driven oncology field. In reviewing each stakeholder’s interests being served by avoiding overuse/misuse, he dismisses the notion that it is naive to expect pharma to want to limit product usage to only the appropriate patients. Patients don’t like it, making their physicians not like it. Payers don’t like it, nor do employers footing the bill for their employees’ medical plans.

His point is well taken. Ultimately, the very crowding of the oncology field with expensive, targeted drugs makes it essential to their reception for all parties to help validate their use as thoroughly as possible. Overuse is no longer fashionable, and it no longer pays! The undeserved bounty of excess utilization was unavoidable in the blockbuster drug era, before tailoring drug to patient was possible. Thankfully, that train is leaving the station. It is in everyone’s interest to treat an enriched patient population, and overuse of these precious products no longer serves pharma’s or anyone’s

interests, lest these products be abandoned as “too risky to be practical.” That is the market dynamic guiding the matter of diffusion.

The new era of personalized medicine has brought with it technology that makes waste usage of new products as unwanted as their slow uptake into clinical practice. That efficiency was always the premise for personalized medicine. The pace of personalized

It is in everyone’s interest to treat an enriched patient population, and overuse of these precious products no longer serves pharma’s or anyone’s interests. medicine’s discoveries changed everything. The call now for expedient diffusion from an expert on payer and oncology manufacturer practices should help inform the matter. The situation augurs for an era of interstakeholder collaboration. This is a very good prospect, long overdue and badly needed by cancer patients, who stand to benefit from this, not from interstakeholder distrust and isolation. The positive tone of personalized medicine is a fresh breeze blowing through healthcare, and nowhere stronger than in oncology treatment. u

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

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SCIENTIFIC CONFERENCES 2013-2014:

AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Co-Chairpersons: Jeffrey A. Engelman, Lee J. Helman, and Sabine Tejpar October 19-23, 2013 • Boston, MA Twelfth Annual International Conference on Frontiers in Cancer Prevention Research Chairperson: Paul J. Limburg October 27-30, 2013 • National Harbor, MD Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes Co-Chairpersons: John M. Maris, Stella M. Davies, James R. Downing, Lee J. Helman, and Michael B. Kastan November 3-6, 2013 • San Diego, CA The Translational Impact of Model Organisms in Cancer Co-Chairpersons: Cory Abate-Shen, A. Thomas Look, and Terry A. Van Dyke November 5-8, 2013 • San Diego, CA Ninth Annual Personalized Medicine Conference Chairperson: Raju Kucherlapati November 6-7, 2013 • Boston, MA Advance registration deadline: Friday, October 11 Sixth AACR Conference on The Science of Cancer Health Disparitites in Racial/Ethnic Minorities and the Medically Underserved Co-Chairpersons: John D. Carpten, Christopher I. Li, and Olufunmilayo I. Olopade December 6-9, 2013 • Atlanta, GA Advance registration deadline: Thursday, October 24 CTRC-AACR San Antonio Breast Cancer Symposium Co-Directors: Carlos L. Arteaga, C. Kent Osborne, and Peter M. Ravdin December 10-14, 2013 • San Antonio, TX Early registration deadline: Thursday, October 31

AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer Co-Chairpersons: Roy Herbst, Elisabeth Brambilla, Pasi Jänne, and William Pao January 6-9, 2014 • San Diego, CA Abstract submission and award application deadline: Monday, October 14 Advance registration deadline: Tuesday, November 26 AACR-Prostate Cancer Foundation Conference on Advances in Prostate Cancer Research Co-Chairpersons: Arul M. Chinnaiyan, William G. Nelson, June M. Chan, and Jonathan W. Simons January 18-21, 2014 • San Diego, CA Cancer Susceptibility and Cancer Susceptibility Syndromes Co-Chairpersons: Alan D. D’Andrea, Phillip A. Dennis, and Pier Paolo Pandolfi January 29-February 1, 2014 • San Diego, CA Abstract submission deadline: Wednesday, November 13 Advance registration deadline: Monday, December 9 RAS Oncogenes: From Biology to Therapy Co-Chairpersons: Frank McCormick, Dafna Bar-Sagi, and Channing J. Der February 24-27, 2014 • Lake Buena Vista, FL Abstract submission and award application deadline: Friday, December 6 Advance registration deadline: Monday, January 13 Cellular Heterogeneity in the Tumor Microenvironment Co-Chairpersons: Mary Helen Barcellos-Hoff, Michele De Palma, and M. Celeste Simon February 26-March 1, 2014 • San Diego, CA Abstract submission and award application deadline: Monday, December 16 Advance registration deadline: Monday, January 13 AACR Annual Meeting 2014 Chairperson: Scott W. Lowe April 5-9, 2014 • San Diego, CA