Personalized Medicine in Oncology September 2014

Unifying Oncologists & Pathologists

A Peer-Reviewed Journal September 2014 • Volume 3 • Number 6

PM O

BIOMARKERS • TARGETED THERAPIES • DIAGNOSTICS

Personalized Medicine in Oncology TM

INTERVIEW WITH THE INNOVATORS Tissue Phenomics: Closing the Gap Between Genomic Information and Patient Outcomes.

An Interview With Thomas P. Heydler, CEO of Definiens............................................Page 314

IMMUNOTHERAPY FDA Approves Pembrolizumab for Advanced Melanoma....................................Page 320

HEMATOLOGIC MALIGNANCIES Highlights From the 6th International Symposium Acute Promyelocytic Leukemia......................Page 324

LUNG CANCER Navigating the Molecular Testing Landscape in Lung Cancer.................................................. Page 334

VALUE-BASED CANCER CARE Determining the Value of Cancer Therapies: A Paradigm Shift Focused on Quality, Outcomes, and Cost........................................................Page 348

THE LAST WORD The Personalized Medicine Coalition and Turning the Tide Against Cancer Through Sustained Medical Innovation.......................Page 350 GLOBAL BIOMARKERS

CONSORTIUM Clinical Approaches to Targeted Technologies ™

The official publication of

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

WORLD CUTANEOUS MALIGNANCIES CONGRESS

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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

T:7”

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.

SEPTEMBER 2014

VOLUME 3, NUMBER 6

TABLE OF CONTENTS INTERVIEW WITH THE INNOVATORS

314

Tissue Phenomics: Closing the Gap Between Genomic Information and Patient Outcomes. An Interview With Thomas P. Heydler, CEO of Definiens

PMO speaks with Mr Heydler about Definiens’ Immunoscore™ technology and its role in reshaping personalized medicine in oncology.IMMUNOTHERAPY

IMMUNOTHERAPY

320

FDA Approves Pembrolizumab for Advanced Melanoma In this exciting era of immunotherapy, pembrolizumab is the first PD-1 blocking drug to receive agency approval.

HEMATOLOGIC MALIGNANCIES

324

Highlights From the 6th International Symposium on Acute Promyelocytic Leukemia A review of recent scientific advances and clinical research in APL and related malignancies.

LUNG CANCER

334

Navigating the Molecular Testing Landscape in Lung Cancer At the 15th Annual International Lung Cancer Congress, a panel of lung cancer experts weighed in on mutational testing through a case discussion.

AMERICAN SOCIETY OF CLINICAL ONCOLOGY

338 339 340 341

342 343 344

What Makes a Treatment “Clinically Meaningful”?

ASCO Workgroup Proposes Consolidated Payments for Oncology Care Pharmacokinetic-Guided Dosing of 5-FU Shown Cost-Effective Routine Imaging Costly in B-Cell Lymphoma but Rarely Picks Up Relapse After Remission Cancer Patients, By and Large, Not Pursuing Costly, Excessive Tests Are Hospital Readmissions for Cancer Patients Preventable?

Ramucirumab Conveys Survival Benefit in NSCLC

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.

306

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www.PersonalizedMedOnc.com

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 Manager Deanna Martinez Project Coordinator Mike Kodada IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Green Hill Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-656-7935 • fax: 732-656-7938

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

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

Houry Leblebjian, PharmD, BCOP Clinical Pharmacy Specialist in MARCH 2013 • VOLUME 4 • NUMBER 2 Hematology/Oncology Dana-Farber Cancer Institute Boston, MA

Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma

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

Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

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

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

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

Assistant Attending Medical Oncologist Lymphoma, Cutaneous Lymphomas, T-Cell Lymphoma Memorial Sloan-Kettering Cancer Center New York, NY

Supported by an educational grant from Celgene Corporation

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

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Providing Critical Insights for Clinical Application Customized Drugs/Biologics Pharmacogenomics Diagnostics & Assays Gene Sequencing Targeted Therapies Immunotherapy Biomarkers Prevention Pathology

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VOLUME 3, NUMBER 6

REGISTER TODAY TABLE OF CONTENTS

(Continued)

ANNUAL CONFERENCE

VALUE-BASED CANCER CARE

345 ASCO Beginning to Address Value 346 Site of Service Influences Value 347 Patients Want But Aren’t Getting Up-Front Discussions About the Cost of Their Cancer Therapy 348 Determining the Value of Cancer Therapies: A Paradigm Shift Focused on Quality,

Outcomes, and Cost

Winston Wong, PharmD

Mr Wong discusses the importance of defining and determining “value” in cancer care and the associated ability to differentiate between regimens that only provide an incremental benefit and those that significantly improve outcomes.

THE LAST WORD

350

The Personalized Medicine Coalition and Turning the Tide Against Cancer Through Sustained Medical Innovation

Edward Abrahams, PhD

Dr Abrahams discusses the PMC initiative that addresses the challenge of sustaining progress against cancer using personalized medicine techniques in this era of significant cost constraints.

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

Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copy­right ©2014 by Green Hill Health­care Com­muni­cations, LLC. All rights reserved. Personalized Medicine in Oncology logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

EDITORIAL CORRESPONDENCE should be ad­dressed to EDITORIAL DIRECTOR, Personalized Medicine in Oncology (PMO), 1249 South River Road, Suite 202A, Cranbury, NJ 08512. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $50.00; institutions, $90.00; single issues, $5.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPART­MENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in PMO do not necessarily reflect those of the editorial board, the editorial director, or the publishers. Publication of an advertisement or other product mention in PMO should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the editorial board nor the publishers assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the editorial director.

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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, FACP, FASCO 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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VALCHLOR® (mechlorethamine) gel is an alkylating drug indicated for the topical treatment of Stage IA and IB mycosis fungoides–type cutaneous T-cell lymphoma (MF-CTCL) in patients who have received prior skin-directed therapy WHEN IT’S TIME TO MANAGE THE CHALLENGES OF STAGE IA AND IB MF-CTCL

VALCHLOR IS ON IT The first and only FDA-approved topical formulation of mechlorethamine (commonly known as nitrogen mustard) • Proven efficacy in a 12-month study 1 • Once-daily gel (special handling and disposal procedures should be followed)

• Dependable formulation manufactured with consistent quality and potency • Comprehensive resources provided by VALCHLOR Support ™

For more information, including how to prescribe, visit www.valchlor.com or call 1-855-4-VALCHLOR (1-855-482-5245).

DOSING AND APPLICATION VALCHLOR is for topical dermatologic use only. Apply a thin film of gel once daily to affected areas of the skin. VALCHLOR is a cytotoxic drug and special handling and disposal procedures should be followed during use. Caregivers must wear disposable nitrile gloves when applying VALCHLOR. Patients and caregivers must wash hands thoroughly after handling or applying VALCHLOR.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS VALCHLOR is contraindicated in patients with known severe hypersensitivity to mechlorethamine. Hypersensitivity reactions, including anaphylaxis, have occurred with topical formulations of mechlorethamine.

WARNINGS AND PRECAUTIONS • Mucosal or eye injury: Exposure of mucous membranes to mechlorethamine such as the oral mucosa or nasal mucosa causes pain, redness, and ulceration, which may be severe.

Exposure of the eyes causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible anterior eye injury may occur. Should eye exposure or mucosal contact occur, immediately irrigate for at least 15 minutes with copious amounts of water, followed by immediate medical consultation • Secondary exposure: Avoid direct skin contact with VALCHLOR in individuals other than the patients due to risk of dermatitis, mucosal injury, and secondary cancers

• Dermatitis: Dermatitis may be moderately severe or severe.

Monitor patients for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections.

Stop treatment with VALCHLOR or reduce dose frequency • Non-melanoma skin cancer: Monitor patients during and after treatment with VALCHLOR • Embryo-fetal toxicity: Women should avoid becoming pregnant while using VALCHLOR due to the potential hazard to the fetus. For nursing mothers, discontinue use of VALCHLOR or nursing • Flammable gel: VALCHLOR is an alcohol-based gel. Avoid fire, flame, and smoking until the gel has dried

ADVERSE REACTIONS The most common adverse reactions (≥5%) were dermatitis (56%), pruritus (20%), bacterial skin infection (11%), skin ulceration or blistering (6%), and skin hyperpigmentation (5%). These reactions may be moderately severe or severe.

Elderly patients aged 65 and older may be more susceptible. Depending on severity, treatment reduction, suspension, or discontinuation may be required.

To report SUSPECTED ADVERSE REACTIONS, contact Actelion Pharmaceuticals US, Inc., at 1-855-4-VALCHLOR (1-855-482-5245) or FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

Please see Brief Summary of Prescribing Information on adjacent page.

REFERENCE: 1. VALCHLOR [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2013.

VALCHLOR®and VALCHLOR Support™ are trademarks of Actelion Pharmaceuticals Ltd. © 2014 Actelion Pharmaceuticals US, Inc. All rights reserved. VAL-00163 0814

A great idea finally gels

VALCHLOR® (mechlorethamine) gel, 0.016% For Topical Dermatological Use Only BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This brief summary does not include all the information needed to use VALCHLOR safely and effectively. See Full Prescribing Information for VALCHLOR. • INDICATIONS AND USAGE VALCHLOR is an alkylating drug indicated for the topical treatment of Stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy.

• CONTRAINDICATIONS The use of VALCHLOR is contraindicated in patients with known severe hypersensitivity to mechlorethamine. Hypersensitivity reactions, including anaphylaxis, have occurred with topical formulations of mechlorethamine.

• WARNINGS AND PRECAUTIONS >> Mucosal or Eye Injury Exposure of the eyes to mechlorethamine causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible anterior eye injury may occur. Advise patients that if eye exposure occurs, (1) immediately irrigate for at least 15 minutes with copious amounts of water, normal saline, or a balanced salt ophthalmic irrigating solution and (2) obtain immediate medical care (including ophthalmologic consultation).

Exposure of mucous membranes such as the oral mucosa or nasal mucosa causes pain, redness, and ulceration, which may be severe. Should mucosal contact occur, immediately irrigate for at least 15 minutes with copious amounts of water, followed by immediate medical consultation. >> Secondary Exposure to VALCHLOR Avoid direct skin contact with VALCHLOR in individuals other than the patient. Risks of secondary exposure include dermatitis, mucosal injury, and secondary cancers. Follow recommended application instructions to prevent secondary exposure. >> Dermatitis The most common adverse reaction was dermatitis, which occurred in 56% of the patients. Dermatitis was moderately severe or severe in 23% of patients.

Monitor patients for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections. The face, genitalia, anus, and intertriginous skin are at increased risk of dermatitis. Follow dose modification instructions for dermatitis. >> Non-Melanoma Skin Cancer Four percent (4%, 11/255) of patients developed a non-melanoma skin cancer during the clinical trial or during one year of post-treatment follow-up: 2% (3/128) of patients receiving VALCHLOR and 6% (8/127) of patients receiving the mechlorethamine ointment comparator. Some of these non-melanoma skin cancers occurred in patients who had received prior therapies known to cause non-melanoma skin cancer. Monitor patients for non-melanoma skin cancers during and after treatment with VALCHLOR. Non-melanoma skin cancer may occur on any area of the skin, including untreated areas. >> Embryo-fetal Toxicity Based on its mechanism of action, case reports in humans, and findings in animals, VALCHLOR can cause fetal harm when administered to a pregnant woman. There are case reports of children born with malformations in pregnant women systemically administered mechlorethamine. Mechlorethamine was teratogenic and embryo-lethal after a single subcutaneous administration to animals. Advise women to avoid becoming pregnant while using VALCHLOR. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. >> Flammable Gel Alcohol-based products, including VALCHLOR, are flammable. Follow recommended application instructions.

• ADVERSE REACTIONS In a randomized, observer-blinded, controlled trial, VALCHLOR 0.016% (equivalent to 0.02% mechlorethamine HCl) was compared to an Aquaphor ®-based mechlorethamine HCl 0.02% ointment (Comparator). The maximum duration of treatment was 12 months. Sixty-three percent (63%) of patients in the VALCHLOR arm and 67% in the comparator arm completed 12 months of treatment.

The body system associated with the most frequent adverse reactions was skin and subcutaneous tissue disorders. The most common adverse reactions (occurring in at least 5% of the patients) are shown in Table 1.

Table 1. Most Commonly Reported (≥5%) Cutaneous Adverse Reactions Comparator VALCHLOR N=127 N=128 % of patients % of patients Any ModeratelyAny ModeratelyGrade Severe or Severe Grade Severe or Severe Dermatitis 56 23 58 17 Pruritus 20 4 16 2 Bacterial skin infection 11 2 9 2 Skin ulceration or blistering 6 3 5 2 Skin hyperpigmentation 5 0 7 0 In the clinical trial, moderately-severe to severe skin-related adverse events were managed with treatment reduction, suspension, or discontinuation.

Discontinuations due to adverse reactions occurred in 22% of patients treated with VALCHLOR and 18% of patients treated with the comparator. Sixty-seven percent (67%) of the discontinuations for adverse reactions occurred within the first 90 days of treatment. Temporary treatment suspension occurred in 34% of patients treated with VALCHLOR and 20% of patients treated with the comparator.

Reductions in dosing frequency occurred in 23% of patients treated with VALCHLOR and 12% of patients treated with the comparator.

Reductions in hemoglobin, neutrophil count, or platelet count occurred in 13% of patients treated with VALCHLOR and 17% treated with Comparator.

• DRUG INTERACTIONS No drug interaction studies have been performed with VALCHLOR. Systemic exposure has not been observed with topical administration of VALCHLOR; therefore, systemic drug interactions are not likely.

• USE IN SPECIFIC POPULATIONS >> Pregnancy Pregnancy Category D Risk Summary Mechlorethamine can cause fetal harm when administered to a pregnant woman. There are case reports of children born with malformations to pregnant women systemically administered mechlorethamine. Mechlorethamine was teratogenic in animals after a single subcutaneous administration. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal Data Mechlorethamine caused fetal malformations in the rat and ferret when given as single subcutaneous injections of 1 mg/kg. Other findings in animals included embryolethality and growth retardation when administered as a single subcutaneous injection. >> Nursing Mothers It is not known if mechlorethamine is excreted in human milk. Due to the potential for topical or systemic exposure to VALCHLOR through exposure to the mother’s skin, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. >> Pediatric Use Safety and effectiveness in pediatric patients have not been established. >> Geriatric Use A total of 79 patients age 65 and older (31% of the clinical trial population) were treated with either VALCHLOR or the comparator in the clinical trial. Forty-four percent (44%) of patients age 65 or older treated with VALCHLOR achieved a Composite Assessment of Index Lesion Severity (CAILS) response compared to 66% of patients below the age of 65. Seventy percent (70%) of patients age 65 and older experienced cutaneous adverse reactions and 38% discontinued treatment due to adverse reactions, compared to 58% and 14% in patients below the age of 65, respectively. Similar differences in discontinuation rates between age subgroups were observed in the comparator group.

Manufactured for: Actelion Pharmaceuticals US, Inc. South San Francisco, CA 94080, USA © 2014 Actelion Pharmaceuticals US, Inc. All rights reserved.

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LETTER TO OUR READERS

PMO: Recognizing the Many Principles Governing the Personalized Medicine Movement Al B. Benson III, MD, FACP, FASCO

Dear Colleague,

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n behalf of our Editorial Board and staff, Iâ&#x20AC;&#x2122;d like to thank you for your readership of Personalized Medicine in Oncology (PMO). We hope that you have become familiar with our mission and the content of PMO. When you flip through our pages and browse our website, you will see that we are at the forefront of the effort to replace empiric trial-and-error treatment with that of personally tailored treatment. We provide an indispensable forum to share information on how to practice personalized medicine. But more importantly, we are the only journal focused on unifying oncologists and pathologists. The collaboration between these 2 specialties helps to identify actionable markers, apply the appropriate therapy, and achieve better patient outcomes.

As you know, a massive amount of information exists related to many principles governing the personalized medicine movement. Topics influenc- The role of molecular ing personalized medicine include: genetics, diagnostics, targeted therapeu- pathology has become of tics, pathology and interdisciplinary team involvement, policy and regulation, paramount importance in and value in cancer care. All play a vital role in bringing personalized medidecision-making. cine to your patients and all are covered in our pages.

In recent years, weâ&#x20AC;&#x2122;ve witnessed tremendous strides toward individualizing treatment through our increased knowledge in molecular pathology. As a result, communication between oncologist and pathologist has never been more critical and the role of molecular pathology has become of paramount importance in decision-making. Issues surrounding molecular pathology and clinical decision making are regularly featured in PMO. PMO is a crucial delivery method in disseminating this information to those in the oncology community. It is our most sincere hope that PMO is a valuable resource to you in the care of your patients.

We welcome your feedback and participation. Please contact us at editorial@the-lynx-group.com with your comments, request, and ideas. Likewise, please contact us if you are interested in participating on our editorial board or peer-review board. We are looking forward to hearing from you.

Sincerely,

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

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Tissue Phenomics: Closing the Gap Between Genomic Information and Patient Outcomes

An Interview With Thomas P. Heydler, CEO of Definiens

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erhaps the most engaging quality of personalized medicine is the astounding diversity of its facets, each of which changes how clinicians approach patient risk identification, profiling, diagnosis, treatment, and follow-up. Understanding the science of genomics essentially opened up the gateway to personalized medicine. More recently, the science of Thomas P. Heydler phenomics is capturing the attention of the biotech community, and it is this topic that constitutes the focus of the following interview with Thomas P. Heydler, CEO of Definiens, who outlines an emerging dimension of personalized medicine by explaining how the role of imaging is redefining the decision-making process by combining and correlating genomic information, tissue-imaging data, and clinical outcomes. Definiens holds that this is the means of achieving true personalized medicine in oncology. The avenue for obtaining this diagnostic information is Definiens’ Cognition Network Technology®, which extracts meaningful, context-specific intelligence from many types of data, including text, numerical data, or images. The goal of this technology is to maximize the value of the data and ultimately aid in decision-making processes. The company’s current focus is on image analysis in life sciences and healthcare.

This technology captures more information contained in histological slides in order to develop novel treatments and bring those treatments to the right patient at the right time. Specifically, Definiens aims to support pharmaceutical companies in bringing targeted drugs to market faster, with smaller and more conclusive clinical trials. Recently, Definiens signed an agreement with Inserm Transfert to sponsor the worldwide consortium for the validation of the Immunoscore™ test, a new approach to cancer therapy. A team led by immunologist Professor Jérôme Galon demonstrated that the number,

type, and location of tumor-infiltrating lymphocytes in primary tumors have prognostic value. Clinical data show that patients with a strong Immunoscore have a better prognosis and that immune response may be a better indicator of risk for recurrence than standard tumor staining. Definiens has developed the underlying technology, enabling the accurate and reproducible quantification of tumor-infiltrating lymphocytes essential to the Immunoscore test.

Under an international task force led by the Society for Immunotherapy of Cancer with the partnership of the European Academy of Tumor Immunology, the Cancer and Inflammation Program, the National Cancer Institute, the National Institutes of Health, and La Fondazione Melanoma, the Immunoscore test is being validated by immunologists and pathologists in 15 countries.

We recently spoke with the CEO of Definiens, Mr. Thomas Heydler, who graciously assented to not only explain Immunoscore technology and its role in reshaping personalized medicine in oncology, but to do so in terms relevant to the clinician’s needs and frames of reference. We agreed at the outset of our conversation that it would serve the interests of clinicians and patients to examine the new phenomics technology in practical terms consistent with practitioners’ needs and interests, avoiding a purely theoretical discussion.

One goal of this interchange was to understand how the infiltration of inflammatory and lymphocytic cells, as well as knowing their number, type, and location in primary tumors, provides oncologists with prognostic value in lung and colon cancers. Before diving directly into the science, it was useful to hear Mr. Heydler explain and position the core work and mission of Definiens. The ensuing dialogue achieved this mission of clarifying their first-in-class technology.

PMO Can you please describe the work that Definiens is doing and how it relates to personalized medicine?

Mr Heydler Definiens is a Tissue Phenomics™ company, which means that we believe there’s a tremendous amount of valuable phenomic information represented in tissue. This information is primarily used by pathologists to make educated decisions to advise oncologists about diagnosis and treatment. Unlike the field of genomics, the challenge facing phenomics is the

Thomas P. Heydler is Chief Executive Officer of Definiens. Mr Heydler holds a Diplom-Ingenieur degree in Electric Engineering and Computer Science from the Technical University in Munich, Germany.

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absence of technologies allowing extraction of information from tissues to help oncologists make better diagnostic and therapeutic decisions. At Definiens, we have made it our objective to fill that void with a process for extracting all the information from tissue in order to understand not only the objects in each cell, but also the relationships of those objects within the tissue. In addition to fully quantifying tissue, we also understand the morphology, and use that information to create a fixed data readout of the tissue that correlates that information with other data sources, such as patient outcomes data. One application of this is to see which markers show the highest correlation between the cancerous tissue and progression-free survival. This combination will help us discover either new prognostic or predictive markers, which are the foundation for tests and then for better diagnostic services.

We are not calling it tissue sequencing, but tissue datafication. And we are hoping to extract all the information we can from the tissue to drive better diagnostic and therapeutic decisions.

PMO That puts it very clearly into focus. It speaks volumes. So tell me, how do oncologists interpret Immunoscore findings to select and titrate drugs differently than they would using the genomic approach, and how does this translate into improved prognosis?

Mr Heydler There’s a big gap between genomic information and patient outcomes. Tissue Phenomics is closing this gap. This is all about how a specific gene is translated into a specific protein, and that protein’s expression in the tissue structure is ultimately the manifestation of a certain disease.

In the Immunoscore field, it’s all about how fit the immune system is. Immunoscore gives the oncologist a score assessing the strength of the patient’s immune system. In order to do this, you have to look to the tissue. Your question is well put, because you’re not looking only to pick a marker and identify the expression of specific markers in the tissue, but more importantly, it’s all about morphology. It’s all about the correlation of lymphocytes and T cells, for example, toward the cancer cells and how those immune cells are grouping in certain areas, such as the core tumor or in the invasive margin. That’s the key indicator on top of the expression of biomarkers­ —combining biomarkers with the morphology—and that gives you a clear indication about whether you have an immune system that is strong and that will actually fight the cancer or not. This is extremely relevant because, if you have a strong immune system and the immune system can fight, it can have a tremendous positive impact on your disease. Even if the patient has a stage 3 cancer, with a strong immune system, he or she could have very long progression-free survival versus

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someone with a very weak immune system—demonstrated by a low Immunoscore—who could die within a year because the cancer cannot be managed.

So knowing the health of the immune system becomes a more and more critical element of managing cancer. And that’s the reason why the whole immune therapy paradigm became kind of the theme in science last year, as one of the breakthrough insights about how to check cancer.

There’s a big gap between genomic information and patient outcomes.

Tissue Phenomics is closing this gap.

PMO How granular does this drill down in terms of informing such things as drug selection? Is it specific enough to inform such decisions as which biologic is going to do the most for this or that cancer or patient and at what dose level?

Mr Heydler Let me step back and talk about 2 fundamental concepts we are dealing with. The conflict arises between a prognostic test and a predictive test.

A prognostic test basically is not related to a specific treatment, whereas a predictive test, also known as a companion diagnostic, is. It tells you which patient group is suited to that specific treatment and it asks you to select the treatment for a certain patient population.

In the context of immuno-oncology, I think both prognostic and predictive tests are relevant. First of all, the Immunoscore is a prognostic test, and the prognostic test tells you whether the patient has a strong or a weak immune system. If the patient has a strong immune system, and you have a phase 1 disease, you don’t have to do anything but wait and watch. If the person has a weak immune system, it basically recommends that you provide treatment. But it doesn’t tell you, since it’s prognostic, which treatment to pick; however, if you arrive at the decision to treat, then you have to make a decision about what to use.

For the next step, you would go through a patient stratification with a predictive test, which allows you to select and determine which treatment you want to use that will strengthen the immune system. This means you take the brake off the immune system by taking the camouflage off the cancer—PD-L1 principle—to improve the immune system, whatever the treatment is.

At Definiens, we are also working together with quite a number of biopharma companies on predictive tests to help them stratify patients in the true personalized medicine sense by identifying the best possible

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treatment. Basically all the major players are embarking on immunotherapy because everybody thinks that’s the way to really move cancer from a really bad disease to a manageable disease.

This is public information. Merck is working on an anti-PD-1 drug. Novartis, Amgen, Roche, Bayer, GSK, and AstraZeneca are all working on this aspect of the disease, whether it’s an anti–CLTA-4 or an anti–PD-1.

You can see there’s a massive wave of R&D money in anticancer therapy. This is where Definiens comes in, because you need a full understanding of the phenomic information to come up with a prognostic score. And you need the same phenomic information to come up with a predictive companion diagnostic. This provides dramatic value to the overall immunotherapy story.

PMO What has your exploratory market research into the knowledge level of oncologists and patholo-

Eventually, we will create an information package allowing the oncologist to come up with specific recommendations.

gists told you in terms of the clinician’s ability to translate these data into practice and to bring this into practice? Is there a knowledge gap that needs to be addressed, how large is it, and have you looked at a strategy for closing such a gap?

Mr Heydler First of all, we as an industry (and I’m talking collectively about the healthcare industry, including biopharma and diagnostic companies) are in the beginning of that learning curve. I would say in general that when you talk to pathologists or oncologists, everybody understands the importance of the immune system.

So I think the generic knowledge is there.

Also, everybody understands that if the immune system is so paramount in fighting cancer, then if you provide the wrong chemotherapy, which basically kills a lot of biological systems, including the immune system, it’s actually counterproductive. That is why I think you see a lot of recurrence in cancer once you’ve done one chemotherapy, because the cancer you’re treating is mutating and is kind of sneaking out—and you have killed the immune system, which can no longer fight the cancer, putting the patient in a bad situation. I think everybody understands that strengthening the immune system is really important.

Now, how do you specifically profile and diagnose a patient? I think this is where the clinician and the pa-

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thologist need help, because they can no longer digest all the data that come out of such a test. So they require computer-aided support. That’s why we are focusing on immunotherapy.

At the end of the day, we, as a company, are making the effort to develop a diagnostic test, whether it’s prognostic or predictive, and to perform the test ourselves so that eventually we can create an information package allowing the oncologist to come up with a specific recommendation about a specific patient with a specific cancer.

But as you know, we are in the beginning of this process. The prognostic side is going through clinical trials as we speak. A lot of biopharma companies have certain candidates in their clinical trials on the therapy side. With that comes companion diagnostics, and that’s something where an oncologist should have those tests in his or her hand and be able to prescribe them to get the exact information about the disease that the patient has.

PMO That is why I asked about the Immunoscore.

When you bring this to them, how many blank stares are there and how many are saying, “Aha, I can put this into play.”

Mr Heydler I think there’s no question about putting it into play. Everybody we are talking to is really excited that we have the opportunity to change the way we can help patients. We are extremely well aware that we have to go through a process. You might start with out-of-network reimbursement in the beginning.

It would have an impact on finances for sure. I think as more and more of those results come out in the trials, we’ll see the guidelines evolve. I don’t think the payers can prevent anyone from communicating the impact, because there’s so much benefit. And there will be pressure from the physicians, there will be pressure from the patients, because as you know, patient groups and advocacy groups are very active these days, and they’re already on this bandwagon.

PMO You need the critical mass of support to get not only utilization but also coverage. Are you then anticipating research that affects the economic burden of cancer with the impact of Immunoscore to be factored into this?

Mr Heydler We are a relatively small and new company. I am sure it might be worthwhile talking to some of the bigger biopharma companies, because I’m pretty sure that they are currently investing heavily to answer exactly that question about the appropriate value proposition. It was a key theme at the 2014 ASCO Conference, which was all about immunotherapy. The large, powerful companies will drive some of the research, and we’re very happy to participate and learn. But I think our focus right now is to really come up with the test

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and the solution and the information that will help practices.

PMO How do you envision the research process moving forward, getting traction, and having others continuing to test Immunoscore? How do you envision that happening in an ideal fashion to expedite the implementation of what you brought to personalized medicine?

Mr Heydler As you have already mentioned, the Immunoscore is already undergoing a global validation effort in order to confirm its value and be able to expand its use and acceptance. The completion of the Immunoscore validation will be a major milestone. The nice thing about Immunoscore and immuno-oncology is that the core principles are pretty generic. So it’s not as if we have to fully home in and concentrate on only one cancer type, such as breast or prostate or colon. In principle you can actually tackle these small variations very quickly in quite a number of cancer types. Therefore, I think the great promise of that approach is that we could offer a very generic approach going forward. I think this could be picked up massively in the next months or 2 years.

PMO How unique has this been? Are you alone in this field? It sounds that way. Essentially are you first in class, are you still solo in this field?

Mr Heydler The tissue phenomics approach, which complements the genome-based approach, requires a very strong bioinformatics analytical technology to extract all the relevant information from the tissue. That’s a very unique technology differentiator for Definiens.

We strongly believe we have proven that through the large number of projects we have. Just to give you a little data point: all the top 20 biopharma companies are customers of ours on the R&D side, and we have done probably more than 2500 projects to show that we can actually extract information from tissue that nobody else can. The reason for that is our proprietary, patented approach, which we call Cognition Network Technology.

This approach mimics the way we humans use our cognitive ways of interpreting things we see.

When you look at your phone, all your eyes see is a certain amount of structures and segments. You know the image, but you also know something about this, and you learn in your life this thing you’re looking at is a telephone. You can see and talk to other people, and only when what you see and what you know come together do you understand what you’re looking at. And that fundamental cognitive principle of what we humans use to interpret images is what we have implemented in our technology. As opposed to pattern recognition, imaging has its tools and can show you only similar patterns. With Definiens’ Cognition Network Technology, however, we can actually understand each

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element we see in the image, and that allows us to use specific interpretations.

This is our unique value. I think so far as the diagnostic side is concerned, we have a very unique differentiator. We are perhaps in a prime position. On the therapy side, as far as immunotherapies are concerned, that’s what biopharma is focusing on and this is what we are using to support them.

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PMO What is the timeline for taking this from the researcher’s end and putting it into the practicing oncologist’s hands?

Mr Heydler There are 2 perspectives. On the prognostic side, we believe that we can bring such a test to market through the georeference lab approach, so you don’t have to go through an extensive approval process, such as you do with the FDA, which takes considerably more time. So the timeline could be in the 2- to 2½year time frame to take samples on the prognostic side of the test. That will happen primarily in my eyes through a georeference lab approach.

Once you combine genomic and phenomic information, you get a complete diagnostic fingerprint of the patient, allowing you to then apply the best possible diagnosis and therapy.

On the predictive side, for companion diagnostics, we will have to go through the FDA approval process, which is intensive. I think the predictive side will take a little longer, and that will be driven by the therapy, by the drug. This will take several years. I imagine it will eventually happen in clinical practice.

PMO The incentive to fast track this is clearly here. What you offer is the ability to avoid clinical blind alleys and to get the care going. I wonder how similar this is to the problem of rheumatoid arthritis.

There’s now a multibiomarker test that provides a clear, objective assessment tool of disease progression—something impossible prior to its development.

And this reminded me of Immunoscore, because prior to that, rheumatologists were, to a large degree, operating in the dark. They hadn’t anything objective to tell them about disease progression.

Mr Heydler I think that’s a pretty good analogy. The fundamental principles you’re describing are absolutely equivalent.

PMO This is really where I think personalized medicine is going. Before we go, do you have any thoughts about how we would define personalized medicine in oncology?

Mr Heydler I think we have a very clear vision in terms of where personalized medicine is going and also where we can help. I think we strongly believe this is where our franchise is. Phenomic information is paramount to really understanding the disposition and the state of a disease in a patient at a given time.

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When you think about genomics information—and it gives you a good prognosis, it gives you information on, perhaps, a genetic mutation—you might learn that you have a certain likelihood that you will develop cancer over time. And only in a very few mutations do we have a guarantee, unfortunately, that you will develop cancer.

The BRCA1 gene is one of the few cases where we have a higher percentage of the likelihood of developing cancer. In general, however, we don’t know.

Now we can actually combine the genomic information and really look into the phenomic expression to come up with the exact diagnostic footprint or profile of the patient. And once you have that, you know exactly where the cancer is and how many cancers you have at the same time. Current molecular testing gives you only a very vague analysis of your genome, but what you really are interested in is having an exact analysis of the most aggressive cell line(s) in your cancer. This is a function of morphology, and you have to find the answer in the right place. You can’t just put it in a tube and mix it and come up with your molecular test. You have patients who have that specific cancer—which again is phenomic information!

That said, I think phenomics is critical, and once you can combine genomic and phenomic information, you get a complete diagnostic fingerprint of the patient, allowing you to then apply the best possible diagnosis and therapy to that individual patient. As an example, let’s say you have 500,000 prostate cancer cases in a big database and you have the exact genomic and phenomic fingerprint of each of those 500,000 patients. Now a new prostate cancer patient comes to the oncologist. The oncologist can run the new fingerprints, the diagnostic fingerprints, of this patient, then take that fingerprint back to the big database and match it to the 10 most similar cases. What therapy has worked? What didn’t work? What was the average survival time? What are some of the side effects? Suddenly you have a wealth of information that can provide treatment in a most personalized fashion. Now the treating oncologist can make the best possible decision, based not only on genomics, but also on specific phenomic information.

PMO And that is the punch line! What an improvement this is in our prospects for healing. Please accept our thanks for this remarkable walk through the field of phenomics and how you are harnessing it to aid in cancer diagnostic and treatment processes.

Mr Heydler You are most welcome. My thanks to you in turn for enabling us to communicate information of our work to today’s practitioners, that they can begin to reframe their expectations for treating their patients with the precision that only personalized medicine makes possible. u

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IMMUNOTHERAPY

FDA Approves Pembrolizumab for Advanced Melanoma First PD-1 Blocking Drug to Receive Agency Approval

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he US Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab for the treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs.

Melanoma, which accounts for approximately 5% of all new cancers in the United States, occurs when cancer cells form in skin cells that make the pigment responsible for color in the skin. According to the National Cancer Institute, an estimated 76,100 Americans will be diagnosed with melanoma and 9,710 will die from the disease this year.

“Pembrolizumab is the sixth new melanoma treatment approved since 2011, a result of promising advances in melanoma research.”

— ­ Richard Pazdur, MD Pembrolizumab is the first approved drug that blocks a cellular pathway known as PD-1, which restricts the body’s immune system from attacking melanoma cells.

Pembrolizumab is intended for use following treatment with ipilimumab, a type of immunotherapy. For melanoma patients whose tumors express a gene mutation called BRAF V600, pembrolizumab is intended for use after treatment with ipilimumab and a BRAF inhibitor, a therapy that blocks activity of BRAF gene mutations.

“Pembrolizumab is the sixth new melanoma treatment approved since 2011, a result of promising advances in melanoma research,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Many of these treatments have different mechanisms of action and bring new options to patients with melanoma.”

The 5 prior FDA approvals for melanoma include: ipilimumab (2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), and trametinib (2013).

The FDA granted pembrolizumab breakthrough

therapy designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies. It also received priority review and orphan product designation. Priority review is granted to drugs that have the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition.

Orphan product designation is given to drugs intended to treat rare diseases.

The FDA action was taken under the agency’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate end point reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. An improvement in survival or disease-related symptoms has not yet been established.

The efficacy of pembrolizumab was established in 173 clinical trial participants with advanced melanoma whose disease progressed after prior treatment. All participants were treated with pembrolizumab, either at the recommended dose of 2 milligrams per kilogram (mg/kg) or at a higher dose of 10 mg/kg. In the half of the participants who received pembrolizumab at the recommended dose of 2 mg/kg, approximately 24% had their tumors shrink. This effect lasted at least 1.4 to 8.5 months and continued beyond this period in most patients. A similar percentage of patients had their tumor shrink at the 10 mg/kg dose.

Safety of pembrolizumab was established in the trial population of 411 participants with advanced melanoma. The most common side effects of pembrolizumab were fatigue, cough, nausea, itchy skin (pruritus), rash, decreased appetite, constipation, joint pain (arthralgia), and diarrhea. Pembrolizumab also has the potential for severe immune-mediated side effects. In the 411 participants with advanced melanoma, severe immune-mediated side effects involving healthy organs, including the lung, colon, hormone-producing glands, and liver, occurred uncommonly. u

Source: FDA News Release. FDA approves Keytruda for advanced melanoma. 2014. Available at: http://www.fda.gov/NewsEv ents/Newsroom/PressAnnouncements/ucm412802.htm. Accessed September 10, 2014.

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Join Us in the Fight Against Metastatic Prostate Cancer Bavarian Nordic, Inc., which specializes in developing cancer immunotherapies, is exploring a targeted immunotherapy for prostate cancer.

Our PROSPECT study is a global, randomized, double-blind, Phase 3 efficacy study of an investigational therapeutic cancer vaccine (PROSTVAC-VF) Âą GM-CSF in men with metastatic, castration-resistant prostate cancer (mCRPC).

To learn more about how you can help your patients fight metastatic prostate cancer, please visit our PROSPECT website:

www.ContinueYourFight.com

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

WCMC2014ConfAd Asize_60914

REGISTER TODAY! www.regonline.com/wcmc2014

HEMATOLOGIC MALIGNANCIES

Highlights From the 6th International Symposium on Acute Promyelocytic Leukemia Lisa A. Raedler, PhD, RPh

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ecently, more than 200 scientists, researchers, and clinicians from around the globe gathered in Rome, Italy, for the 6th International Symposium on Acute Promyelocytic Leukemia (APL).

Held every 4 years since 1997, this comprehensive congress reviewed recent scientific advances and clinical research in APL and related malignancies.

Two internationally recognized APL experts served as the meeting’s chairs: Francesco Lo-Coco, MD, professor of hematology at University Tor Vergata, Rome, Italy, and Miguel A. Sanz, MD, PhD, head of the department of hematology and bone marrow transplant unit, University Hospital La Fe in Valencia, and professor of medicine at the University of Valencia, Spain. Dr Lo-Coco directs the APL subcommittee of the Italian Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) group. Dr Sanz leads the Spanish Programa Español de Tratamiento en Hemotología (PETHEMA) group, where he manages the working parties of APL, acute myeloid leukemia (AML), and infections in neutropenic patients.

Intensive study of the biology of APL has resulted in a remarkably thorough understanding of its pathogenesis, as well as the identification of druggable targets.

Intensive study of the biology of APL has resulted in a remarkably thorough understanding of its pathogenesis, as well as the identification of druggable targets.1 Cure rates in newly diagnosed patients with APL, which were essentially nil in the early 1970s, now exceed 70%.2,3 This impressive achievement reflects collaborative laboratory and clinical study. Initially led by innovative investigators in China and France and then by GIMEMA, PETHEMA, and other dedicated cooperative oncology groups throughout the world, efforts to improve clinical outcomes in this rare subtype of AML have culminated in the ultimate reward for both patients and practicing physicians.4,5 Today, APL serves as a paradigm for the treatment of

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patients with other acute and chronic leukemias.3 In addition to clinical and research updates on unpublished work in APL, the 6th International Symposium on APL educated participants about critical issues related to early patient identification, risk stratification, therapeutic management, molecular monitoring, and supportive care. The symposium also served as a forum for international collaboration and clinical networking for practitioners in developing countries. Finally, the congress offered young investigators the opportunity to interact with global leaders in APL research, share ideas, and learn from experts.

What Is APL? APL, the M3 subtype of AML, has distinct biologic and clinical features.1-3 Morphologically, APL is characterized by an accumulation of immature white blood cells (WBCs), called promyelocytes, in the bone marrow.6 Cytogenetically, APL is distinguished by the presence of a translocation of genetic material between 2 chromosomes (t[15;17]), specifically a fusion of the promyelocytic leukemia (PML) gene on chromosome 15 to the retinoic acid receptor alpha (RARA) gene on chromosome 17.7 In normal cells, PML encodes a protein that suppresses tumors and interacts with proteins that are active in cell proliferation and apoptosis. Alteration of PML in APL prohibits these important cell functions. The protein produced from the fused gene PML-RARA, known as PML-RARa, causes abnormal cell proliferation and blocks differentiation of WBCs at the promyelocyte stage. As these promyelocytes accumulate in the bone marrow, the formation of normal WBCs is hindered.6,8 Red blood cell and platelet production is also reduced.8 Because they have low levels of WBCs, red blood cells, and platelets, patients with APL commonly report bruising, petechiae, epistaxis, hematuria, fever, fatigue, pallor, anorexia, weight loss, and joint pain.8 Many patients with APL are at high risk of death from internal hemorrhaging within a few hours after presentation, such that APL is considered a medical emergency. If APL is suspected based on clinical presentation and cell morphology, targeted therapy and supportive transfusion therapies should be initiated immediately. Cytogenetic testing is then conducted to

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HEMATOLOGIC MALIGNANCIES

oco and Sanzthe outlined fascinating confirm diagnosisthe of APL and proceed with induction therapy. starting with its identification in 1957, APL is relatively rare, accounting for 10% acycline-based chemotherapy in the to 15% of the approximately 14,600 adults diagnosed with AML in the United States use of vitamin's first A derivative develeach year.9,10 In a recent analysis of a data set nese herbal medicine in 1987), to newand from the US Surveillance, Epidemiology, End evaluated Results (SEER) (1992-2007), f therapy in registry the 21st cen-

13 Figure.APL: APL: Highly Fatal to Highly Curable13 Figure FromFrom Highly Fatal to Highly Curable

Responses with anthracycline chemotherapy

1973

Response to ATRA (vitamin A derivative)

1987

High cure rates with ATRA + chemotherapy

1993

High cure rates with ATRA + chemotherapy

2004-2006

the age-adjusted annual incidence of APL was 0.23 per 100,000 persons.11 The median age at APL diagnosis was 44 years, which is younger than most patients with AML (methan 20dian years work in webased win on age atofdiagnosis wasAPL, 66 years, 11,12 nts are 2006-2010 cured. data).

We have defined the

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1977

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1990

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1996

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2006-2012

Chemotherapy-free results

nancy Evolution reversibility….There APL indicates acute promyelocytic leukemia: ATO, arsenic trioxide; ATRA, all-trans retinoic acid. of APL Treatmentis no more Adapted with permission from Francesco Lo-Coco, MD, and New Evidence in Oncology.

Once a highly fatalwe malignancy, xic drugs.

Weconsidered now know that can APL has evolved into a highly curable condinant cells….Why do we have these tartion with use of targeted therapy.2-4 Today, administration of the newbetween agents, withscior without cyto- ate) appropriate? for patients with low-risk APL? For patients with ? Because of the dialogue toxic chemotherapy, results in complete remission (CR) intermediate-risk APL? Should these patients also • In APL, the PML-RARA fusion gene can be quanticians….All of us have been involved in in the large majority of patients newly diagnosed with receive chemotherapy during induction? monitored polymerase s story;APL, weasfought andwith werelapsed suc- or refractory tatively well as inAPL patients • Must patients withusing high-risk APL receive chain chemo- reacAPL. therapy during induction? Which cytotoxic agent is tion (PCR) assays to document disease burden and o-Coco, September 29, 2013 In their opening remarks at the 6th International most effective? Is an anthracycline always necessary? molecular Inconsolidation whom is PCR APL Symposium, Drs Lo-Coco and Sanz outlined the confirm • What is the role remission. of cytarabine in ther-monfascinating history of APL, starting with Which patients are candidates for consolidation How often should testing ESTIONS IN THE TREATMENT OF its identification itoringapy?appropriate? in 1957, usage of anthracycline-based chemotherapy in with cytarabine based on risk features?

H APLthe early 1970s, the use of vitamin A derivatives first occur?

• What is the role of therapeutics in maintenance developed from Chinese herbal medicine are candidates mainte- with is the Which ideal patients management of for patients L is recognized as a success story for in 1987, •to What therapy? new combinations of therapy evaluated in the 21st cennance with which therapeutic agents based on their newerrisk therapies?

What can be done to overcome edicine,tury nuances (Figure).13in the diagnosis, risk status? than 20 years work in APL, we win challenges • In whatwith circumstances centraltherapies? nervous system access tois these eatment,“After and more monitoring of ofpatients because patients are cured. We have defined the dogma (CNS) prophylaxis (eg, intrathecal [IT] methotrexe overlooked, and reversibility….There treatment dilemmas of malignancy is no more need for ate) appropriate? cytotoxic drugs.

We nowboth know Dr thatSanz we can modulate • In APL,EARLY the PML-RARAfusion can be quantiheir introductory remarks, PREVENTING DEATH INgene APL malignant cells….Why do we have these targeted theratatively monitored using polymerase chain reaction o Grignani of theofUniversity Perugia In addition toassays questions regarding treatment pies? Because the dialogueof between scientists and cli(PCR) to document disease burden and con-selecof us have that been involved in a great success firm molecular In presenters whom is PCR monitorseveralnicians….All clinical questions remained tion, APL experts andremission. meeting highlighted story; we fought APL and we succeeded.” – Dr Lo-Coco, ing appropriate? How often should testing occur? the APLSeptember community: the importance early ofintervention 29, 2013.

• What isof theoptimizing ideal management patients with and therapies?

What can APL be done to overcome supportivenewer care.

Patients with often present to optimal nonchemotherapeutic choice Clinical Questions in the Treatment of Patients challenges with access to these therapies? s with low-risk With APL APL? For patients with Although APLthese is recognized as aalso success story for Preventing Earlyevents Death in APLare the primary e-risk APL? Should patients Hemorrhagic translational medicine, nuances in the diagnosis, risk In addition to questions regarding treatment selecmotherapy during induction? stratification, treatment, and monitoring of patientscause with tion, APL expertsdeath and meeting highlighted early inpresenters patients with nts withAPL high-risk APL receive chemo-dilemmas re- theofimportance can be overlooked, and treatment of optimizing early intervention and main. During their cytotoxic introductoryagent remarks,isboth Dr Sanz supportive care. Patients with APL often present to ing induction?

Which APL, particularly during the initial and Dr Francesco Grignani of the University of Perugia emergency departments or to physicians’ offices with ive? Is inanItaly anthracycline neces-that remained signs and symptoms of severe coagulopathy. Hemorrhagoutlined several always clinical questions

days of induction ic events are the primarytherapy. cause of early death in patients

unanswered by the APL community: • What is the optimal nonchemotherapeutic choice

with APL, particularly during the initial days of induc-

role of cytarabine in consolidation therpatients are candidates for consolida325 www.PersonalizedMedOnc.com Medicine in Oncology Volbased 3, No 6 on 2014 l Personalized l September tarabine risk features? emergency rooms or to physicians’ offices with l signs e role of therapeutics in maintenance and symptoms of severe coagulopathy. Hemorrhagic

HEMATOLOGIC MALIGNANCIES

tion therapy. Despite the availability of effective targeted therapy, an analysis of 1400 patients with APL in the US SEER database (1992-2007) documented an early death rate of more than 17%, and only a modest change in the rate of early death over this 15-year time frame.11 In comparison, international APL cooperative group trials report rates of early death—typically defined as “death during or within 7 or 30 days from the start of induction chemotherapy, or as death during induction therapy”— of less than 10%.14

When clinical findings and cell morphology (peripheral blood examination) suggest APL, ATRA should be started immediately.

In light of data like these, several experts presenting at the 6th International APL Symposium emphasized that early death is now the greatest contributor to treatment failure in this otherwise highly curable cancer.14 SEER data and other real-world registry data reveal a significant need for hematologists and healthcare providers (HCPs) across a wide range of medical specialties to appreciate the acute challenges associated with APL. Because they are often the first to suspect APL, emergency department specialists and other HCPs can have a major impact on early death and cure rates in APL.11 Several APL Symposium presentations verified the reality of high early death rates through analyses of patient registries and other databases. During an oral session, Dr R. Rahme of the French Belgian Swiss APL Group reported a 9% early death rate using retrospective data from APL clinical trials conducted in France.15 Using a population-based analysis of Canadian registry data, Dr Matthew Seftel of the University of Manitoba in Winnipeg, Canada, reported an early death rate of 22% among patients with APL.16 To address the need for more effective preventive approaches, Dr Anand Jillella of Georgia Regents University in Augusta, Georgia, presented his research, “A Successful Model to Decrease Early and Preventable Deaths in Acute Promyelocytic Leukemia Through the Use of a Simplified Algorithm and Expert Support in Experienced as Well as Smaller Leukemia Treatment Centers in the US.”17 He reported that use of streamlined treatment guidelines, along with support from APL experts, effectively decreased the rate of early deaths in APL in selected Georgia hospitals. Larger-scale implementation of this strategy is now under way in an at-

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tempt to decrease early mortality in APL throughout the states of Georgia and South Carolina.

Treatment Of Patients With Newly Diagnosised APL APL is unique among myeloid leukemias due to its sensitivity to all-trans retinoic acid (ATRA), a derivative of vitamin A. Unlike cytotoxic chemotherapies, ATRA does not directly kill malignant cells. Rather, treatment with ATRA induces terminal differentiation of malignant myeloid cells into mature neutrophils. Cancer cells develop into mature blood cells, progressing through full differentiation, and become nonmalignant.13,18 Because of the risk of early death secondary to hemorrhage, Dr Sanz and other APL experts reminded symposium participants of the importance of emergent initiation of ATRA treatment and aggressive blood product support for patients with newly diagnosed APL. When clinical findings and cell morphology (peripheral blood examination) suggest APL, ATRA should be started immediately.19 In patients with newly diagnosed APL, ATRA combined with anthracycline-based chemotherapy for induction, followed by 2 years of consolidation and then maintenance, has become the standard of care.19,20 In his lecture regarding first-line treatment of adults with APL, Dr Sanz recalled the initial trial of AIDA (ATRA plus idarubicin) by the Italian cooperative group GIMEMA, which was conducted in 1993 with more than 600 patients newly diagnosed with APL. This trial reported a CR rate of 94% and a 6-year overall survival (OS) rate of 78%.21 Since then, multiple clinical trials have established impressive long-term remission rates in patients with APL receiving ATRA and chemotherapy.21,22 Dr Sanz noted that, while receiving AIDA on protocol, 25% of patients with newly diagnosed APL experienced differentiation syndrome (DS), also known as cytokine release syndrome, a potentially fatal complication characterized by fever, peripheral edema, hypoxemia, respiratory distress, hypotension, renal and hepatic dysfunction, and rash.23,24 When DS is suspected, dexamethasone should be started immediately and maintained until symptoms are eliminated. In patients whose DS symptoms are severe, ATRA should be discontinued. Dr Sanz also reminded the audience that it is appropriate to reduce doses of anthracycline-based chemotherapy in both older patients and in children and adolescents diagnosed with APL in order to minimize morbidity.

In patients with APL, the PML-RARA fusion gene can be quantitatively monitored using PCR assays to document disease burden and confirm molecular remission status. Dr Sanz recommended PCR assessment upon completion of consolidation therapy. Performance of

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bone marrow biopsy to evaluate response after induction is “too early” and often provides misleading information.

After completion of consolidation, bone marrow evaluations should be performed every 3 months during the first 3 years, and then periodically depending on the patient’s individual risk and clinical status.23 Dr Sanz noted that evidence establishing the optimal duration of PCR monitoring is not yet available.

The treatment of patients with newly diagnosed APL continues to evolve. Given the known activity of arsenic trioxide (ATO) in relapsed APL, Dr Sanz and colleagues have explored whether ATO-based options are viable alternatives to chemotherapy in newly diagnosed patients. He cited a recent publication by GIMEMA that reported efficacy of ATO plus ATRA in patients with low-risk APL; that is, those whose WBC count was 10 × 109 per liter at diagnosis.25 Three additional studies have examined induction with “triplet therapy” of ATO combined with ATRA and chemotherapy.26-28 This triplet regimen, followed by ATRA plus ATO in consolidation and ATRA plus chemotherapy as maintenance, was shown to be effective in all patients with APL regardless of risk status.26 Randomized studies comparing induction with ATO plus ATRA versus ATRA plus chemotherapy are currently under way in patients with newly diagnosed low- and intermediate-risk APL.29

Treatment of Patients with Relasped APL In their presentations regarding the management of relapsed APL, Dr Pierre Fenaux of the French Belgian Swiss APL Group and Dr Martin Tallman of Memorial Sloan Kettering Cancer Center in New York congratulated the APL community for converting relapsed APL into an extremely rare occurrence, particularly among patients with low- and intermediate-risk APL.25 • Although rare, APL relapses occur in 1 of 3 forms30: • Hematologic or clinical relapse is a symptomatic recurrence that typically occurs within the first 3 years of diagnosis.

• Molecular relapse is detected by rising PML-RARA transcript levels using independent bone marrow samples and PCR analysis by 2 different laboratories.

These patients are often asymptomatic.

Extrahematologic relapses are rare. They often occur in the CNS and are usually correlated with molecular relapse in the marrow. Risk factors for extrahematologic relapse include high WBC count at diagnosis, CNS bleeding during induction, use of high-dose cytarabine, and use of IT infusion therapy. Because ATO is now used more frequently in induction, and because the agent crosses the blood–brain barrier, Dr Fenaux predicted that CNS relapses will occur less often in the future.

Dr Fenaux highlighted steps in the evolution of treat-

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ment for relapsed APL, starting with chemotherapy-­ based regimens and culminating in highly effective ATO-based combinations.30 ATO, which was discovered in China, has consistently demonstrated the ability to generate sustained molecular remissions when used in patients with relapsed APL who were refractory to ATRA-containing regimens.31-33 Unlike ATRA, ATO binds the PML moiety of the PML-RAR oncoprotein, leading to its degradation and resulting in leukemia cell apoptosis.34 The efficacy of ATO in patients with relapsed and refractory APL is well established.35 In a multicenter trial of single-agent ATO, molecular CR was documented in 86% of 40 patients with APL who had relapsed after receiving ATRA-based induction.32 In light of its clear activity and favorable tolerability profile in APL, ATO is now incorporated into large-scale cooperative group studies as a component of induction.

The efficacy of ATO in patients with relapsed and refractory APL is well established.

Multiple speakers at the 6th International APL Symposium noted that the cause of relapsed and refractory APL is not fully understood. However, it has been hypothesized to be correlated with unfavorable prognostic factors, such as the presence of FLT3 mutations, the BCR3 isoform of PML-RARA, expression of CD56, and additional cytogenetic aberrations beyond translocation t(15;17).

In this context, Dr Hugues de Thé of Université Denis Diderot, Paris, France, highlighted an example of a rare cytogenetic aberration: the presence of a promyelocyte leukemia zinc finger (PLZF)-RARA fusion gene.

In approximately 1% of the cases of APL, RARA fuses with other genes. Among these variant mutations, the t(11;17)(q21;q23) translocation, which generates PLZFRARA, is most common. PLZF-RARa–positive APL is clinically distinct from PML-RARa–positive APL in that ATRA-based therapy is typically ineffective.36

Therapy-Related APL Like other acute leukemias, APL can occur as a primary or secondary cancer. Dr Armin Rashidi of Eastern Virginia Medical School in Norfolk, Virginia, presented data suggesting that approximately 12% of all cases of APL are therapy-related (t-APL), and about 3% to 13% of all cases of therapy-related AML are actually t-APL.37

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Table Clinical Outcomes of Patients With APL Who Received Chemotherapy-Based or ATO-Based Regimens After Relapse38 All Patients (N = 151)

Patients Not Receiving SCTa (n = 38)

C-B, % (n = 67)

A-B, % (n = 84)

P Value

CR

85

92

.11

Molecular CR

78

84

.38

5-Year OS

40

56

5-Year DFS

31

5-Year RFS

34

Outcome Measure

C-B, % (n = 22)

A-B, % (n = 16)

P Value

.01

56

19

.11

39

.07

42

19

.49

48

.09

42

29

.63

Patients Receiving Autologous SCT (n = 67)

Patients Receiving Allogeneic SCT (n = 24)

C-B, % (n = 20)

A-B, % (n = 47)

P Value

C-B, % (n = 14)

A-B, % (n = 10)

P Value

5-Year OS

55

80

.04

56

43

.77

5-Year DFS

40

54

.06

29

21

.48

5-Year RFS

44

57

.13

31

57

.34

A-B indicates ATO-based; APL, acute promyelocytic leukemia; ATO, arsenic trioxide; C-B, chemotherapy-based; CR, complete remission; DFS, disease-free survival; OS, overall survival; RFS, relapse-free survival; SCT, stem cell transplantation. a Because of mobilization failure, early relapse before planned SCT, or ineligibility.

He noted that even though the incidence of t-APL appears to be rising, the APL community’s understanding of t-APL stems mainly from sporadic case reports rather than from formal study.

After a systematic review of the English literature through March 15, 2013, Dr Rashidi and colleagues identified a total of 326 t-APL cases. From their analysis of these case reports, they offered the following observations37: • t-APL affects predominantly middle-aged adults (median age at diagnosis, 47 years; female-to-male ratio, 1.7 to 1) • The incidence of t-APL appears to be increasing • The 4 most common primary antecedent conditions were breast cancer, hematologic malignancies (often lymphoma), multiple sclerosis, and genitourinary malignancies • Topoisomerase II inhibitors and radiation are the most common potential risk factors • Radiation-related t-APL does not appear to have a longer latency interval than chemotherapy-related APL • Despite different DNA damage “hot spot” sites, t-APL has no significant clinical or pathologic differences compared with de novo APL; t(15;17) is the sole cytogenetic abnormality in the vast majority of patients with t-APL • More than one-third of patients with t-APL come to

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medical attention incidentally (ie, due to abnormal laboratory findings); mucocutaneous bleeding is the most common symptom; most (79%) patients with t-APL have clinical disseminated intravascular coagulation (DIC) • The remission rate of t-APL is about 80%, which is comparable to that seen in de novo APL.

Poster Highlights More than 40 posters were presented during the 6th International Symposium on APL, covering topics ranging from prognostic factors to management of APL in pediatrics and the elderly. Summaries of 4 posters in 3 categories are provided below. Abstracts of all 43 posters can be found at www.apl2013.com/doc/ABSTRACT_ BOOK.pdf.

[1] Chemotherapy versus ATO in Relapsed APL Dr Pau Montesinos of Valencia, Spain, and other researchers involved with the PETHEMA, HOVON, PALG, and GATLA cooperative research groups, presented a poster entitled “Long-Term Outcome of 151 Patients with Relapsed APL Receiving Second-Line with Chemotherapy- or Arsenic Trioxide-Based Regimens.”38 Because long-term outcomes of salvage therapy using an ATO-based approach relative to chemotherapy-based regimens are not well understood, Dr Montesinos and colleagues analyzed the clinical out-

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come of 151 patients with APL who relapsed after initial therapy (ATRA plus anthracycline) and who received either second-line chemotherapy- or ATO-based regimens.

From June 1997 to May 2013, 151 patients (94 male, 57 female; median age, 42 years [range, 2-81 years]) relapsed after initial therapy in the PETHEMA trials. Patients presented with either molecular relapse (n = 47) or hematologic relapse (n = 104; 24 of which involved the CNS).

Sixty-seven of these relapsed patients received salvage therapy with chemotherapy-based regimens (ie, induction with mitoxantrone, cytarabine, and ATRA [n = 45]; etoposide, mitoxantrone, and cytarabine [n = 7]; or other regimens [n = 15]). Patients who were ineligible for stem cell transplantation (SCT) received consolidation with or without maintenance therapy.

From October 2003, 84 patients received salvage therapy with ATO-based regimens: induction with ATO alone (n = 59), ATO and ATRA (n = 19), or

ATO and chemotherapy (n = 6), followed by 1 consolidation cycle of ATO plus ATRA. When the postconsolidation bone marrow PCR results were negative, autologous SCT was recommended. When postconsolidation bone marrow PCR results were still positive, allogeneic SCT was planned. Patients who were ineligible for SCT received maintenance therapy with ATO plus ATRA with or without low-dose chemotherapy.

Baseline characteristics—sex, relapse risk at primary diagnosis, morphologic and BCR subtype, age at relapse, and type of relapse—were similar in both patient cohorts. Although not significant, patients rescued with chemotherapy-based regimens presented with more “early” relapses within 18 months after initial APL diagnosis than did those rescued with ATO-based regimens (55% vs 43%, respectively; P = .13). CR and molecular CR data are summarized in the Table.38 Median follow-up was 95 months (range, 24-167 months) in the chemotherapy-based group, and 33 months (range, 3-100 months) in the ATO-based group. The

Keynote Address by Dr Timothy Ley of Washington University in St. Louis, Missouri

D

ring the first day of the 6th International Symposium on APL, Dr Timothy Ley, an internationally renowned hematologist/oncologist and cancer biologist, presented the keynote address entitled “The APL Genome.”41 Dr Ley has uncovered the pathogenesis of AML and other blood disorders, and was one of the first scientists to systematically identify genetic mutations responsible for the initiation and progression of AML subtypes, including APL. In his introductory remarks, Dr Ley recalled a recent conversation with a medical student who questioned the need to study APL, a disease in which the majority of patients are cured.2,3 He answered the student and the audience by stating, “We study APL because it can teach us what we need to learn in other hematologic diseases.”

Dr Ley then reviewed the normal process by which “random, innocent” mutations occur in hematopoietic stem cells in our bone marrow. As mutation-carrying stem cells divide, those mutations are carried forward.

By age 50 years, humans have approximately 500 mutations in their stem cell genome, “most of which do no harm whatsoever.” However, in rare cases, a genet-

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ic change initiates a founding clone for leukemia. Dr Ley explained that founding clones have special abilities, including the ability to give rise to AML and to “spin off” additional mutations or subclones.

In APL (and chronic myeloid leukemia), the founding clone is also the specific target of drug therapy. In the case of APL, the unique genetic change—t(15;17), which results in the fusion gene PML-RARA—can be effectively addressed with ATRA and ATO. In contrast, relapsed APL features both the founding clone and new subclones (or “relapse subclones”): “PMLRARA does not act alone.” Dr Ley predicted that optimal treatment regimens for relapsed APL will target both the founding clone (PML-RARA), as well as specific “cooperating mutations,” such as FLT3.

Dr Ley’s ongoing discoveries in APL, the hypotheses they generate, and the subsequent attempts to develop and evaluate agents that target specific genetic mutations represent exciting opportunities for genetic and translational researchers, as well as drug developers. Dr Ley closed his lecture by stating that, even in APL, one of the most curable leukemias, “We are not yet done: there is much more to learn!”

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5-year OS, disease-free survival (DFS), and relapse-free survival (RFS) results for both groups are also shown in the Table.

This long-term study of a large series of patients with relapsed APL documented high CR rates with both ATO-based and chemotherapy-based salvage regimens.

Salvage therapy with ATO-based regimens was more likely to allow autologous SCT (per negative PCR) and resulted in improvements in 5-year OS, DFS, and RFS for patients with relapsed APL.

[2] Early Use of ATRA In their poster, “Outcome Effects of Early All-Trans Retinoic Acid in Acute Promyelocytic Leukemia: A Multicentric Study,” Dr Rashidi and colleagues noted that APL has long been considered a hematologic-oncologic emergency.39 Upfront initiation of ATRA before molecular confirmation is standard of care in all university-affiliated hospitals in the United States. In contrast, non–university-affiliated community hospitals may not always follow this standard. In this retrospective multicenter study, Dr Rashidi and colleagues investigated whether delaying ATRA until cytogenetic confirmation affects early outcomes in APL.

Upfront initiation of ATRA before molecular confirmation is standard of care in all university-affiliated hospitals in the United States.

Three Virginia and West Virginia hospitals—University of Virginia (Charlottesville), West Virginia University (Morgantown), and Sentara Hospital (Norfolk, VA)—contributed consecutive patients with APL to the study. The mean age of patients was 48 (±17) years, and 57% were female. Bleeding (40%), anemia symptoms (29%), and infections (19%) were the most common presenting symptoms (n = 65). According to Dr Sanz’s risk stratification, 23%, 43%, and 34% of patients were low, intermediate, and high risk, respectively.

More than half of the patients (60%) had DIC on admission. Another 4 of the patients (15%) who did not have DIC on admission developed it later. Approximately one-quarter of patients with APL (24%) had additional cytogenetic abnormalities. More than one-third of patients (38%) were transferred to an intensive care unit (ICU) during their hospital stay.

APL was suspected in 76% of patients within the first 2 days of admission, and in 16% between days 3 and 5.

ATRA-containing chemotherapy was used in 92% of

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patients, with the remainder dying before treatment initiation. Twenty patients (32%) who received ATRA developed ATRA syndrome.

ATRA was administered on the day APL was morphologically suspected in 28 patients (44%); there was a delay of at least 1 day in the remainder. In 39 cases (56%), ATRA was postponed despite suspicion of APL. Early death, within the same hospitalization, occurred in 13 patients (19%), 7 of which were due to catastrophic intracranial or intrapulmonary hemorrhage. Patients were then divided into 2 groups: Group A, early death; Group B, no early death.

There were no significant differences between the groups with regard to hospital type (university-affiliated or community), age, sex, presence of additional cytogenetic abnormalities, development of ATRA syndrome, whether or not ATRA was delayed, and the number of days ATRA was delayed. However, DIC on admission and ICU care were significantly more common among Group A than Group B patients (P <.01). Also, patients in Group A had significantly higher risk scores than those in Group B (P<.01).

Researchers concluded that patients with APL in Group A had a worse prognosis, not because of different treatment strategies, but simply because they were “sicker.” With inclusion of more data, Dr Rashidi and colleagues will continue to evaluate how delay in ATRA treatment affects early outcomes.

[3] Minimal Residual Disease In their poster entitled “Monitoring Minimal Residual Disease (MRD) in Patients (pts) with Acute Promyelocytic Leukemia (APL) Treated with All-Trans-Retinoic Acid (ATRA) and Arsenic Trioxide (ATO),” Dr Lorella Melillo and colleagues of the Department of Hematology of the Casa Sollievo della Sofferenza in San Giovanni Rotondo, Italy, reported results of a prospective study of bone marrow minimal residual disease (MRD) monitoring in patients with APL treated with ATO plus ATRA.40 Detection of the PML-RARA fusion gene using bone marrow MRD monitoring is known to be an effective predictor of outcomes in patients treated with ATRA plus chemotherapy. However, the kinetics of leukemia clearance with the use of ATO plus ATRA in induction are significantly different from those with the use of ATRA plus chemotherapy (ie, AIDA protocol). To assess the value of MRD monitoring in ATO-plus-ATRA recipients, Dr Melillo and colleagues followed 6 patients with APL who were treated with this combination, 3 of whom had newly diagnosed APL and 3 who had relapsed disease (2 with bone marrow plus CNS relapse).

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MRD was monitored upon completion of induction and after consolidation, as well as every 2 months during maintenance for the first 2 years and then every 6 months thereafter. A total of 72 bone marrow samples were obtained for quantitative PCR analysis. Another 120 bone marrow samples were obtained from 12 different patients with APL who were treated with the AIDA protocol during the same period.

All 6 patients treated with ATO plus ATRA achieved molecular CR, with 4 patients alive and in molecular CR at the end of the study. Three patients with relapsed APL who were successfully retreated with ATRA plus ATO underwent allogeneic bone marrow transplants, but 2 died secondary to relapsing disease at +8 and +12 months from bone marrow transplant, respectively. In 1 of 3 patients treated at diagnosis, PCR results were transiently positive after achievement of molecular CR, but the patient had not experienced hematologic relapse after 30 months of follow-up.

Preliminary data demonstrated a strong correlation between quantitative PCR for PML-RARA values and patient outcomes. The authors concluded that serial MRD monitoring can be a predictor of RFS in patients with APL treated with ATO plus ATRA without chemotherapy.

Dr Thoraya Adbel Hamid of the National Cancer Institute at Cairo University in Egypt presented the poster “Minimal Residual Disease (MRD) Detection in Acute Promyelocytic Leukaemia and Its Relation to Clinical Outcome.”42 Dr Hamid and colleagues studied the PML-RARA fusion gene with real-time PCR (RT-PCR) before and after therapy to assess its prognostic value and impact on therapeutic decision-making. They calculated levels of PML-RARA by different methods, including normalized copy number (NCN), which is calculated as copy number of PML-RARA divided by copy number of ABL multiplied by 10,000.

This study included 41 patients with newly diagnosed APL. RT-PCR was performed before treatment and then after consolidation. Induction and consolidation included ATRA and daunorubicin or idarubicin for 3 courses.

Maintenance therapy was given with 6-mercaptopurine, methotrexate, and ATRA for 2 years.

Of the 41 patients in the study, 30 achieved hematologic remission and underwent MRD detection, 8 failed to achieve CR, and 3 died early. The decrease in expression level of PML-RARA using NCN after consolidation was highly significant.

During the observation period of 39 months (range, 1-56 months), 6 patients relapsed. The time between detection of molecular relapse and appearance of hematologic relapse ranged from 1 to 3 months, with most

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cases clustering in the third month. The DFS rate was 69%, while OS was 77% (mean, 50 months).

Patients with low-risk APL had significantly longer DFS and OS versus patients with high-risk APL. Researchers also demonstrated a highly significant correlation between a 2 or more log reduction of PML-RARA after consolidation and improved DFS. Dr Hamid and colleagues concluded that MRD monitoring is essential for follow-up on patients with APL, for prediction of relapse, and for choice of therapy. The PML-RARA NCN method that was used was both simple and accurate, and enabled standardization among laboratories. u

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39. Rashidi A, Goudar R, Sayedian F, et al. Outcome effects of early all-trans retinoic acid in acute promyelocytic leukemia: a multicentric study. Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy. Abstract P20.

40. Melillo L, Minervini MM, Bodenizza C, et al. Monitoring minimal residual disease (MRD) in patients (pts) with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy. Abstract P07.

41. Ley TJ. The APL genome. Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy.

42. Hamid TA, Alla FG, Garaar E, Raslan H. Minimal residual disease (MRD) detection in acute promyelocytic leukaemia and its relation to the clinical outcome.

Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy. Abstract P11.

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LUNG CANCER

Navigating the Molecular Testing Landscape in Lung Cancer Experts discuss how they use mutational testing

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he expansion of tumor genetic profiling into the clinic has led to effective, targeted treatments for patients but created a daily dilemma for oncologists: What to do with the results of these tests?

At the 15th Annual International Lung Cancer Congress, a panel of lung cancer experts weighed in on the topic through a case Roy Herbst, MD discussion presented by Roy Herbst, MD, and Juliane M. Juergensmeier, PhD, of Yale Cancer Center, New Haven, CT. Dr Herbst is ensign professor of medicine, professor of pharmacology and chief of medical oncology. Dr Juergensmeier is research scientist in medical oncology and heads up the Yale Precision Medicine Tumor Board.

Yale Precision Medicine Tumor Board: Truly Multidisciplinary At the Yale Precision Medicine Tumor Board, according to Juergensmeier, a multidisciplinary panel of experts comes together “to interpret complex genetic findings.” The board includes clinical medical oncologists, pathologists (anatomic and molecular), radiologists, surgeons, pharmacists, basic and translational researchers, geneticists, bioinformaticians, and advanced practice nurses.

Tumor genetic profiling has created a daily dilemma for oncologists: What to do with the results of these tests?

In non–small cell lung cancer (NSCLC), the group currently evaluates the results of genetic profiling assays but expects to soon add gene expression profiling by immunohistochemistry and immune assays as well. Yale uses 3 levels of genetic profiling: an 8-gene panel, a 50gene panel, and a 409-gene panel. Most involve next-generation sequencing; whole exome sequencing is also available.

“This information is submitted for discussion and treatment recommendations, primarily with a targeted agent or enrollment on a clinical trial based on the molecular profile,” she said. “But more often than

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not, we find mutations that are hard to interpret.”

While Yale is able to direct many eyes to one test result, oncologists in the community often lack for this expertise. A show of hands in the conference audience indicated few oncologists have access to onsite laboratories or molecular tumor boards.

A Typical Case: What Test Do You Order?

As a means of familiarizing the audience with gene expression profiling, Herbst and Juergensmeier presented a typical case from Yale and asked conference faculty to comment.

The 77-year-old patient was a former smoker with newly diagnosed early-stage NSCLC (T2N1). Imaging revealed a 25x14 irregular left upper lobe paramediastinal parenchymal lesion abutting the pleura. Tumor samples from lobectomy revealed a 4-cm moderate-to-well differentiated adenocarcinoma of the lung with 50% papillary, 30% acinar, and 20% micropapillary histologies.

The panel first discussed what genetic testing, if any, is warranted in this patient. According to Juergensmeier, either a limited genetic panel (primarily looking for EGFR mutations and ALK fusion) or broad genetic profiling would be appropriate.

Paul Bunn, Jr, MD, professor and James Dudley Chair in Cancer Research at the University of Colorado Denver School of Medicine, said his center’s policy is to perform molecular tests on such a patient at diagnosis.

“The majority of such patients will relapse, and it’s good to know ahead of time how to treat this patient when that happens,” he said.

David Gandara, MD, professor of medicine and chief of the thoracic oncology program at the University of Davis Comprehensive Cancer Center in Sacramento, CA, commented on the tumor’s mixed histology, each with its own predilection for having an EGFR mutation or ALK fusion. “The issue is, which part of the tumor will you send for mutation testing?” he asked. The heterogeneity within the sample can be an issue in the case of multiple histologies, he said.

Bunn countered that this may not be an issue. Researchers from MD Anderson Cancer Center recently showed that in the presence of a driver mutation, heterogeneity tends to be low in NSCLC, he said. “While there can be some heterogeneity, it’s highly likely that in this

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Table

Adenocarcinoma of the Lung, Actionable Mutation

Gene

Normal Protein Function

EGFR (Epidermal Growth Factor Receptor)

Ligand binding to the RTK triggers receptor homo- and/ or heterodimerization and autophosphorylation on key cytoplasmic residues which recruit adapter proteins like GRB2 that in turn activate complex downstream signaling of at least 4 major downstream signaling cascades, including the RAS-RAFMEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules.

Spectrum of Mutations in Cancer

Comments on Patient’s Mutation

Mutated or amplified in a wide variety of cancers, especially lung, colon, and brain.

EGFRVIII deletion prominent in glioblastoma.

p.Glu746_Ala750del (c2235_2249 delGGAATTAAGAGAAGC) is most prevalent EGFR exon 19 deletion in NSCLC (exon 19 deletions are approximately 48% of all EGFR mutations). Registered and investigational agents: 1st-generation reversible tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib; 2nd-generation irreversible TKI afatinib; 3rd-generation mutational-specific TKIs CO-1686, AZD9291.

patient you would find the same mutation in each of those histologic areas,” he maintained.

Corey Langer, MD, Professor of Medicine and Director of Thoracic Oncology at Abramson Comprehensive Cancer Center in Philadelphia, emphasized that this is an early-stage patient, and noted, “There’s no data that we alter outcomes in the early-stage, curable setting with any targeted agent. You are perfectly justified doing any gene profiling test, but doing none is also quite reasonable.”

Results of 409-Gene Panel The 409-gene panel was run on this patient, and non-tumor DNA from a histologically normal lymph node was used as a reference, to exclude germine changes.

The molecular pathologist identified 4 gene alterations with significant frequency. These included mutations, and their tumor DNA frequencies, in ERCC4 (49%), CDKN4A (39%), EGFR (33%), and FGFR (26%). Both EGFR and CDKN4A mutations could have a major effect on the patient’s disease, but a targeted agent is currently available for only the EGFR mutation.

ERCC4 would have a minor effect, and FGFR4 would have no effect on the cancer.

Herbst noted that this patient has the typical exon 19 EGFR mutation, for which EGFR inhibitors are available. The additional mutations could be of interest for this patient in the future, as new targeted agents become approved.

The Yale pathologist’s report on the actionable mutation (Table) describes the effects of the mutation and

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lists approved treatment options and relevant experimental agents.

“Clinicians need to get used to seeing these reports,” Bunn said. “Not all mutations are the same, and this will be even truer for KRAS than for EGFR. You will need to pay attention to just what these mutations are.”

The Treatment of This Patient Should this patient be treated with chemotherapy, a first-, second-, or third-generation EGFR inhibitor, an investigational agent (ie, targeting CDKN4A), or a combination of chemotherapy plus an EGFR inhibitor?

Bunn maintained that chemotherapy is the best option. He said he would discuss the results of genetic testing, and tell the patient: (1) there is evidence that treatment with an oral EGFR inhibitor will reduce the risk of recurrence, (2) with discontinuation of treatment the cancer will probably recur, (3) there is no evidence that this approach will improve survival over chemotherapy alone.

“Obviously, this is controversial,” he acknowledged.

“Some oncologists would offer an EGFR inhibitor with or without chemotherapy, but I would discuss this with my patient, and my personal recommendation would be chemotherapy.”

Herbst agreed that adjuvant chemotherapy is recommended, with “consideration” of an EGFR inhibitor. He added that any treatment delay is not advisable. “The last thing we want is for whole exome testing to take so long that by 10 days we don’t have the results for EGFR and ALK testing, which we know are important.” u

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THIRD ANNUAL CONFERENCE

October 31November 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 and immunotherapy 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 the 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

The 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

•

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

REGISTER TODAY! www.PMO-Live.com

This activity is supported, in part, by independent educational grants from Lilly USA. 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 OCTOBER 3, 2014 Submit an abstract for the Third Annual PMO Live Conference.

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.pmo-live.com/conference/abstracts

AGENDA*

FRIDAY, OCTOBER 31 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 PMO Live Conference, a Global Biomarkers Consortium — Opening Remarks – Jorge E. Cortes, MD – Roy S. Herbst, MD, PhD

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

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

9:45 am - 11:05 am General Session III: Incorporating Molecular Biomarkers into the Therapy of Hematologic Malignancies — Case Studies on “How I Treat” • Myeloid hematologic malignancies – Jorge E. Cortes, MD • Chronic lymphocytic leukemia – William Wierda, MD, PhD • Multiple myeloma – Sagar Lonial, MD • Lymphoma – Anas Younes, MD 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 – Jorge E. Cortes, MD – Roy S. Herbst, MD, PhD

Break *Agenda subject to change.

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ASCO 2014

What Makes a Treatment “Clinically Meaningful”?

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wo presentations at ASCO struck Jennifer Malin, MD, PhD, medical director of oncology at WellPoint, Inc, as good examples of value in cancer care, while many others did not make the value-based list. Malin described these studies at an ASCO Highlights of the Day session.

Jennifer Malin, MD, PhD

ASCO’s Proposed Criteria for Clinically Meaningful Outcomes Malin’s perspective was based on criteria that ASCO recently proposed as a means of evaluating clinical trial results in terms of “clinically meaningful outcomes” (Ellis LM, et al. J Clin Oncol. 2014;32:1277-1280). Depending on the tumor and prior treatment, ASCO proposed that any new regimen for metastatic disease should convey improvement in median overall survival (OS) of 2.5 months to 6 months.

“There are often discussions with patients about what are meaningful outcomes, and these ‘value’ discussions often end up in debates as to whether a week, a month, a year is meaningful.”

—Jennifer Malin, MD, PhD “Powering studies to achieve these end points would be worth consideration. It would ensure that we make advances that provide clinically meaningful outcomes to patients, and it would also lead to smaller trial designs and would speed up innovation,” she predicted.

Studies Showing Value Among studies presented at ASCO that were clearly clinically meaningful were a study in a poor-prognosis subset of lymphoma and one in early-stage, HER2-positive breast cancer.

A phase 2 study of 64 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) showed that the addition of lenalidomide to R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone; R2CHOP) appeared to reduce the negative prognostic significance of the non-germinal center B-cell (nonGCB) phenotype (a subset of DLBCL) (Abstract 8520).

At 2 years, progression-free survival (PFS) for this subset

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was 60% and OS was 75% with the R2CHOP regimen, mirroring outcomes in the GCB patients.

This represented a 2-year relative increase in OS of 30% at an estimated total drug cost of $73,682 and an incremental drug cost (for adding lenalidomide to R-CHOP) of $26,540.

“This regimen improves OS in patients previously known to have a poor prognosis. This is definitely a clinically meaningful improvement in outcome and provides great value, certainly in comparison to many other studies presented at ASCO,” she commented.

The second study was a meta-analysis of 5 randomized adjuvant trastuzumab trials. The analysis focused on 4220 HER2-positive patients with mostly lymph node– positive tumors ≤2 cm, a group for whom the benefit of trastuzumab has not clearly been established (Abstract 508).

Ciara O’Sullivan, MD, of the National Cancer Institute, reported that trastuzumab reduced recurrences and deaths by about 30% in all groups except for patients with 1 or no positive lymph nodes, whose mortality risk was reduced by just 2%.

“Trastuzumab clearly provides tremendous value for these patients, at a total drug cost of $81,336 and incremental cost of $76,601,” she said. “It may have limited value, however, in the group with zero to 1 positive nodes.”

Examples of Lack of Value Malin then described several studies that illustrated a lack of clinically meaningful outcomes and therefore value.

One was a phase 1 study of escalating doses of cabozantinib plus abiraterone in castration-resistant prostate cancer in which a prostate-specific antigen decline of >75% was observed in 63% of men with the 20 mg dose and in 13% with the 40 mg dose (Abstract 5027). The investigators noted the combination’s tolerability and preliminary efficacy, which they claimed “support the investigation of this combination for further clinical development.”

According to Malin, however, the findings indicated “limited to no improvement in outcomes,” and carried a total drug cost of $92,410 and an incremental drug cost of $32,521.

Another study evaluated the benefit of adding bevacizumab to trastuzumab/docetaxel in the neoadjuvant breast cancer setting, finding a 20% relative increase in

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the rate of pathologic complete response (Abstract 507).

For this, the total drug cost was $103,976, and the incremental cost was $77,267.

The novel agent trebananib was evaluated in combination with paclitaxel and trastuzumab in patients with HER2-positive advanced breast cancer in a phase 1b study (Abstract 502). While the median PFS was approximately 18 months, deemed encouraging by the investigators, the estimated total drug and incremental drug costs – $325,530 and $170,000, respectively – gave Malin pause.

“When our new drugs cost $170,000, we need to look for significant improvements in outcomes,” she commented.

Can Data Like These Guide Conversations?

Oncologists could use data such as these to have more

meaningful conversations with patients about treatment options, Malin suggested.

“There are often discussions with patients about what are meaningful outcomes, and these ‘value’ discussions often end up in debates as to whether a week, a month, a year is meaningful,” she said.

A pivotal study by Weeks J, et al (N Engl J Med. 2012;367:1616-1625) revealed that 25% of patients with advanced lung cancer and about 35% of patients with metastatic colorectal cancer believed it was “very likely” their treatments could cure them.

“I posit that patients are looking for cures. If they understood the more marginal benefits that our treatments bring, they may be more likely to understand the trade-offs in toxicity and cost, and be more likely not to want them,” she said. u

ASCO Workgroup Proposes Consolidated Payments for Oncology Care

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alling the current fee-for-service re­imbursement model “medicine’s dark secret” – one that has jeopardized value-based cancer care – a member of the ASCO Payment Reform Workgroup presented a novel proposal for consolidated cancer care at the Community Oncology Town Hall.

“Working towards a better payment system for oncology care, instead of just complaining about the one that we have, has been liberating and exhilarating,” said Jeffery Ward, MD, the immediate past chair of ASCO’s Clinical Practice Committee and an oncologist at the Swedish Cancer Institute in Seattle, WA. The diverse group had as its premise the need to hear voices from across the clinical oncology spectrum, the goal being “a uniform reformation of oncology care that can be applied to all cancer care settings.”

Need to Depart From Fee-for-Service The concept moves the reimbursement system away from fee-for-service. “Fee-for-service medicine is a barrier to personalized care. It’s an antiquated reimbursement system that only pays for care when it involves physician ‘touches’ and the infusion of drugs,” Ward said.

“It only pays for some services, failing to reimburse at all for other essential services provided in oncology offices and clinics. It fails to reward decision making that brings greater quality, efficacy, or value to the care

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equation, and conversely it incentivizes inefficiency and the overuse of the most expensive Jeffery Ward, MD services to maximize reimbursed service,” he continued.

At its heart, he said, fee-for-service medicine takes the focus off the patient and centers care around the physician, failing to achieve the personalized care that is the general aim in oncology now.

“It’s time to open the current model to scrutiny, recognize how incongruent it is to the future of cancer care and replace it,” he maintained.

“Working towards a better payment system for oncology care, instead of just complaining about the one that we have, has been liberating and exhilarating.”

—Jeffery Ward, MD The Workgroup’s Proposal The group explored numerous concepts for payment reform, and ultimately crafted and released (in May) a consolidated, patient-centered payment model.

“We asked our committee members, if you could throw out all you know and start over – not just tweak a broken system – how would you like to get paid for

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what you do?” he said. “What we developed has at its core monthly bundled payments that are adjusted for (ie, rewarded for) quality, pathway utilization, resource utilization, and clinical trial participation.”

The model does not ignore the importance of drug purchasing, but contains a vehicle for integrating the current 6% margin into the reimbursement mix, “which will remove the stigma of drug margins from our profession.”

Monthly Payment Tiers At the model’s core are monthly payments that vary according to the treatment activity of the patient.

These payments are developed by taking the gross revenue for typical clinical services and combining them into a lump sum. “It’s forgetting where the revenue came from, and rearranging it into these payments,” Ward explained.

“We believe ASP [average sale price] +6% could be folded into this bucket and added to ‘treatment month’ payments once an alternative to buy-and-bill is developed and sufficiently tested,” he said.

The new payments would not track directly with existing CPT codes; they are intended to cover services that are not compensated today. New aggregate revenue would be no less than the aggregate amount of current revenue for typical oncology practices. The relative sizes of payments would reflect the relative amount of time and

cost incurred for the activities in the payment period.

These distinct periods include new patient payments, treatment month payments, active monitoring month payments, and transition-of-treatment payments. These monthly payments would be phased in over time, and some components of fee-for-service would be continued, such as laboratory tests, imaging, and bone marrow biopsy and transplant.

Expected Impact of This Proposal The adoption of this model should give practices flexibility to build innovative processes of care that will allow them to assume accountability for quality and value of the care they give. Ultimately, the model would also remove the current financial penalty for using lower-cost drugs or for treating with oral drugs. It would also simplify billing, replacing 63 codes with 9.

The end result should be cost savings through reductions in the use of the hospital and emergency department, in testing and surveillance, and in the administration of oncolytics and supportive drugs.

Oncologists should be rewarded for participating in these savings.

In closing, Ward indicated, “ASCO is not wedded to this plan....We plan to refine it and may offer other alternative payment plans....We envision the possibility that you will be able to choose from a menu of alternative payment systems.” u

Pharmacokinetic-Guided Dosing of 5-FU Shown Cost-Effective

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sing a commercially available assay to guide dosing of 5-fluorouracil (5-FU) for the treatment of metastatic colorectal cancer is cost-effective based on a survival advantage over dosing based on body surface area, according to an analysis conducted by Daniel Goldstein, MD. Currently, the standard treatment for metastatic colorectal cancer is a regimen of 5-5-FU given with leucovorin and oxiliplatin (FOLFOX). Dosing is typically calculated by body surface area, but this method of dosing may result in substantial inter-individual variability in drug exposure, frequently resulting in high toxicity levels, he said.

Development of an immunoassay for 5-FU now allows pharmacokinetic (PK)-guided dose adjustments of FOLFOX to individualize chemotherapy treatments.

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The results of 2 separate studies showed that this method improves overall survival (OS) and decreases toxicity versus body surface area-guided dosing in patients with metastatic colorectal cancer.

“The issue of personalizing the dosing of 5-FU has been around for quite some time,” he said. “This is probably 1 of the first tests that has shown to be validated and have clinical utility, but it’s in its infancy.”

Recognition of the benefits of PK-guided dosing led Goldstein to compare the cost-effectiveness of PK FOLFOX to traditional body surface area FOLFOX in patients with metastatic colorectal cancer. Dose adjustments of 5-FU based on PK can be made using an immunoassay for 5-FU, said Goldstein, a hematology and medical oncology fellow at Emory University, Atlanta, although he acknowledged that presently,

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PK-guided dosing is not being extensively used. “It is not used so much in the U.S. at the moment,” he said.

“When you use the PK test to guide the dosing, you do get improved overall survival and decreased toxicity.

The test is only $400 to $500, so we did a cost-effectiveness analysis to see if this extra spending on the test has value.”

The cost-effectiveness of PK FOLFOX was compared with body surface area FOLFOX, through the use of a Markov model. Published data on progression-free survival (PFS) and OS were used to estimate progression and mortality risk.

Costs for chemotherapy administration and management of adverse events were established based on Medicare reimbursement rates for hospital and physician services. Drug costs were based on the Medicare and Medicaid prices. All costs were calculated averages of 2013 price ranges in US dollars.

Calculated into the cost estimation were drug costs (Medicare and Medicaid Services average sales price),

administration costs, and costs for grade 3/4 adverse events. The cost of the PK test was assumed to be $400.

Primary outcomes were measured in incremental cost per quality-adjusted life-year (QALY) gained. PK FOLFOX was found to provide 2.03 additional QALYs at a cost of $50,205, compared with body surface area FOLFOX with 1.46 QALYs at a cost of $37,173. The incremental cost-effectiveness ratio (ICER) was $22,696/QALY. This ICER was well below the $50,000 willingness to pay threshold in all one-way sensitivity analyses. In probabilistic sensitivity analyses, 99% and 95% had ICERs below $42,000/QALY and $34,000/ QALY, respectively.

The main cost driver for PK FOLFOX was the $400 PK test that was used for 4 cycles to establish optimal doses, said Goldstein. The main driver of benefit was improved PFS and OS. “Given the cost-effectiveness profile and OS advantage with PK FOLFOX, it should be evaluated further in comparative effectiveness studies,” he noted. u

Routine Imaging Costly in B-Cell Lymphoma but Rarely Picks Up Relapse After Remission

S

urveillance imaging of asymptomatic patients in first remission following treatment for diffuse large B-cell lymphoma offers little clinical benefit at substantial cost, according to Philadelphia researchers.

Strategies utilizing 2 years of routine computed tomography (CT) or positron emission tomography (PET)/ CT scans were associated with minimal survival benefit compared with follow-up without routine imaging.

“Surveillance imaging limited to 4 scans over 2 years is associated with significant aggregate costs,” said Scott F. Huntington, MD, an oncology fellow at Abramson Cancer Center, University of Pennsylvania, Philadelphia.

The goal of routine surveillance imaging is detection of early relapse, but “interestingly, there’s increasing data showing that the majority of patients who have diffuse large B-cell lymphoma who relapse will be symptomatic.

So the utility of imaging is questioned,” he said.

He and colleagues created a decision-analytic Markov model and compared 3 surveillance strategies in 55-year-old patient cohorts: 1) standard follow-up without surveillance imaging; 2) routine follow-up with biannual CT scans for 2 years; or 3) routine follow-up with biannual PET/CT scans for 2 years.

The transition state model used 6-month length cy-

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cles with transition probabilities and clinical utilities derived from published studies. Costs were based on the Medicare fee schedule, and future cost/benefits were discounted at a rate of 3% annually.

“There’s increasing data showing that the majority of patients who have diffuse large B-cell lymphoma who relapse will be symptomatic.” ­ —Scott F. Huntington, MD The baseline model was biased to favor imaging strategies by associating asymptomatic imaging-detected relapses with improved clinical outcome, said Huntington. Quality-adjusted utility, lifetime costs, and incremental cost-effectiveness ratios were calculated for each follow-up strategy.

Conclusions were tested by multiway sensitivity analyses that varied the rate of asymptomatic relapse detection, likelihood of favorable International Prognostic Index (IPI) with asymptomatic relapse, and the impact of IPI on salvage therapy outcome.

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“One trial found that patients with image-detected disease were more likely to have lower IPI scores, so they were basically having more favorable outcomes post-transplant,” he said. “The data from that trial was used to bias toward imaging.”

The benefit of imaging-based follow-up remained small after quality-of-life adjustments. Costs associated with imaging-based surveillance strategies are considerable, and incremental cost-effectiveness ratios were $202,300/quality-adjusted life-year (QALY) for CT strategies and $312,600/QALY for PET/CT strategies. Incremental cost-effectiveness ratios for imaging strategies remained >$100,000/QALY or were dominated by routine follow-up in multiway sensitiv-

ity analyses over clinically relevant ranges.

“The question is if routine surveillance imaging, or serial surveillance imaging, should be used, and there are providers who suggest against surveillance imaging,” Huntington said. “Certainly you want to see patients routinely, every 3 to 6 months, and perform a close history and physical exam because that is actually the majority of relapse—the patient is symptomatic. The patient may have changing symptoms or recurrent night sweats, and we may see new physical exam findings and new laboratory findings.”

“Usually, routine surveillance imaging is not picking up those relapses,” he said. “Even in the best case scenario for the utility of imaging, it’s still not likely to be cost effective.” u

Cancer Patients, By and Large, Not Pursuing Costly, Excessive Tests

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ontrary to belief, there appears to be little demand on the part of cancer patients for unsuitable, high-cost, low-value cancer-related tests or therapies.

Further, oncologists and nurse practitioners are not frequently ordering such services, found Keerthi Gogineni, MD. Data from a survey of oncologists and Keerthi Gogineni, nurse practitioners revealed that “the freMD quency of requested testing was unusual in itself. In only about 9% of 3,800 encounters did a patient ask for something,” she said. “The likelihood of acting on inappropriate requests was even lower. When we asked the providers to rank the appropriateness of that request, it was pretty infrequent that even they thought it was an inappropriate request, and even less likely that they would act on an inappropriate request.”

Contrary to belief, there appears to be little demand from cancer patients for unsuitable cancer-related tests.

Gogineni, a medical oncologist at the Abramson Cancer Center, University of Pennsylvania, Philadelphia, and colleagues assessed whether and how often patients are seeking from their providers expensive or low-value therapies and treatments. Past studies have

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indicated that many patients with cancer, as well as oncologists and the public, believe that health care costs are, to some extent, propelled by patients seeking unneeded treatments, she said.

For the study, oncologists and nurse practitioners at 2 sites affiliated with an academic cancer center were questioned soon after patient visits to measure how often patients demanded potentially unnecessary treatments, whether the demands were acceptable to providers, whether physicians followed through on the requests, and lastly why the providers chose to agree to certain tests.

A total of 2050 encounters were assessed for the study. Of those, 73.1% of patients were white (mean age, 60 years). A total of 42% had stage IV or refractory disease; 66.3% were receiving active therapy, about half of whom (49.5%) had symptom-treating objectives. Twenty-six clinicians were surveyed.

In 8.6% of encounters, patients requested some form of testing (177/2050). Clinicians were recommended to rank the appropriateness of patient requests on a 10-point Likert scale (1 = not at all appropriate; 10 = extremely appropriate). Clinicians viewed requests by patients as inappropriate in just 13.6% of encounters (24/177).

More than 80% of requests were categorized as appropriate. These included requests for imaging, blood work, and pain/nausea treatments. Providers denied patients’ requests in 18.1% of cases (32/177); for 84.4% (27/32) of these instances, physicians reported they declined the test or therapy because they viewed it as

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unnecessary or saw no clinical advantage to doing it. In <1% of cases (4/2,050) would the provider request a test or therapy considered unsuitable.

Patients with early-stage cancers were more likely to make an inappropriate request, said Gogineni. Latestage patients undergoing surveillance were nearly twice as likely to make an inappropriate request compared with those receiving treatment.

Of note, researchers also found that patients who were being treated with a goal to cure were more often

seeking unneeded treatments compared with those who were being treated to comfort for palliative reasons.

To limit low-value care, the researchers suggest educating patients on evidence-based surveillance because patients in the early stages of cancer who are under observation are often more likely to seek out inadvisable treatments or therapies. In this survey, patients undergoing observation were 9 times more likely to make inappropriate requests than those with advanced stages of cancer. u

Are Hospital Readmissions for Cancer Patients Preventable?

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ospital readmissions in cancer patients reflect the high burden of this disease, which is often refractory, and therefore are not reasonably preventable. Consequently, applying readmission penalties to this population, as is being done with noncancer index admissions, is not appropriate, says Andrew S. Epstein, MD. “The vast majority of readmissions in this population do not represent lapses in care, judgment, or discharge management during the index admission, and are not reasonably preventable,” he said.

The Centers for Medicare and Medicaid Services, in an effort to improve patient care and reduce costs, has initiated the Hospital Readmission Reduction Program. This currently applies to certain noncancer index admissions and defines readmission as an admission occurring within 30 days of a discharge. Reimbursement penalties are incurred for readmissions that are deemed preventable.

Cancer readmissions are presently not included in the program, but there is concern among oncologists that these could soon be targeted. Because they have not been extensively evaluated, a study was conducted at Memorial Sloan Kettering Cancer Center (MSKCC), New York City, to determine whether or not cancer readmissions might be reasonably preventable.

From a database of 876 cancer patients who had been discharged and then readmitted within 30 days to the Gastrointestinal Oncology Service of MSKCC, Epstein and colleagues randomly selected 50 cases. The admissions occurred between September 2008 and March 2013. Two study authors manually reviewed each case to assess reasons for index admission and readmission, nature of the index admission discharge plan, and whether the readmission was preventable.

“We were hypothesizing that our patients with this

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disease are so sick and vulnerable that the readmissions are not preventable,” he said.

Andrew S. “Preventable” was defined prestudy as a Epstein, MD readmission that could probably have been avoided by either: 1. Prolonging the index admission until a realistically attainable medical improvement had occurred, or 2. Making agreed upon, practical changes in the index admission discharge plan Cases that were identified as potentially preventable readmissions were then critically reviewed by 3 study authors to determine a consensus.

Of the 50 cases, the most common diagnosis categories for either index admission or readmission were infection, pain, or GI issues. Readmission diagnoses differed from index admission diagnoses in 64% of the cases.

In 5 cases, there was disagreement between the care team and the patient/family about the index admission discharge plan. While this disagreement did not result in preventable readmissions, “it is an extremely important minority of patients to try to deliver care to in the future through…better communication about the risks, benefits, and alternatives of certain treatments or discharge plans,” acknowledged Epstein, assistant attending physician, Division of Gastrointestinal Medical Oncology, Department of Medicine at MSKCC. Review of the records revealed the fragile health and/or refractory admitting diagnoses of all patients.

Diagnoses may have improved or resolved and then recurred despite appropriate treatment, he indicated.

Only 1 readmission of the 50 cases was found to have been preventable. This readmission involved a patient who was discharged with a recommendation for an outpatient procedure that was not scheduled. The find-

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ings indicate that readmissions for cancer patients are not reasonably preventable in the vast majority of cases. In this population, readmissions are common due to the devastating nature of the disease.

“We hope that if cancer patients are ever considered for inclusion under this readmission reduction program, these data would refute the inclination to include them,” he said. u

Ramucirumab Conveys Survival Benefit in NSCLC

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he investigational monoclonal antibody ramucirumab improved overall survival (OS) when added to docetaxel, versus chemotherapy alone, in patients with stage IV non-small cell lung cancer (NSCLC), according to a phase III trial highlighted in a press briefing at ASCO. “This is the first treatment to have shown a Maurice Pérol, MD significant survival advantage over chemotherapy alone in second-line therapy of NSCLC, and the first treatment in approximately a decade to improve outcomes in the second-line setting,” said Maurice Pérol, MD, head of thoracic oncology at Cancer Research Center of Lyon, France.

“This study met the primary endpoint of OS, reducing the risk of death by 14% and prolonging median survival by 1.4 months,” Pérol reported. The combination reduced the risk of progression by 24%.

“Ramucirumab represents a potential new option for treatment in the second-line setting,” Pérol suggested.

Ramucirumab, which recently became FDA-approved for advanced gastric cancer, targets VEGFR-2 and thus blocks the formation of new blood vessels to feed the tumor. If further studies validate these findings and the drug is approved by the FDA, it would be the first antiangiogenic drug approved for second-line NSCLC treatment.

The improvement in survival was demonstrated in patients with both squamous and nonsquamous histology – but the median OS benefit, though statistically significant, was quite modest. Nevertheless, he said the drug could be useful in patients lacking a specific mutation (EGFR, ALK) that would make them candidates for targeted therapy.

In EGFR-mutated patients, the approved second-line chemotherapy includes docetaxel, pemetrexed, and erlotinib and median OS with these agents is 7 to 9 months.

REVEL Details The double-blind, placebo-controlled, phase 3 REVEL trial enrolled 1253 patients with stage IV

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NSCLC (26% with squamous histology) that progressed on standard platinum-based therapy. Patients were randomized to treatment with ramucirumab plus docetaxel or docetaxel plus placebo.

The combination significantly improved response rate (RR), progression-free survival (PFS), and OS compared with docetaxel alone. The median PFS was 4.5 months with the novel agent versus 3 months without (P< 0.0001), and median OS was 10.5 months versus 9.1 months (P=0.0235), respectively.

The safety profile was in line with other angiogenesis inhibitors. No increase in pulmonary hemorrhage was observed with the combination.

Is 1.4 Months Additional Survival Meaningful?

“This combination shows good activity in the difficult-to-treat second-line setting of NSCLC,” said Gregory Masters, MD, of the Helen F. Graham Cancer Center, Newark, DE, who moderated a press conference where these data were presented.

Masters fielded questions regarding the drug’s true value, specifically, whether 1.4 months’ additional survival represented “value,” and especially in light of ASCO’s recent recommendation that new NSCLC treatments (in the first-line setting) extend survival by at least 3 months.

He responded that the drug may be a small step along the pathway that ultimately constitutes improvement. “Progress is slow and step-wise, and we build one step at a time. The cumulative progress is what we find encouraging…A study like REVEL may not change the way we treat NSCLC, but it can influence our design of further studies,” he said, adding that there is a mandate to “balance benefit with cost, and figure out how best to treat patients.”

Don Dizon, MD, of Massachusetts General Hospital, Boston, who represented ASCO at the press briefing, commented that the 3-month OS threshold is “guidance” but is not the “be-all and end-all” for investigational studies. “When we decide that a treatment has value, we consider three key things: efficacy, toxicity, and cost,” he said. u

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ASCO Beginning to Address Value

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SCO is starting to address the issue of value in cancer care, “moving the needle” away from cost, according to Lowell E. Schnipper MD, chair of the ASCO Task Force on Value in Cancer Care, who described ASCO’s aims.

This is not about the absolute dollars expended but what these dollars buy for patients who may be experiencing financial as well as physical toxicity, he said.

The issue is not just about cost, he emphasized. “Cost demeans the purpose for which we are all gathered here, which is to improve patient care,” he said.

He said the task force is focusing on “patient-centeredness.” “We chose not to take a macroeconomic incentive, but to consider the doctor and patient and how they are thinking about the variables that we take into account every day in cancer care,” said Schnipper, the Berenson professor in medicine, Harvard Medical School, Boston.

ASCO’s Statement on Value In Spring 2013, the ASCO Board of Directors engaged in a strategic discussion on value around the following statement: • Increasingly, the desired care for oncology patients will be assessed on the value of that care, rather than the cost • This is an opportune moment for ASCO to take the lead in defining value and suggesting how value should be integrated into treatment decisions Schnipper referred to the concepts put forth by Michael Porter, a leading proponent of healthcare reform: value should be defined around the customer, the creation of value for patients determines “the rewards” for all other actors in the healthcare system, and the success of a value-based treatment is measured through outcomes, not by volume of services delivered.

“Porter makes the point that patient-centeredness is one of the key elements as we think about the value equation,” he said. “It’s appropriate for a physician to use all health-related resources in an appropriate manner that is resource-efficient. This implies doing our best for our patients and understanding that doing so will positively impact the body politic.”

Variables Affecting Value ASCO is now addressing the multiple elements that comprise value: unwanted variation in quality and outcome, harm to patients, waste and failure to maximize value, health inequalities and inequities, and failure to prevent disease. These issues are now being addressed.

The Quality Oncology Practice Initiative (QOPI)

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and CancerLinQ should help reveal the degree of variation in clinical practice, which ties into safety. The task force has identified 5 common practices that are not eviLowell E. dence-based and recommended they not be Schnipper MD routinely used. Experimental models of payment reform are being tested. ASCO is increasingly addressing obesity and tobacco control for cancer prevention.

Creating a Usable Tool for Oncologists The goal of ASCO’s Value Initiative is to create a transparent, clinically driven, methodologically sound method for defining and assessing relative value of cancer care options, which ultimately would “drive change” among payers and industry and encourage the promotion of high-value care, Schnipper said.

“Cost demeans the purpose for which we are all gathered here, which is to improve patient care.” ­ —Lowell E. Schnipper, MD “We want to give oncology providers the skills and tools to assess the relative value of therapies and use these in discussing treatment options with patients,” he said. “And we want patients to have ready access to information that will help them understand the relative value of treatment options that meet their unique needs.”

The tool would describe the different clinical scenarios, treatments, benefits, toxicity, and cost. This information would result in labeling a treatment as having no value, low value, medium value, or high value. In non– small cell lung cancer, for example, the parameters will be entered into a value equation that includes treatment regimen, median overall survival, hazard ratio, progression-free survival, palliative data, time to next treatment, toxicity, and total cost of care.

For example, for the first-line treatment of non–small cell lung cancer, carboplatin/paclitaxel yields a median overall survival of 8.2 months and costs $374; cisplatin/ pemetrexed offers 10.3 months’ survival and costs $6183; paclitaxel/carboplatin/bevacizumab results in a 12.3month survival and costs $8329.

“We are wrestling with data like these to provide a value system that would provide some degree of nuance

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and distinguishability among regimens,” he said. The algorithm would also consider the different toxicity profiles and the treatment setting, as similar degrees of drug-induced toxicity will be viewed differently in early disease versus metastatic disease.

“Ultimately, we hope to finalize a way of quantifying with a numerical score, which ideally would summate to

100,” he said, and would be proportionate to the degree of benefit.

The test will be whether this approach takes hold and develops traction, he added. “As an impartial organization, ASCO is poised to raise these issues and think about the problem. We hope policy makers will pick up on this concept.” u

Site of Service Influences Value

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he growing affiliation of community oncology practices with hospitals and other networks is an obstacle to achieving value in cancer care, according to Lee Newcomer, MD, senior vice president of oncology, women’s health and genetics for UnitedHealthcare.

In an ASCO session on value in cancer Lee Newcomer, care, Newcomer referred to the wide differMD ential between what payers spend for cancer care delivered in freestanding oncology offices, versus what they pay for the same services in the hospital setting.

UnitedHealthcare, he said, pays the Centers for Medicare and Medicaid Services (CMS) rate plus 22% for chemotherapy delivered in the oncologist’s office. Should the same chemotherapy be delivered by the same oncologist practicing in a hospital-owned facility, the company pays the CMS rate plus 146%. “This is 6.6 times more money for exactly the same service,” he noted.

The growing affiliation of community oncology practices with hospitals is an obstacle to achieving value in cancer care.

“Here’s a vivid example,” he continued. “A Midwest practice with a large volume with our insurance company was acquired by a hospital system. Overnight, we had a new fee schedule. The same treatments by the same doctors increased our cost by $5 million a year. This was a single acquisition by a single institution.”

He predicted that employers will react to such changes by mandating substantially higher copays and instituting financial penalties for seeking care in institutions with higher fee schedules in the absence of additional value.

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Not All Hospitals Equally Deserving Under these circumstances, he said it is important to distinguish those institutions that conduct research, and therefore need additional funding, from hospitals without a research mission “but that are simply charging more money and making a profit from the cancer center to support other parts of the hospital,” he said.

The argument put forth by hospitals is that their cancer program funds other departments and services that are not profitable. “But I am wondering if it’s fair to make cancer patients, who are already tremendously burdened by their illness, to pay more money to support something else at the same time,” he said. “I don’t think that’s the right thing to do.”

Newcomer suggested that patients and consumers may inhabit the same body but hold 2 different perspectives on their health insurance. “We have to pay attention to how the consumer thinks, because the consumer is our customer,” he said. “But while a consumer buys a health plan, a patient uses that health plan.”

Patterns of compliance suggest that even when patients derive great value from their plans, they still consider them expensive. “In our specialty pharmacy program for oral drugs, we have increased treatment compliance by 50% through our pharmacy teams, but with only a $50-a-month copay for a drug worth $5000 a month, compliance is still only 58%,” he noted.

“Consumers are saying, ‘We are not sure healthcare is worth spending our money on,’ and that’s concerning to me,” Newcomer remarked.

Perhaps tongue-in-cheek, but provocative, is a plan proposed by some opinion leaders. “The insurer would say to the patient, ‘You now have metastatic disease.

We are about to spend $100,000 taking care of you,’” he said. “‘Should we do that? Or should we just give you the check?’ This would certainly have patients looking at the concept of value more closely than they do today.” u

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Patients Want But Aren’t Getting Up-Front Discussions About the Cost of Their Cancer Therapy

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ost cancer patients want cost-of-treatment discussions. When they do take place, these discussions do not lead to negative feelings in most patients, according to a survey of cancer patients.

Unfortunately, few oncologists participating in a separate survey felt comfortable when discussing cost with patients, found Ronan J. Kelly, MD, and colleagues.

We have demonstrated that patients do want to know the costs of their treatment, and that these costs are not routinely being discussed in academic medicine.

They presented their research during a poster session at the 50th annual meeting of the American Society of Clinical Oncology (ASCO).

“We have demonstrated that patients do want to know the costs of their treatment, and that these costs are not routinely being discussed in academic medicine,” according to Kelly, director of the Gastroesophageal Cancer Therapeutics Program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.

Spending on cancer drugs is projected to increase nearly 40% by 2020, as new cancer diagnoses in the United States continue to increase.

In 2007, the ASCO Cost of Care Task Force recommended that the cost of chemotherapy should be introduced into the patient–physician discussion from the outset, the authors note. It is unknown if these discussions are occurring in academic institutions and what, if any, impact they have on the physician/ patient relationship.

In their study, the National Comprehensive Cancer Network (NCCN) guidelines and the eviti Advisor platform (a digital library of evidence-based standards for cancer care) were jointly used during the physician/ patient consultation to demonstrate treatment options

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and to display the costs at the time of prescribing to providers and patients with advanced or metastatic lung, colorectal, or breast cancer. The consultations took place between February 2013 and October 2013.

Eighteen oncologists were interviewed and 96 of 107 invited patients attending Johns Hopkins participated in the study. More than Ronan J. Kelly, 80% (78/96) responded that it is “quite imMD portant” or “extremely important” for them to know their out-of-pocket costs. More than twothirds, however, have never discussed cost information with their provider.

“Decisional conflict is extremely low by patient report after cost discussions using the eviti Advisor platform, with 81% of patients reporting no negative feelings arising,” according to Kelly.

Only 5 of 18 (28%) oncologists reported feeling comfortable when discussing costs with patients, and only 1 (6%) regularly asked patients about their financial well-being. Despite this lack of comfort, 83% of providers believed that the NCCN guidelines should contain cost information.

A greater emphasis on the shared decisionmaking process involving up-front cost discussions…should empower patients.

Between 2000 and 2010, patient responsibility for the cost of care quadrupled to more than $4000.

“For the first time, we show that there are minimal conflicts and no harm to the doctor-patient relationship when costs are introduced,” notes Kelly. “A greater emphasis on the shared decision-making process involving up-front cost discussions combined with evidence-based outcomes should empower patients to make better educated choices and may ultimately help bend the cost curve downwards.”

“Additional training to prepare clinicians for how to discuss costs with their patients is needed,” he said. u

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Determining the Value of Cancer Therapies: A Paradigm Shift Focused on Quality, Outcomes, and Cost Winston Wong, PharmD

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ccording to the 2013 Annual Report on Progress Against Cancer published in 2014 by the American Society of Clinical Oncology (ASCO), cancer death rates have declined by 21% among men and by 12% among women since the 1990s, and more than 13 million cancer survivors are Winston Wong, alive in the United States today.1 This is in PharmD part thanks to the growing understanding of cancer at the molecular level, which enables the development of new targeted therapies. The question remains, however, at what cost did we achieve these improvements?

The economic environment within the healthcare sector presents challenges from the perspective of all stakeholders. Those stakeholders who are at financial risk for the provision of patient care are facing con-

ASCO announced its effort to develop a working definition of “value” based on clinical benefit, toxicity, and cost of treatment regimens. stant challenges. No other medical specialty is more sensitive to this financial struggle than oncology. The value of technology is more easily understood in some areas of oncology practice, such as genomic profiling.

Genomic profiling provides the oncologist with the necessary information to manage the patient with cancer more effectively, and to select the most appropriate treatment regimens, whether targeted or nontargeted therapies.

Commenting on the recent ASCO annual report, ASCO past president Clifford A. Hudis, MD, chief, Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, New York City, noted, “We are Winston Wong, PharmD, is president of W-Squared Group, Longboat Key, Florida and former associate vice president of pharmacy management, CareFirst BlueCross BlueShield, Baltimore, Maryland.

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witnessing the acceleration of our shift into a new era of medicine in which our knowledge of the molecular basis and activity of cancers leads to ever more precise treatments that offer increased efficacy and reduced toxicities.…Precision medicine is now a reality for an increasing number of patients.”

Thus, genomic profiling provides value in its potential to improve outcomes, improve the patient experience, and reduce healthcare cost. The inefficiency of not being able to administer targeted therapies leads to variability in the clinical outcome, as well as adds unnecessary toxicities to patients, and increases overall care costs to healthcare stakeholders and the entire US healthcare system. The value of these tests remains largely unrecognized by payers.

Personalized medicine, however, comes at a cost.

Discussing the “State of Cancer Care in America: 2014,” Lowell E. Schnipper, MD, chair, ASCO’s Value in Cancer Care Task Force, outlined the goals of the task force, citing the report’s finding that the US annual cost of providing cancer care is projected to reach $173 billion by 2020, representing a 40% increase from 2010.2 Clearly, we cannot sustain this cost trend.

The cost of new treatment regimens is a major contributor to this ever-rising cost trend. Results of a new study presented at ASCO 2014 by Rena Conti, PhD, assistant professor of health policy and economics, University of Chicago, show that even after adjusting for inflation and improved survival, the cost of antineoplastic drug prices has increased 5% to 7% annually between 1995 and 2013 ($1200 vs $9700 monthly).

There is little disagreement by healthcare stakeholders that this cost trend is unsustainable.

According to the World Health Organization, the healthcare costs per capita in the United States are ranked the highest compared with other countries; however, the quality of our healthcare system is ranked number 37 among 191 countries. The reasons for this are beyond the scope of this discussion, but as an industry, we must work to develop a process by which we can evaluate the value of treatment regimens objectively, and with transparency.

The value determination of a treatment regimen

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should be based on clinical efficacy, safety and tolerability, and cost, and should encompass the interests of all stakeholders, including patients, providers, and payers. All too often, one stakeholder significantly influences the treatment decision-making process, frequently with little regard to other stakeholders.

Determining “value” will force us to evaluate treatment regimens in a very different way. By defining value, we will be able to differentiate between regimens that only provide an incremental benefit and those that significantly improve outcomes, as well as taking into consideration the question, “at what cost?”

The question is—how do we define and determine value? Earlier this year, ASCO announced its effort to develop a working definition of “value” based on clinical benefit, toxicity, and cost of treatment regimens.

The goal of that initiative is to develop a standard methodology by which treatment options can be assessed. The goal is that oncologists should be well versed in the methodology of value assessment, and be able to explain and present the value of treatment options to their patients. It is expected that patients will then be able to make an informed decision regarding their treatment direction.

As payers gradually begin to accept this methodology, payers will then be able to assess the value of treatment options from their perspective, through the use of claims data, to help guide their policy decisions and benefit designs. Ideally, upfront collaboration among payers and providers would bring together the clinical

expertise of the oncologist and the utilization and financial data of payers to form the “value score” that could be assessed by the patients.

Collaboration among payers and providers would bring together the clinical expertise of the oncologist and payers to form the “value score” that could be assessed by the patients.

The barriers to success in oncology, as noted by ASCO, include the need to show quality, efficiency, and transparency, and the challenge of addressing the rising costs of new cancer treatments, related tests, and services. Although many in the oncology team would consider these goals lofty, it is a much needed paradigm shift away from focusing on cost alone, and instead refocusing on outcomes, quality, and cost combined. u

References

1. Patel JD, Krilov L, Adams S, et al. Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer from the American Society of Clinical Oncology. J Clin Oncol. 2014;32:129-160.

2. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010–2020. J Natl Cancer Inst. 2011;103:117-128.

Reprinted with permission from Value-Based Cancer Care. © 2014 Engage Healthcare Communications. Wong W. Determining the Value of Cancer Therapies: A Paradigm Shift Focused on Quality, Outcomes, and Cost. VBCC. 2014;5:1.

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THE LAST WORD

The Personalized Medicine Coalition and Turning the Tide Against Cancer Through Sustained Medical Innovation Edward Abrahams, PhD President Personalized Medicine Coalition

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lthough we no longer talk about a â&#x20AC;&#x153;war on cancer,â&#x20AC;? there is one part of the metaphor that remains useful. In a military campaign, we employ multiple weapons against the enemy. So too in our effort to combat cancer, or the over 200 identifiable forms of that disease that will kill more than Edward 600,000 Americans annually, we need to deAbrahams, PhD ploy all the resources at our disposal, just as we would if we were in a war.

That imperative has focused the attention of the Personalized Medicine Coalition (PMC) on the many public policies that can and do either accelerate or impede progress against cancer in addition to increasing funding for basic research.

We have to consider all the multiple variables that determine how quickly the new basic science is translated into better clinical care. Facilitating targeted and more effective cancer treatments depends on it.

If we are serious about taking advantage of the recent breakthroughs in our ability to understand the molecular pathways of cancer as well as the new tools that have been developed to precisely diagnose the disease, we have to consider all the multiple variables that determine how quickly the new basic science is translated into better clinical care. Facilitating targeted and more effective cancer treatments depends on it.

The challenge of sustaining progress against cancer in an era of significant cost constraints has defined our thinking, and shaped an initiative that PMC, together with the American Association for

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Cancer Research and Feinstein Kean Healthcare, calls Turning the Tide Against Cancer Through Sustained Medical Innovation.

Two overarching questions define this initiative.

First, how do we support the ongoing and promising shift away from one-size-fits-all, trial-and-error treatment to patient-centered cancer research and care that rests on the principles of personalized medicine? Issues for consideration include identifying research efforts that generate evidence that leads to better outcomes for patients; increasing patient engagement in value-based decision-making at the point of care; and developing more effective tools for measuring outcomes important to patients.

Second, in a new era of constrained budgets and the escalating price of new cancer drugs, how do we address the issue of the value of research and cancer care? Here the issues for consideration include refining tools for assessing value, especially to the patient but also to the health system generally; what incentives can be put in place to encourage innovation and medical progress; and what kinds of evidence do we need to better inform payment and coverage decisions, including alternative payment models that align with emerging science.

With policy makers, drug developers, payers, physicians, scientists, and patients, PMC, along with its partners, will host a second conference in a continuing series to consider these opportunities and challenges on October 9 at the Knight Conference Center at the Newseum in Washington, DC. In addition to defining the issues, we will also outline a number of policy recommendations for consideration, which we contend can and will make an enormous difference in the future of cancer research and care.

Please join us in Washington on October 9. For more information about the conference or to register, please go to www.turningthetideagainstcancer.org. u

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Dear Physician Colleague...

Your Support Is Critical

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

Lillie D. Shockney, RN, BS, MAS

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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).

OBTAIN CONTINUING EDUCATION through online courses, including navigation basics, implementing a survivorship program, community outreach, personalized medicine, tumor topic–specific programs, best practices, and many more.

RECEIVE A $100 DISCOUNT on registration to the Fifth Annual AONN+ Conference at the Walt Disney World Dolphin Hotel in Orlando, Florida!

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

www.AONNonline.org

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.

SCIENTIFIC CONFERENCES 2014-2015

7th AACR Conference on The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved Co-Chairpersons: Ethan Dmitrovsky, Rick A. Kittles, Electra D. Paskett, and Victoria L. Seewaldt November 9-12, 2014 • San Antonio, TX The 10th Anniversary Personalized Medicine Conference Co-Chairpersons: Raju Kucherlapati and Scott Weiss November 12-13, 2014 • Boston, MA EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics Co-Chairpersons: Jean-Charles Soria, Lee J. Helman, and Jeffrey A. Engelman November 18-21, 2014 • Barcelona, Spain Tumor Immunology: A New Chapter Co-Chairpersons: Robert H. Vonderheide, Nina Bhardwaj, Stanley Riddell, and Cynthia L. Sears December 1-4, 2014 • Orlando, FL 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 Co-Chairpersons: William C. Hahn, Lynda Chin, and William R. Sellers February 7-9, 2015 The Fairmont • San Francisco, CA Computational and Systems Biology of Cancer Co-Chairpersons: Andrea Califano, Brenda Andrews, and Peter Jackson February 8-11, 2015 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

Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers Co-Chairpersons: Rakesh K. Jain, Peter Carmeliet, Helen Chen, Harold F. Dvorak, and Napoleone Ferrara March 5-8, 2015 • Orlando, FL AACR Annual Meeting 2015 Program Committee Chairperson: Lewis C. Cantley April 18-22, 2015 • Philadelphia, PA Advances in Brain Cancer Research Co-Chairpersons: Eric C. Holland, Franziska Michor, Martine F. Roussel, and Michael D. Taylor May 27-30, 2015 • Washington, DC Metabolism and Cancer Co-Chairpersons: Ralph J. DeBerardinis, David M. Sabatini, and Almut Schultze June 7-10, 2015 • Bellevue, WA Cancer Biostatistics Workshop Director: Steven Piantadosi June 7-13, 2015 • Lake Tahoe, CA AACR Precision Medicine Series: Integrating Real-Time Genomics and Cancer Therapy Co-Chairpersons: Charles L. Sawyers, Elaine R. Mardis, and Arul M. Chinnaiyan June 13-16, 2015 • Salt Lake City, UT EACR-AACR-SIC Special Conference Special Conference on Anticancer Drug Action and Drug Resistance: From Cancer Biology to the Clinic Organizing Committee: Moshe Oren, Riccardo Dolcetti, Richard M. Marais, Daniel S. Peeper, Pasi Jänne, Alice T. Shaw, Paola Chiarugi, and Silvia Giordano June 20-23, 2015 • Florence, Italy Pediatric Oncology Co-Chairpersons: Scott Armstrong, Charles G. Mullighan, Kevin M. Shannon, and Kimberly Stegmaier November 9-12, 2015 • Fort Lauderdale, FL Developmental Biology and Cancer Co-Chairpersons: Hans Clevers, Stuart Orkin, Suzanne Baker November 30-December 3, 2015 • Boston, MA