Personalized Medicine in Oncology August 2014

Unifying Oncologists & Pathologists

A Peer-Reviewed Journal August 2014 • Volume 3 • Number 5

PM O

BIOMARKERS • TARGETED THERAPIES • DIAGNOSTICS

Personalized Medicine in Oncology TM

INTERVIEW WITH THE INNOVATORS Personalized Medicine and Value: An Interview With Faculty at the Fourth Annual Conference of the Association for Value-Based Cancer Care...................................................Page 254

THE BIOMARKER RAS and Colon Cancer: What You’re Missing.......................................Page 264

IMMUNOTHERAPY Blocking Immune Checkpoints in Metastatic Melanoma......................................................Page 275 Anti–PD-1 Antibodies in NSCLC and Renal Cell Carcinoma .............................................Page 294 Enthusiasm High for Anti–PD-1 Agents.........Page 296

VALUE-BASED CANCER CARE Value-Based –­ Insurance Not Such An Easy Sell............................................................. Page 298

THE LAST WORD The Case for Personalized Medicine: Defining the Field and Envisioning the Future of Healthcare.................................................Page 299

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

The official publication of

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

In partnership with

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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.

AUGUST 2014

VOLUME 3, NUMBER 5

TABLE OF CONTENTS INTERVIEW WITH THE INNOVATORS

254

Personalized Medicine and Value: An Interview With Faculty at the Fourth Annual Conference of the Association for Value-Based Cancer Care

A thoughtful exchange between PMO and AVBCC faculty evaluating the cost-value issues particular to cancer treatments and their impact on patient care and outcomes.

THE BIOMARKER

264

RAS and Colon Cancer: What You’re Missing

PMO is pleased to offer the department “The Biomarker” to discuss the identification of biomarkers in patients with cancer and the prognostic/predictive impact and clinical decision-making implications of that marker.

Sonia L. Ali, MD; Darren S. Sigal, MD

IMMUNOTHERAPY

275

Blocking Immune Checkpoints in Metastatic Melanoma Igor Puzanov, MD, MSCI, FACP Dr Puzanov discusses new treatments in immune and targeted therapy that improve overall survival in patients with advanced melanoma.

AMERICAN UROLOGICAL ASSOCIATION ANNUAL MEETING

286 287

Improved Survival With Antiandrogen After ADT in Metastatic CRPC PSA Trend Analysis May Help Avoid Unnecessary Biopsies

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 Manager, Client Services Travis Sullivan tsullivan@the-lynx-group.com Editorial Directors Kristin Siyahian ksiyahian@the-lynx-group.com Anne Cooper acooper@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 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 Manager Jini Gopalaswamy Project Coordinators Mike Kodada Deanna Martinez IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Administrative Coordinator Stephanie Ramadan 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

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SCIENTIFIC CONFERENCES 2014-2015

Marsha Rivkin Center for Ovarian Cancer Research-AACR 10th Biennial Ovarian Cancer Research Symposium Co-Chairpersons: Kathleen Cho, Sandra Orsulic, Mary L. “Nora” Disis, and Saul E. Rivkin September 8-9, 2014 Seattle, WA

EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics Scientific Committee Co-Chairpersons: Jean-Charles Soria, Lee J. Helman, and Jeffrey A. Engelman November 18-21, 2014 Barcelona, Spain

Targeting PI3K-mTOR Networks in Cancer Co-Chairpersons: Lewis C. Cantley, Jose Baselga, Joan S. Brugge, Brendan D. Manning, and Malte Peters September 14-17, 2014 Philadelphia, PA

Tumor Immunology and Immunotherapy: A New Chapter Co-Chairpersons: Robert H. Vonderheide, Nina Bhardwaj, Stanley Riddell, and Cynthia L. Sears December 1-4, 2014 Orlando, FL

Hematologic Malignancies: Translating Discoveries to Novel Therapies Chairperson: Kenneth C. Anderson Co-Chairpersons: Scott Armstrong and Riccardo Dalla-Favera September 20-23, 2014 Philadelphia, PA Advances in Melanoma: From Biology to Therapy Co-Chairpersons: Suzanne L. Topalian, Keith T. Flaherty, and Levi A. Garraway, September 20–23, 2014 Philadelphia, PA 13th Annual International Conference on Frontiers in Cancer Prevention Research Program Committee Chairperson: Phillip A. Dennis September 28-October 1, 2014 New Orleans, LA Seventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and Medically Underserved Co-Chairpersons: Ethan Dmitrovsky, Rick A. Kittles, Electra D. Paskett, and Victoria L. Seewaldt November 9-12, 2014 San Antonio, TX

San Antonio Breast Cancer Symposium Co-Directors: Carlos L. Arteaga, Ismail Jatoi, and C. Kent Osborne December 9-13, 2014 • San Antonio, TX Myc: From Biology to Therapy Co-Chairpersons: James E. Bradner, Martin Eilers, Dean W. Felsher, and Carla Grandori January 7-10, 2015 • La Jolla, CA Translation of the Cancer Genome February 7-9, 2015 Co-Chairpersons: William Hahn, Lynda Chin, and William Sellers Computational and Systems Biology of Cancer February 9-11, 2015 Co-Chairpersons: Andrea Califano, Brenda Andrews, and Peter Jackson The Fairmont, San Francisco, CA AACR-Society of Nuclear Medicine and Molecular Imaging Joint Conference: Molecular Imaging in Cancer Biology and Therapy Co-Chairpersons: Carolyn J. Anderson, Christopher H. Contag, and David Piwnica-Worms February 11-14, 2015 • San Diego, CA

AUGUST 2014

VOLUME 3, NUMBER 5

REGISTER TODAY TABLE OF CONTENTS

(Continued)

ANNUAL CONFERENCE

AMERICAN SOCIETY OF CLINICAL ONCOLOGY

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291 292

293 294 295 296

Federal Spending on Cancer Research and Access to Care Called Woefully Inadequate

by ASCO President Less May Be More With Zoledronic Acid Oncologists Want to Discuss Cost of Treatments With Patients but Believe They Are Not Well Equipped to Do So Ibrutinib Tops Ofatumumab as Second-Line Therapy for CLL Anti–PD-1 Antibodies in NSCLC and Renal Cell Carcinoma Bevacizumab Not Cost-Effective in Metastatic Colorectal Cancer Enthusiasm High for Anti–PD-1 Agents

VALUE-BASED CANCER CARE

298

Value-Based Insurance – Not Such an Easy Sell

THE LAST WORD

299 The Case for Personalized Medicine: Defining the Field and Envisioning the Future of Healthcare

Edward Abrahams, PhD

In Dr Abrahams’ inaugural column, he reviews the tenets of the Personalized Medicine Coalition’s signature document, The Case for Personalized Medicine.

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.

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October 31November 1, 2014

Marriott Marquis San Francisco, CA REGISTER TODAY!

www.regonline.com/gbc2014 CONFERENCE CO-CHAIRS

Jorge E. Cortes, MD

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EDITORIAL BOARD

EDITORS IN CHIEF Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania

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

Al B. Benson III, MD Northwestern University Chicago, Illinois

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

SECTION EDITORS Biomarkers Pranil K. Chandra, DO PathGroup Brentwood, Tennessee

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

Darren Sigal, MD Scripps Clinic Medical Group San Diego, California 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

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Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona Mark S. Boguski, MD, PhD Harvard Medical School Boston, Massachusetts Gilberto Castro, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil Madeleine Duvic, MD The University of Texas MD Anderson Cancer Center Houston, Texas Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland 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

Nikhil C. Munshi, MD Dana-Farber Cancer Institute Boston, Massachusetts Steven O’Day, MD John Wayne Cancer Institute Santa Monica, California Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois Hope S. Rugo, MD University of California, San Francisco San Francisco, 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 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

Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington Gene Morse, PharmD University at Buffalo Buffalo, New York

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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 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.

to learn more!

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

Director, Quality Control Barbara Marino Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean

FACULTY Kenneth C. Anderson, MD Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics Kraft Family Professor of Medicine Harvard Medical School Dana-Farber Cancer Institute, Boston, MA

Tina Flaherty, ANP-BC, AOCN Nurse Practitioner Division of Hematologic Malignancies Dana-Farber Cancer Institute Boston, MA

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Discussions in Personalized Treatment for Lymphoma: Do We Have Consensus?

CONTRIBUTING FACULTY Chair Stephanie A. Gregory, MD

The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/Rush University Chicago, IL

Sonali M. Smith, MD

Associate Professor Section of Hematology/Oncology Director, Lymphoma Program The University of Chicago Medical Center Chicago, IL

Mitchell R. Smith, MD, PhD Director of Lymphoid Malignancies Program Taussig Cancer Institute Cleveland Clinic Cleveland, OH

2014 PROSPECTUS

Steve M. Horwitz, MD

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YEAR ANNIVER SARY

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LETTER TO OUR READERS

PMO: Advancing the Practitioner’s Ability to Provide Customized Care to Patients Dear Colleague,

U Al B. Benson III, MD

ntil recently, cancer treatment relied solely on histological diagnosis for determining systemic therapy. Aside from considerations related to a patient’s underlying comorbidities and performance status, there was minimal deviation from an organ-of-origin– based treatment strategy. This relatively primitive understanding of malignancy failed to exploit biological and molecular differences within each cancer type to allow for selection of a more rational therapy and thereby improve patient outcomes. However, exciting strides are currently being made in the field of cancer research and treatment, both with solid tumors and hematologic malignancies, and the available treatment options and physician’s ability to tailor therapies to individual patients have markedly expanded.

Our quest is to advance the practitioner’s ability to provide customized care to his or her patients. We will accomplish this by focusing on technologies and therapeutics available to clinicians and their impact on diagnostic, prognostic, and predictive medicine.

In this issue, you will find an in-depth article on immune checkpoint blockades in metastatic melanoma as well as an update on RAS analysis in colon cancer. The information presented in both articles is critical to oncologists on the front-lines of treating these diseases.

Also in this issue, you’ll hear from the president of the Personalized Medicine Coalition (PMC), Dr Edward Abrahams – the new host of our department The Last Word. Dr Abrahams provides an overview of the signature document of the PMC, The Case for Personalized Medicine.

Thank you for your loyal readership. On behalf of the entire editorial board, it is our pleasure to serve you.

Sincerely,

Al B. Benson III, MD Coeditor in Chief Personalized Medicine in Oncology

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INTERVIEW WITH THE INNOVATORS

Personalized Medicine and Value: C. Daniel Mullins, PhD

An Interview With Faculty at the Fourth Annual Conference of the Association for Value-Based Cancer Care

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ore than 250 oncology healthcare professionals, practice managers, and managed care executives recently convened in Los Angeles, California, for the Fourth Annual Conference of the Association for Value-Based Cancer Care Linda Bosserman, (AVBCC). The expert faculty, with backMD grounds in cancer care, healthcare policy, and managed care, provided a comprehensive program addressing the evolution of the value equation as it relates to cancer therapies.

The mission of AVBCC is to provide a forum for payers, providers, and the entire Andrew Stainthorpe, PhD

PMO Thank you for meeting with us. To begin, please tell us how you define the concept of value in healthcare, and why it is so important today?

Dr Mullins The notion of value in healthcare is incredibly important, and there’s perhaps no better therapeutic area than oncology Gary Palmer, MD to look for value in healthcare. This is because there are so many new treatments that have come on the market in the last few years, and many more treatments that are in development. When we have options, we look for value, because we know that we can find health outcomes that will help people to live longer with better quality of life for their Michael A. remaining time as a cancer survivor.

Kolodziej, MD

C. Daniel Mullins, PhD, is a professor and former department chair of the Pharmaceutical Health Services Research Department at the University of Maryland School of Pharmacy.

Linda Bosserman, MD, is a community medical oncologist at Wilshire Oncology.

Andrew Stainthorpe, PhD, is associate director of the National Institute of Health and Care Excellence.

Gary Palmer, MD, is senior vice president, Medical Affairs, at Foundation Medicine.

Michael A. Kolodziej, MD, is the national medical director, Oncology Solutions, Office of the Chief Medical Officer, Aetna.

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oncology team to consider and evaluate the cost-value issues particular to cancer treatments and their impact on patient care and outcomes. This unique focus is achieved through discussions and collaborations with those involved in evaluating therapies, treating patients, and paying for care.

PMO had the pleasure of interviewing several AVBCC faculty members, including Linda Bosserman, MD, of Wilshire Oncology; Michael A. Kolodziej, MD, of Aetna; C. Daniel Mullins, PhD, of the University of Maryland School of Pharmacy; Gary Palmer, MD, of Foundation Medicine; and Andrew Stainthorpe, PhD, of the National Institute of Health and Care Excellence. What follows is our insightful exchange.

When we introduce cost into the equation, we see that there are value messages. We need to be able to understand those value messages and compare across our options, so that patients, in consultation with their healthcare providers, can make informed decisions.

It’s not just patients, however, that are looking for value. Insurance companies, both private and public payers, are looking for value. They are looking for evidence of cost and evidence of improved health outcomes. These 2 series of evidences taken together determine value.

PMO For our American contingency, what are the main value-based concerns for oncologists in the United States?

Dr Bosserman As we learn more about the growing costs of cancer care and the burden of patient copay, we have to better understand the full impact of the treatment we’re giving to patients. That means outcomes – not just progression-free survival and overall survival, but also the toxicities, the side effects, and the costs of the overall regimen to the patient.

Dr Kolodziej I think the biggest challenge that oncologists in the United States are facing is the uncertainty of the reimbursement environment. It’s concerning to think you may not be able to continue to deliver care in the fashion that you would like.

Dr Palmer There are many value-based concerns among oncologists in the United States. I think any

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therapy that a physician uses is probably selected by considering both its clinical effectiveness and its cost.

It’s difficult, though, to take the overall cost of the healthcare system into account. Tests such as Founda­ tionOne, I think, may very well have a good economic picture in the whole healthcare system. We can take the place of many other tests that are done. If our test is used earlier, the targeted therapies that it suggests may take the place of some forms of chemotherapy. I think taking that global approach to healthcare costs is important.

It’s hard for oncologists to do that. They, of course, are concerned mostly about benefits to their patients. But they’re also concerned about whether they can get a test paid for and the access to the patient. I think some of the more global approaches to pricing and economic impacts are of importance to the oncologist, even though they might not have a good sense as to how that all works.

PMO Dr Stainthorpe, what are the main value-based concerns for oncologists in Europe?

Dr Stainthorpe The main value-based concern for oncologists is having a broad range of medicines that provide benefits to patients with minimal side effects. As oncologists, we need first-, second-, and third-line, or a range of options for patients that show value.

PMO Should oncologists concern themselves with cost issues, specifically the cost of treatment to payers and to patients? Or is this beyond their clinical focus?

Dr Mullins The job of oncologists is changing. While we can’t expect oncologists to be economists, it is important that oncologists recognize that cost is an important consideration for their patients. As such, they need to be sensitive to the cost issues.

We don’t expect that a physician would know the price of every new drug that comes on the market. But we would expect that their offices would be set up so that patients can get their questions answered, not just about which drugs work best for patients like themselves, but also the cost to the insurer, as well as the cost to the patient, for getting these life-saving and life-improving drugs.

Dr Bosserman In today’s environment, there is no way the oncologist can avoid understanding the costs and outcome issue if we’re going to help our patients evaluate the value of their treatment regimens, including total treatment course, toxicity profiles, expected outcomes, and what their cost is going to be.

Dr Stainthorpe Cost is a societal factor in the provision of medicines. Oncologists should work in the best interests of their patients and provide the treatments that give patients the most benefit, the fewest side effects, and the best chances of survival. Some clinicians may step outside that care provision service and move into providing advice on reimbursement. In those situ-

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ations, then, cost should be part of the considerations.

Dr Kolodziej The question has now come up as to whether oncologists are not just responsible for the care of the individual patient but also stewards of a scarce resource.

This notion became politicized around rationing care, and that’s not what this is about. This is about recognizing that there are treatments that are roughly equal in terms of efficacy, but they’re not equal in terms of costs, and just helping patients in a shared decision model to make good choices in how they want to spend their healthcare dollar.

Should oncologists concern themselves with cost issues, specifically the cost of treatment to payers and to patients? Or is this beyond their clinical focus?

Dr Palmer I agree that oncologists have to concern themselves with cost issues. Back when I first started to see patients, we really didn’t take cost into account.

We didn’t know what the cost of many therapies or tests actually were. Now, most oncologists I know do consider costs. I think since they order therapies, to have a sense as to how it impacts the healthcare system is a good idea.

PMO There’s a growing push toward involving the patient in treatment decisions, including the cost of treatment. Should this apply to oncology as well, or does the fact that we are dealing with a life-and-death situation in oncology change the equation?

Dr Palmer I feel fairly strongly that it has changed the equation. There’s been a big movement to involve patients in decision making and to move away from the old style of a paternal-type doctor who tells you what to do.

I think patients need to be aware of their choices. If they decide not to spend the money, that’s fine. However, there will still be patients who won’t want to discuss it, who feel that whatever the doctor recommends is what they’re going to do. But having a frank discussion about not only the benefits of treatment but also the potential costs, both side effect and financial, is something that should happen.

Dr Mullins At some level, cancer patients have always been thinking about cost. They just haven’t been talking about costs with their providers. The new patient-centered focus in healthcare suggests that patients will have new conversations with their doctors. This will

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include conversations about how much they’re willing to pay for treatments.

In some cases, patients aren’t taking their medicines because they can’t afford them. What we need to do is set up social services for these individuals so they can afford their medicines.

Dr Bosserman As an oncologist who has practiced for 35 years, I think patients want to be actively involved.

Sometimes they may appoint a family member to assist with this, but they want to know the truth.

They have marketing materials about treatments.

They are on the Internet. But they also want to understand from their doctor the comprehensive treatment program, expected health outcomes, short- and longterm toxicities, and patient copay responsibility.

In our own practice, we have found it essential to provide patients with individual chemotherapy teaching and also separate financial teaching.

I think patients want to be actively involved. Sometimes they may appoint a family member to assist with this, but they want to know the truth.

PMO Dr Mullins, we’d like to ask you how members of the Academy of Managed Care Pharmacy can affect policy decisions with patient care in the United States.

Dr Mullins One of the bodies that’s going to weigh in on the cost-effectiveness of cancer therapies is the Academy of Managed Care Pharmacy. This managed care group of professionals systematically reviews evidence on both effectiveness and cost and is strategically positioned to help bring some sense to the discussion about value in healthcare in general and value in oncology.

PMO Is there a concern that cost-effectiveness analyses do not adequately consider the impact of side effects?

Dr Mullins Methods for conducting comparative effectiveness research, as well as cost-effectiveness research, are evolving. We have good methods for evaluating the effectiveness of treatments, but sometimes when it comes to cost, we leave things out.

As an example, sometimes we look at survival benefits and major effectiveness components, but we forget about some of the adverse events or side effects that are really important to patients.

Some of these may not lead the patient to go back to see their doctor. They may not lead to a hospitalization or an emergency department visit, but they represent a

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significant burden to patients. Those types of costs, which are sometimes hidden costs, need to be part of a cost-effectiveness analysis in order for us to understand the true value of using improved therapies that reduce side effects.

PMO There was a lot of talk regarding quality in healthcare. Quality often conflicts with the cost of care.

Is there a way to reconcile this?

Dr Mullins There’s a perception that quality and costs are always at odds with each other. As a general rule, life-saving treatments that provide a high quality of life do come at a higher cost, but what people forget is that sometimes we provide poor quality of care. That leads to the wasteful spending that we hear policy makers talk about.

When we provide low-quality care for patients with cancer, we end up having to spend more to fix the problems that we create because of that poor quality, so it’s not always the case that quality and cost go in opposite directions. When we provide high-quality care, we can save money by reducing wasteful spending, fixing problems that we could have avoided.

PMO Dr Bosserman, are you concerned with the level of copay faced by many patients with cancer?

Dr Bosserman Patients’ copay is a daily issue our doctors and staff have to deal with. Particularly, even in the Senior Advantage Plans, patients are getting 20% copays back on increasingly expensive regimens. For many this is unaffordable.

It isn’t just copays for chemotherapy or other treatments; it’s copays for visits, for medications, and for multiple treatment courses that are really becoming unaffordable to patients.

More and more of our patients are coming back and saying, “I can’t afford that regimen. What are the alternatives? What are the costs? What are the trade-offs with a cheaper option?” We as physicians have had to learn it.

And our staffs have had to learn it.

We’ve put in active programs for copay assistance when possible, because we’re in a partnership with our patients to have treatments that improve their health.

PMO Opening this up to the group, what can and should be done to alleviate the cost burden on patients with cancer?

Dr Stainthorpe The cost of oncology products can be ameliorated to some extent for payers and patients by using imaginative reimbursement approaches. Some may involve risk shares. Some may involve other managed entry schemes that pay by outcomes, and those can help with the burden of cost for patients and payers.

Dr Kolodziej The fashion by which we do help patients recognize the path to making a good value-driven decision requires several things that are not in the system

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right now. The first is price transparency. It is unbelievable how little providers and patients know about how much things cost. That’s got to change.

In addition to considerations of transparency in cost, there needs to be some improvement in the ability to educate patients about what is the real outcome that’s associated with a certain decision. This especially is relevant in cancer when the patient has an incurable, advanced malignancy, and choices may have wildly different value propositions associated with them, both in terms of monetary cost and in cost to the patient in terms of quality of life and impact on family and caregivers.

Dr Bosserman When you look at the growing burden on individual patients paying for cancer care, we need to come together as payers, providers, industry, and government and ask ourselves why cancer patients have an unfair burden of their copays compared with other diseases, and what a fair copay is for treatments.

If we were in an ideal world in a value-based system, we might have no copays for things that were highly effective and increased cure or markedly improved survival and quality of life.

Perhaps as we got into further lines of treatment with lesser, even questionable benefit, there would be more responsibility on the part of the patient.

There are many ideas out there, but we have got to come up with a solution, because right now it’s becoming unaffordable for patients in America.

PMO Is there one theme that underlines patient care no matter where it is delivered in the United States?

Dr Bosserman There is one theme that ought to underline everything we do – we are in medicine to improve our patients’ health: to use our scientific knowledge and our years of training – 12 to 14 years for an oncologist – to work with our patients to meet their needs, educate them, and walk with them through the path of their treatment – whether it’s for prevention, cure, or end-of-life – to improve their health, or relieve suffering.

PMO There is continued concern regarding the consequences of community practices being absorbed into the hospital setting. How does the setting in which care is offered impact the quality of care?

Dr Bosserman In the past 10 years, 85% of patients in America have received their treatment in the community.

In Southern California, I’m not sure there will be many practitioners left within 2 years. They’re going to join academic centers, hospitals, or systems.

In the big picture, this could become very beneficial to patients. If you look at the Kaiser system in California, which has 40% market share, it’s a completely integrated system. Between the pharmacy, the medical benefits, the

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physicians, the surgeons, the oncologists, the radiation oncologists, supportive care, rehabilitation, hospice, and survivorship, it’s all integrated on behalf of that patient.

Ultimately, a patient should understand the health outcomes, the survival rates, the quality of life, and the cost in system A versus B or C. Because, right now, the consumers have no way to know if the care they’re getting is in their best interest and for their best outcome.

In Southern California, I’m not sure there will be many practitioners left within 2 years. They’re going to join academic centers, hospitals, or systems.

PMO What do you think are the key components of high-quality breast cancer care?

Dr Bosserman As a breast cancer specialist, there are many components to breast cancer quality care, from the point of view of the patient, the health plan, and the clinician. If you look at reengineering care from day 1, when a woman is first diagnosed, we have to determine if there is someone to talk with her, to comfort her, to walk her through the system. Can she get into treatment immediately to begin dealing with whatever the aspects of her diagnosis are? Does she have information about how she’s going to get through treatment, what her health outcome expectations would be, and what the treatment plan is? It means, for most women, having a core biopsy and becoming educated on the features of that cancer.

I think high quality means you have someone to navigate, whether it’s a medical oncologist or a nurse navigator, who helps you walk through and coordinate your care, understand the costs, and have the psychosocial, emotional, and family support that’s critical to caregivers and to patients. Then it ensures that every patient, with their specific diagnosis, has a personalized care plan taking the patient’s preferences into consideration. Are they in childbearing age? Are they menopausal? Are they already having menopausal symptoms? Do they have bone loss? Do they have hyperlipidemia? How do we coordinate their overall health with their breast cancer treatment to achieve the best health outcome?

Those are the quality metrics that patients want to know. If they have advanced disease, they want to know a team is going to help relieve their symptoms and help them with the emotional issues.

If they are breast cancer survivors, they have signifi-

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cant emotional challenges, concerns, and side effects that need long-term management and support.

PMO What can be done to increase awareness among legislators, public officials, and government committees about the needs of cancer patients?

Dr Bosserman We work in a very political world of regulators and policy makers. It’s very important that the oncology community fully engage with legislators, policy bodies, and national organizations to bring the voice and concerns of patients with cancer to the attention of those who make these policies. Organizations like ASCO [American Society of Clinical Oncology], ACCC [Association of Community Cancer Centers], as well as the state societies are very important in bringing this real voice on the ground to our national policy makers.

PMO What can physicians and practice managers do to boost awareness and participation in clinical trials?

What can be done to increase awareness among legislators, public officials, and government committees about the needs of cancer patients?

Dr Bosserman At my practice, we promote our clinical trials at our practice level. We also encourage patients to find out about clinical trials.

In reality, the ClinicalTrials.gov website does not work well. I’ve done searches, trying to find active treatment protocols for patients. It’s more complicated than patients can sort through themselves with eligibility and ineligibility requirements, and then when you think you have active clinical trials and you make phone calls, you find out that they’re not available. That system needs to be improved.

As we educate patients about clinical trials, they’re very open to participation, but they want it to be integrated into their health plan, into their treatment routine, and as close to home as is possible.

It’s a very important value to patients, but the system itself needs to be revamped, even though we’re making people aware of it at the practice level.

PMO What insider tips would you share with members of the patient’s healthcare team – that being nurses, navigators, PAs [physician assistants], NPs [nurse practitioners], to facilitate access of care for their patients?

Dr Bosserman Most of us, whether we’re in an academic or community practice, are now working in a team approach, teams of medical oncologists, surgeons,

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radiation oncologists, plastic surgeons, and physical therapists, but also within our team in the practice.

At the practice level we have secretaries who do intake and financial analysis and access and authorization. We have medical assistants who gather and enter data and talk to patients about medications and get their vital signs.

We have nurses who deliver chemotherapy. We have advanced practice practitioners, the APPs, otherwise known as nurse practitioners, and PAs, and the physicians themselves, who determine, review, and oversee treatment plans and toxicities, and we have our administrators to facilitate all the work as well as the billing and collections to run the practice, and compliance to ensure we are doing things the right way.

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

That’s often a challenge to explain to patients and make sure they’re comfortable with the whole team being there to meet their needs.

PMO What are the advantages of Commission on Cancer accreditation? What are the disadvantages of not being accredited?

Dr Bosserman Accreditation is important for setting standards, whether you want to get ASCO QOPI [Quality Oncology Practice Initiative] certified or American College of Surgeons or Commission on Cancer certified.

The hospitals use the Commission on Cancer to certify their programs.

It has certainly encouraged community hospitals to put resources toward the work, elevating the work of tumor boards, documentation, educational outreach for the community, and having special cancer screening days in the community and at academic centers.

While I think it’s important, I don’t think patients pay much attention to the level of accreditation. As the money has dried up at the community hospitals, I have seen a significant cutback in their willingness to put up funding for the certification that no one is requiring.

Setting standards is wonderful, so we can all be on the same page together and try to do our best as teams, but they also have to have realistic funding and value-­ based relevance.

PMO Why should people participate in associations and networks like AVBCC? Dr Kolodziej After spending more than 20 years in clinical practice, I moved to the health plan. I quickly learned all the things I didn’t know.

The great thing about participating in an organization like AVBCC as opposed to participating in ASCO or NCCN [National Comprehensive Cancer Network],

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which are really good clinical platforms, is that there are aspects of cancer care that you just don’t think about every day but are potentially tremendously impactful in how you’re going to do your job and do it well.

I come to the AVBCC meeting and I meet somebody from NICE [National Institute for Health and Care Excellence]. Talking to the guy is fascinating because of the way care is delivered in the UK as opposed to the US. Or I hear people who spend their whole day thinking about the employer approach to healthcare and the diversity of thought, and the willingness of the people who get invited to participate is great. It’s just a way to expand your horizon, and really, maybe refocus the way you look at the question.

I’ve been fortunate to participate in the AVBCC meetings since its inception 4 years ago. One thing that’s absolutely striking is how much things have changed year over year. There are very few forums where the rapidity of that change is presented in an organized format with really top-notch talent discussing it. I’m looking forward to seeing how things change between this year and next year, because I’m sure things will be quite different a year from now.

There are a limited number of publications that accurately capture the very timely information regarding the evolution of care delivery in oncology, and Value-Based Cancer Care is one of them. The content is well reported and accurate.

Dr Bosserman Associations and networks like AVBCC, COA, ASCO, and ACCC are the organizations that represent the issues that we, as clinicians, and our patients are facing.

We need to be speaking to our policy makers. We need to realize that legislation is critical. Government has a major role not only in funding cancer care appropriately, but funding the NIH, funding research, having appropriate regulations that let us bring new advances to our patients in an effective way. We can’t do it alone.

Working in organizations where we can come together with all the stakeholders, bring the best of those ideas together, develop new solutions, new pilots, and new ways of us doing better care, having more research, and doing it at the lowest cost possible, is going to help all of us in meeting the needs of our patients going forward.

PMO Should the FDA take drug cost into account, considering the approval of very expensive medications, similar to the way this is done by NICE in the UK? Dr Stainthorpe The FDA has a regulatory function that is probably best kept without looking at the costs of the medicines. That role is probably best for an independent HDA [health data analytics] organization like NICE. In Europe, the role of the EMA [European Medicines Agency] and of the HDA organization are 2

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separate things. That model works very well there.

PMO How do oncologists handle the cost of treatment in the UK? What advice do you have for the United States?

Dr Stainthorpe Oncologists should take advantage of the best guidance available from the research that’s being conducted by the industry and by other clinicians, and that should feature all the relevant outcomes. It should take into account issues related to patient benefit, quality of life, and relevant information about the service impact and the even wider societal benefit in sort of a value-based assessment approach.

PMO As physicians move toward personalizing cancer treatment based on the patient’s unique genetic profile, tumor protein expression, and molecular pathways, has research kept pace with this demand?

Should the FDA take drug cost into account, considering the approval of very expensive medications, similar to the way this is done

by NICE in the UK? Dr Stainthorpe To an extent, it has. The more we know about an individual’s genetic makeup, the more the medicines can be targeted to their needs, and the more benefit they will gain. Subgroups are being identified already, and the direction of travel is to find ways to use markers that can focus that medicine provision more specifically, so you’ll get less waste and you’d get better performance and you’d get a known outcome.

Yes, research is heading that way, but there’s still a long way to go.

PMO What are some of the challenges of bringing personalized medicine to Asia and Europe?

Dr Stainthorpe The challenges of bringing personalized medicine to Europe and the rest of the world are the same. It’s finding out more about the mechanisms by which disease pathways work and the ways in which markers can be found to identify those so you get better diagnostic tests, and then you can tailor the medicines to provide either amelioration of the condition and respites, or ultimately, the aim would be to provide a cure.

PMO Dr Palmer, as cancer therapies have evolved, we’ve learned that underlying alterations in DNA have a substantial impact on cancer proliferation. Based on this understanding, how is Foundation Medicine working to improve cancer therapies and personalize medicine at a molecular level?

Dr Palmer Cancer is basically a disease of the ge-

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nome. We know that most cancers are caused by changes at the DNA level, whether it’s caused from radiation or cigarette smoking or unknown factors. DNA changes are really what drive cancer.

At Foundation Medicine, we have developed a fully informative genomic profile to determine those relevant DNA changes that can then lead directly to therapies for the patients. We can find all classes of alterations, mutations, copy number alterations, and amplifications in 1 test with very small amounts of tissue.

By doing our test, the oncologist and the patient will likely be able to find any and all treatable alterations in the DNA that are relevant to his or her tumor.

PMO It is estimated that more than 1.6 million people in the US will face a cancer diagnosis this year. Based on your experience, not just as a medical oncologist but also within Foundation Medicine and the pharma and biotech industries, what advice would you give these patients as they try to understand their cancer as well as current treatment options?

How well are the research efforts within academia, as well as pharma and biotech industries, translated into meaningful outcomes in personalized medicine?

Dr Palmer Cancers, of course, present at different stages. There are cancers that present very superficially on the skin that can be removed from a surgeon’s point of view.

I think that understanding alterations in the DNA, which is what our tests FoundationOne and FoundationOne Heme do, is most relevant when treatment beyond surgery is needed, when the cancer has spread. That’s still a lot of patients, though. In fact, one could argue all patients with metastatic disease could potentially benefit from knowing the DNA drivers of their cancer. That’s the group that is going to benefit from having drugs available to retard the growth of the cancer.

PMO As physicians move toward personalizing cancer treatment based on a patient’s unique genetic profile, tumor protein expression, and molecular pathways, has research kept pace with this demand?

Dr Palmer I think in many ways research is ahead of where the clinician and the patient are at this point. A large part of what we need to do at Foundation Medicine is educate the physician and the patients that a test like ours is available today to give them full information about their DNA and what drives the cancer.

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Most oncologists think this is something that’s going to happen down the road, but the research has gotten to the point now where a test like ours is available today. I think in many ways the research is ahead of where the clinician and the patients are.

We still have a long ways to go, for instance, trying to find out how genes and alterations interact with each other to drive cancer rather than just finding them individually. At Foundation Medicine, we’re leading that field by closing what we call the clinical genomic loop, coordinating clinical information along with the alterations that we find so we really can get a complete picture of how the DNA changes are affecting the cancer.

PMO How well are the research efforts within academia, as well as pharma and biotech industries, translated into meaningful outcomes in personalized medicine?

Dr Palmer I think we’re getting there very quickly.

One of the big questions is, how do these research findings translate, as you say, to treatment for patients? We can find what’s driving a particular cancer, but the question is, will a treatment directed at that particular change in the DNA actually affect the outcomes of patients?

We’re getting more and more data, in fact, that knowledge is directly transferable across different tumors to the outcome of patients. I think the research is translating, actually, quite well to patient benefit as we go forward.

PMO How can we better establish clinical utility for tests that are being conducted in personalized medicine?

Dr Palmer It’s very important to take all of these research developments, finding new changes in the DNA, and actually show that they are benefiting patients – so-called clinical utility that these are useful findings in the clinic. Of course, you need to go that 1 step from finding, let’s say, a new mutation in DNA to showing that, in fact, this does help patients.

But the paradigm is changing. Each patient can have a somewhat different profile of their tumor, so to do a study that lumps together patients of different profiles can be difficult.

We’re coming to grips with that now; there are designs; new studies are being instituted all the time that take that into account. Already we have many case reports of drugs working against the profiles in particular patients.

We are currently doing several studies like this to make those findings as generalizable as possible. For example, if we find a new alteration, never been seen before, we can be fairly certain if a drug will, in fact, work against that new alteration, based on the mechanism and the biology.

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PMO Are there any applications that Foundation Medicine has used in oncology clinical work that can relate to other categories, such as cardiovascular, neurology, and rheumatology?

Dr Palmer At this point, Foundation Medicine is exclusively an oncology company. But our next-generation sequencing technique, with which we can deep sequence hundreds of genes with world-class laboratory capability and world-class computational biology capability, certainly has potential applicability outside of oncology.

Immunotherapy comes to mind. Immunotherapy now is an up and coming area of cancer therapy. We may start to look at immune genes and immune therapy. This could have applicability to autoimmune diseases, for instance, outside of cancer. I think the answer is yes, this technique could very well be valuable in diseases other than cancer.

PMO Dr Kolodziej, Aetna is working on new collaborations with provider organizations. Are these collaborations also targeting oncology providers?

Dr Kolodziej All of the pilots that I’m working on are specifically for oncology providers. We have predominantly been focusing on community-based providers as opposed to institutional providers.

There are a lot of reasons for that. We want to promote community oncology as a delivery model. We think it’s a very efficient and high-value model, so we want to do what we can to promote that model.

We’ve also been somewhat involved in looking at how oncology fits into an integrated delivery system, so models in which, for example, a hospital system wants to become an ACO [accountable care organization], and thinking about how oncology fits with that ACO. PMO Please describe how these provider-payer collaborations are different from the traditional payer-provider relationships.

Dr Kolodziej The traditional payer-provider relationship is really a transactional one. There’s very little exchange of clinical information, there’s little exchange of cost information, and there is no exchange around outcomes.

One of the major changes is that the lines of dialogue are really opened up in these relationships. They also involve looking at alternative payment models, so that in exchange for good clinical performance, we want to reward the providers who participate with us in these programs by giving them more money.

The system is cost constrained, so it’s not that we’re looking to put more money in the system. Rather, most of our pilots involve taking the savings that we can generate, and sharing that with the practice.

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All of them to this point still operate on a fundamental fee-for-service basis, but we do think, ultimately, that the knowledge we gain from this relationship that we form with the practices will allow us to evolve into a more episode-based reimbursement model. That’s a little ways away.

The majority of Americans get health insurance through employer-sponsored health insurance plans, and Medicare is another big payer.

PMO Does any of the provider-payer pilots that you’re engaging in involve downside risk?

Dr Kolodziej At this point, we can view the pilots that we’re involved in as pay for performance, so there is, by definition, no downside risk. However, as we become more comfortable with performance metrics of practices and cost structures of various delivery systems, I think it’s inevitable that we will get to a situation where downside risk is involved.

PMO Do you already have data to show the impact of this new collaborative approach, such as improved patient outcomes, improved efficiencies, or new reimbursement approaches?

Dr Kolodziej Our work in this area is relatively young, and not mature. We have some preliminary experience in work that’s been done in the last couple of years.

Specifically, we have some data from work that we’ve done with US Oncology in Texas, in the commercial population, where we showed that implementation of a strategy that focused on evidence-based medicine, practice-based case management, and an enhanced end-of-life program did result in about a 12% reduction in ER and hospitalization rates. There was clearly measurable impact there.

We also have some pilots in the clinical decision support space, or the pathways space, that confirm that there is value to implementing that type of a program with respect to the cost of care. The magnitude of benefit is on the order of 15%.

We have a lot of pilots that are just getting off the ground and are at this point accruing patients. We haven’t even looked at the claims on those patients yet.

We’re trying to do a lot of subtly different delivery models with different type providers, because different type providers have different aptitudes for delivering on this enhanced clinical support model. Ask me in a year.

I’ll have a lot more information then.

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PMO What are the main expectations from this value-based approach to patient care?

Dr Kolodziej The expectations we have really depend on what prism you look through at the question. For example, what we expect from the patient perspective is that they’re going to like the care they’re getting; they’re going to feel much more closely aligned with their physician and their physician’s staff, and, at the end of the day, they’ll spend less time in the ER, less time in the hospital, and have measurable improvement in the quality of care.

From the payer perspective, we’d like to control cost and be able to measure and promote quality. Ultimately, we’d like to be able to say, “These are our guys. We like the way they do things, and we want to promote them.”

Then, from the provider perspective, what we like to do is help the practices by giving them data and having dialogue with them, help the practices evolve so that they will be, really, potentially in a very dominant position in their respective markets, so that they can be the go-to provider for the health plan and for our self-insured customers.

PMO Cost growth is a major issue in healthcare, but, especially in oncology. Are you concerned with the level of cost sharing that is being faced by patients with cancer today?

Dr Kolodziej The majority of Americans get health insurance through employer-sponsored health insurance plans, and Medicare is another big payer.

Over time, and especially now, there’s been a lot of discussion about passing over some of these price increases, cost increases, to the patient. I think that’s really a challenge. It’s a challenge for patients, and it’s a challenge for the plan, because we do not want patients to make bad decisions because of cost.

We do not want to promote nonadherence with oral drugs, for example, because of cost, and yet we would like patients to feel that they have some skin in the game, that their decisions are not cost insensitive.

There’s a very fine line here because of the cost of cancer therapy.

I think we have to be really careful about how far this goes. We should also never forget that the maximum amount of out-of-pocket cost has been defined by the ACA. This may not seem like a lot of money if you are a doctor or a lawyer, but for the average American family, it’s a heck of a lot of money. How we ask patients to participate in a value-driven fashion, that’s going to be a real trick.

PMO Do you expect that ACOs will have a positive impact on oncology and on patients with cancer?

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Dr Kolodziej The delivery model of integrated care or ACOs has become a very popular solution to sev­ eral of the challenges we face in medical care. The ability of that system to improve cancer care is a little bit unclear right now. This is not exclusive to cancer care. I think it’s true of all subspecialties here. The way that the subspecialists fit in with the structure of what is predominantly a primary care delivery model has yet to be defined.

We talk about this all the time. To some extent we say, “If we can make an oncology practice really function as a medical home, then that is exactly the kind of practice that will succeed in an ACO model.”

PMO Can ACOs improve quality and lower or at least contain costs?

Dr Kolodziej The real potential advantage of an ACO from a cancer perspective is improved integration of care, coordination of care. Every oncologist in the world will tell you, and it doesn’t matter if they are employed by a hospital or not, that the quality of the dialogue between other physicians and the oncologist is just not good enough. The communication is commonly precipitated by emergencies, and it’s absolutely maddening to all providers involved.

PMO Are there specific initiatives at Aetna that other health plans can adopt for value-based cancer care?

Dr Kolodziej The law of the land precludes me from knowing too much about what other health plans are doing. We do talk to each other about our vision. I think when you come to a meeting like the AVBCC meeting, you realize that there’s a certain consistency in the vision people have.

I think a lot about smaller health plans that may lack the oncology expertise to build the programs we are building. If we can get practices to really fire on all cylinders, they have a very, very compelling case to bring their dominant regional payer into the discussion and utilize the platform that we help them build so they could succeed with that payer. I think that that is the most likely way this is going to happen.

The relative consistency and approach of all the major national payers suggest that all of us want practices to think about how they’re using evidence-based medicine. All of us are interested in getting a better endof-life approach, some sort of standardized process where you have dialogue with a patient and find out what’s important to them. And all of us are interested in keeping people out of the ER and hospital, because ER use and at least half of hospitalizations are wasteful and potentially avoidable.

PMO Thank you all very much for talking with us today and our best to you for continued success. u

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Dear Physician Colleague...

Your Support Is Critical

5

YE A R A N N I V E R S A RY

Lillie D. Shockney, RN, BS, MAS

5

Program Director, Academy of Oncology Nurse & Patient Navigators University Distinguished Service Assoc Professor of Breast Cancer, Depts of Surgery & Oncology; Admin Director, The Johns YE A R Hopkins Breast Center; ANNI VERSARY Admin Director, Johns Hopkins Cancer Survivorship Programs; Assoc Prof, JHU School of Medicine, Depts of Surgery, Oncology & Gynecology and Obstetrics; Assoc Prof, JHU School of Nursing

Show continued support for your oncology nurse and patient navigator colleagues by referring them to join forces with me and more than 4500 of their colleagues. Recommend they become a member of AONN+ today so they may take advantage of our exclusive benefits and educational opportunities.

Together we can increase our network and define the future of oncology navigation.

Your colleagues will have an opportunity to: CONNECT with nurse navigators close to home, exchange practice tips, and get involved in community outreach initiatives that improve care in your region.

ACCESS tools and resources for your patients and their caregivers through our members-only online resource center.

SUBMIT ABSTRACTS AND PRESENT research findings, programs, and results with their navigation and survivorship care colleagues.

GET INVOLVED in our community of nurse navigators; share best practices, clinical resources, and advocate for your patients and their profession.

ACCESS COMPLIMENTARY SUBSCRIPTIONS to the Journal of Oncology Navigation & Survivorship ® (the official journal of AONN+), The Oncology Nurse-APN/PA®, and Personalized Medicine in Oncology ™ (digital version).

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Best regards, Lillie D. Shockney, RN, BS, MAS Program Director, Academy of Oncology Nurse & Patient Navigators

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AONN2014 Lillie Support Asize_40714

AONN+ is the largest national specialty organization dedicated to improving patient care and quality of life by defining, enhancing, and promoting the role of oncology nurse and patient navigators.

THE BIOMARKER

RAS and Colon Cancer: What You’re Missing Sonia L. Ali, MD Clinical Fellow, Hematology/Oncology Scripps Clinic San Diego, California Darren S. Sigal, MD Division of Hematology/Oncology Scripps Clinic Medical Group San Diego, California

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hen first introduced almost a decade ago, monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) offered patients with unresectable metastatic colorectal cancer (mCRC) new hope. Large phase 3 trials evaluating panitumumab (Vectibix) and cetuxSonia L. Ali, MD imab (Erbitux) in pretreated patients with mCRC showed that the 2 anti-EGFR antibodies produced similar improvements in survival end points measured in weeks and in response rates of up to 10% compared with best supportive care.1,2 Despite the statistical significance of these outcomes, their clinical impact was marginal. An increasingly sophisticated understanding of the EGFR pathway Darren S. Sigal, revealed that KRAS played a central role in propagating EGFR signaling and potentially MD explained the muted impact of panitumumab and cetuximab.3,4 About 40% of patients with mCRC have a mutation in KRAS exon 2 resulting in a constitutively active molecule that drives the EGFR-KRASBRAF-MAPK pathway independent of EGFR signaling. Small retrospective studies indicated that mutated KRAS exon 2 was a negative predictive biomarker for anti-EGFR antibodies.5,6 Consistent findings from retrospective analyses of the initial randomized panitumumab and cetuximab trials confirmed that KRAS mutational status was predictive for the use of antiEGFR antibodies.7,8 Standard of care evolved to restrict anti-EGFR antibody use to patients with a wild-type KRAS exon 2 colorectal cancer.

Incorporating KRAS exon 2 into clinical care imDr Ali received her medical degree from St. George’s University, St. George’s, Grenada, and is currently practicing as a first-year fellow in the Division of Hematology/Oncology at Scripps Clinic.

Dr Sigal received his medical degree from the University of California, Los Angeles, and is currently practicing in the Division of Hematology/Oncology at Scripps Clinic Medical Group. He is an active investigator in the GI Cancer Program at Scripps Clinic.

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KEY POINTS Expanded RAS analysis enhances the negative and positive predictive value for anti-EGFR antibodies compared to KRAS exon 2 testing alone ➤ Wild-type RAS status predicted benefit for antiEGFR antibodies in combination with irinotecanand oxaliplatin-based chemotherapy ➤ Bevacizumab or anti-EGFR antibodies can appropriately be included in front-line therapy for wild-type KRAS exon 2 patients. It is still not clear if wild-type RAS patients preferentially benefit from an up-front anti-EGFR antibody ➤

proved the selection of patients who would potentially benefit from anti-EGFR antibodies. Again, it was suggested that patient selection could be further optimized. Additional mutations had been reported in KRAS exons 3 and 4, as well as NRAS exons 2, 3, and 4, that were also putative negative predictive biomarkers for anti-EGFR antibodies.9-12 NRAS has structural and functional homology to KRAS, suggesting it, too, had predictive value for anti-EGFR antibodies.13-15 Due to their low prevalence (Table 1), studies supportive of the predictive role for expanded RAS testing were small and retrospective, limiting their clinical impact. Recently, a prospective-retrospective analysis of a large phase 3 trial showed that expanded RAS testing, including KRAS and NRAS exons 2 (codons 12 and 13), 3 (codon 61), and 4 (codons 117 and 146), identified up to an additional 18% of RAS mutations among wild-type KRAS exon 2 patients.16 Expanded RAS testing enhanced the negative and positive predictive value of KRAS exon 2 testing alone for anti-EGFR antibodies.16,17 Finally, BRAF has also been evaluated for its potential predictive role in utilizing anti-EGFR antibodies.

Early studies revealed that colorectal cancer cell lines with BRAF V600E mutations were resistant to anti-­

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EGFR antibodies, suggesting that BRAF mutations could also serve as a negative predictive biomarker.4,18 These preclinical findings were supported in small retrospective analyses.14,18 However, larger trials and meta-analyses reveal a much more complicated picture.

This manuscript will review the recent literature of expanded RAS and BRAF testing as predictive biomarkers for anti-EGFR antibodies and address their incorporation into patient care.

Table 1 RAS and BRAF Mutation Rates16 Mutation

Rate (%)

KRAS exon 2 at codons 12 and 13

40

KRAS exon 3 at codon 61

4

KRAS exon 4 at codon 117 or 146

6

NRAS exon 2 at codon 12 or 13

3

NRAS exon 3 at codon 61

4

Expanded RAS Analysis NRAS exon 4 at codon 117 or 146 0 Oxaliplatin-Based Chemotherapy BRAF exon 15 at codon 600 8 in the Front-Line Setting Two trials have demonstrated improved predictive value from expanded RAS analysis, including KRAS ed RAS testing improved the positive and negative and NRAS exons 2, 3, and 4, for anti-EGFR antibodies. predictive value versus KRAS exon 2 alone for anti-足 PRIME was a phase 3 trial that randomized 1183 paEGFR antibodies. Specifically, the improvement in OS tients with mCRC to FOLFOX4 (leucovorin, fluoroamong wild-type KRAS exon 2 patients treated with uracil [5-FU], and oxaliplatin) with or without panitupanitumumab and the reduction in OS among mutated mumab, and the first to prospectively perform KRAS KRAS exon 2 patients treated with panitumumab betesting in the front-line setting.16 Within the wild-type came statistically significant with expanded RAS testKRAS group, panitumumab improved progression-free ing (Table 2). survival (PFS) and overall survival (OS) compared Retrospective analysis of the OPUS trial also evalwith chemotherapy alone (9.6 vs 8.0 months, P=.02 uated the effect of anti-EGFR antibody therapy and 23.9 vs 19.7 months, P=.072, respectively). Con(cetuximab) combined with oxaliplatin-based chemoversely, patients with mutated KRAS not only failed to therapy in the front-line setting of patients with unrederive any benefit from anti-EGFR antibody therapy, sectable mCRC.19 In this study, 337 patients were they were actually harmed. Mutated KRAS patients randomly assigned to either FOLFOX alone or in who received panitumumab experienced reduced PFS combination with cetuximab. Of these 337 patients, and OS (7.3 vs 8.8 months, P=.02 and 15.5 vs 19.3 317 were included in an unplanned retrospective months, P=.068, respectively). Prospective-retrospecanalysis to determine the predictive value of KRAS. tive analysis of PRIME prespecified a statistical design Wild-type KRAS exon 2 patients who received cetuxto assess the predictive impact of expanded RAS testimab had a 23% improvement in overall response rate ing. Among patients with wild-type KRAS exon 2, 108 (ORR; 57% vs 34%, P=.0027) and a 1.1 month impatients (17%) harbored additional RAS mutations. provement in median PFS (8.3 vs 7.2 months, Wild-type RAS patients had improved PFS and OS P=.0064) compared with patients receiving chemo(10.1 vs 7.9 months, P=.004 and 26.0 vs 20.2 months, P=.04, Table 2 Predictive Value of KRAS Exon 2 and Expanded RAS in Oxaliplatin-Treated Patients in PRIME16 respectively) when administered FOLFOX FOLFOX + FOLFOX + plus panitumumab verPanitumumab FOLFOX P Value Panitumumab FOLFOX P Value sus FOLFOX alone. InWild-Type Exon 2 Mutated Exon 2 ferior PFS and OS were observed in the mutat- Median PFS (months) 9.6 8.0 .02 7.3 8.8 .02 ed RAS cohort treated Median OS (months) 23.9 19.7 .072 15.5 19.3 .068 with FOLFOX plus panitumumab compared Wild-Type Expanded RAS Mutated Expanded RAS with FOLFOX alone 10.1 7.9 .004 7.3 8.7 .008 (7.3 vs 8.7 months, Median PFS (months) 26.0 20.2 .04 15.5 18.7 .04 P=.008 and 15.5 vs Median OS (months) 18.7 months, P=.04, OS indicates overall survival; PFS, progression-free survival. respectively). Expand-

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therapy alone. No differences were noted for OS. Similar to the results from PRIME, patients with mutated KRAS exon 2 had inferior clinical end points with the addition of cetuximab. Statistical reductions in ORR and PFS were noted (34% vs 54%, P=.0290 and 5.5 vs 8.6 months, P=.0153, respectively), while a numerical decrease in OS occurred (13.4 vs 17.5 months, P=.20). Recently, of 179 wild-type KRAS samples in OPUS, 118 were evaluable for additional RAS mutation screening beyond KRAS exon 2.20 Ad-

cohort (ORR, 40% vs 61.3%, P=.1966; median PFS, 7.2 vs 9.7 months, P=.1135; OS, 16.3 vs 28.5 months, P=.0199, respectively).21 Although these results reinforce the 2 studies described above, the absence of a cohort that did not receive cetuximab limits this study’s commentary on the predictive value of expanded RAS testing.

Irinotecan-Based Chemotherapy in the Front-Line Setting CRYSTAL was a phase 3 trial that randomized 1198 mCRC patients to irinotecan-based chemotherapy with or without the addition of cetuximab.2 An updated retrospective analysis of CRYSTAL had an ascertainment Similar to the results from the PRIME study, rate of 89% (n=1063) of samples for KRAS testing from patients with mutated KRAS exon 2 had the intention-to-treat population and identified mutated 22 inferior clinical end points with the addition KRAS exon 2 in 37%. Statistically significant improvements in OS (23.5 vs 20.0 months, P=.0093), PFS (9.9 of cetuximab. vs 8.4 months, P=.0012), and ORR (57.3% vs 39.7%, P≤.001) were observed for wild-type KRAS exon 2 patients in the cetuximab-containing treatment arm versus ditional RAS mutations were found in 36 samples the chemotherapy-alone group (Table 4). A retrospec(31%). Exclusion of these additional RAS mutations tive expanded RAS analysis of CRYSTAL among 430 resulted in a statistically significant improvement in (65%) of the wild-type KRAS exon 2 patients was preresponse rate and trends toward improved PFS and OS sented at ASCO 2014.23 New RAS mutations were idenfor the group receiving cetuximab (Table 3). Inferior tified in an additional 63 patients (15%). Cetuximab did clinical end points were observed in the expanded not confer any benefit to patients with any RAS mutaRAS mutation cohort receiving cetuximab (Table 3). tion and those with wild-type KRAS exon 2 with a new In a third retrospective study, 148 patients with RAS mutation. However, patients with wild-type RAS mCRC wild-type KRAS exon 2 were randomized to had clinically and statistically significant improvements FOLFOX with weekly versus every-2-week cetuximab. in response and survival end points when administered Ex­­panded RAS analysis uncovered 24 patients (16%) FOLFIRI (leucovorin, 5-FU, and irinotecan) plus cetuxharboring additional RAS mutations with decreased imab compared with FOLFIRI alone. Wild-type RAS ORR, PFS, and OS compared with the wild-type RAS patients also had improved clinical end points when compared with wildtype KRAS exon 2 Value of KRAS Exon 2 and Expanded RAS in Oxaliplatin-Treated Patients in patients (Table 4).

Table 3 Predictive OPUS19 Expanded RAS testing also resulted FOLFOX + FOLFOX + in incremental imCetuximab FOLFOX P Value Cetuximab FOLFOX P Value provements in end Wild-Type Exon 2 Mutated Exon 2 points with irino­­te­can-based chemoORR (%) 57.0 34.0 .0027 34.0 54.0 .0290 therapy and cetuxMedian PFS (months) 8.3 7.2 .0064 5.5 8.6 .0153 imab in the FIRE-3 Median OS (months) 22.8 18.5 .39 13.4 17.5 .20 trial, which will be discussed later.24 Wild-Type Expanded RAS

Mutated Expanded RAS

ORR (%)

61.1

30.4

.008

36.2

48.7

.11

Median PFS (months)

12.0

5.8

.018

5.6

7.8

.018

Median OS (months)

20.7

17.8

.50

13.4

17.8

.089

ORR indicates overall response rate; OS, overall survival; PFS, progression-free survival.

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Salvage Setting In the first phase 3 second-line trial that prospectively assessed KRAS status, 1186 patients who

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had progressed on 1 prior Value of KRAS Exon 2 and Expanded RAS in Irinotecan-Treated Patients in line of therapy were ranTable 4 Predictive22,23 CRYSTAL domized to FOLFIRI with or without panitumu­mab.

FOLFIRI + FOLFIRI + Of the 1083 patients with Cetuximab FOLFIRI P Value Cetuximab FOLFIRI P Value wild-type KRAS exon 2, Wild-Type Exon 2 Mutated Exon 2 those administered FOLFIRI plus panitumumab ORR (%) 57.3 39.7 <.001 31.3 36.1 .35 had improved PFS (5.9 vs Median PFS (months) 9.9 8.4 .0012 7.4 7.7 .26 3.9, P=.004) and ORR (35% vs 10%, P<.001) Median OS (months) 23.5 20.0 .0093 16.2 16.7 .75 compared with those reWild-Type Expanded RAS Mutated Expanded RAS ceiving FOLFIRI alone.

A nonstatistical OS ORR (%) 66.3 38.6 <.0001 31.7 36.0 .40 trend also favored the paMedian PFS (months) 11.4 8.4 .0002 7.4 7.5 .47 nitumumab-containing Median OS (months) 28.4 20.2 .0024 16.4 17.7 .64 arm.17 These data have been confirmed with lonFOLFIRI indicates leucovorin, fluorouracil, and irinotecan; ORR, overall response rate; OS, overall ger follow-up (median survival; PFS, progression-free survival.

PFS, 6.7 vs 4.9 months, P=.023; ORR 36% vs 10%, P≤.0001).25 Recently, a retrospective-prospective biomarker analysis 3-arm randomized study evaluating the benefit of addof this trial identified an additional 18% of patients ing cetuximab to front-line oxaliplatin-based chemowith mutated RAS among those with known wild-type therapy. In an unplanned retrospective analysis of 194 KRAS exon 2.26 Wild-type RAS patients treated with wild-type KRAS exon 2 patients, the addition of cetuxFOLFIRI plus panitumumab had improved PFS and OS imab again did not improve clinical outcomes. outcomes compared with those with wild-type KRAS exon 2 alone. In contrast, patients with any RAS mutation, including those with wild-type KRAS exon 2, deWild-type RAS patients receiving FOLFIRI rived no additional benefit from the use of panitumu­ plus panitumumab had improved PFS and mab (Table 5).

Mutated RAS and Anti-EGFR Antibodies Despite the positive predictive value of wild-type KRAS exon 2 for anti-EGFR antibodies described in the previous trials, these results have not been universal. The NORDIC-VII and MRC COIN trials showed no benefit from the addition of anti-EGFR antibodies to an oxaliplatin-based chemotherapy regimen in a cohort of wild-type KRAS exon 2 patients in the firstline setting.27,28 MRC COIN was a phase 3 trial that prospectively randomized 729 wild-type KRAS (at exons 2 and 3) patients to front-line FOLFOX or XELOX (capecitabine plus oxaliplatin) with or without cetuximab. The primary end point was OS. No advantage was identified from the use of cetuximab according to survival end points (OS, 17 vs 17.9 months, P=.67; PFS, 8.6 vs 8.6 months, P=.8) compared with chemotherapy alone. Cetuximab also conferred no advantage among a cohort of wild-type RAS patients (at KRAS codons 12, 13, and 61; NRAS codons 12 and 61) prospectively assessed in this study. NORDIC-VII was a

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OS outcomes compared with those with wild-type KRAS exon 2 alone.

Two main explanations can be proposed for the discrepant outcomes between MRC COIN and NORDIC-VII and the other anti-EGFR antibody trials.

First, the method of 5-FU delivery may affect the beneficial impact of anti-EGFR antibodies. In an exploratory analysis of MRC COIN, cetuximab only improved PFS among the one-third of patients who received infusional 5-FU (FOLFOX) and not among the two-thirds of patients treated with capecitabine (XELOX).29 With a two-third reduction in the pool of patients who could benefit from cetuximab, the study lost statistical power to identify a difference. NORDIC-VII utilized bolus 5-FU (Nordic FLOX regimen) instead of the more standard infusional 5-FU (FOL­ FOX), but no subgroup analysis was performed in this trial according to 5-FU delivery.

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Predictive Value of KRAS Exon 2 and Expanded RAS in Irinotecan-Treated Patients in 18117,26

Table 5

FOLFIRI + Panitumumab

FOLFIRI

P Value

FOLFIRI + Panitumumab

FOLFIRI

P Value

Wild-Type Expanded RAS

Wild-Type Exon 2 ORR (%)

35.0

10.0

<.001

41.0

10.0

Median PFS (months)

5.9

3.9

.004

6.4

4.4

.006

Median OS (months)

14.5

12.5

.12

16.2

13.9

.08

FOLFIRI indicates leucovorin, fluorouracil, and irinotecan; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

Second, patients with mutated KRAS exon 2 and RAS mutations had inferior outcomes when administered anti-EGFR antibodies in combination with oxa足 liplatin-based chemotherapy. In PRIME, patients with mutated KRAS exon 2 administered panitumumab had a statistical decrease in PFS (7.3 vs 8.8 months, P=.02) and trended to worse OS (15.5 vs 19.3 months, P=.068) compared with chemotherapy alone. Similar outcomes were noted in OPUS among mutated KRAS exon 2 patients treated with cetuximab, with a statistical decrease in PFS (5.5 vs 8.6 months, P=.0153) and numerical decline in OS (13.4 vs 17.5 months, P=.20). Anti-足 EGFR antibodies also proved to be harmful among

Because MRC COIN and NORDIC-VII did not test for a complete expanded RAS panel, up to 18% of mutated RAS patients may have been missed. patients with any RAS mutation, as part of expanded RAS testing (KRAS and NRAS exons 2, 3, and 4), who also received oxaliplatin-based chemotherapy, with reduced survival end points (Table 2). Finally, even in MRC COIN, mutated KRAS patients had worse survival outcomes when treated with cetuximab. These results may partially be due to a putative suppressive effect of wild-type RAS over mutated RAS where anti-EGFR antibodies block wild-type RAS, disinhibiting RAS and driving tumor progression.30 This would not explain why anti-EGFR antibodies are not deleterious when administered to patients with mutated KRAS exon 2 or RAS in combination with FOLFIRI.17,22,26

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Nevertheless, because MRC COIN and NORDIC-VII did not test for a complete expanded RAS panel, up to 18% of mutated RAS patients may have been missed. Since this unidentified group of mutated RAS patients would have deleterious outcomes when treated with anti-EGFR antibodies, they would actively have averaged out any benefits from them.

Anti-EGFR Antibodies Versus Bevacizumab in Wild-Type KRAS and RAS Patients FIRE-3 was a phase 3 trial that randomized 592 previously untreated wild-type KRAS exon 2 patients to FOLFIRI with either bevacizumab (Avastin) or cetuximab.31 The primary end point was ORR, with PFS and OS serving as secondary end points. Despite similar ORR and PFS results between the 2 groups, patients treated with cetuximab had improved OS (28.8 vs 25 months, P=.0164). For reasons that are not clear, differences in OS did not appear until nearly 2 years after randomization. Since a similar percentage of patients in each group received second-line therapy, one explanation for this phenomenon may have been the lack of a standardized second-line therapy. It is also possible that the impact of second-line therapy was affected by the front-line therapy, suggesting that appropriate monoclonal antibody sequencing needs further investigation. Updated results from a preplanned analysis of expanded RAS testing in 488 patients (82%) confirmed the OS benefit in wildtype RAS patients (33.1 vs 25.9 months, P=.01) treated with cetuximab compared with bevacizumab.24 PEAK was a randomized phase 2 study that evaluated the use of FOLFOX with either panitumumab or bevacizumab in 285 previously untreated patients with wild-type KRAS exon 2 mCRC.32 As with FIRE-3, improvements in OS were seen with panitumumab compared with bevacizumab (34.2 vs 24.3 months, P=.009).

Again, as in FIRE-3, PFS was similar between arms. In a prespecified expanded RAS subgroup analysis of PEAK, wild-type RAS patients in the panitumumab cohort achieved statistical improvements in PFS (13 vs 9.5 months, P=.029) and increased the numerical benefit for OS (41 vs 29 months, P=.058).

Recently presented at ASCO 2014, CALGB 80405 was a phase 3 trial that randomized 1137 patients with

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previously untreated wild-type KRAS exon 2 mCRC to either bevacizumab or cetuximab in combination with either FOLFOX or FOLFIRI according to physicianâ&#x20AC;&#x2122;s choice.33 This study began accruing unselected patients in 2005, but based on accumulating data, study amendments mandated inclusion of only wildtype KRAS exon 2 patients, and a combination bevacizu­mab plus cetuximab treatment arm was eliminated. OS was the primary end point. No differences were found between the chemotherapy/bevacizumab and chemotherapy/cetuximab cohorts for OS (29.04 vs 29.93 months, P=.34) or PFS. Two key weaknesses of this study were that FOLFOX was the preferred chemotherapy backbone in nearly 75% of cases, and that expanded RAS analysis was not performed. As described earlier in this review, about 18% of wildtype KRAS exon 2 patients will have additional RAS mutations. These additional RAS mutations have been shown to be deleterious when patients are administered oxaliplatin-based chemotherapy in combination with an anti-EGFR antibody. Inclusion of these unidentified mutated RAS patients could have concealed any survival benefit from cetuximab.

In contrast to FIRE-3 and PEAK, which showed improved OS among wild-type KRAS and RAS patients administered an anti-EGFR antibody, CALGB 80405 did not. It is hard to discount the survival advantage seen in FIRE-3 and PEAK, but they were secondary end points, and it had been difficult to explain the lack of improvement in PFS. Also, a meta-analysis did not identify differences in OS between anti-EGFR antibodies and bevacizumab.34 In addition, a randomized phase 2 second-line trial that assigned 182 wild-type KRAS patients to FOLFIRI with either panitumumab or bevacizumab did not show any differences between the study arms for any clinical end points.35 CALGB 80405 was the largest phase 3 trial, and its primary end point was OS. Based on the totality of these data, there probably is no difference in survival outcomes among wildtype KRAS exon 2 patients treated with either bevacizumab or an anti-EGFR antibody. However, lack of expanded RAS testing in CALGB 80405 still makes preferential anti-EGFR antibody use among wild-type RAS patients reasonable.

BRAF BRAF is a proto-oncogene encoding a serine-threonine kinase that acts as a downstream effector of KRAS in the EGFR-KRAS-BRAF-MAPK signaling pathway. The BRAF V600E mutation accounts for approximately 90% of BRAF mutations, occurring in less than 15% of colon adenocarcinomas.18,36,37 In a small retrospective analysis of 11 patients with mCRC pos-

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sessing both wild-type KRAS exon 2 and mutated BRAF, none responded to anti-EGFR antibodies.18 Similar results were also noted in a separate small report.14 Since anti-EGFR antibodies had a response rate of less than 20% in all wild-type KRAS exon 2 patients, it was not clear if these results reflected predictive or prognostic value of mutated BRAF V600E.

In a small retrospective analysis of 11 patients with mCRC possessing both wildtype KRAS exon 2 and mutated BRAF, none responded to anti-EGFR antibodies.

Retrospective analyses of much larger well-designed prospective trials reinforced the negative prognostic power of BRAF V600E mutation. CAIRO2 was a phase 3 trial that randomized 755 previously untreated patients with mCRC to the combination of XELOX plus bevacizumab with or without cetuximab.38 Retrospective review identified 45 patients with wild-type KRAS exon 2 and mutated BRAF. These patients had decreased PFS and OS independent of whether they received cetuximab.39 Similar results were noted upon retrospective studies of the CRYSTAL and PRIME trials, pointing to the powerful negative prognostic value of mutated BRAF.16,22 The limited prevalence of BRAF mutations makes demonstrating statistical significance difficult, but mutated BRAF patients did appear to have numerical improvements in response and survival end points when treated with anti-EGFR antibodies, suggesting that they may still be of benefit.

A meta-analysis that compiled the results of the OPUS and CRYSTAL trials did not demonstrate statistical differences in outcomes between cohorts with both wild-type KRAS exon 2 and mutated BRAF that did, or did not, receive anti-EGFR antibodies.40 However, those patients administered anti-EGFR antibodies experienced important trends of improved outcomes for OS, PFS, and ORR that approached statistical significance. Despite the lack of statistical significance in this meta-analysis, the numerical improvements in outcome are clinically important. When considering these results together with the lack of BRAF V600E predictive value for anti-EGFR antibodies in the CAIRO2, CRYSTAL, and PRIME trials, 2 conclusions can be made. First, BRAF V600E is a very poor negative prognostic marker. Second, patients with BRAF V600E mutations can still benefit from anti-EGFR antibodies and should not be excluded from their use. However,

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recently presented at ASCO 2014, preliminary reports with promising results for coinhibition of BRAF and other targets, such as EGFR, MEK, or PI3K/AKT, may resurrect the predictive role of BRAF.41-45

Conclusion This manuscript reviewed the rapidly evolving role of expanded RAS testing as a predictive biomarker for anti-EGFR antibodies in patients with mCRC. Expanded RAS analysis involved assessing for tumor mutations in KRAS or NRAS at exons 2 (codons 12 and 13), 3 (codons 61), and 4 (codons 117 and 146). Multiple retrospective and retrospective-prospective studies determined that expanded RAS analysis improved the negative and positive predictive value compared with KRAS exon 2 alone. Although preplanned expanded RAS analysis made panitumumab studies the most rigorous, expanded RAS testing also conferred increased predictive value for cetuximab. It is important to highlight that expanded RAS analysis was beneficial among patients administered either an irinotecan- or oxaliplatin-based chemotherapy regimen.

A prescient clinical trial will continue to focus on excellent study design with specimen storage for an almost certain future retrospective analysis.

These results have 2 main implications for patient care. First, expanded RAS testing should be performed prior to the use of panitumumab and cetuximab. Second, patients who are wild-type KRAS exon 2 can receive either front-line bevacizumab or an anti-EGFR antibody. However, patients with wild-type RAS may still benefit preferentially from the use of a front-line anti-EGFR antibody.

Future biomarker clinical study design is now confronted with the challenge of essentially peering into the future. As evidenced by the KRAS/RAS story, not only can new biomarkers emerge, but well-accepted biomarkers can also assume new roles. A prescient clinical trial will continue to focus on excellent study design with specimen storage for an almost certain future retrospective analysis. u

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21. Brodowicz T, Vrbanec D, Kaczirek K, et al. FOLFOX4 plus cetuximab administered weekly or every two weeks in first-line treatment of patients with KRAS and NRAS wild-type (wt) metastatic colorectal cancer (mCRC). J Clin Oncol.

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22. Van Cutsem E, Köhne C-H, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29:2011-2019.

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24. Stintzing S, Jung A, Rossius L, et al. Mutations within the EGFR signaling pathway: influence on efficacy in FIRE-3 – a randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. J Clin Oncol. 2014;32(suppl 3). Abstract 445.

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tinuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012;30:1755-1762.

28. Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet.

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29. Adams RA, Meade AM, Seymour MT, et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011;12:642-653.

30. To MD, Rosario RD, Westcott PMK, et al. Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis. Oncogene. 2013;32:4028-4033.

31. Heinemann V, von Weikersthal LF, Decker T, et al. Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK0306 (FIRE-3). J Clin Oncol. 2013;31(suppl). Abstract LBA3506.

32. Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer [published online April 21, 2014]. J Clin Oncol.

33. Venook AP, Niedzwiecki D, Lenz H-J, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol. 2014;32(suppl). Abstract LBA3.

34. Kumachev A, Yan M, Berry SR, et al. A comparison of biologics in first-line advanced colorectal cancer: a Bayesian network meta-analysis of EGFR inhibitors and bevacizumab. J Clin Oncol. 2014;32(suppl 3). Abstract 543.

35. Hecht JR, Cohn AL, Dakhil SR, et al. SPIRITT (study 20060141): a randomized phase II study of FOLFIRI with either panitumumab (pmab) or bevacizumab (bev) as second-line treatment (tx) in patients (pts) with wild-type (WT) KRAS metastatic colorectal cancer (mCRC). J Clin Oncol. 2013;31(suppl 4).

Abstract 454.

36. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954.

37. Phipps AI, Buchanan DD, Makar KW, et al. BRAF mutation status and survival after colorectal cancer diagnosis according to patient and tumor characteristics.

Cancer Epidemiol Biomarkers Prev. 2012;21:1792-1798.

38. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360:563-572.

39. Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer.

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40. Bokemeyer C, Van Cutsem E, Rougier P, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012;48:1466-1475.

41. Geel RV, Elez E, Bendell JC, et al. Phase I study of the selective BRAF V600 inhibitor encorafenib (LGX818) combined with cetuximab and with or without the α-specific PI3K inhibitor BYL719 in patients with advanced BRAF-mutant colorectal cancer. J Clin Oncol. 2014;32(suppl). Abstract 3514.

42. Bendell JC, Atreya CE, André T, et al. Efficacy and tolerability in an openlabel phase I/II study of MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in combination in patients (pts) with BRAF V600E mutated colorectal cancer (CRC). J Clin Oncol. 2014;32(suppl).

Abstract 3515.

43. Hong DS, Morris VK, Fu S, et al. Phase 1B study of vemurafenib in combination with irinotecan and cetuximab in patients with BRAF-mutated advanced cancers and metastatic colorectal cancer. J Clin Oncol. 2014;32(suppl). Abstract 3516.

44. Corcoran RB, Atreya CE, Falchook GS, et al. Phase 1-2 trial of the BRAF inhibitor dabrafenib (D) plus MEK inhibitor trametinib (T) in BRAF V600 mutant colorectal cancer (CRC): updated efficacy and biomarker analysis. J Clin Oncol.

2014;32(suppl). Abstract 3517.

45. Tabernero J, Chan E, Baselga J, et al. VE-BASKET, a Simon 2-stage adaptive design, phase II, histology-independent study in nonmelanoma solid tumors harboring BRAF V600 mutations (V600m): activity of vemurafenib (VEM) with or without cetuximab (CTX) in colorectal cancer (CRC). J Clin Oncol. 2014;32(suppl).

Abstract 3518.

Interview With the Innovators An exclusive PMO series

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THIRD ANNUAL

WORLD CUTANEOUS MALIGNANCIES CONGRESS

™

October 29 – October 31, 2014 • Marriott Marquis • San Francisco, CA A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, and cutaneous T-cell lymphoma.

CONFERENCE CHAIR

WORLD CUTANEOUS MALIGNANCIES CONGRESS

Sanjiv S. Agarwala, MD Bethlehem, PA

PROGRAM COMMITTEE

Axel Hauschild, MD Kiel, Germany

Paul Nghiem, MD, PhD Seattle, WA

Pierluigi Porcu, MD Columbus, OH

Aleksandar Sekulic, MD, PhD Scottsdale, AZ

™

TARGET AUDIENCE

This educational initiative is directed toward medical and surgical oncologists, dermatologists, and radiation oncologists involved in the treatment of patients with cutaneous malignancies. Fellows, nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionals interested in the treatment of cutaneous malignancies are also invited to participate.

EDUCATIONAL OBJECTIVES

After completing this activity, the participant should be better able to: • Review the molecular biology and pathogenesis of malignant melanoma, CTCL, BCC, and MCC, including how they relate to targeted therapy • Describe how to tailor therapeutic options and optimal sequencing for individual patients with melanoma, CTCL, BCC, and MCC • Utilize emerging data and recent advances with new molecular targets for the treatment of patients with metastatic melanoma, CTCL, BCC, and MCC into clinical practice • Identify new technologies for the prevention and early detection of cutaneous malignancies

PHYSICIAN CONTINUING MEDICAL EDUCATION

Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and Center of Excellence Media. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION*

The Postgraduate Institute for Medicine designates this live activity for a maximum of 9.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. *This CME/CE activity complies with all requirements of the federal Physician Payment Sunshine Act. If a reportable event is associated with this activity, the accredited provider managing the program will provide the appropriate physician data to the Open Payments database.

DISCLOSURE OF CONFLICTS OF INTEREST

Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COIs are thoroughly vetted and resolved according to PIM policy.

The existence or absence of COIs for everyone in a position to control content will be disclosed to participants prior to the start of each activity.

AMERICANS WITH DISABILITIES ACT

Event staff will be glad to assist you with any special needs (ie, physical, dietary, etc). Please contact Linda Sangenito prior to the live event at 732-992-1520.

This activity is jointly provided by Postgraduate Institute for Medicine and Center of Excellence Media, LLC.

For more information please visit www.CutaneousMalignancies.com

AGENDA*

WEDNESDAY, OCTOBER 29 3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception/Exhibits

THURSDAY, OCTOBER 30 6:45 am - 9:15 am

Breakfast Product Theaters

9:15 am - 9:30 am

Break

9:30 am - 9:45 am Welcome to the Third Annual World Cutaneous Malignancies Congress - Setting the Stage for the Meeting – Sanjiv S. Agarwala, MD 9:45 am - 11:45 am General Session I The Molecular Biology of Cutaneous Malignancies Implications for Personalized Therapy • Understanding the molecular biology of malignant melanoma: a clinical perspective – Antoni Ribas, MD • The molecular basis of basal cell carcinoma (BCC) – James MacDonald • Cutaneous T-cell lymphoma (CTCL): molecular aspects of disease development and response to targeted agents – Anjali Mishra, PhD • Immunologic characterization of tumor cells in CTCL: application to clinical practice – Rachel Clark, MD, PhD • Virus-positive and virus-negative Merkel cell carcinoma (MCC): implications for the clinician – Isaac Brownell, MD, PhD Question & Answer Panel Discussion

• Ongoing clinical studies in BCC – Aleksandar Sekulic, MD, PhD • New systemic therapies in CTCL: beyond the old paradigms – Steve Horowitz • Emerging treatment options in MCC: chemotherapy and alternative approaches for metastatic disease – Shailender Bhatia, MD Question & Answer Session 4:35 pm - 5:15 pm Tumor Board Breakout Sessions • Attendee cases in malignant melanoma • Attendee cases in BCC • Attendee cases in CTCL and MCC 5:15 pm - 7:00 pm

FRIDAY, OCTOBER 31

Cocktail Reception/Exhibits

7:00 am - 8:00 am

Breakfast

8:00 am - 8:15 am

Break

8:15 am - 8:30 am Review of Thursday’s Presentations and Preview of Today’s Sessions – Sanjiv S. Agarwala, MD

11:45 am - 12:00 pm Break

8:30 am - 9:30 am General Session IV Prevention and Early Detection • Early detection of primary tumors in melanoma – Susan M. Swetter, MD • A new serologic assay for early detection of recurrent MCC – Paul Nghiem, MD, PhD • An update on the SCREEN trial: skin cancer screening in Germany – Axel Hauschild, MD Question & Answer Session

12:00 pm - 1:00 pm

9:30 am - 9:45 am

Meet the Experts/Lunch in the Exhibit Hall

1:00 pm - 2:15 pm General Session II Current Treatment Algorithms in Cutaneous Malignancies • Current approaches to therapy in malignant melanoma: the US perspective – Antoni Ribas, MD • Current approaches to therapy in malignant melanoma: the EU perspective – Axel Hauschild, MD • Current treatment options for advanced BCC – Karl Lewis, MD • Current treatment options in CTCL – Pierluigi Porcu, MD • Update on NCCN guidelines for the management of MCC – Christopher K. Bichakjian, MD 2:15 pm - 2:30 pm

Break

2:30 pm - 2:50 pm Keynote Debate International Focus on Melanoma: Case Presentation Followed by US vs EU vs Latin America Debate on Therapy – Sanjiv S. Agarwala, MD; Héctor Martínez Saíd, MD; Axel Hauschild, MD 2:50 pm - 4:35 pm General Session III Emerging Therapies, Combos, and Targeted Agents • Changing arena of adjuvant therapy in malignant melanoma – Reinhard Dummer, MD, PhD

Break

9:45 am - 11:10 am General Session V What’s Hot in New Drugs and Clinical Trial Data • Anti–PD-1 antibodies ± ipilimumab in melanoma – Caroline Robert, MD, PhD • Real-world management of BCC: the RegiSONIC study – Jean Tang, MD, PhD • New data on lymphoma biology with applications to CTCL – Leandro Cerchietti, MD • Rationale and status of immune targeted therapies for MCC – Isaac Brownell, MD, PhD Question & Answer Session 11:10 am - 11:25 am Keynote Panel Discussion Is There a Role for “Conventional Therapies” for Cutaneous Malignancies in the Era of Targeted Agents? – Sanjiv S. Agarwala, MD; Axel Hauschild, MD; Paul Nghiem, MD, PhD; Pierluigi Porcu, MD; Aleksandar Sekulic, MD, PhD 11:25 am - 11:30 am

Closing Remarks – Sanjiv S. Agarwala, MD

*Agenda subject to change.

For full faculty information please visit www.CutaneousMalignancies.com

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EDITORIAL IMMUNOTHERAPY

Blocking Immune Checkpoints in Metastatic Melanoma Igor Puzanov, MD, MSCI, FACP Vanderbilt University Medical Center Nashville, Tennessee

Igor Puzanov, MD, MSCI, FACP

T

he incidence of metastatic melanoma has been on the rise in the past 3 decades, along with one of the fastest increasing death rates among cancers. In particular from 2006 to 2010, the incidence rates among whites increased by 2.7% per year, and the death rates among white males 50 years or older increased by 1.1%.1 In the United States alone, it is estimated that 76,200 new cases will be diagnosed in 2014, and an estimated 9710 people will die of their disease. For years, few therapeutic options were available for patients with advanced unresectable stage III or stage IV melanoma, the first-line therapy consisting of chemotherapy (paclitaxel with or without a platinum agent), biochemotherapy (temozolomide or dacarbazine), and immunotherapy (high-dose interleukin-2 [HD IL-2]). Less than 20% of patients treated with HD IL-2, the most effective of the treatments, have a response, and only about one-third of them experience a complete response.2 In addition to toxicity and unavailability of this treatment for patients with some preexisting conditions (cardiopulmonary complications, brain metastases), the impact on overall survival (OS) in patients with metastatic melanoma was negligible. With the lacking standard of care for the next step of the therapy, patients were encouraged to enroll in a clinical trial.

With the rising incidence of metastatic melanoma around the world, one of the deadliest cancers with 5-year survival rates of around 16%, recent advances in targeted therapies and immunotherapies are beginning to lift the heavy cloud of this diagnosis and light the way toward potentially curative treatments. For the first time in the history of this disease, there are treatments that significantly improve OS of the patients.

Cancer Immune Evasion In recent years, the results from early immunotherapy

KEY POINTS For the first time, new treatments in immune and targeted therapy that improve overall survival in patients with advanced melanoma have been identified and are becoming available to patients ➤ Either sequential or concurrent combinations of these novel therapies hold even more promise in the future of melanoma treatment as well as other malignancies. To maximize clinical benefit and safety, further prospective randomized trials will have to optimize the potential combinations ➤ With choices between immune checkpoint blockade followed by targeted therapy, dual immune checkpoint blockade, immune checkpoint blockade, and existing immune therapies or chemotherapies, new guidelines will have to be carefully designed – which will come first? ➤ Because not all patients respond to immune checkpoint blockade, predictive and prognostic markers must be established to identify the patients who may benefit from these new, expensive treatments ➤ For better assessment of treatment efficacy, changes in the criteria for clinical benefit are needed since immunotherapies appear to elicit clinical benefit often without the standard clinical response, and some patients seem to respond even in the presence of apparent progressive disease ➤

trials ignited a seed of hope in the oncology community.3,4 Cancer immunotherapy was chosen as the breakthrough of the year in 2013 by the American Academy for the Advancement of Science, a recognition usually reserved for exciting advances in the basic sciences, and

Dr Puzanov is currently an associate professor of medicine at Vanderbilt University School of Medicine and the director of melanoma clinical research at Vanderbilt-Ingram Cancer Center in Nashville, TN. He received his MD from Charles University in Prague, Czech Republic.

His major interests are phase 1 drug development with emphasis on combination immune and targeted therapy development in melanoma and renal cell carcinoma as well as novel drug design. He has published over 30 original articles and serves as a reviewer for major oncology journals and as a section editor for Personalized Medicine in Oncology and associate editor for International Journal of Targeted Therapies in Cancer.

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immune evasion is now being studied extensively as an emerging hallmark of cancer.5,6 Growing understanding of the mechanisms involved in tumor progression has sprouted active research in the area of immunotherapy, and new targets in the immunoregulatory pathways are being validated in laboratories around the world. The big shift from the general view of tumors as homogeneous masses of malignant cells to something more similar to a rapidly growing organ with its own functions and specific, ever-changing microenvironment resulted in many new insights, including the dual role of the immune system in cancer – on the one hand tumor-suppressive and on the other hand tumor-promoting.7,8

Until recently, the only immune therapeutic option in the progressed disease consisted of administration of HD IL-2, a recombinant form of the powerful T-cell growth factor.

This duality can be explained through the concept of immunoediting, in which the immune system is capable of not only destroying malignant cells but also enabling tumor proliferation either by selecting for less immunogenic cells, thus creating tumor variants able to thrive in an immunocompetent host, or by creating conditions in the tumor microenvironment that are favorable for tumor outgrowth.9 Upon the emergence of transformed cells, the immune system is activated via a variety of mechanisms, including activation of receptors on innate immune cells by ligands coexpressed on the nascent transformed cells and recognition of tumor-specific antigens by the immune receptors on lymphocytes of the adaptive immune system, and proceeds to eliminate the tumor before it becomes clinically apparent. From the results of studies in mouse models, the immune components necessary for effective elimination depend on the specific tumor characteristics such as its origin (spontaneous or carcinogen-induced), its location, and its growth rate.8 As is now supported by numerous mouse model studies, some special tumor cell variants may escape the elimination and enter the equilibrium phase in which the adaptive immune system maintains these cell populations in check, often for many years, without clinical detection.10-14 During this process, the immune system “shapes” the tumor cells into viable, potentially highly aggressive tumors with low immunogenicity. Under special circumstances, such as immune system deterioration due to age or environmental effects, changes in the tumor population

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caused by the immune editing processes, or changes in the immune system functions caused by immunosuppressive activity of the tumor, it is possible for the tumor to escape this maintenance phase and begin to proliferate and manifest clinically.9 The mechanisms of immune evasion by cancer cells include alterations leading to reduced immune recognition, such as loss of antigens or antigen processing function within the tumor cell or loss of major histocompatibility complex (MHC) class I proteins responsible for antigen presentation; secretion of immunosuppressive factors, such as transforming growth factor-β, that are capable of disabling the infiltrating effector immune cells, including natural killer (NK) cells and CD8+ cytotoxic T lymphocytes; recruitment of inflammatory cells that are actively immunosuppressive, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells; expression of immunomodulatory ligands, such as PD-L1 and PD-L2, that inactivate cancer-specific effector T cells via binding to the immune checkpoint receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death-1 (PD-1) receptor, and B7.1 receptor.8,15-19 From these, the last one termed “immune checkpoint blockade” is the most pertinent to the recent therapeutic successes achieved in the field of immunotherapy.

The Biology of Immune Checkpoints Most practicing oncologists treating melanoma are familiar with immunotherapy in the form of adjuvant interferon-α (IFN-α) in the early stage of the disease, but IFN-α is not effective in the metastatic setting.20,21 Until recently, the only immune therapeutic option in the progressed disease consisted of administration of HD IL-2, a recombinant form of the powerful T-cell growth factor. This therapy can achieve modest response rates (overall response rates [ORRs] around 16%-20%) and long-lasting responses; however, it is limited to patients with excellent performance status, no preexisting cardiopulmonary complications, and no active brain metastases.2 With these limitations, the new advances in the field of immunotherapy bring exciting options for patients with this deadly disease.

The newest treatments aim to reactivate or unblock immune checkpoints on tumor-specific T cells that are being held in check by the tumor, thus preventing the immune system from destroying it. The most studied checkpoints are the CTLA-4 and PD-1 receptors – both expressed on activated T cells and involved in downregulation of the immune response at separate points of the process (Figure).

To activate naive and memory T cells, 2 simultaneous signals are required – first, antigen-presenting cells,

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such as dendritic cells, present the antigen on the MHC molecule to the T-cell receptor on the surface of the T cell; second, the CD28 receptor on the surface of the T cells binds B7 protein on the antigen-presenting cell. During normal immune response, CTLA-4 functions as a modulator of the early activation of T cells to prevent overactivation of the immune system.22,23 The rate of the transport of the receptor to the membrane is dependent on the strength of the T-cell receptor signal.

Once CTLA-4 is transported to the T-cell surface, it binds B7 protein with higher affinity than CD28, thus effectively hijacking the activation process and dampening of the T-cell activation. Therefore, blocking the CTLA-4 receptor with a monoclonal antibody and preventing its binding of B7 protein would reinstate signal 2, leading to relative restoration of T-cell activation. Experiments with CTLA-4 knockout mice showed early lethal immunotoxicity, demonstrating the importance of this checkpoint in regulating T-cell response and predicting the potentially serious immune-related side effects of treatments involving inhibition of this receptor.24 The second well-studied immune checkpoint target, the PD-1 receptor, is present on T cells in the periphery during ongoing inflammation and in the tissues involved in tumorigenesis. Major roles of PD-1 are limiting the activity of activated, antigen-specific T cells in the periphery and preventing autoimmune reactions.25,26 The 2 ligands for PD-1 are PD-L1 and PD-L2, which are upregulated in tissues during inflammation.27,28 PD-L1 is expressed on many cell types, including hematopoietic, endothelial, and epithelial, in response to proinflammatory cytokines such as IFN-γ, while PD-L2 is expressed in dendritic cells and macrophages in response to interleukin-4. The PD-1 receptor and its ligands play an essential role in sustaining the immunosuppressive conditions within the tumor environment.29 Activated T cells express PD-1 to varying degrees, and the concurrent presence of the receptor and upregulation of the ligands at the inflammation site insures protection of the surrounding tissues.29 In addition to PD-L1 upregulation due to inflammation, many solid tumors have been shown to express PD-1 ligands, including melanoma, lung, colon, and breast, and PD-L1 expression also correlates with poor prognosis in many cancers.30-33 Thus, unlike in the case of CTLA-4 blockade, PD-1 blockade targets the tumor site more directly because PD-1 is present on tumor-specific T cells within the tumor microenvironment. In addition, PD-1 and PD-L1 knockout mice do not develop serious spontaneous autoimmune responses in the first year and only exhibit aggravated tissue responses to infection or accelerated disease in autoimmune-prone strains.34-37 These

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observations point to the possibility of milder immune side effects to be expected with immunotherapy targeting this checkpoint.

CTLA-4 Blockade in the Clinic The first checkpoint blockade therapy approved in the United States was ipilimumab (Yervoy, previously known as MDX-010). Ipilimumab is a fully human monoclonal antibody against CTLA-4; it was approved by the FDA for the treatment of metastatic melanoma in 2011 based on the results of the phase 3 trial that demonstrated for the first time a significant survival benefit in previously treated patients with advanced unresectable metastatic melanoma.38 In this pivotal study, 676 patients with HLA-A*0201–positive, previously treated melanoma were randomized to receive ipilimumab alone, ipilimumab with glycopeptide 100 (gp100) vaccine, or gp100 vaccine alone, where ipilimumab was administered at the dose of 3 mg/kg q3wk for up to 4 doses. The median OS, the primary end point of this study, was significantly higher in groups receiving ipilimumab (10.0 and 10.1 months, respectively) than in the vaccine-alone group (6.4 months; hazard ratio [HR] 0.68; P≤.003).

Grade 3/4 immune-related adverse events (irAEs) were 10% to 15% for ipilimumab and ipilimu­mab plus gp100, and 3% for gp100 alone. OS at 2 years was 22% for the ipilimumab group and 24% for the ipilimumab plus gp100 vaccine group, compared with 14% for the gp100alone group.

During normal immune response, CTLA-4 functions as a modulator of the early activation of T cells to prevent overactivation of the immune system.

Similarly positive results were published a year later in the first-line setting where, in a randomized phase 3 trial, 502 patients with treatment-naive metastatic melanoma were randomized 1:1 to receive either ipilimumab (10 mg/kg) plus dacarbazine (850 mg/m2) or dacarbazine (850 mg/m2) plus placebo, administered at weeks 1, 4, 7, and 10, followed by dacarbazine alone q3wk through week 22.39 OS at 1 year was 47% in the ipilimumab-dacarbazine group versus 36% in the dacarbazine-placebo group. This study brought ipili­ mumab into the first-line setting and showed differing patterns of toxicity depending on the context of administration. Grade 3/4 adverse events were more frequent for ipilimumab in combination with chemo-

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e. Illustration of the Distinct theofCTLA-4 Illustration of the Roles Distinct of Roles the CTLA-4and andPD-1 PD-1 Receptors inNivolumab, a fully human IgG4 antibody Figure blocking PD-1, has been shown to produce duReceptors in Modulating the T-Cell Activation ulating the T-Cell Activation

rable responses in patients with melanoma, renal cell carcinoma (RCC), and non–small cell lung cancer (NSCLC). In a phase 1 study in patients with advanced melanoma, NSCLC, castration-resistant prostate cancer, RCC, and colorectal cancer, nivolumab was administered at doses ranging from 0.1 to 10 mg/kg q2wk.40 Objective response rates were observed in 28% of the melanoma patients (26 of 94), with grade 3/4 irAEs occurring in 14% of all patients, the worst being pulmonary toxicity.

In a phase 1 trial of nivolumab in 107 heavily pretreated patients with advanced melanoma, the ORR was 31% in a dose range from 0.1 mg/ kg to 10 mg/kg q2wk, with the best ORR of 41% achieved at 3 mg/kg, the dose chosen for phase 3 trials.41 Median duration of response at this dose was 75 weeks, median progression-free survival (PFS) 9.7 months, and median OS 20.3 months. Overall 1-year survival rate was 62%, with median duration of response 24 months and median OS 17.3 months; 2-year OS was 48%, and 3-year OS was 41%. Patients who experienced an immune-related response (best reduction in target lesions from baseline ≥30% in the presence of new lesions or after initial progressive disease [PD], or PD for ≥3 tumor assessments with best change in tumor burden ≤20% from baseline) can achieve similar OS outcomes as those with objective response according to RECIST. Nivolumab monotherapy produced durable responses, with some continuing following the discontinuation of therapy.

In a subset of patients, the PD-L1 expression While CTLA-4 controls the activation of naive or memory T cells in response correlated with favorable ORR, PFS, and OS. CTLA-4 controls the activation ofby naive or memory cells responsePD-1 to antigen to antigen presentation the dendritic cellsT in the in periphery, mod- presentation by The Tmost dritic cells in the periphery, PD-1 modulates the activity of already activated antigen-specific cellscommon adverse events were lowulates the activity of already activated antigen-specific T cells at the site of grade and manageable. Nivolumab is currently inflammation the tumor microenvironment. ite of inflammation or in or theintumor microenvironment. being assessed in 3 ongoing phase 3 stud­ ies (NCT01721746, NCT01721772, and therapy – 56% for the ipilimu­mab-dacarbazine combo NCT01844505). and 28% for dacarbazine – and the pattern of irAEs Even more promising results were reported for anothalso changed to more frequent hepatotoxicity (20%) er anti–PD-1 agent, pembrolizumab (lambrolizumab, and less frequent colitis (2%). Notably, despite showMK-3475), a highly selective, humanized monoclonal ing safety and higher efficacy at the 10 mg/kg dose, the IgG kappa isotype antibody against PD-1. In preliminary FDA approved ipilimumab only at 3 mg/kg. dose-escalation studies, pembrolizumab was safe and demonstrated clinical responses at all doses tested (1, 3, PD-1/PD-L1 Blockade in the Clinic and 10 mg/kg administered q2wk). The same dosing Currently, the results from early studies of 3 anti–PD-1 regimen was further evaluated in 135 patients with adagents have been reported, including nivolumab (formerly vanced melanoma (KEYNOTE-001, NCT01295827).42 known as MDX-1106/BMS-936558/ONO-4538), pemThe confirmed response rate across all dose cohorts was brolizumab (MK-3475), and pidilizumab (CT-011).

38%, and 52% in the cohort receiving 10 mg/kg. The

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median PFS was 36 weeks, and 1-year OS was 81%. The most common adverse events were low-grade and included fatigue, rash, pruritus, and diarrhea.

In an expansion of the KEYNOTE-001 trial, 411 ipi­ limumab-naive or -refractory melanoma patients were enrolled and given pembrolizumab either 2 or 10 mg/kg q2wk or q3wk.43-45 The ORR by RECIST v1.1 (central review) was 34%, with durable responses achieved by both ipilimumab-naive and ipilimumab-treated patients.

In addition, 88% of responses were still ongoing at the time of the report, with median duration of response not reached at the time of analysis (range, 6+ to 76+ weeks).

Median PFS was 5.5 months, and 1-year OS was 69%.

No new safety signals were observed, and the toxicity was manageable across all doses. Preliminary analysis of the correlation of the tumor PD-L1 expression and clinical response revealed improved ORR and PFS in patients with higher PD-L1 expression levels; however, antitumor activity was also observed in patients with low baseline PD-L1 expression.46 Currently, pembrolizumab is in clinical development for other advanced solid tumors, including NSCLC, RCC, and hematologic malignancies, as well as in combination trials with other therapies (Table).47 The safety and tolerability of pidilizumab, an anti– PD-1 IgG1k monoclonal antibody, was assessed in phase 1 trials in patients with hematological malignancies at doses ranging from 0.2 to 6 mg/kg q3wk. The maximum tolerated dose (MTD) was not established, and some clinical activity was demonstrated (PFS, ORR) in diffuse large B-cell lymphoma and folicular lymphoma.48,49 In a phase 2 study in patients with progressive stage IV melanoma, 100 patients were randomized to 2 doses of pidilizumab (1.5 and 6.0 mg/kg q2wk) and stratified to ipili­ mumab-naive and ipilimumab-pretreated.50 The primary end point, ORR, was missed at only 6%, while the 1-year OS was 64%. Even though the treatment was well tolerated at all doses and the outcomes were independent of dose or pretreatment, the study was small and not adjusted for the potential influence of subsequent therapies on OS. Increasing the dose to improve ORR may lead to more serious irAEs due to binding of the complement by the IgG. The lower immune-related toxicity observed with anti–PD-1 agrees with the immune effects observed in the PD-1 knockout mouse models compared to CTLA-4 knockouts. Furthermore, the localization of PD-1 receptors within the tumor microenvironment confers more specific targeting of T cells. In addition, the PD-1 receptor is induced on the surface of B cells and NK cells, thus the release of PD-1 blockade further reactivates not only the tumor-specific T cells of the adaptive immune system but also the antitumor response of the innate immune

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system branch. In the case of pembrolizumab, the use of the IgG4 immunoglobulin with a stabilizing S228P Fc alteration may also contribute to the milder irAEs observed with this antibody, since this IgG subtype does not engage Fc receptors and does not activate complement upon binding to T cells during their activation.

In preliminary dose-escalation studies, pembrolizumab was safe and demonstrated clinical responses at all doses tested (1, 3, and 10 mg/kg administered q2wk).

Encouraging results are coming out of early trials with anti–PD-L1 antibodies, BMS-936559 (MDX 1105) and MPDL3280A, which prevent the binding of the ligand to its receptor. Among 52 evaluable patients with advanced melanoma treated with BMS-936559, the objective response rate was 17%, and 27% of patients had stable disease at 24 weeks or more.51 In another phase 1 study with the PD-L1 antibody MPDL3280A, patients with metastatic melanoma were given the agent every 3 weeks for up to 1 year.52 Among 43 evaluable patients, the ORR was 28%, and PFS at 24 weeks was 41% by RECIST. Grade 3/4 irAEs included hepatotoxicity, fatigue, and decreased lymphocytes; no high-grade pneumonitis or colitis were observed. Although with similar ORR, the patients with PD-L1–positive tumors had a higher disease control rate (80%) compared with those with PD-L1–negative tumors (60%) by immunohistochemistry. Relative to baseline, the tumor samples of responders showed enhanced immune cell infiltration, PD-L1 induction, and increased granzymes, tumor necrosis factor-α, and IFN-γ.

Combination of Checkpoint Immunotherapy Combining or sequencing of various immunotherapies will require further detailed assessment due to the unique set of potential side effects. The Table lists selected ongoing combination trials of immune checkpoint therapies and other therapies in melanoma. The late onset and long duration of some immune-related side effects of ipilimumab therapy in some patients often require prolonged treatment with multiple steroids, which may disqualify these patients from receiving HD IL-2 in the future. Thus, for patients who qualify to receive HD IL-2, it may be sensible to use it first followed by ipili­mumab, as it was shown that CTLA-4 blockade is equally effective in both immunotherapy-treated and -naive patients.53 An ongoing phase 2 trial is evaluat-

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Table

Selection of Ongoing Clinical Trials of Combination Immunotherapy and Other Agents in Advanced Melanoma

Combination Dual Checkpoint Blockade

Dual Immunotherapy

Agents

Targets

NCT Identifier

Phase

Expected Enrollment

Study Description

Outcome

Estimated Completion

Ipilimumab Nivolumab

CTLA-4 PD-1

NCT01844505

2

915

Niv 2 mg/kg q2wk; Niv + Ipi; Ipi 3 mg/kg q3wk

OS

2016

Lirilumab (BMS-986015) Nivolumab

KIR PD-1

NCT01714739

1

162

Dose escalation Lir + 3 mg/kg Niv

Safety

2017

BMS-986016 Nivolumab

LAG3 PD-1

NCT01968109

1

168

Part A: dose escalation of Lir. Part B: dose escalation Lir + Niv

Safety

2018

Ipilimumab GM-CSF

CTLA-4 DCs, macrophages, granulocytes

NCT01134614

2

220

Arm 1: Ipi plus GM-CSF. Arm 2: Ipi

OS

2013

Ipilimumab Indoximod

CTLA-4 IDO

NCT02073123

1

56

Dose escalation of indoximod + Ipi 3 mg/kg

Safety

2015

Ipilimumab INCB024360

CTLA-4 IDO

NCT01604889

1/2

136

Open-label, dose-escalation phase followed by a blinded, randomized phase

Safety, OS

2015

NCT01708941

2

88

Nonresectable melanoma; 3 mg/ kg or 10 mg/kg alone or in combination with HD IFN-alpha

PFS (up to 10 years)

2014

Ipilimumab High-dose IFN-alfa2b

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Ipilimumab GR-MD-02

CTLA-4 Galectin

NCT02117362

1

22

3 + 3 phase 1 design with dose escalation of GRMD-02 along with 3 mg/kg Ipi

Safety

2015

Ipilimumab T-VEC

CTLA-4 Oncolytic virus/ GM-CSF secretion

NCT01740297

1/2

149

T-VEC intra足 tumoral injection with added Ipi in week 6 for 4 doses compared with Ipi alone

Safety, efficacy

2017

Ipilimumab HD IL-2

CTLA-4 T cells

NCT01856023

4

100

Arm 1: 2 courses 1-year OS of HD IL-2 followed by 1 course of Ipi. Arm 2: 1 course of Ipi followed by 2 courses of HD IL-2

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Table

Selection of Ongoing Clinical Trials of Combination Immunotherapy and Other Agentsâ&#x20AC;Ścontinued

Combination

Plus Targeted Therapy

Agents

Targets

NCT Identifier

Phase

Expected Enrollment

Study Description

Ipilimumab NY-ESO-1 vaccine

CTLA-4

NCT01810016

1

27

Ipi plus NYESO-1 OLP4 vaccine with or without Montanide, or NY-ESO-1 protein vaccine with Montanide

Safety, immune response

2014

Pembrolizumab PegIFN-2b Ipilimumab

PD-1 CTLA-4

NCT02089685

1/2

195

3 arms: Pembro + PegIFN-2b; Pembro + Ipi; Pembro alone

Safety, PFS

2017

Ipilimumab Dabrafenib Trametinib

CTLA-4 BRAF V600 MEK

NCT01767454

1

72

Doublet arm: D 150 and 100 mg bid + Ipi 3 mg/kg on week 2.

Triplet arm: dose escalation T + safe dose D + Ipi 3 mg/kg

Safety

2014

Pembrolizumab Trametinib Dabrafenib

PD-1 MEK BRAF V600

NCT02130466

1/2

204

Pembro + D + T; Placebo + D + T; Pembro + D; Pembro + T

Safety, PFS

2017

MEDI4736 Trametinib Dabrafenib

PD-L1 MEK BRAF V600

NCT02027961

1/2

69

Arm 1: MEDI4736 + T + D. Arm 2: MEDI4736 + T

Safety, MTD

2017

Ipilimumab Dabrafenib Trametinib

CTLA-4 BRAF V600 MEK

NCT01940809

1

40

Arm A: Ipi + D + T. Arm B: Ipi + T. Arm C: Ipi + D

Safety, biomarkers

2015

Ipilimumab Bevacizumab

CTLA-4 VEGF

NCT01950390

2

168

Stage III/IV unresectable melanoma. Arm A: Ipi. Arm B: start Bev, add Ipi in the 8th cycle

OS

2016

Ipilimumab Panobinostat

CTLA-4 HDAC

NCT02032810

1

36

Dose escalation of panobinostat + Ipi

MTD

2017

Tubulin CTLA-4

NCT01827111

2

64

Pac 150 mg/m2 IV on days 1, 8, 15, 28 + Ipi 3 mg/kg q3wk

PFS

2017

CTLA-4 DNA

NCT01409174

1/2

64

Ipi starting at 1 mg/kg + standard-dose chemo/ other agents

Tumor response

2017

Plus Paclitaxel Chemotherapy Ipilimumab

Ipilimumab Temozolomide Cisplatin IFN IL-2

Outcome

Estimated Completion

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Table

Selection of Ongoing Clinical Trials of Combination Immunotherapy and Other Agents…continued

Combination

Agents

Targets

NCT Identifier

Phase

Expected Enrollment

Study Description

Ipilimumab Doxycycline Temozolomide

CTLA-4 iNOS DNA

NCT01590082

1/2

58

Doxycycline bid 1 week before cycle 1 of Ipi + temozolomide qd days 1-4 every cycle

Estimated Completion

Outcome ORR, OS, TTP

2016

BRAF V600 indicates mutant serine/threonine-protein kinase B-Raf; CTLA-4, cytotoxic T-lymphocyte antigen-4; DCs, dendritic cells; GM-CSF, granulocyte-macrophage colony-stimulating factor; HDAC, histone deacetylase; HD IL-2, high-dose interleukin-2; IDO, indoleamine 2,3-dioxygenase; iNOS, inducible nitric oxide synthase; KIR, killer cell immunoglobulin-like receptor; LAG3, lymphocyte activation gene; MEK, mitogen-activated protein kinase kinase; MTD, maximum tolerated dose; ORR, overall response rate; OS, overall survival; PD-1, programmed death-1 receptor; PD-L1, PD-1 ligand 1; PFS, progression-free survival; TTP, time to progression; T-VEC, talimogene laherparepvec; VEGF, vascular endothelial growth factor.

Data from www.ClinicalTrials.gov. Accessed May 29, 2014.

ing the combination of ipilimumab and HD IL-2 (NCT01856023).

Another combination being tested is the concurrent or sequential blockade of CTLA-4 and PD-1 with ipi­ limumab and nivolumab (NCT01844505). The rationale behind this combination stems from the fact that many cancers use both receptors at the same time during immune evasion, and immune cells express multiple independent checkpoints. In addition, preclinical studies show that tumor cells are capable of upregulating PD-L1 in response to CTLA-4 checkpoint blockade, thus simultaneous or adequately sequenced blockade of both receptors should ensure maximum restoration of T-cell activity.54 In a phase 1 study in melanoma patients, the MTD was determined to be 3 mg/kg ipilimumab and 1 mg/kg nivolumab q3wk for 4 doses in the concurrent regimen.55 For all patients treated with the concurrent regimen (n=52), the ORR was 40%; in evaluable patients treated at the MTD (n=17), the ORR was 53%. The disease control rate was 65%. Unprecedented in checkpoint blockade monotherapy studies, the concurrent administration of this combination led to a rapid and deep tumor regression in a substantial proportion of patients – tumor reduction of 80% or more was observed in 16 patients at 12 weeks, including 5 with complete response. Grade 3/4 irAEs similar to those observed in monotherapy studies occurred in 53% of patients and were mostly reversible.

At a 2-year follow-up of the initial cohorts treated with concurrent therapy (N=53; nivolumab 0.3, 1, or 3 mg/ kg; ipilimumab 1 or 3 mg/kg), an unmatched OS of 79% was reported. In the cohort (n=17) treated with 1 mg/kg nivolumab and 3 mg/kg ipilimumab, the dose chosen for phase 2 and 3 trials, the 1-year OS was 94%, and 2-year OS was 88%.56 A phase 3 trial (NCT01927419) evaluat-

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ing the combination of ipilimumab and nivolumab compared with either agent alone in the treatment of metastatic melanoma is under way.

In an ongoing phase 2 immunotherapy combination study, ipilimumab with granulocyte-macrophage colony-stimulating factor (GM-CSF) versus ipilimumab alone is being evaluated in patients with advanced melanoma (NCT01134614). Preliminary results show that the addition of GM-CSF reduces the incidence of serious adverse immune reactions caused by ipilimumab, especially pulmonary and gastrointestinal toxicity.57

Combination of Immunotherapy With Targeted Therapy Alongside the recent developments in immunotherapies, other exciting advancements in the treatment of metastatic melanoma are happening in the area of targeted therapies in which small molecule inhibitors target the components of the MAPK pathway, such as oncogenic BRAF V600 (a protein kinase that activates the MAPK pathway) and MEK (the only known substrate of the BRAF V600 protein).58 Constitutive activation of the MAPK pathway results in unchecked proliferation, evasion of senescence and apoptosis, tissue invasion and metastasis, and evasion of immune response.59 Approximately 40% to 50% of melanomas harbor the activating BRAF V600 mutations, making these targets particularly relevant in this disease. Vemurafenib and dabrafenib are oral enzyme inhibitors of the oncogenic BRAF V600 protein kinase. Data from phase 3 clinical trials suggest that both vemurafenib and dabrafenib improve patient outcomes, with vemurafenib showing an OS benefit and dabrafenib showing improved median PFS.60-62 More positive results are seen in the development of trametinib, which inhibits the MEK protein. Inhibition of

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MEK leads to decreased cell signaling and proliferation in cancer cells. In phase 3 trials, trametinib demonstrated significant improvement in median PFS and median OS compared with chemotherapy treatment.63 While targeted therapies have rapid onset of response, are well tolerated, and result in a clinical benefit to the patient, they don’t produce durable response upon suspending the treatment, and the tumors invariably develop resistance leading to disease progression.64 This is in contrast to immunotherapies, which are characterized by slow onset of clinical benefit, delayed and often longterm side-effects, but also durable responses following the treatment completion. With these facts in mind, a rationale for sequencing or combining these 2 therapeutic approaches emerges. Indeed, in a retrospective study, the sequential use of ipilimumab followed by vemurafenib in BRAF V600–positive melanoma appears to improve the clinical outcomes compared with vemurafenib followed by ipilimumab, in which many patients rapidly progressed without the opportunity to finish the ipilimumab treatment.65 A recently reported extension of this sequencing study in melanoma patients confirms these findings: patients initiated with ipilimumab achieved median OS of 14.5 months compared with 9.9 months for the group receiving vemurafenib first. In patients who received the BRAF inhibitor first and who didn’t complete the ipilimumab treatment, the median OS at the end of BRAF inhibition was 1.2 months compared with 12.7 months for those who did.66 Careful considerations regarding potential combinations must be in place, as some targeted therapies may cause decreased adaptive immunity as seen in preliminary in vitro studies with trametinib but not observed with vemurafenib. Concurrent administration of ipilimumab and vemurafenib in a phase 1 trial (NCT01400451) led to dose-limiting hepatotoxity and early termination of the trial.67 Other combination trials are under way (Table). Combinations of anti–PD-L1 antibodies with vemurafenib or dabrafenib may produce safer, more tolerable treatments, as side effects of these monotherapies appear milder compared with side effects from agents blocking CTLA-4. Combination of trametinib with an anti–PD-L1 agent should be considered to reduce toxicities and to increase targetable tumor types beyond BRAF-mutated ones to possibly RAS as well as others.

Conclusion and Future Directions In the past 10 years, the treatment of metastatic melanoma has seen a tremendous development, and patients are beginning to experience this exciting progress with more effective treatment becoming accessible at a faster pace.

The ongoing clinical trials testing combination immunotherapy with other therapies are summarized in the Table.

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The next big questions to answer will be finding good predictive and prognostic markers. One potentially useful predictive marker, PD-L1 expression, appears to predict improved response to checkpoint blockade; however, some proportion of patients with low PD-L1 levels also experience clinical benefit from these treatments.

Further clarity into these questions will be gained with additional analysis of factors affecting tumor infiltration by lymphocytes, as these are associated with better prognosis for patients. In addition, changes in response evaluation are needed for patients undergoing immunotherapy; such as changes can be accomplished by adding

Careful considerations regarding potential combinations must be in place, as some targeted therapies may cause decreased adaptive immunity. immune response criteria to RECIST. Furthermore, combination targeting of other immune checkpoint receptors, addition of cytokines (IFN-α), IDO blockade, and use of oncolytic viruses (such as talimogene laherparepvec [T-VEC]) hold a promise to further improve the outcomes of patients with melanoma as well as with other tumors in the near future.

Acknowledgment This manuscript was prepared with the help of medical writer Alexandra Hess, PhD. u References

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25. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704.

26. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682-687.

27. Dong H, Zhu G, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365-1369.

28. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261-268.

29. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212.

30. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793800.

31. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467-477.

32. Sfanos KS, Bruno TC, Meeker AK, et al. Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+. Prostate. 2009;69:1694-1703.

33. Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114:1537-1544.

34. Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141-151.

35. Okazaki T, Tanaka Y, Nishio R, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med. 2003;9:1477-1483.

36. Wang J, Yoshida T, Nakaki F, et al. Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes. Proc Natl Acad Sci U S A. 2005;102:1182311828.

37. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682-687.

38. Hodi FS, Oâ&#x20AC;&#x2122;Day S, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.

39. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.

40. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.

41. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab.

J Clin Oncol. 2014;32:1020-1030.

42. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134-144.

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43. Hamid O, Robert C, Ribas A, et al. Randomized comparison of two doses of the anti-PD-1 monoclonal antibody MK-3475 for ipilimumab-refractory (IPI-R) and IPI-naive (IPI-N) melanoma (MEL). J Clin Oncol. 2014;32(suppl). Abstract 3000.

44. Hodi FS, Ribas A, Daud A, et al. Evaluation of immune-related response criteria (irRC) in patients (pts) with advanced melanoma (MEL) treated with the anti-PD-1 monoclonal antibody MK-3475. J Clin Oncol. 2014;32(suppl). Abstract 3006.

45. Joseph RW, Elassaiss-Schaap J, Wolchok JD, et al. Baseline tumor size as an independent prognostic factor for overall survival in patients with metastatic melanoma treated with the anti-PD-1 monoclonal antibody MK-3475. J Clin Oncol.

2014;32(suppl). Abstract 3015.

46. Kefford R, Ribas A, Hamid O, et al. Clinical efficacy and correlation with tumor PD-L1 expression in patients (pts) with melanoma (MEL) treated with the anti-PD-1 monoclonal antibody MK-3475. J Clin Oncol. 2014;32(suppl). Abstract 3005.

47. Eroglu Z, Hoffner BW, Hamid O. Checkpoint inhibition of PD-1: the promise of pembrolizumab (MK-3475) and beyond. Immunotherapy in Oncology (suppl to Personalized Medicine in Oncology):2014;1:8-14.

48. Armand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stemcell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol. 2013;31:4199-4206.

49. Westin JR, Chu F, Zhang M, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 2014;15:69-77.

50. Atkins MB, Kudchadkar RR, Sznol M, et al. Phase 2, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma. J Clin Oncol.

2014;32(suppl). Abstract 9001.

51. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-2465.

52. Hamid O, Sosman JA, Lawrence DP, et.al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). J Clin Oncol. 2013;31(suppl). Abstract 9010.

53. Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res. 2011;17:6958-6962.

54. Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107:4275-4280.

55. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133.

56. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol. 2014;32(suppl). Abstract LBA9003.

57. Hodi FS, Lee SJ, McDermott DF, et al. Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus Ipi alone in metastatic melanoma: E1608. J Clin Oncol. 2013;31(suppl). Abstract CRA9007.

58. Johnson DB, Sosman JA. Update on the targeted therapy of melanoma. Curr Treat Options Oncol. 2013;14:280-292.

59. Hocker TL, Singh MK, Tsao H. Melanoma genetics and therapeutic approaches in the 21st century: moving from the benchside to the bedside. J Invest Dermatol.

2008;128:2575-2595.

60. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.

61. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707-714.

62. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.

Lancet. 2012;380:358-365.

63. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-114.

64. Rizos H, Menzies AM, Pupo GM, et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014;20:1965-1977.

65. Ascierto PA, Simeone E, Giannarelli D, et al. Sequencing of BRAF inhibitors and ipilimumab in patients with metastatic melanoma: a possible algorithm for clinical use. J Transl Med. 2012;10:107-114.

66. Ascierto PA, Simeone E, Sileni VC, et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Cancer Invest. 2014;32:144-149.

67. Ribas A, Hodi FS, Callahan MK, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368:1365-1366.

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

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2014 AUA ANNUAL MEETING

Improved Survival With Antiandrogen After ADT in Metastatic CRPC

T

reatment with enzalutamide after progression with androgen deprivation therapy (ADT) led to a significant improvement in survival for men with metastatic castration-resistant prostate cancer (mCRPC). Patients randomized to placebo had a median radiographic progression-free survival (rPFS; primary end point) of 3.9 months, whereas the median had not been reached in the enzalutamide group, as reported at the 2014 American Urological Association Annual Meeting..

“In both the intention-to-treat population and in the subgroup of patients with nonvisceral disease, treatment with enzalutamide significantly delayed the progression of metastatic disease, reduced the risk of death, and delayed the time to initiation of cytotoxic chemotherapy,” said Christopher P. Evans, MD, chair, department of urology, UC Davis, Sacramento. “Consistent benefits also were seen in the visceral disease group.”

The drug inhibits binding of androgens to the androgen receptor, inhibits androgen receptor nuclear translocation, and inhibits androgen receptor–mediated DNA binding.

“Enzalutamide added to androgen deprivation therapy at progression provides meaningful clinical benefit to men with metastatic castration-resistant prostate cancer.”

Enzalutamide disrupts androgen signaling by affecting 3 activities involving the androgen receptor. The drug inhibits binding of androgens to the androgen receptor, inhibits androgen receptor nuclear translocation, and inhibits androgen receptor–mediated DNA binding. In the postdocetaxel setting, enzalutamide treatment resulted in improved survival and rPFS (Scher HI, et al. N Engl J Med. 2012;367:1187-1197).

Evans reported data from the phase 3 PREVAIL trial involving men with mCRPC who had progressed with ADT but who had not yet received chemotherapy. Inclusion criteria limited enrollment to patients who were asymptomatic or who had only mild symptoms. Patients continued ADT and were randomized to enzalutamide 160 mg daily or placebo. The trial had coprimary end points: rPFS and overall survival (OS).

Investigators in the multicenter international trial enrolled and randomized 1717 patients. A final OS

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analysis was planned to occur after 765 events had occurred. The trial ended prematurely after a planned interim analysis demonstrated statistically significant advantages in favor of enzalutamide.

The total patient population included 204 patients with visceral involvement. The men had a median age of approximately 71 years, and approximately 50% had a Gleason score of ≥8 at diagnosis. Almost 90% of the patients had had previous antiandrogen exposure, and approximately one-fourth had undergone radical prostatectomy.

Overall, approximately 80% of the patients had bone metastases, and more than 50% of them had soft-tissue disease.

The median treatment duration was almost 17 months in the enzalutamide arm versus 4.7 months in the placebo group (P=.001), and the magnitude of benefit was similar in patients with and without visceral involvement. Treatment duration in the subgroup with visceral disease was 14 months with enzalutamide and 3.7 months with placebo. Almost 70% of patients in the enzalutamide arm completed at least 12 months of treatment, said Evans.

At the interim analysis, median OS was 32.4 months (upper confidence interval not yet reached) with enzalutamide and 30.2 months with placebo, representing a 30% reduction in the hazard ratio (HR; P<.001). Patients without visceral disease also had significant improvement in OS (not yet reached vs 30.2 months with placebo; HR 0.692; P=.001). In the patients with visceral involvement, OS at the interim analysis favored enzalutamide (27.8 vs 22.8 months), but the upper limit of the confidence intervals had yet to be reached in either treatment arm.

Approximately 70% of patients in the placebo group received at least 1 additional therapy versus 40% in the enzalutamide arm. Treatment with enzalutamide more than doubled the time to chemotherapy (28.0 vs 10.8 months; HR 0.349; P<.001), although that analysis is ongoing.

Enzalutamide was associated with slightly more adverse events, including serious adverse events (31.6% vs 26.2%) and grade ≥3 adverse events (42.3% vs 37.3%).

The time to a first grade ≥3 adverse event was prolonged in the enzalutamide arm (22.7 vs 13.7 months), and discontinuation related to adverse events (5.6% vs 5.3%) and fatal adverse events (3.5% vs 3.7%) occurred in a similar proportion of each group. u

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2014 AUA ANNUAL MEETING

PSA Trend Analysis May Help Avoid Unnecessary Biopsies

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elaying a prostate-specific antigen (PSA)-triggered prostate biopsy to allow for additional PSA assessments might have avoided more than 70% of subsequent biopsies, according to a study of negative biopsies for 28,000 men.

An analysis based on deceleration of PSA growth rate suggested that 80% of negative biopsies might have been avoided. A decline to a level below the prebiopsy PSA growth rate might have eliminated 72% of the biopsies, as reported at the 2014 American Urological Association Annual Meeting.

“This analysis of the diverse Veterans Affairs population suggests that a delay in a biopsy to allow for additional PSA testing may help avoid the biopsy,” Thomas Neville, PhD, founder and CEO, Soar BioDynamics, and colleagues concluded in a poster presentation.

“In many cases, subsequent PSA trends showed a decrease that could have reduced unnecessary biopsies by 72%. The fastest growth in PSA per year was also the most likely to decrease, with a 93% potential reduction in biopsies.”

Aggressive, potentially lethal prostate cancers exhibit a faster PSA growth rate compared with low-risk, indolent cancers. Most lethal prostate cancers produce smooth exponential growth in PSA above a no-cancer baseline, according to Neville. As the PSA growth rate increases, so does the lethality of the prostate cancer.

Benign conditions can also spark an increase in PSA growth rate, but unlike in aggressive cancers, the increase is often followed by a decline, which provides strong justification to delay a biopsy, Neville continued.

To estimate the potential of PSA growth rate trends to reduce unnecessary prostate biopsies, the researchers analyzed the Veterans Affairs health system database, which comprises 33 million PSA test results for 14 million men. The investigators searched for men who had negative prostate biopsies from 2001 to 2012 and at least 3 PSA measurements in the 2 years before biopsy plus at least 1 PSA measurement after the biopsy. The search yielded 28,314 men aged 50 to 75 years.

Using the resulting data from PSA tests, the investigators calculated estimates for 4 PSA-based parameters: the baseline cutoff value associated with no cancer, the PSA values associated with cancer, trends in cancerassociated PSA values over time, and annual cancerassociated PSA growth rate.

Neville and colleagues identified men who had decreases in PSA after a prostate biopsy that had been as-

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sociated with an increasing PSA trend. The investigators grouped the men according to PSA growth rate and calculated the proportion of men who had postbiopsy declines in PSA for each PSA growth rate category.

The results suggest that the proportion of biopsies that could have been avoided increased with the baseline PSA growth rate. For example, 52% of biopsies could have been avoided for men with the slowest PSA growth rates of 0% to 5%. The estimated biopsy avoidance rate reached 93% for men whose PSA growth rates exceeded 100%.

“This analysis of the diverse Veterans Affairs population suggests that a delay in a biopsy to allow for additional PSA testing may help avoid the biopsy.”

—Thomas Neville, PhD, and colleagues The investigators then calculated the PSA levels associated with an 80% probability of finding cancer on biopsy across the categories of PSA growth rate. The calculations suggested that a PSA level of 5.2 ng/dL would be the 80% threshold value for men who had PSA growth rates of 15% to 30%. By contrast, a PSA level of 2.5 ng/dL would be the threshold for 80% cancer probability among men with PSA growth rates of >100%.

Long-term PSA monitoring can help distinguish the nature of a PSA elevation, such as an initial increase followed by a decrease, frequently observed in association with benign prostate conditions, Neville and colleagues noted in their presentation.

The results suggest several screening strategies to take advantage of the information provided by PSA trend analysis. PSA testing beginning when men are in their 40s could be used to establish a baseline for long-term trend analysis. Dynamic trend analysis could help inform PSA testing intervals and lead to earlier identification of lethal prostate cancers. Multivariable algorithms could be developed to individualize decision making regarding prostate biopsies.

“These new screening methods have the potential to identify early the men at greatest risk of life-threatening disease, while reducing unnecessary biopsies and over­ diagnosis, treatment, and side effects,” the investigators concluded. u

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THIRD

ANNUAL CONFERENCE

GLOBAL BIOMARKERS Clinical Approaches to CONSORTIUM Targeted Technologies ™

™

October 31 – November 1, 2014 • Marriott Marquis • San Francisco, CA

CONFERENCE CHAIRS Jorge E. Cortes, MD

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

Roy S. Herbst, MD, PhD

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

CONFERENCE OVERVIEW

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology.

Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

TARGET AUDIENCE

This activity has been designed to meet the educational needs of medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology/hematology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid cancers or hematologic malignancies, and interested in the use of molecular biomarkers to help optimize patient care. Research scientists interested in the field of molecular biomarkers in oncology are also invited to participate.

DESIGNATION OF CREDIT STATEMENTS ACCREDITATION STATEMENT

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and Center of Excellence Media, LLC. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION

The Postgraduate Institute for Medicine designates this live activity for a maximum of 9.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

AMERICANS WITH DISABILITIES ACT

Event staff will be glad to assist you with any special needs (ie, physical, dietary, etc). Please contact Linda Sangenito prior to the live event at (732) 992-1520.

DISCLOSURE OF CONFLICTS OF INTEREST

Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. The existence or absence of COI for everyone in a position to control content will be disclosed to participants prior to the start of each activity.

Jointly provided by Postgraduate Institute for Medicine and Center of Excellence Media, LLC

EDUCATIONAL OBJECTIVES

After completing this activity, the participant should be better able to: • Assess emerging data and recent advances in the discovery of molecular biomarkers on the management of patients with solid tumors and hematologic malignancies •

Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors and hematologic malignancies

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Outline the practical aspects and value-based considerations of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

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This activity is supported, in part, by independent educational grants from Lilly.

For further information concerning Lilly grant funding visit www.lillygrantoffice.com.

This activity is also supported, in part, by an educational grant from Prometheus.

Current at time of printing.

SUBMIT AN ABSTRACT BY SEPTEMBER 5, 2014 Submit an abstract for the Third Annual Global Biomarkers Consortium. This is an opportunity to share research, programs, and results with your peers. This session will facilitate communication among the various professionals and programs to advance the knowledge of all our members and those in attendance.

www.globalbiomarkersconsortium.com/conference/abstracts

AGENDA*

FRIDAY, OCTOBER 31

• Myeloid hematologic malignancies – Jorge E. Cortes, MD • Chronic lymphocytic leukemia – William Wierda, MD, PhD • Multiple myeloma – Sagar Lonial, MD • Lymphoma – Anas Younes, MD

7:00 am - 12:00 pm Registration 11:45 am - 2:15 pm Product Theaters 2:15 pm - 2:30 pm

Break

2:30 pm - 2:40 pm

Welcome to the Third Annual Conference of the Global Biomarkers Consortium — Opening Remarks

2:40 pm - 4:15 pm

General Session I: Cancer Care in the Era of Molecular Biomarkers • Personalized medicine in oncology: therapeutic advances from cytotoxic chemotherapy to molecularly targeted agents – Razelle Kurzrock, MD • Understanding cancer at the molecular level – Caroline Robert, MD, PhD • Standardization of molecular biomarker testing – Mark Sausen, MD • Implications of molecular diagnostics on clinical trial design – John J. Wright, MD, PhD Question & Answer Session

4:15 pm - 4:30 pm

Break

4:30 pm - 5:30 pm

General Session II - Part 1: Incorporating Molecular Biomarkers into the Therapy of Solid Tumors — Case Studies on “How I Treat” • Melanoma – Sanjiv S. Agarwala, MD • Breast cancer – Hope Rugo, MD Question & Answer Session

5:30 pm - 7:00 pm

Welcome Reception and Exhibits

11:05 am - 12:00 pm Keynote Lecture: Markers of Resistance to Targeted Therapies – Alberto Bardelli, PhD Question & Answer Session 12:00 pm - 1:00 pm Meet the Experts and Lunch in the Exhibit Hall 1:00 pm - 1:15 pm

Break

1:15 pm - 2:00 pm

Tumor Board Breakout Sessions • Attendee cases in solid tumors • Attendee cases in hematologic malignancies

2:00 pm - 2:15 pm

Break

2:15 pm - 3:30 pm

General Session IV: Molecular Biomarkers for the Early Detection of Cancer: Are They Ready for Prime Time?

• Developing and validating biomarkers via the Early Detection Research Network (EDRN-NCI) – Sudhir Srivastava, PhD, MPH • Beyond PSA: novel molecular biomarkers for prostate cancer – Mark Rubin, MD • Airway biomarkers for lung cancer detection in the post-NLST era – Avi Spira, MD, MSc • Early detection biomarkers for breast cancer – Karen Anderson, MD, PhD Question & Answer Session

3:30 pm - 3:45 pm

Break

3:45 pm - 4:00 pm

Keynote Lecture: Actionable Genomic Alterations in Oncology – Phil Stephens, PhD

4:00 pm - 4:50 pm

General Session V: Regulatory and Economic Aspects of Personalized Medicine in Oncology • Understanding the regulatory aspects of personalized medicine in oncology – Andrew Stainthorpe, PhD • A debate on health economics and molecular biomarkers: can we afford personalized medicine in oncology?

– Gary Johnson, MD, MS, MBA, and Ken Schaecher, MD, FACP, CPC Question & Answer Session

4:50 pm - 5:00 pm

Closing Remarks

SATURDAY, NOVEMBER 1 7:00 am - 8:00 am

Product Theater

8:00 am - 8:15 am

Break

8:15 am - 8:30 am

Review of Friday’s Presentations and Preview of Today

8:30 am - 9:30 am

General Session II - Part 2: Incorporating Molecular Biomarkers into the Therapy of Solid Tumors — Case Studies on “How I Treat” • Melanoma – Sanjiv S. Agarwala, MD • Colorectal cancer – Axel Grothey, MD Question & Answer Session

9:30 am - 9:45 am

Break

9:45 am - 11:05 am General Session III: Incorporating Molecular Biomarkers into the Therapy of Hematologic Malignancies — Case Studies on “How I Treat”

*Agenda subject to change.

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ASCO 2014

Federal Spending on Cancer Research and Access to Care Called Woefully Inadequate by ASCO President Sequester Threatens Progress Made in Cancer

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he impact of federal budget cuts on cancer research is threatening progress against cancer and access to increasing demand for cancer services, said ASCO President Clifford Hudis, MD, in his presidential address. He called for achievement of “social justice in cancer care” by loosening purse strings for research and by assuring better access to high-quality care.

Hudis implored legislators to “understand the price our patients pay for inaction and gridlock on this issue.”

The 50th annual ASCO meeting, the theme of which was “Science and Society,” was attended by approximately 33,000 people representing more than 100 countries and featured 5100 submitted abstracts.

Although components to the cost of cancer care are numerous, one unsolved problem is the lack of a rational relationship between pricing and value.

In keeping with that theme, Hudis said that the 40% projected increase in cancer cases and survivors suggests the need for expanding clinical resources “if we are to achieve our goal of assuring that every patient has access to high-quality cancer care. If we intend to achieve social justice in cancer care, we simply need more public and private resources.”

The current federal budget allocates 0.1% to spending on cancer research. “We need societal awareness of the fact that an investment of 0.1% of our federal budget cannot begin to address the problem we face,” said Hudis, chief of the breast medicine service at Memorial Sloan Kettering Cancer Center, New York City. “Research on a disease that affects one-third to one-half of all Americans garners less than 1 dollar of every thousand spent federally.”

The practical impact of these cuts is felt directly or indirectly every day by oncologists and patients. “We must raise awareness of the remarkable return all of society receives on its investment in federal research so that it can be increased,” he said.

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Striving for Social Justice He also sounded off on social justice in cancer care, saying that disparities in access to high-quality care must be addressed.

“To delineate the challenges we face in providing quality care and to develop solutions to uneven access now and in the foreseeable future, in April of 2014, ASCO issued its first annual assessment of the State of Cancer Care in America,” he said. The report describes ways ASCO is trying to adapt to a growing demand for services, the rapidly evolving healthcare environment, and the economic pressures associated with maintaining access to care.

In addition to sustaining innovation through a robust national cancer research program, specific investments are needed in the development and testing of new healthcare delivery and payment models designed to preserve access to high-quality care in local communities, where most cancer care is delivered.

Rewarding Value “Our goal with these models is to reward value, as opposed to volume,” said Hudis. “We need to control payment reform and our focus on the quality of care we deliver, or others will quickly step in and define all of this for us. We must end persistent financial threats to clinical practice, especially in vulnerable communities, that are caused by sequester-related cuts and the flawed sustainable growth rate formula that drives physician payment.”

To achieve social justice in cancer care, “value in cancer care” must be defined to optimally use society’s precious resources, he said. When breakthroughs in care are available, as in the United States, the rising cost of care is having predictable negative consequen­ ces – patients bearing more of this cost, leading to declines in compliance, he said.

“Ask yourselves where it could ever make sense to have a copay for an oral cancer treatment that saves and extends life and avoids more toxic and expensive alternatives,” he said. “A financial disincentive for compliance is irrational no matter how you look at it.”

Although components to the cost of cancer care are numerous, one unsolved problem is the lack of a ratio-

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nal relationship between pricing and value. The challenge lies in preserving innovation while improving access and affordability.

The potential for industry and providers to collaborate to identify a productive way forward is great. “One that preserves capital flow and reward for innovators, but that provides even more access to care,” said Hudis.

“We must be creative and innovative, and we can if we work together.”

To this end, ASCO is organizing a Summit on Value in Cancer Care that involves all stakeholders.

The aim is to provide a “value framework” to help clinicians and patients more fully understand the likely benefits of specific treatment plans for their cancers.

“By understanding the full range of choices – their expected benefit, toxicities, as well as cost – patients can make choices that best suit their personal circumstances,” he said. u

Less May Be More With Zoledronic Acid

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n breast cancer patients with bone metastasis, less frequent infusion of zoledronic acid was as effective as the standard monthly dose, the randomized OPTIMIZE-2 study showed.

“We found that less frequent treatment may reduce the risk of serious side effects, with the additional benefits of reduced inconvenience to the patient and less cost,” said Gabriel N. Hortobagyi, MD, professor of medicine at The University of Texas MD Anderson Cancer Center, Houston, at ASCO 2014.

Zoledronic acid 4 mg given every 3 months was as effective as infusions given every 3 to 4 weeks, which is the FDA-approved schedule.

OPTIMIZE-2 compared the schedules in 403 women with breast cancer and bone metastases who had received at least 9 doses of an IV bisphosphonate (either zoledronic acid or pamidronate) before enrolling in the study.

The rate of skeletal-related events was 22% in the monthly group and 23.2% in the every-12-week group, indicating that less frequent dosing is not inferior. Other efficacy measures, such as time to first skeletal-related event and bone turnover markers, were also similar between the arms, and safety profiles were similar as well.

ASCO press briefing moderator Patricia Ganz, MD, a supportive care specialist from the University of California, Los Angeles, commented, “It’s not necessary for women to come in every 4 weeks.”

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The data are important because there are no evidence-based guidelines for the optimal treatment schedule after 1 year of treatment.

Importantly, less frequent dosing seemed to ameliorate some of the safety concerns for bisphosphonates as a class. As with all agents in the class, “zoledronic acid has some safety concerns,” said Hortobagyi, indicating osteonecrosis of the jaw (ONJ), long-bone fractures (ie, atypical femoral fractures), and chronic kidney function impairment.

The data are important because there are no evidence-based guidelines for the optimal treatment schedule after 1 year of treatment.

The less frequent dosing in this study was associated with fewer cases of ONJ (0 vs 2), and lower rates of renal impairment (7.9% vs 9.6%). No patients experienced long-bone fractures.

Since the study size was, in Hortobagyi’s terms, “relatively modest,” and there were some “design limitations,” he said the findings should be “interpreted with caution.” u

THIRD ANNUAL CONFERENCE

GLOBAL BIOMARKERS CONSORTIUM

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Clinical Approaches to Targeted Technologies

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October 31 – November 1, 2014 • Marriott Marquis • San Francisco, California

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Oncologists Want to Discuss Cost of Treatments With Patients but Believe They Are Not Well Equipped to Do So

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ncologists responding to a national electronic survey overwhelmingly believe that discussing out-of-pocket costs of therapy with patients is important, and that both out-of-pocket costs as well as societal cost of therapy will play a larger role in cancer treatment decisions over the next 5 years.

Results of the survey were reported by Laura L. Tenner, MD, during a poster presentation at the 50th annual ASCO meeting.

Physicians are communicating with patients about cost at about the same rate as they did 5 years previously – 43% in 2008 versus 48% in 2013.

The attitudes and perceptions by US oncologists about the cost of cancer care in the wake of the implementation of the Affordable Care Act (ACA) were assessed through an electronic questionnaire deployed over 4 months in 2013.

“Because of the competing obligations placed on physicians by the ACA, physicians may have to become adept at engaging in shared decision making and communication concerning cost and resource distribution,” said Tenner, who was an oncology fellow at Indiana University, Indianapolis, when she presented these data and is now a faculty member in the department of oncology at the University of San Antonio Cancer Institute and Research Center.

The survey generated a 16% response rate, with responses from oncologists from 35 states. Forty-one percent of respondents were in private practice, 30% were employed at a university medical center, 17% at a community hospital, and 5% at a health maintenance organization.

“Back in 2008, about 40% of physicians said that they communicated to their patients about costs of therapy most of the time or always, and we wanted to see if that has changed because of the ACA coming in,”

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Tenner said. “Under the ACA, physicians will only be able to do what has proven to be efficacious, so they’re going to have to start having those difficult discussions with patients.”

She found that physicians are communicating with patients about cost at about the same rate as they did 5 years previously – 43% in 2008 versus 48% in 2013.

“What has changed is that physicians are wanting more cost-effectiveness and comparative effectiveness data to be able to make those decisions,” she said. “They feel like they don’t have the resources right now to be able to effectively communicate with patients about cost of therapies and decision making.”

Some 89% of respondents strongly or somewhat strongly agreed that it was important to discuss out-ofpocket costs with patients, and 66% strongly or somewhat strongly agreed that discussing healthcare system costs with patients was important.

Seventy percent reported that out-of-pocket costs of therapy influence their treatment decisions, and 60% agreed that out-of-pocket costs and healthcare system costs of cancer treatments were likely or extremely likely to have a larger effect on their decisions regarding which cancer treatments to recommend to patients in the future under the ACA. Eighty-seven percent said that more comparative effectiveness research is needed, and 91% desired more cost-effectiveness research. Eighty-five percent agreed that communicating the cost of therapies with patients was needed.

Two-thirds responded that physicians are the ones who should decide the value of certain drugs, while only 4% said that government should decide good value. Slightly more than half (53%) favored more government price controls of health resources. Almost two-thirds (62%) thought that the health system cost of therapy would have a larger effect on treatment decisions.

“These data suggest that educational efforts aimed at improving oncologists’ tools for communication about the costs of cancer care would be valuable,” said Tenner. u

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Ibrutinib Tops Ofatumumab as Second-Line Therapy for CLL

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or the second-line treatment of chronic lymphocytic leukemia (CLL), ibrutinib improved not only progression-free survival (PFS) but also overall survival (OS), the phase 3 RESONATE study showed.

In conjunction with the ASCO presentation, the study was published online in the New England Journal of Medicine.

“Ibrutinib beat a standard comparator in CLL for the first time,” said John C. Byrd, MD, of the Ohio State University Comprehensive Cancer Center in Columbus. “If I were a patient with CLL, I would want this drug. In the relapsed and refractory setting after 1 prior therapy, there is no good reason not to give this drug outside of a few circumstances.”

Ibrutinib is a first-in-class irreversible inhibitor of Bruton’s tyrosine kinase, and the drug has been given breakthrough therapy designation by the FDA. The RESONATE study randomized previously treated patients with CLL and small lymphocytic leukemia to oral ibrutinib or IV ofatumumab. The overall response rate was 42.6% for ibrutinib versus 4.1% for ofatumumab (P<.001). At a median follow-up of 9.4 months, 86% of patients on ibrutinib had durable responses and were continuing on treatment with minimal side effects.

“This is remarkable, especially considering that standard CLL therapies typically produce a 35% to 40% response rate,” Byrd commented.

Improvement in PFS and OS, and Well Tolerated At 6 months, PFS rates were 83% in the ibrutinib arm versus 49% in the ofatumumab arm. Median PFS was not yet reached in the ibrutinib arm and was 8.1 months with ofatumumab (P<.0001), representing a 78% reduction in the risk of progression. The impact on PFS was observed in all patient groups, including the elderly and those with deletions in chromosome 17p, ie, the poor-prognosis subsets.

OS was significantly improved at 90% with ibrutinib versus 81% with ofatumu­ mab, representing a 57% reduction in risk of death (P<.0049). The improvement in survival remained significant despite the crossover of 57 patients who had progressed on ofatumumab.

Both regimens were fairly well tolerat- John C. Byrd, MD ed, with similar rates of major hemorrhage and renal toxicities; rates of atrial fibrillation were higher with ibrutinib, while neuropathy was more common with ofatumumab. The risk of diarrhea often observed with ibrutinib was modest and manageable in most patients, he said.

“The findings of phase 2 and the confirmatory phase 3 study show ibrutinib should be used for all relapsed refractory CLL.” – John C. Byrd, MD Call to Embrace Ibrutinib “The findings of phase 2 and the confirmatory phase 3 study show ibrutinib should be used for all relapsed refractory CLL,” Byrd maintained.

Gregory Masters, MD, of the Helen F. Graham Cancer Center, Newark, DE, who moderated an ASCO press conference, seemed to agree. “It is impressive to see an OS benefit in CLL. ...This drug’s efficacy can potentially transform the treatment of CLL, replacing more toxic therapy,” he said.

Ibrutinib will soon undergo phase 3 testing in mantle cell lymphoma with bendamustine/rituximab as the comparator. Ibrutinib is also in phase 3 study as firstline therapy for CLL. u

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THIRD ANNUAL

WORLD CUTANEOUS MALIGNANCIES CONGRESS

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Marriott Marquis • San Francisco, CA

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Anti–PD-1 Antibodies in NSCLC and Renal Cell Carcinoma

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ttendees at ASCO got a look at maturing data for the anti–PD-1 monoclonal antibody nivolumab in non–small cell lung cancer (NSCLC) and at early results for this drug in other tumor types. They also heard early results for pembrolizumab. In phase 1 and 2 trials, these immunotherapies made a strong Scott Gettinger, showing.

MD The phase 1 multicohort CA209-012 trial evaluated nivolumab as a single agent and in combination with ipilimumab, chemotherapy, and erlotinib. Nivolumab monotherapy in the first-line setting produced responses in 30% of patients, with median duration of response not reached. “Responses are ongoing in 4 of 6 (67%) responders,” reported Scott Gettinger, MD, of Yale Cancer Center, New Haven, CT.

Could 2 immune checkpoint inhibitors be better than 1? That question was asked in 1 cohort of the CA209-012 trial.

Progression-free survival (PFS) at 24 weeks was 60%, median PFS was 47.2 weeks in patients with nonsquamous histology and 15.1 in those with squamous tumors; 1-year overall survival (OS) was 75%, and median OS was not reached at the time of analysis.

All the responders expressed the PD-L1 ligand, ie, were “PD-L1–positive,” which some believe might serve as a biomarker of activity. In this subgroup, the results were most impressive, with 1-year OS of 80%.

Nivolumab Plus Ipilimumab Could 2 immune checkpoint inhibitors be better than 1? That question was asked in 1 cohort of the CA209012 trial involving 49 chemotherapy-naive patients treated with nivolumab plus ipilimumab, followed by nivolumab monotherapy until progression. Depending on dose and histology, objective responses were observed in 11% to 33% of patients. Responses were ongoing in 75% of responders at the time of analysis.

At 24 weeks, median PFS ranged from 20% to 51%, and median PFS was 14.4 to 16.1 weeks. Median OS was 44 weeks in one subset and was not reached in the other arms. Response rates and median PFS were similar whether patients were PD-L1–positive or PD-L1–negative.

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“The findings suggest this combination may be suitable for PD-L1–positive and –negative patients,” according to Scott Antonia, MD, of H. Lee Moffitt Cancer Center, Tampa, FL.

Nivolumab Plus Chemotherapy or Erlotinib Antonia also presented results on the 56 patients who received nivolumab plus a platinum-based chemotherapy doublet, followed by nivolumab until progression. Responses were observed in 33% to 47% of patients in both squamous and nonsquamous histology subsets. Outcomes were most impressive in the subgroup receiving pemetrexed/cisplatin plus nivolumab 10 mg/kg, with a 24-week PFS rate of 71% and 1-year OS of 87%.

Another cohort of 21 patients was treated with nivolumab combined with erlotinib. Responses were observed in 19%, 3 ongoing at the time of analysis, with an estimated duration of response of more than 1 year. PFS at 24 weeks was 51%, median PFS was 29.4 weeks, 1-year survival was 73%, and median OS was not yet reached.

“Responses were seen in patients who had previously received multiple lines of EGFR inhibitor therapy, as well as patients with T790M mutations [which are difficult to treat],” said Naiyer A. Rizvi, MD, of Memorial Sloan Kettering Cancer Center, New York City.

Combining PD-1 blockade with therapies that target mutant EGFR signaling may enhance responses and provide durable benefit, the authors concluded.

Pembrolizumab (MK-3475) in Previously Treated Patients Another phase 1 study of 217 previously treated patients with NSCLC found strong antitumor activity for pembrolizumab. The objective response rate was 20% and was higher among patients expressing PD-L1 (23%) versus those who did not (9%). Of the PD-L1–positive patients who responded, 82% remain on treatment, according to Edward B. Garon, MD, of the University of California, Los Angeles.

Nivolumab in Renal Cell Carcinoma Results from the phase 2 CheckMate-010 trial in advanced kidney cancer showed that single-agent nivolumab produced responses in 20% to 22% of patients and yielded 1-year survival rates of 63% to 72% in patients with prior antiangiogenic treatment. In

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previously treated patients, median OS was 25 months with 2 mg/kg dosing.

In a phase 1b trial of previously treated as well as treatment-naive patients, nivolumab combined with ipi­ limumab produced responses in 43% to 48% and was associated with 24-week PFS rate of 65%.

“These data are encouraging as we seek to identify new treatments for patients, particularly those who progress following treatment with antiangiogenic therapy, as they have limited options,” said Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York City.

events, and 3 patients died of drug-related toxicities (1 each from colitis, pulmonary hemorrhage, and toxic epidermal necrolysis).

Tolerability of Anti–PD-1 Agents The toxicities associated with anti–PD-1 agents are primarily immune-related and transient, though some can be concerning, the investigators acknowledged.

As a single agent, nivolumab was associated with adverse events in 85% of patients, but only 20% were grade 3/4. For the combination of nivolumab and ipi­ limumab, grade 3/4 adverse events were reported by 49% across the arms, primarily during induction, not maintenance. Pneumonitis grade 3/4 occurred in 6% and was reversible. Serious diarrhea and colitis occurred in 8%, and liver enzymes were elevated in 6%.

One-third of patients discontinued due to adverse

When given with chemotherapy, treatment-related grade 3/4 adverse events occurred in 45%, most commonly pneumonitis, fatigue, and acute renal failure.

Many were laboratory abnormalities reported in 1 patient each. In combination with erlotinib, the toxicities were predictable.

With pembrolizumab, almost two-thirds of patients had at least 1 drug-related adverse event of any grade, and 10% had grade 3/4 toxicity. Grade 3/4 pneumonitis was observed in 4 patients.

Investigators of the studies have suggested that clinicians can learn to manage the immune-related toxicities associated with anti–PD-1 agents. u

“The findings suggest this combination may be suitable for PD-L1–positive and –negative patients.”

– Scott Antonia, MD

Bevacizumab Not Cost-Effective in Metastatic Colorectal Cancer

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he addition of bevacizumab to chemotherapy for metastatic colorectal cancer is not cost-effective,” according to Daniel A. Goldstein, MD, of Emory University, Atlanta, GA, who led a cost-effectiveness analysis that earned an ASCO Merit Award at the annual meeting.

The lack of cost-effectiveness was demonstrated at a willingness-to-pay threshold of $100,000 per qualityadjusted life year (QALY) in first-line therapy and in second-line therapy when continued beyond progression, he reported at ASCO. Previous studies from the United Kingdom, Canada, and Japan have indicated a lack of cost-effectiveness for the biologic in the first-line setting, but data from the US perspective have been lacking, as have data for bevacizumab continued beyond disease progression.

While not all studies have been positive, it has be-

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come standard practice to use bevacizumab with 5-fluorouracil (5-FU)-based chemotherapy in both the firstand second-line settings, he noted.

Goldstein and colleagues developed 2 Markov models to compare the cost and the effectiveness of 5-FU, leucovorin, and oxa­liplatin (FOLFOX) with or without bevacizumab in first-line treatment, and subsequent chemotherapy with 5-FU, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab in the second-line setting.

Weibull models were fitted to the published survival curves and were used to extrapolate the cause-specific mortality and progression risks. Costs for administration and management of adverse events were based on Medicare reimbursement rates for hospital and physician services, and drug costs were based on Medicare 2013 average sale prices. The cost of 2 weeks of bevacizumab was figured at $2649.

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Table

QALYs, ICERs in First- and Second-Line mCRC Settings

“No ICER fell below $100,000 in the first or second line, and we ran this model 10,000 times,” he said. “All fell well above $100,000 and FOLFOX + FOLFIRI + $50,000 QALYs.” Outcome FOLFOX Bevacizumab FOLFIRI Bevacizumab The lowest willingness-to-pay thresholds were Discounted Life $225,000 per QALY in the first-line setting and Years (LY) 1.79 2.20 0.99 .15 $370,000 in the second-line setting.

QALYs 1.32 1.61 0.64 0.75 Goldstein added that similar results have been shown when bevacizumab is used in metastatic Cost ($) $33,640 $102,994 $7653 $46,864 lung cancer, where the published ICER is ICER ($/LY) $168,746 $234,797 $560,000 per QALY. ICER ($/QALY) $250,814 $363,066 “The drug could potentially be cost-effective if a biomarker were to be found,” he predicted, FOLFIRI indicates 5-fluorouracil (5-FU), leucovorin, and irinotecan; FOLFOX, 5-FU, leucovorin, and oxaliplatin; ICER, incremental cost-effectiveness ratio; “but so far the search for this has been elusive.” mCRC, metastatic colorectal cancer; QALY, quality-adjusted life years.

Sandra L. Wong, MD, assistant professor of surgery and a researcher at the Center for Healthcare Outcomes & Policy at the University of Cost-Effectiveness Not Shown for Bevacizumab Michigan, discussed the study. She commented that a The use of bevacizumab in the first-line metastatic plenary presentation at ASCO, the CALGB 80405 setting provided an additional 0.29 QALYs (0.41 life study, found that the addition of bevacizumab (or years) at an additional cost of $69,354. The incremental cetuximab) increased median overall survival to an cost-effectiveness ratio (ICER) was $240,814 per QALY, impressive 25+ months. “There are increasing costs Goldstein reported. with the addition of this drug, but it’s commensurate Continuing bevacizumab beyond progression (with with a rise in overall survival,” she commented.

FOLFIRI) provided an additional 0.11 QALYs (0.16 “Dr Goldstein’s study is nicely done and has prolife years) above FOLFIRI alone, at an additional cost duced robust data that show, however, that no matter of $39,211. The ICER here was $363,066 per QALY the willingness-to-pay threshold, there is not cost(Table). effectiveness with bevacizumab,” she said. Wong sugIn each of the 1-way sensitivity analyses, the ICER gested that the researchers update the study, using the of bevacizumab exceeded $100,000 per QALY. The CALGB 80405 results.

ICER of bevacizumab was greater than $100,000 per “Looking at cost-effectiveness helps inform our conQALY in more than 99.9% of probabilistic sensitivity versations with patients, to minimize cost and maxianalyses. mize benefit, leading to value,” she said. u First-Line Setting

Second-Line Setting

Enthusiasm High for Anti­–PD-1 Agents

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udging by the high attendance at sessions where data on the anti–PD-1 antibodies were presented, oncologists can hardly wait to have these immunotherapies in the clinic.

The key ASCO data in stage III/IV melanoma are presented here.

Jeffrey Weber, MD Data on Nivolumab Maturing

The long-term follow-up of the pivotal phase 1 trial of nivolumab showed ongoing responses in 56% of 107 patients treated with the single agent. At a median follow-up of 22 months, the median overall survival (OS) was 17.3 months, and OS rates were 63% at

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1 year, 48% at 2 years, and 41% at 3 years. In the subset receiving the optimal dose, 3 mg/kg, median progression-free survival (PFS) was 9.7 months, and median OS was 20.3 months, reported Stephen Hodi, MD, of the Dana-Farber Cancer Institute, Boston, MA. Jeffrey Weber, MD, of H. Lee Moffit Cancer Center and Research Institute in Tampa, FL, who discussed the paper, commented, “For the totality of patients, many with 3 and 4 prior regimens, and some with performance status 2, these are very good data.”

Nivolumab Plus Ipilimumab Many melanoma experts predict that the best way to

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use the immune checkpoint inhibitors will be in combination. In a study presented by Mario Sznol, MD, of Yale School of Medicine, New Haven, CT, this double hit paid off.

The concurrent treatment of nivolumab and the anti–CTLA-4 antibody ipilimumab led to a 2-year OS rate of 79%, and 88% of responders had ongoing responses at the time of analysis. Grade 3/4 toxicity was 62%, but the investigators felt this was manageable with the proper education of clinicians.

“While this is a small trial, those are very impressive 2-year survival data,” Sznol said. “Concurrent therapy with nivolumab and ipilimumab results in what I believe to be an unprecedented 2-year survival.”

Sznol reported updated data for the initial 53 patients treated with concurrent combination treatment regimens in the phase 1 CA209-004 trial he reported at ASCO last year, and he announced preliminary response data for a new cohort of 41 patients treated with the regimen being used in the subsequent phase 2/3 trials.

All 94 patients had stage III or IV melanoma and could have received up to 3 prior systemic therapies, although 55% had no prior systemic treatments.

In the original cohort, the 1-year OS rate was 85%, and 2-year survival was 79%. The overall response rate was 42%, with confirmed complete responses increasing from 10% to 17%. To accommodate patients who had “unconventional” responses (ie, immune-related partial responses and stable disease), the researchers used an “aggregate clinical activity rate,” and this was 70%.

In the new 41-patient cohort, the objective response rate was 43%, with 10% complete responses, and the aggregate clinical activity rate was 53%. Altogether, 82% of responses were ongoing at the time of analysis.

Now with 2 cohorts evaluated, he said, “We feel very confident that the activity of this combination regimen is real.”

Combining ipilimumab with nivolumab did result in increased toxicity compared with therapy with either agent alone, including grade 3/4 side effects in 62% of the 94 patients. These events, however, “were manageable and reversible with algorithms that were established for ipilimumab,” Sznol said.

The most common grade 3/4 toxicities were increased lipase and amylase – reversible laboratory abnormalities.

One drug-related death occurred in the latest cohort, a consequence of colitis.

Weber commented on the combination: “The responses were outstanding. Eight of 9 patients in cohort 2 remain in response, as do 16 of 17 in the most recent cohort,” he noted. “And for the original 53 patients, 2-year survival is 79%. In metastatic melano-

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ma, it doesn’t get any better than that. ...I cannot help but be impressed.”

Enrollment has been completed for a phase 3 trial comparing nivolumab plus ipilimumab with nivolumab or ipilimumab alone and a phase 2 trial comparing nivolumab plus ipilimumab with ipilimumab alone.

Pembrolizumab Hits the Mark The newest agent is pembrolizumab (MK-3475), whose activity in the phase 1 KEYNOTE-001 dose-finding study was impressive enough to earn it a spot at an ASCO press briefing. In May 2014, the FDA granted pembrolizumab (called lambrolizumab at that time) a priority review designation.

“For the totality of patients, many with 3 and 4 prior regimens, and some with performance status 2, these are very good data.”

– Jeffrey Weber, MD “These are early data, but they tell us we are on to something really important,” said Antoni Ribas, MD, PhD, professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles.

At the press briefing, Steven O’Day, MD, clinical professor of medicine at the University of Southern California, Keck School of Medicine, Los Angeles, agreed, noting the “remarkable” finding that almost 90% of patients achieved durable responses, with a toxicity profile that is “almost unheard of in metastatic cancer.”

In the dose-finding trial with 411 patients, pembrolizumab produced responses in 34%, including 28% of patients whose disease progressed on ipilimumab. At 1 year, 88% of responders were continuing to respond, with the longest response so far being 76 weeks. Median PFS was 5.5 months, and the estimated OS rate at 1 year was 69%. Median OS was not reached at the time of analysis.

The tolerability of the drug was also noteworthy.

“This is one of the most benign therapies I’ve ever used in my clinic,” Ribas noted, reporting a rate of grade 3/4 events of 10% to 12%.

The data were less impressive for another investigational anti–PD-1 antibody, pidilizumab, which produced responses in only 5% to 6% of pretreated patients, though 1-year OS was encouraging at 64.5%. A subset of patients received subsequent treatment with ipilimumab, and their survival rate rose to 80%. u

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VALUE-BASED CANCER CARE

Value-Based Insurance – Not Such an Easy Sell

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he need to design insurance coverage that promotes value in cancer care is no longer a matter of debate, but how to accomplish it remains a huge challenge, according to Lee Newcomer, MD, senior vice president, oncology, genetics, and women’s health, UnitedHealthcare, who discussed value in cancer care from the payer’s perspective at ASCO 2014.

Newcomer was a speaker at the session, “Can We Find Common Ground? Stakeholder Perspectives on Value in Cancer Care.”

He began by reminding attendees “why we are having this discussion.” The average household income is currently about $50,000, and 50% of this goes to pay for insurance premiums and out-of-pocket expenses. Even worse, given the current trend, by 2028 the average household will spend 100% of its income on healthcare expenses, he noted.

“This is a trend that cannot be sustained. We have to start having discussions about value, and we are going to have to say that there are certain things that should not be covered. The issue is how to do this in a way that will be rational and fair,” he said.

Can Patients Understand Value-Based Design?

Insurance benefits are not based on value; most are designed around structures, he noted. The idea behind copayment or coinsurance “is for the patient to pause and ask, ‘Is this worth the money?’ Copays were never intended to be large enough to keep people from getting important, high-value care, but to keep them from selecting lower-value care, if they have to pay the first $50 or a percentage.”

“Unfortunately, this is not discriminatory based on the procedure,” he continued. “It’s simply discriminatory based on price.”

To be successful, a value-based insurance program, “first and foremost,” needs “a nonbiased external reference that will create a fair differential between high-value and low-value services. A high-value service might offer complete coverage, with no requirement for patient participation, while a low-value service would mandate participation – one-third, one-half, even 100% participation if it lacks true value.

“It will be difficult for consumers to understand this for every service they will receive,” he said. These thresholds must be set externally because payers “will always be perceived as making these decisions on a financial basis only,” Newcomer suggested. “It doesn’t matter how high-integrity the process is, the bias is real in the consumer mind.”

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He noted that ASCO has started “wrestling with this issue” through the Choosing Wisely campaign. “Having ASCO set references would be a key to getting these in place,” according to Newcomer.

Consumer education will also be critical to the success of value-based design, as the insured population is already unclear about their benefits. “In a value-based program, we are asking consumers to take on an increasingly large amount of information that may be even harder to digest,” he said. “For a consumer to sort out a 2-month versus 4-month survival benefit, or grade 5 versus grade 4 toxicities could be overwhelming.”

“Trying to make this concept easily accessible to consumers, helping them find out the value of a given treatment, is a daunting task and has been a major barrier to getting value-based insurance in place,” he said.

Issues for Payers Equally overwhelming for systems programmers within a payer system will be sorting out the different diagnoses and treatment regimens and assigning different coinsurance amounts to these. The number of permutations could overwhelm any computer system, Newcomer added.

Furthermore, who decides, and how will it be determined what the patient participation will be for each of these scenarios? “Where do we draw the line where we say one thing should be free, and another should have 30% participation?” Newcomer posed. “No matter where we draw the line, someone will be unhappy.”

On the positive side, once these thresholds are determined, it will be easier for payers to set prices. The more generous the benefit, the higher the overall price of the premium, and this should help consumers begin to understand the concept of value, he predicted.

“The thing that’s the hardest is simply not paying for anything at all,” he continued. For example, in the Choosing Wisely campaign, ASCO has already recommended that metastatic breast cancer patients receive only single-agent chemotherapy (except under certain circumstances), but insurance carriers restricting payment to single agents would elicit strong public reaction, he predicted.

“The immediate perception of value-based insurance is that it’s simply being done to save money,” Newcomer posed. “Putting these programs in place will have to be a gradual process accompanied by education.”

In closing, Newcomer emphasized that, like it or not, in the setting of limited resources, decisions about high- versus low-value services must be made. “Payers need reliable information on value, and so do patients,” he said, “so they can apply their preferences and make smart decisions.” u

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EDITORIAL THE LAST WORD

The Case for Personalized Medicine: Defining the Field and Envisioning the Future of Healthcare Edward Abrahams, PhD President Personalized Medicine Coalition

“In a time of unprecedented scientific breakthroughs and technological advancements, personalized health care has the capacity to detect the onset of disease at its earliest stages, pre-empt the progression of disease, and, at the same time, increase the efficiency of the health care system by improving quality, accessibility, and affordability.” – The Case for Personalized Medicine, 4th ed.

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his is the mantra of the Personalized Medicine Coalition (PMC). By understanding individual variation at the molecular level, we can improve patient outcomes while also increasing the efficiency of the healthcare system. Targeting the right therapies to the right patients at the right time, personalized medicine presents the opportunity to treat patients before they get sick, avoid side effects and adverse events, and eliminate unnecessary interventions, including costly hospitalizations, thereby both saving the healthcare systems that incorporate personalized medicine money but also improving their care of individual patients.

In order to realize these opportunities, however, it is imperative that we encourage investment in developing the targeted drugs and sophisticated diagnostics that will allow healthcare providers to personalize treatment and that we also align our public policies to support, rather than hamper, the development of the field. Taking these steps will allow us to both preserve innovation and address the burgeoning costs that beset healthcare budgets around the world.

Indeed, this is already happening. Whereas in 2006, there were 13 prominent examples of personalized medicine drugs, treatments, and diagnostic products on the market, today there are 113, illustrating the steady progress of the field and its ability to improve the health of patients who benefit from them.

PMC contends that personalized medicine is an evolving and integrated system in which physicians use molecular diagnostic tests to determine which medical treatments work best for individual patients. By combining the data from those tests with an individual’s medical history and circumstances, healthcare providers, with input from their patients, can develop targeted treatment and prevention plans.

The Case for Personalized Medicine, PMC’s signature document that defines the field and outlines how we envision the future, explains how personalized medicine can: • Shift the emphasis in medicine from reaction to prevention • Direct the selection of optimal therapy and reduce trial-and-error prescribing Edward • Help avoid adverse drug reactions Abrahams, PhD • Increase patient adherence to treatment • Improve quality of life • Reveal additional or alternative uses for medicines and drug candidates • Help control the overall cost of healthcare Some have suggested that the case for personalized medicine is obvious and does not need a brief that describes its benefits and points out the obstacles impeding its development and delivery. We disagree. We have written The Case for Personalized Medicine to encourage continued investment in personalized medicine, believing that it holds the key to better healthcare and a more efficient, less costly health system.

The challenge for our time – and it is one that I am pleased to note that the National Institutes of Health, FDA, and the pharmaceutical and diagnostic industries have all embraced – is to figure out how to translate the emerging science and technology into practice faster so that patients and the public benefit sooner than later.

We are on the precipice of a new era in medicine, one that is based on a richer appreciation of individual variation and the development of new tools to decipher them. We need to do everything within our power to help advance the promise that patients are looking for and the healthcare system requires. u

To view The Case for Personalized Medicine in its entirety, please visit www.personalizedmedicinecoalition.org/Resources/ The_Case_for_Personalized_Medicine.

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