Personalized Medicine in Oncology - October 2014

Unifying Oncologists & Pathologists

A Peer-Reviewed Journal October 2014 • Volume 3 • Number 7

PM O

BIOMARKERS • TARGETED THERAPIES • DIAGNOSTICS

Personalized Medicine in Oncology TM

INTERVIEW WITH THE INNOVATORS Persistence and the Expedition to Mine the Immune System for Cancer Cures: An Interview With Dr James Allison of MD Anderson Cancer Center.......................... Page 366

PROSTATE CANCER Predictors of Hormone Responsiveness in Prostate Cancer............................................. Page 376

BREAST CANCER CME Faculty Perspectives: Latest Treatment Advances for Individualized Care of Breast Cancer....................................................Page 382

WORLD CUTANEOUS MALIGNANCIES CONGRESS Abstracts From the Third Annual WCMC.......Page 394

PMO LIVE Abstracts From the Third Annual PMO Live: A Global Biomarkers Consortium Initiative.... Page 406

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

The official publication of

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

WORLD CUTANEOUS MALIGNANCIES CONGRESS

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

WORLD CUTANEOUS

In partnership with

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

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

RECHARGE THE POSSIBILITIES

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

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

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

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

www.istodax.com

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

15% ~60% 25%

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

9.2 months

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

1.8 months a

(~2 cycles) median time to Objective Response

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

8.3 Nursing Mothers It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

OCTOBER 2014

VOLUME 3, NUMBER 7

TABLE OF CONTENTS INTERVIEW WITH THE INNOVATORS

366

Persistence and the Expedition to Mine the Immune System for Cancer Cures: An Interview With Dr James Allison of MD Anderson Cancer Center

PMO speaks with Dr Allison about the exciting field of immunotherapy and the Moon Shots Program at MD Anderson Cancer Center.

PROSTATE CANCER

376

Predictors of Hormone Responsiveness in Prostate Cancer

Pongwut Danchaivijitr, MD; Saby George, MD The authors conduct a review of existing markers that can potentially predict response to androgen deprivation therapy.

BREAST CANCER CME

382

Faculty Perspectives: Latest Treatment Advances for Individualized Care of Breast Cancer

Lisa A. Carey, MD; Lillie D. Shockney, RN, BS, MAS; Atheer A. Kaddis, PharmD The faculty of this continuing educational activity review emerging data from ASCO and ESMO and discuss the clinical relevance of these advances.

WORLD CUTANEOUS MALIGNANCIES CONGRESS

394

Abstracts From the Third Annual WCMC The WCMC is 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. We offer the abstracts that will be presented at the meeting.

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

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

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PUBLISHING STAFF Senior Vice President/Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Group Director, Sales & Marketing John W. Hennessy jhennessy2@the-lynx-group.com Publisher Russell Hennessy rhennessy@the-lynx-group.com Manager, Client Services Travis Sullivan tsullivan@the-lynx-group.com Editorial Directors Kristin Siyahian ksiyahian@the-lynx-group.com Anne Cooper acooper@the-lynx-group.com Strategic Editor Robert E. Henry Senior Copy Editor BJ Hansen Copy Editor Rosemary Hansen Production Manager Melissa Lawlor 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 Managers Alyson Bruni 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

October 2014

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Vol 3, No 7

The Oncotype DX® assay reveals the unique biology of a tumor, presenting a more complete and individualized picture of the patient’s cancer. It is essential information that can fundamentally change decisions about treatment.

With over 440,000 patients tested worldwide,

the Oncotype DX portfolio—assays for breast, colon, and prostate—is a world leader in applying genomic science to cancer treatment planning.

For more information on using the Oncotype DX assay with appropriate patients, visit OncotypeDX.com/portfolio.

The genomic answer in cancer treatment planning.

Genomic Health and Oncotype DX are registered trademarks of Genomic Health, Inc. © 2014 Genomic Health, Inc. All rights reserved. GHI10330_0414

breast | colon | prostate

OCTOBER 2014

VOLUME 3, NUMBER 7

RegisteR today TABLE OF CONTENTS

M ay 3-6, 2015

(Continued)

PMO LIVE ABSTRACTS

406

Abstracts From the Third Annual PMO Live: A Global Biomarkers Consortium Initiative

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

AnnuAl ConferenCe

TH

AN

AMERICAN SOCIETY FOR RADIATION ONCOLOGY

Novel Treatment-Specific Genetic Marker on the Horizon

RSARY VE NI

409

EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY

410 411 412

Combo of BRAF and MEK Inhibitors Improves Survival in Advanced Melanoma Nivolumab: Impressive Responses in Melanoma Record-Breaking Survival in HER2 Metastatic Breast Cancer

AMERICAN SOCIETY OF CLINICAL ONCOLOGY

414 415

Omni Shoreham Hotel Washington, DC

HER2-Derived Vaccine Cuts Recurrences in High-Risk Breast Cancer LH-RH Agonist Preserves Fertility When Added to Chemotherapy in Younger Breast Cancer Patients

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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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

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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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EDITORIAL BOARD

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

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

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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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

Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona

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

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

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

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio

Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida

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

David Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee

Gregory Kalemkerian, MD University of Michigan Ann Arbor, Michigan

Moshe Talpaz, MD University of Michigan Medical Center Ann Arbor, Michigan

Howard L. Kaufman, MD Rush University Chicago, Illinois

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

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

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

Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington Gene Morse, PharmD University at Buffalo Buffalo, New York

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LETTER TO OUR READERS

Personalized Medicine in Oncology Proudly Presents the Third Annual World Cutaneous Malignancies Congress and PMO Live: A Global Biomarkers Consortium Initiative Dear Colleague,

P Sanjiv S. Agarwala, MD

ersonalized Medicine in Oncology (PMO) is pleased to present the third annual meetings of both the World Cutaneous Malignancies Congress (WCMC) and PMO Live: A Global Biomarkers Consortium Initiative. These will take place consecutively in San Francisco, California, October 29– November 1, 2014.

As Coeditor in Chief of PMO, Conference Chair of the WCMC, and faculty for PMO Live, it is my pleasure to offer information to you about the purpose and benefits of these meetings.

The WCMC was created in light of the astonishing recent advances made in the field of cutaneous malignancies. As an oncologist who treats melanoma, it wasn’t long ago that we did not have many therapeutic options for patients with melanoma, and outcomes were poor. Currently, there is tremendous progress being made and, consequently, much to keep up on. The agenda for the WCMC covers recent advances and includes debates and discussions on controversial topics, extensive panel discussions with case scenarios, multidisciplinary tumor boards, Q&A sessions, as well as translational workshops focusing on future strategies in development for the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, and malignant melanoma. This is the premiere meeting focusing on the optimal treatment of patients with cutaneous malignancies.

Immediately following the WCMC, we are proud to present PMO Live: A Global Biomarkers Consortium Initiative (formally known as the Global Biomarkers Consortium). This meeting is of paramount importance because PMO Live is the educational forum for the genomic era in oncology, addressing precision medicine techniques, biomarkers, pathways, and clinical application across all cancer types.

However, it’s not only about the science and clinical application; part of the mission of PMO Live is to raise awareness among general practitioners, regulatory authorities, and payers to address the myriad of issues brought up by the coming paradigm shift in cancer treatments.

In this issue of PMO, you will find abstracts from each of these meetings. Our December issue will feature summaries, reviews, and case studies from each meeting. For more information, please visit www. cutaneousmalignancies.com and www.pmo-live.com.

Sincerely,

Sanjiv S. Agarwala, MD Coeditor in Chief Personalized Medicine in Oncology

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Committed to Immuno-Oncology Research Dedicated to furthering research in Melanoma Immuno-Oncology research is increasing our understanding of the immune system’s role in fighting cancer, as well as how cancer cells evade recognition and attack.1 Over the past few years, research has significantly deepened our understanding of the body’s immune response to cancer and the role of immunotherapy, particularly in melanoma.2 At Bristol-Myers Squibb, our research has focused on how melanoma cells can escape multiple immune mechanisms to evade the body’s natural response to cancer cells.1 Through our ongoing clinical development programs, we continue to investigate ways to help restore the body’s natural ability to fight melanoma.1,3

Visit us at ImmunoOncology.com References: 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4)12:252-264.

2. Maio M. Melanoma as a model tumour for immuno-oncology. Ann Oncol. 2012;23(suppl 8):viii10-viii14. 3. Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology. 2007;121(1):1-14.

©2014 Bristol-Myers Squibb Company

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INTERVIEW WITH THE INNOVATORS

Persistence and the Expedition to Mine the Immune System for Cancer Cures: An Interview With Dr James Allison of MD Anderson Cancer Center

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he recent triumphant emergence of immuno-oncology as a powerful cancer treatment venue with rich potential has the oncology community’s full attention. While the spell lasts, we do well to learn not only the empirical considerations of this stunning “overnight success after a 30-year quest,” but the underlying principles that sustained it along the James Allison, PhD way. Persistence, indeed tenacity, is essential to the pursuit of cures for anything as deeply complex as cancer. It is the fundamental pillar on which research goals and grand visions depend for the time they need to incubate and mature into substance. Persistence, even more than genius, is the cardinal virtue of medicine, and all stakeholders must practice it: providers, payers, corporate shareholders, research teams, pharmaceutical marketers, accountable care organizations, and, of course, patients, their families, and caregivers.

A talk on the power of persistence was delivered in an arresting, offbeat keynote address delivered at the 2005 Annual Meeting of America’s Health Insurance Plans (AHIP). There a packed hall of 3500 healthcare professionals received the very last analogy they might have expected on medical progress. Celebrity author Malcolm Gladwell, perhaps best known for his bestseller The Tipping Point, made his case for persistence in drug research using the unlikely example of the road to success of...Fleetwood Mac. Yes, Fleetwood Mac. This particular British hippie rock group formed in 1967 and, unlike so many instant apparitions of the British rock invasion that often died out as quickly as they hit the Top 40, Mac underwent years of trial and error before finding its stride, its sound, and its public. The broad applicability of this band’s experience is not fleeting for Gladwell either: he delivered another keynote address adapting its princiDr Allison is professor and chair of The University of Texas MD Anderson Cancer Center Department of Immunology in the Division of Basic Science Research. He directs MD Anderson’s Immunology Platform and is Deputy Director of the David H. Koch Center for Applied Research in Genitourinary Cancers, Department of Genitourinary Medical Oncology Research.

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ples to educational innovation at an annual meeting of the National Educational Computing Conference a few years later. In his AHIP address he showed the length of time for the band to find its identity, leaving a trail of failed albums along the way until they achieved a trademark sound that defined them as an iconic band selling “...more than 100 million albums worldwide, making them one of the best-selling bands of all time.”

Of paramount significance, he remarked, is the contrast between the patience of record corporate leaders then and since. The music corporate culture stayed with Fleetwood Mac as it changed its lineup and its sound, unlike the current recording companies that demand a quick return on investment. This stifles experimentation, and Gladwell observed how this can hollow out medical innovation just as thoroughly as it does musical innovation. The maxim is that those who expect a venture or a great performer to succeed overnight ignore the realities of enterprises of great depth.

Gladwell holds to the premise “…that effort is more important than talent. ‘When we look at people who come to master something...we have a tendency to telescope how long that learning took place – to think that the learning happened overnight.’...In fact, almost every successful individual or organization puts in at least 10,000 hours of practice first, which averages out to about 4 hours a day for 10 years. Successful learning begins not with talent, but with an approach to the task, an approach that says, ‘I believe that my effort is crucial for getting somewhere.’”

Whether or not healthcare researchers pursuing the immune system instead of tumors were listening to Gladwell’s concept, they adopted it. Immuno-oncology has begun to hit its stride, with the journal Science naming it Breakthrough of the Year for 2013. An article this year in BIOtech Now encapsulated the process with its title: “Immuno Oncology – A 30-Year Overnight Success Story.”1 The pattern it chronicled of the pit bull determination in the immuno-oncology epic might have been lifted from Gladwell’s description of Fleetwood Mac’s series of album failures after an initial success, its changing lineup of musicians led by a visionary who needed time to perfect his craft. The BIOtech Now

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article vindicates Gladwell’s hypothesis: “For such a seemingly simple yet powerful idea of using one’s own army of immune cells against tumorous ones, the field has endured countless setbacks….” It progressed, regressed, and emerged triumphant “… from a promising hypothesis to a new modality of cancer treatment of today.”1 Recently, Personalized Medicine in Oncology had the privilege of discussing the journey of immuno-oncology with one of its pioneers: Dr James Allison of The University of Texas MD Anderson Cancer Center. Here he

shares his experience and insights into how this paradigm shift in cancer management is moving forward, what caused its “overnight success” after 30 years of failure, and how it relates to the premises of personalized medicine. The following highlights just begin to shed light on the results of this persistent quest to crack the code of the immune system on behalf of cancer treatment, helping practicing oncologists and indeed the entire spectrum of stakeholders to appreciate the profound changes in expectations for cancer care that this portends.

PMO Thank you for talking with us about the phenomenon of immuno-oncology: a 30-year “overnight success story.” Can you describe its plight and how it finally turned the corner?

Dr Allison There are basically 3 reasons why people for decades have been interested in manipulating the immune system as a means of treating cancer. The first one is specificity. T cells, the part of the immune system we’re talking about today, largely recognize peptides, short bits of proteins that are presented on the surface of cells in the context of structures called MAC antigens.

The immune system is trained to recognize self, so if it’s self-peptides, nothing happens, but if a peptide is recognized as foreign, then the T cell will kill it.

What’s really apparent now due to a lot of recent work is that not only do T cells recognize what used to be called cancer differentiation antigens, but recent evidence suggests that what T cells are recognizing are important molecules called neoantigens that are generated by mutations inherent to the cancer process itself. Cancer is really a disease of genomic instability and results in accumulation of mutations that eventually result in drivers or oncogenes that cause a cell to become a cancer cell. Along the way there are a lot of mutations that really don’t have much functionality in the tumor cell.

The tumor biologists pretty much ignored them for a long time, but those are what the immune system can recognize. Bert Vogelstein and I proposed it about 8 years ago. But now there’s emerging data from a number of labs all over the world that report that’s what T cells really see in cancer cells: these mutant peptides.

So that being the case, the specificity of T cells is for the process that causes cancer itself and not for any particular type of cancer.

The second thing about the immune system is that it has memory. Once you generate a family of T cells that can recognize an individual peptide, their descendants will most likely stay with you for the rest of your life. If you get a flu vaccine or something, you’re protected for

a time until the flu changes, but for a lot of childhood diseases the immunity lasts a long time. No drug can do that. You give the drug and it’s gone after a while, and if it hasn’t taken everything out, it hasn’t worked.

The third thing is adaptability. The immune system is even more adaptable than the cancer cells. The problem with the genomically targeted therapies is the adaptability of the cancer cell. You target one molecule that’s causing the cancer and you can kill all the cells that express that molecule either by mutating that molecule, or by selecting for variants in other molecules that result in activation of a different pathway. The immune system is not fazed by such mutations because it is potentially capable of mounting responses to the products of “passenger” mutations not related to the ones that drive the tumor cells, but also to new antigens generated by the new driver mutations that allow the tumor to escape the original drug and result in resistance.

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There are ways theoretically that tumor cells can protect themselves, but if a patient responds once, they tend to respond again if they need to.

But as the tumor cell changes, the immune system is designed to protect you against virtually anything nature can throw at it, including tumor antigens, mutant peptides, and so there’s really no resistance to immunotherapy. There are ways theoretically that tumor cells can protect themselves, but if a patient responds once, they tend to respond again if they need to.

For these reasons people have been trying to employ immunotherapy for decades, and we’ve known what tumor antigens are for 15 to 20 years now. We know a lot about how the peptides are processed and present on the surface of cells. We know about the features of the innate

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immune system that are required to initiate an immune response. But yet attempts to really mobilize the immune system to protect against cancer have really not been very successful.

I think that’s because we didn’t really recognize how complicated the process is. In the late ’80s when we started our work in this area, it was thought that recognition of antigens was by itself enough. It was thought that recognition of antigens by the T-cell antigen receptor was by itself enough to activate a T cell. But then by the late ’80s it became evident that wasn’t the case, that there was another molecule called a costimulatory molecule that had to be engaged. This costimulatory receptor, called CD28, had to be engaged by structures that are really found only on antigen-presenting cells, so you really need 2 signals: an antigen-specific one and then this costimulatory signal that’s not specific to an antigen.

So it’s sort of like the ignition switch and the gas pedal.

It was thought that the T cells stopped by a process called activation-induced cell death – that after a time they just basically burned themselves out and died.

There was a molecule called CTLA-4 that had been identified in the early ’90s in a lab headed by Pierre Goldstein in France. All that was known about it was that it was expressed in activated T cells but not in resting T cells. But it was highly homologous, structurally very much like CD28, and it was shown that it bound to the same molecules and had the same counterreceptors as CD28. So it was suggested it was another costimulatory molecule. You have to stop immune responses or else they’ll just take over your body, because T cells divide very fast once they are activated. So at the time, it was thought that the T cells stopped by a process called activation-induced cell death – that after a time they just basically burned themselves out and died.

But when we started studying CTLA-4, as did a colleague named Jeffrey Bluestone who was at the University of Chicago at that time, we proposed in the mid ’90s that actually CTLA-4 was not another costimulatory molecule, it was an inhibitory molecule, and its expression was turned on when you tried to activate a T cell.

This was kind of controversial for a while, but finally the data were overwhelming and began to be accepted.

But when we realized this, I had the notion that maybe what was going on with the therapeutic vaccine strategy was that when you try to vaccinate, you give the “on” signal, but also as a result of that, this initiates the ex-

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pression of CTLA-4, which is the brakes, and that the harder you try to give the “on” signal you get an “off” signal, and after a while the cells can’t respond because they just accumulate the CTLA-4, which keeps them from dividing.

That was the idea. The idea was, well, if you just take the brakes off by blocking CTLA-4, then T cells could keep running for a while longer and maybe have enough time to mop up more tumor cells. We showed that in mice and published it. It was first presented in 1995 and then published again in 1996, showing that just injection of monoclonal antibodies specific for this one molecule, CTLA-4, was enough to unleash the immune system in mice to allow it to cause rejection of tumors and also the induction of lifelong immunity to the same tumor.

That was what led to production. We teamed up with a company called Medarex. They made the first fully human monoclonal antibody to CTLA-4 and took it into clinical trials about 2001 and saw responses in metastatic melanoma, even in the phase 1 trial. By 2011, after a number of phase 1/2 trials and finally a randomized placebo-controlled trial in metastatic melanoma, it was shown to increase survival by 4 months.

It was the first drug of any kind that had ever done that in a randomized clinical trial. It was 4 months, and that was enough to get it approved by the FDA. I was shocked because that was what a lot of people paid attention to.

But the really interesting thing about those results was that very often the tumors progressed for a time before they started regressing. The usual way of evaluating cancer drugs is progression-free survival. But tumors have to shrink. The definition of resistance is when the tumor grows in the face of the drug. That happened in many patients and in all of our mice. In every mouse experiment we did, the tumors grew before they went away. By those criteria that we used in the clinic, all of our mouse experiments were failures, even though in many experiments we cured 95% to 100% of the mice.

In any event, because of those complications, Meda­ rex and Bristol-Myers Squibb changed the end point from progression-free survival to overall survival, so the trial took almost 5 years to complete because you just had to measure survival before it could be unblinded. But when the trial was finally unblinded, not only was that 4-month increase in median survival achieved, but there was a tail where at about 2.5 years to 3 years, the survival curve flattened out at 20% and stayed there for 3.5 years, 4 years, 4.5, 5 years. Recently, there was an almost 5000-patient retrospective study of people that had been treated, and what it showed is that after about 3 years patients really don’t succumb to cancer, they succumb to something else, and that’s after a single treatment.

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Then another molecule called PD-1 was identified. It was another immune checkpoint or inhibitory molecule.

A completely independent system, completely different molecule, ligands.

After the success of CTLA-4, there was a big rush to get PD-1 evaluated, and it turned out that it did the same thing. It’s different in some ways. Its ligands are completely different, and one of them can be expressed on tumors, whereas the ligands of CTLA-4 and CD28 are expressed only on antigen-presenting cells.

The PD-1 data were presented in 2012 at ASCO. The PD-1 results showed much the same as CTLA-4. There were a lot of responders: 20% to 30% of patients in many kinds of cancer.

It’s interesting to note that neither of these drugs target the cancer cell at all. They target the immune system, so it’s a completely different way of going about treating cancer, because you basically ignore the cancer.

PMO That’s just amazing, the entire reorientation of the target. What are you after?

Dr Allison We’re not after killing the tumor cells, we’re after unleashing the immune system. My assumption when I started this is taken basically from the immune system’s viewpoint: cancer is cancer. The immune system doesn’t really know or care if it’s melanoma or kidney cancer or lung cancer. It just knows there’s stuff in the cell that ought not to be there.

When PD-1 came along, what became apparent is that some patients who didn’t respond to anti–CTLA-4 did respond to anti–PD-1 and vice versa. Again, PD-1 works differently. Instead of interfering with the costimulatory molecule, what it does is recruit a phosphatase.

It interferes with antigen receptor signaling. In other words, rather than taking the brakes off, it interferes with the ignition switch, if you will. But that being the case, we reasoned that if you put them together, they might work...they’re not redundant. If you put them together, it might be additive. And that proved to be the case.

In data presented at ASCO in 2013, it was a test of the antibodies in combination in metastatic melanoma, and fully 50% of the patients showed tumor shrinkage.

Actually 65% showed some tumor shrinkage; 50% shrunk enough to be objective responses.

There was a follow-up this year at ASCO, a survival study, because those data matured in the combination trial enough to really look at survival. It’s a small-numbers study, but the 1-year survival with the optimum doses of each antibody was 94%, and the 2-year survival was 88%, so almost 9 of 10 patients were alive 2 years after treatment.

Remember, the cutoff with anti–CTLA-4 is 3 years.

Patients that make it 3 years are pretty much done. So

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that number is probably going to drop. It wasn’t a randomized study. It could have been selection, but even so, the number that’s falling out is going to be high.

Anyway, that’s the excitement, and although most of the studies are being done in metastatic melanoma, data are coming along also in lung cancer and in kidney cancer that are very similar, so now the effort is to bring that combination of drugs to many other types of cancer.

Bristol-Myers Squibb is sponsoring a single trial that we’re doing here that targets pancreatic cancer, triple-negative breast cancer, gastric cancer, and small cell lung cancer.

It’s too early to say what’s going to happen, but there’s no reason why there shouldn’t be some success.

PMO That’s extremely promising. Thank you for a very complete answer to the chronology of its pathway to becoming 2013’s breakthrough of the year. With all that potent effect, what is its adverse event profile?

Dr Allison The hope was that the immune system is so precise and specific that there would be no collateral damage, if you will, and all the things would just affect the tumor cells. In fact, in the mouse models that we did, we never saw any adverse events except occasional depigmentation in the mice with melanoma, which was expected. And in the monkey toxicity studies at very high doses, there was also no toxicity observed.

Neither of these drugs target the cancer cell at all. They target the immune system, so it’s a completely different way of going about treating cancer.

But early on one of the concerns was that there are adverse events in people, particularly with anti– CTLA-4: really severe diarrhea. The thing about this is you’re taking the brakes off the immune system. It’s so powerful that it’s too much to hope that that can be done without any bad consequences at all.

That was pretty frightening. With time, algorithms were developed for dealing with this. They involve just systemic administration of steroids. Some version of that can almost always deal with the adverse events, and then you can taper the patients off of the steroids, as the inflammatory responses that are causing the problems don’t come back. So it’s not autoimmunity, and that’s very important, because a lot of people say autoimmunity accompanies this. That’s not really true. That’s very, very rare.

There are other problems to contend with: colitis, uveitis, hepatitis, but they’re almost all reversible. As a consequence of developing algorithms to deal with these adverse events, over time their frequency and severity

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have really decreased. But they aren’t gone. Patients have to be watched.

PMO What is the patients’ health-related quality of life as they’re taking this? How are they feeling?

Dr Allison Initially there’s tiredness. Once the diarrhea or the rash goes away, I think it’s good. I know a number of patients that were treated in the early days who were uncomfortable while they were being treated, but later on they were fine. I think it’s extremely better than the adverse events associated with conventional chemotherapies. It’s not even comparable.

PMO What do you think the long-term overall survival potential is with this approach to treatment?

Dr Allison As I said, in melanoma – and here I’m talking about intent to treat, just some patient that walks in the door that’s healthy enough to receive treatment – I think with metastatic melanoma it’s going to be perhaps as high as 70%. Right now, at 2 years it’s almost 90%. Again, with anti–CTLA-4, with ipilimumab by itself, the long-term survival was roughly 20%. And that’s a study of 5000 patients.

PMO Are we closing in on patients not dying of cancer with this treatment?

Dr Allison Well, I’m not unbiased, but I would say I think we will be able to deal with the majority of patients with metastatic melanoma. I see no inherent reason why that couldn’t be true of other tumor types as well. Lung is going to be the big target, and that’s in process right now. I think there’s reason for a lot of optimism.

With immune therapies you’re not killing the tumor cell directly. What you’re doing is unleashing the immune response.

PMO Can you summarize the basic distinctions between targeted conventional and genomically targeted therapies versus immune therapies?

Dr Allison When you give conventional therapies that kill the tumor cells, the tumors generally start shrinking right away. That’s what the cytotoxic drugs are designed to do, to kill the cell. The same is true for most of the genomically targeted therapies. They shut off the motor that’s driving the cell to be a cancer cell, and if anything keeps growing or if a new tumor forms in the face of it, that drug is not going to stop it.

On the other hand, with immune therapies you’re not killing the tumor cell directly. What you’re doing is unleashing the immune response. There are lots of reasons why the tumors may get larger. One is it may just take time for the immune system to mobilize in sufficient numbers of T cells to actually kill the tumor cells.

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A second thing that has actually been observed is that the tumors swell because they’re filling up with T cells, because T cells go in there and it’s hand-to-hand combat, if you will. When the tumors get bigger, you stick a needle in them, and what you find are activated T cells and a bunch of carcasses of tumor cells. Very often there are no live tumor cells in the biopsy even though the tumor’s gotten bigger. And the same is true if you look at CT scans, and this explains, I think, why the objective response underestimates the survival response. Again, this isn’t like something that goes in and kills the tumor cells and they just go away. This is warfare.

The T cells, while they’re killing the tumor cells, are spitting out inflammatory things like gamma interferon and tumor necrosis factor-alpha (TNF-α), and the cytotoxic T cells are putting out granzyme. So it’s killing cells. It’s low-class warfare, producing a lot of scar tissue that hangs around that the CT scan cannot identify...it simply shows up as a spot on a CT scan.

Allow me to speculate on the other thing that may happen, though I don’t know if it’s been well documented. It’s possible that there is a small sphere of residual tumor cells being kept in check by the immune system, so there could even be some residual tumor cells being held back in a process called equilibrium that Bob Schreiber at Washington University has talked about.

The question is whether the patient has no apparent disease, because many of those patients do have dots on CT scans. But we’re not treating the CT scan, we’re treating the patient. Being alive is more important than having a clean scan, I think.

PMO It’s eminently rational that you would have these carcasses, this debris. It’s the warfare aspect of this.

This is a different kind of war that’s going on.

Dr Allison Again, we’re not directly killing the tumor cells. We tried to do that, but unless you have the immune system involved when you treat with a cytotoxic, whether targeted therapy or otherwise, unless you take out every tumor cell, it’s going to come back. It may be in some cases you don’t have to, because the immune system will catch on and keep it in check, but the whole method of engaging cancer is different.

PMO It certainly is. What is the status of concomitant treatment modalities with this approach? I’m wondering how clear this is going to be at the clinical level, at the practicing level. In other words, when to use it.

There arises the matter of the range of other medications to use or not to use. What gets displaced, what doesn’t get displaced in the treatment?

Dr Allison I think with time a few things will become apparent. One is in addition to CTLA-4/PD-1, there are more of these molecules. A few of them are in clinical development. So it may be that it takes a combination of

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blocking, as the example of blocking CTLA-4 and blocking PD-1 together at the same time is much more effective than either one independently. So it may be that in that last 20% of melanoma or whatever, there may be a third molecule or a third and fourth molecule that’ll work. But maybe that also differs in different tumor types, particularly since many of these T-cell inhibitory molecules have things on them that can bind them, and so that could play a role. I don’t see why it shouldn’t. I mean, this really is personalized medicine, right? It’s your immune system. It’s educated to recognize your normal cells and protect your cells against something, so it’s personalized medicine of the highest order.

It would be ridiculous to say for that reason that it’s going to replace targeted therapies, but there is one place where I think it will continue to be used. We’ve been talking up until now about just giving these immune checkpoint blockers without anything else. These incredible responses have been seen in many kinds of cancer. My own feeling, understanding the mechanism, is that they all work on T cells that have been primed, and so when you give these by themselves, there’s got to be tumor death coming from someplace. It may just be that every now and then some tumor lesion gets so big that it cuts off food supply or oxygen supply or something and starts dying, and that causes inflammation and alerts the immune system to come in and respond to bits of tumor that are being dumped out. But if you can make that happen, if you could kill tumor cells, I think you could start everything faster and get responses in a much higher fraction of patients.

I think if you’ve got non–small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation that’s driving it, which is very common, and there are drugs that can work through that mutant EGFR that cause amazing tumor shrinkage very quickly but only last a few months for the reasons I mentioned earlier, the tumor cells can adapt and become resistant. But you could really amplify the effectiveness of those drugs, I think, and we’ve done this a bit in mice, by initially coming in with that genomically targeted agent against NSCLC, for example – something that kills, that works through that molecule and kills tumor cells and then immediately follow that with the immune therapies.

Of course, in the case of metastatic melanoma, vemurafenib is a drug that targets the BRAF mutation that’s found in about 60% of people with melanoma. Again, it’s short-lived, but already the response rate with a combination of anti–CTLA-4 and anti–PD-1 is higher than the response rate to vemurafenib.

I think some of these targeted therapies are going to fade.

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PMO When you treat patients for autoimmune adverse events of the new immuno-oncology drugs, does the treatment, like steroids, nullify the positive effects of the immunotherapy?

Dr Allison The treatment with steroids to alleviate the adverse events surprisingly enough does not interfere with the antitumor effects, at least if it occurs late. Let’s turn that around. There are still plenty of responses in patients that have received steroids. It may be because the cells that are responding to the tumor cells may already have been primed. Memory T cells are resistant to the effects of steroids, so it may just be that. Anyway, they don’t seem to interfere much.

It’s your immune system. It’s educated to recognize your normal cells and protect your cells against something, so it’s personalized medicine of the highest order.

PMO Why is retreatment with immunotherapy often effective, but retreatment with chemotherapy and nonimmunotherapy, targeted therapy, seldom effective?

Dr Allison The reason that tumor cells become resistant or don’t respond after they become resistant to chemotherapy and targeted therapies is the tumor cell has figured out how to evade.

PMO That memory you talked about before?

Dr Allison In the immune system you’ve got memory, but also if the tumor changes by a process involving generation of new mutations, that makes the initial drug ineffective. The immune system can respond to the mutation itself, whatever it’s in. The immune system is designed to protect you against anything nature throws at it.

The antigen receptors on T cells are generated by a fairly random process and then selected to not attack anything that’s in your normal cells. It’s pretty effective, because other immune diseases are pretty rare. It’s been estimated that as many as 1015 different antigen receptors can be generated by the immune system. That’s billions of times more than the total number of cells in anybody’s body, and it can change because it’s an ongoing process.

You’ve got probably 100 million different T-cell receptors in your body. A set of them gets activated to a tumor and then the tumor changes and something new comes up, and some different T cells will just move in. The immune system is even more plastic, even more adaptable than the tumors.

PMO Why do certain cancer cells survive initial treatment?

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Dr Allison It’s possible that there are certain molecules that are involved in expression of antigens on the cell surface. If there are mutations in those, then the tumor cells lose the ability to present the targets that T cells would recognize. That so far has not proven to be an issue in these sorts of treatments, as far as I know. You can select for mutations, for example, that would make a tumor cell resistant to killing by gamma interferon.

Gamma interferon binds to receptors on cells and activates a chain of signals down to the cell that says, “Kill it.” And if you have a mutation anywhere in the tumor cell, anywhere in that pathway, then that mechanism of killing, for example, becomes ineffective. That has been observed, but that’s also rare.

Nobody saying “Let’s treat cancer” would ever have taken a look at CTLA-4. It just wouldn’t happen then because the knowledge wasn’t there.

But those are describing ways that individual tumor cells might escape. I think a bigger question is, why do some patients with cancer respond and some don’t? We don’t really have a good answer for that. It may be that some tumor cells express multiple checkpoint molecules, and you have to block them all. Or maybe the T cells just aren’t being effectively primed. If that’s the case, then you can take care of that by just adding a cytotoxic genomically targeted drug along with immunotherapy.

I think the answer to the question of why some patients don’t respond really lies in combination therapies.

I’m an optimist and not unbiased about the power of the immune system, but I think our experience in mice has shown that we have rarely, if ever, found a tumor model that we couldn’t selectively attack by using the appropriate combination of agents.

PMO Introductory statements to an article in the November 16, 2012, issue of Nature Immunology state: “Immunology beats cancer: a blueprint for successful translation.” It goes on to say, “Immunology offers an unprecedented opportunity for the science-driven development of therapeutics. The successes of antibodies to the immunomodulatory receptor CTLA-4 and blockade of the immunoinhibitory receptor PD-1 in cancer immunotherapy, from gene discovery to patient benefit, have created a paradigm for driving such endeavors.” I’d like your thoughts on whether that is going to clear things up for everybody? Is this a good way to encapsulate the concept, or would you state it differently?

Dr Allison I think that’s right on. Let’s back up a bit

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– early on, people were just saying, let’s get the immune system, let’s do this, we’ll activate it this way, we’ll activate it that way, we’ll activate it the other way, let’s throw IL-2 at the tumors, whatever. None of those early attempts at immunotherapy were really based on understanding of mechanisms, whereas CTLA-4 is a case in point. Nobody really understood what it did until Jeff Bluestone’s lab and mine said this is a negative regulator, and once we saw that, we asked, are there really enhanced immune responses if you take the brakes off? So we said okay, here’s 1 molecule. Let’s take it off. Actually, I was astounded when we saw what happened in mice with just 1 molecule blocked, and it was enough in many, many mouse models to get tumors to shrink and get long-lived immunity. So it came out of mechanistic studies. Nobody saying “Let’s treat cancer” would ever have taken a look at CTLA-4. It just wouldn’t happen then because the knowledge wasn’t there.

There was such a rush. In the clinic people didn’t really pay all that much attention to mechanism, so mouse models in my lab and other ones were doing it, and that provided the rational basis. I’m sure PD-1 blockade and CTLA-4 blockade together would have come about anyway, but we provided a mechanistic reason for understanding why those two were so good together...and that was from mouse studies.

I think in the future what we’ve got to do is really study patients. So that’s what we’re doing here in the immunotherapy platform as part of the Moon Shots Program at MD Anderson. A colleague of mine at MD Anderson named Dr Padmanee Sharma is a clinical oncologist that specializes in urinary cancers. And she was interested not so much in clinical response, although that’s what you’re after, but in understanding the cellular molecular mechanism. So what she pioneered is something that we’re following now as we can, and that’s treating patients who are going to surgery. It’s hard to learn a lot from a biopsy specimen, although it’s better than nothing. But if you really want to understand what’s happening and get enough T cells out to understand not only their phenotype but their function, you must treat a patient and then get the whole organ with the normal tissue, the tumor tissue, etc, and see the impact of the drug. This is what she’s done now in bladder cancer and in prostate cancer.

When you do these things along with mouse studies, you can get data from the patients that allow you to generate hypotheses, and you can then test them using the mouse models where you have genetically modified mice in which you think a given molecule is important, so you can see how well the drug works when that molecule isn’t around.

Here’s a case in point. Dr Sharma treated bladder and

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prostate cancer patients with anti–CTLA-4, and these were patients with localized disease, and these are small trials, 10- to 12-patient trials. Every single patient showed a several-fold elevation of a kind of T cell called an ICOS-positive T cell – which stands for inducible costimulator. ICOS is another molecule in the CD28, CTLA-4 family, but it’s distinct and has its own ligands and everything. At any rate, you wouldn’t expect to find T cells expressing that in tumors, because they make the wrong kind of cytokines. You want a T cell in a tumor to make gamma interferon and TNF-α. This happened in all her patients, and so it serves as a good pharmacodynamic model for CTLA-4 therapy, because if you give the drug and you don’t see these cells, that means it’s probably not going to work and maybe something’s wrong with the patient’s immune system.

We did a collaborative study – her studies were done in patients with localized disease. But when I was still at Memorial Sloan Kettering with Dr Jedd Wolchok, Dr Sharma told us about this, so then we looked at melanoma patients. It turned out you could divide melanoma patients into patients in which ICOS increased and stayed increased for the whole 3 months of therapy.

Standard anti–CTLA-4 treatment is 4 doses at 3-week intervals. The frequency of T cells expressing the ICOS molecule went up at least 2-fold and stayed there for the 3 months of treatment, and then there were others that didn’t. So if you divided those and asked how long they lived, it turns out the median survival of the patients in whom that frequency did not increase, or only went up a little bit and then came back down, was about 8 months.

In the patients in whom it went up and stayed up for 12 weeks, the median survival was 20 months. That’s not going to tell you who’s going to respond and who’s not going to respond prior to treatment, because this only happens after treatment. It may tell you who’s not going to respond, though, because if it doesn’t increase, the chances of anything happening are not good in that study. There need to be more numbers.

That leads to the hypothesis that ICOS might be important in the therapeutic effect of anti–CTLA-4. So you can make that hypothesis, except in clinical data you could also say well, maybe the patients in whom it didn’t go up, they’ve just been treated so much with chemotherapies and whatever that their immune system was beaten up and was nonresponsive.

So you can’t answer that question, you can’t distinguish between those 2 possibilities really in patients.

What Dr Sharma did with our help was to study the efficacy of anti–CTLA-4 in mice that genetically lacked ICOS. What she found is that the anti–CTLA-4 treatment only worked about half as well or less in mice that lacked ICOS. So that now gives us not only a pharmaco-

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dynamic marker but tells us that this is important in the function. Now ICOS is a costimulatory molecule, so a signal through it will help an immune response.

So this experience raises the possibility that if you block CTLA-4, then you see these ICOS-positive cells appear and you didn’t give a signal through the ICOS molecule, the anti–CTLA-4 might work a lot better; and indeed that’s the case. In mice we showed that if you give an ICOS signal while you’re blocking CTLA-4, it increases the efficacy by at least 4-fold. We recently published this in the Journal of Experimental Medicine.

In any event, this can lead to a whole new way of treating cancer where you combine blocking negative signals with giving positive signals, all targeting the immune cells, not the cancer cell. That’s where we’re going with this research: to really understand the mechanism in the patients. Confirm it in mouse models and then take you to the next level. That sort of paradigm is what I think that sentence that you read is talking about, about developing a drug that targets ICOS.

...a new way of treating cancer where you combine blocking negative signals with giving positive signals, all targeting the immune cells, not the cancer cell.

PMO You are bringing this new strategy into focus, not only for the researchers, but the oncologists in the trenches too.

Dr Allison What’s apparent now, and I think is probably the reason for this discussion, is that if you go to a major medical center and you have metastatic melanoma, you’re most certainly going to get anti–CTLA-4, or ipilimumab, and increasingly 1 of the 6 anti–PD-1 targeting agents that are out there. It’s really slow to make it into the community.

PMO Yes, the diffusion of this knowledge is critical.

Dr Allison Right, and I think in part that’s because of lack of understanding of the adverse events and others.

PMO Yes, addressing the full array of facets of this thing called immuno-oncology will require extensive drilling down into its components and its value. We could not have asked for a better introduction into the topic than what you have provided us here today. Thank you for this outstanding contribution to our knowledge of this paradigm shift in the making.

Dr Allison It was my pleasure. u

Reference

1. Avery M. Immuno Oncology: A 30-Year Overnight Success Story. BIOtechNOW. February 20, 2014. www.biotech-now.org/health/2014/02/immuno-oncology-a30-year-overnight-success-story#. Accessed August 24, 2014.

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THIRD ANNUAL

WORLD CUTANEOUS MALIGNANCIES CONGRESS

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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

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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

PROSTATE CANCER

Predictors of Hormone Responsiveness in Prostate Cancer Pongwut Danchaivijitr, MD Saby George, MD Roswell Park Cancer Institute, Buffalo, New York

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rostate cancer is the most common noncutaneous cancer in men and the second most common cause of cancer-related death.1 Normal prostate cells and prostate cancer cells require the presence of androgen for growth and survival. In Pongwut advanced prostate cancer, androgen Danchaivijitr, MD deprivation therapy (ADT), medically or surgically, has been the mainstay. Initially, androgen-sensitive prostate cancer cells stop dividing and undergo apoptosis. Eventually, some cells evolve to become castration-resistant prostate cancer (CRPC).2 Once CRPC develops, treatment options are limited along Saby George, MD with shortened overall survival (OS).

To date, despite extensive research, there is no clinically meaningful predictive biomarker available for selecting treatment for prostate cancer.

Here we conduct a review of existing markers that can potentially predict response to ADT.

Gleason Score The Gleason score (GS) grading system is a dominant prognostic factor for both localized and metastatic prostate cancer, both hormone-sensitive and castration-resistant disease, and an independent predictor of duration of hormone sensitivity.3-10 Traditionally, GS is classified homogenously into low/intermediate risk (GS ≤7) and high risk (GS ≥8). Rusthoven et al collected data through the Surveillance, Epidemiology, and End Results database to assess outcomes of prostate cancer Dr Danchaivijitr is a Hematology/Oncology Fellow at Roswell Park Cancer Institute. His clinical interests are genitourinary cancer and new drug developments.

Dr George is a Medical Oncologist, Assistant Professor of Medicine and Oncology at Roswell Park Cancer Institute. He is a clinical/translational investigator with focus on prostate and kidney cancer. His interests include aggressive variants of prostate cancer and developing novel treatment strategies in both prostate and kidney cancer.

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KEY POINTS In the genomic era, more genetic variants could be discovered and incorporated into the prognostic/ predictive model along with traditional biomarkers ➤ Currently the only “biomarker-guided” strategy for advanced prostate cancer treatment is up-front androgen deprivation therapy ➤ Developing strategies to identify tumors that would respond to first-line and second-line hormonal manipulations would allow for the appropriate early use of cytotoxic agents in the other group of patients ➤ With appropriate early application of cytotoxic agents in the adjuvant or neoadjuvant setting, we could see higher rates of cures in this disease in the near future ➤

based on GS. ADT was utilized in a majority of patients.

At 4 years of follow-up, there were highly significant differences between GS 7 versus 8, 8 versus 9, and 9 versus 10 (all P<.001) in multivariate analysis for both OS and prostate cancer–specific survival. Gleason pattern of 5 in GS of 6 to 10 was an independent poor prognostic factor.11 Benaim et al conducted a retrospective study in 150 patients with advanced prostate cancer treated with ADT. A GS of 8 to 10 was also associated with shorter response to ADT in metastatic hormone-sensitive prostate cancer.9

Minor Histologic Subtypes Adenocarcinoma comprises more than 95% of prostate cancer. Most prostate cancer treatment studies are based on adenocarcinoma histologic subtype. Minor histologic subtypes include neuroendocrine (small cell) carcinoma, transitional cell carcinoma, ductal prostate cancer, basal cell carcinoma, carcinosarcoma, and stromal sarcoma. These usually do not respond to ADT and are characterized by rapid clinical progression. Most patients die within 2 years despite aggressive chemotherapeutic regimens. Neuroendocrine carcinoma is one of the most common of the minor subtypes and can

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present as a primary tumor or transformed after ADT. These correlate with poor prognosis due to activation of multiple signaling pathways and lack of androgen receptor.12-14 These subtypes are usually associated with relatively lower prostate-specific antigen (PSA) values despite the presence of distant metastatic disease.

PSA and PSA Kinetics PSA is the most utilized biomarker to diagnose, classify risk, and monitor treatment response of prostate cancer. It could also serve as a predictive marker for duration of response after ADT.15 Data from Southwest Oncology Group Trial 9346 (SWOG 9346, INT-0162) demonstrated that patients who achieved PSA nadir (<0.2 ng/mL) at 7 months after ADT had significantly better OS compared with patients who did not (hazard ratio [HR] 0.17; P<.0001). Patients who achieved a PSA between 0.2 and 4.0 ng/mL also had significantly better OS (HR 0.30; P<.0001).16 Sasaki et al conducted a study of primary continuous ADT in patients with bone metastasis. Patients who achieved PSA nadir (<0.2 ng/mL) had a significantly longer OS (HR 3.73; P=.003). Time to nadir (TTN) PSA was also a good predictive marker for disease progression. In the same study, TTN >9 months was associated with increased OS compared with TTN <9 months both in patients who achieved PSA nadir and those who did not.17 Many studies have reported different significant PSA nadir and TTN to predict OS18,19 and androgen-independent progression.20,21 PSA nadir <0.1 ng/mL was shown to be a predictive marker for better response and delayed development of CRPC in intermittent ADT.22 To date, there is no optimal PSA nadir or TTN cutoff after ADT to predict OS. In general, we believe that rapid PSA reduction correlates with more prostate cancer cell death, a longer remission period, and increased OS. Many studies have shown that longer TTN correlates with longer OS. The possible explanation is tumor heterogeneity which contains a large number of PSA producing CRPC, which was initially suppressed with ADT then a subset of aggressive cancer cells regrow rapidly in low androgen environment.18,23 This knowledge could be used to select second-line hormonal manipulations versus chemotherapies.

Androgen, Androgen Receptor, and AndrogenResponsive Elements Androgen is the main driver of prostate cancer cell growth. Measuring 6-month post-ADT testosterone level showed a positive correlation with survival along with GS and 6-month post-ADT PSA.24 However, the adrenal gland produces androgens, which could contribute to prostate cancer cell growth after initiating ADT.25

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In a later stage, the prostate cancer cell can produce androgen intracellularly and stimulate cell proliferation.

Measuring intratumoral androgen could be a potential marker of response, but data have been inconsistent.26,27 To date, there is no recommendation for using the androgen level to measure response to second-line hormonal manipulation.

Unlike breast cancer, in which the estrogen receptor has been well established as a prognostic and predictive marker, the androgen receptor (AR) in prostate cancer has not been validated in large studies to be a predictive marker of ADT. AR expression was uniformly positive in all pretreated prostate cancer but was lost in CRPC and more frequently lost in neuroendocrine-differentiated cancer cells.28 In pretreated patients, high AR content is a favorable prognostic factor29 and predictor of response.30 It was also demonstrated that lower GS cancer cells have a higher level of AR expression.29 The same study also showed that patients with tumors that had more than 48% AR-expressing cells had a better outcome. This clearly demonstrates that there is cell

The adrenal gland produces androgens, which could contribute to prostate cancer cell growth after initiating ADT. heterogeneity in a tumor that may have higher-grade (low AR-expressing) and lower-grade (high AR-expressing) elements. This leads to the hypothesis that the higher the percentage of high-grade cells in a tumor (which are essentially less sensitive to hormonal manipulation by ADT), the faster that tumor becomes castration resistant.

However, Sun et al studied variations of AR and estrogen receptor alpha and beta by using single nucleotide polymorphisms (SNPs), and results showed that common genetic variations were not associated with aggressiveness and response to ADT.31 AR expression and function can be changed over the course of treatment. In post-ADT, resistant mechanisms develop as follows: 1. Increased AR gene amplification: Tumor adapts to grow in a low androgen state and up-regulates AR by gene amplification, especially a tumor that has initially responded well to ADT and has a response duration of more than 12 months.32,33 2. AR gene mutations: This mechanism helps prostate cancer cells evade ADT. Mutation occurs in multiple sites of AR gene.34,35 Mutated AR can be activated by many types of hormonal agonists/antagonists or even the absence of steroid.35,36

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Androgen-Responsive Elements (AREs): After Androgen Binds to AR The androgen/AR complex binds to a specific promoter region of AREs in order to regulate gene expression and cell growth.37 Huang et al studied 55 common SNPs within AREs in 601 patients treated with ADT. After multivariate analysis, FBOX32 rs7830622 (HR 1.69; P=.004) and FLT1 rs9508016 (HR 1.52; P=.028) remained as significant predictive factors for all-cause mortality. Combination of SNPs showed a higher HR of 3.33, P<.001. However, this study was conducted in a Chinese population.38 Bao et al studied 19 prostate cancer variants in the same patient cohort. After multivariate analysis, rs16901979 remained a significant predictor for prostate cancer–specific mortality (HR 0.58; P=.002)

The androgen/AR complex binds to a specific promoter region of AREs in order to regulate gene expression and cell growth. and all-cause mortality (HR 0.64; P=.002).39 These results suggest that an integrated conventional and genetic variant predictive model can accurately predict outcome of prostate cancer patients receiving ADT. Once a patient is diagnosed as having CRPC, abiraterone and enzalutamide are approved agents for treatment in the pre- and post-docetaxel setting. Antonarakis et al studied androgen-receptor isoform encoded by splice variant 7 (AR-V7) in circulating tumor cells, which lack a ligand-binding domain but has an active transcription factor. Patients who had positive

AR-V7 had a poor PSA response to both abiraterone and enzalutamide compared with patients with negative AR-V7 (0% vs 68%; P=.004, and 0% vs 53%; P=.004, respectively). These findings translate into shorter progression-free survival and OS in both groups.40 However, this study was done in a small patient population and requires a larger-scale prospective validation.

Circulating Tumor Cells Initially, circulating tumor cells (CTCs) were utilized as a prognostic and predictive marker in mCRPC after chemotherapy. Patients who had CTC ≥5 cells/7.5 mL of blood had significantly poorer prognosis (median OS 11.5 vs 21.7 months; P<.001).41 Patients who had CTC <5 cells/7.5 mL after chemotherapy demonstrated an increased median survival of 20.7 months versus 9.5 months for patients whose CTC did not decline. Okegawa et al conducted a single-institution study in treatment-naive metastatic prostate cancer in Japan that showed CTC ≥5 cells/7.5 mL of blood was associated with a shorter androgen responsiveness time of 17 months compared with 32 months in patients with CTC <5 cells/7.5 mL.42 Goodman Jr et al conducted a prospective study in 33 treatment-naive metastatic prostate cancer patients in a western population. After multivariate analysis, baseline CTC remained an independent predictive marker for duration and depth of responsiveness to ADT. This study also suggested a CTC cutpoint of 3 cells/7.5 mL of blood instead of the traditional 5 cells/7.5 mL of blood in a treatment-naive group in order to maximize a predictive value. However, this was a very small patient cohort, and more prospective studies are needed to validate this finding.43

Proposed Algorithm for Systemic Therapy Considerations

Gleason Score 7 (3+4)

ADT Followed by Second-Line Therapies

Gleason Score 8-10 and (4+3 with tertiary 5 pattern)

ADT + Chemotherapy as First-Line Treatment. Then Second-Line Strategies.

Adenocarcinoma

Metastatic Prostate Cancer

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Neuroendocrine

Chemotherapy

Other Histologic Subtypes

Chemotherapy vs Clinical Trial

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The androgen signaling pathway was also studied in CTC. After selective candidate gene products, PSA and prostate-specific membrane antigen remained markers consistently up-regulated following AR activation and AR suppression, respectively.44 Miyamoto et al studied an androgen signaling pattern using a combination of these markers in both treatment-naive and CRPC patients. Results showed that the androgen signaling pathway was uniformly expressed in treatment-naive patients and heterogeneously expressed in CRPC patients, likely due to acquired resistance, which led to inconsistent response to ADT. However, active AR signaling during a treatment with abiraterone was also associated with poor treatment outcome.45

Germline Mutation Due to insufficient predictive factors for ADT responsiveness, genetic variations were studied using SNPs. Yang et al studied androgen transporter genes in 538 patients receiving ADT. Patients who carried SLCO2B1 and SLCO2B3 genotypes had a significantly shorter time to progression on ADT.46 Kohli et al studied germline mutations associated with sex steroid biosynthesis and metabolisms using a total of 746 SNPs in 304 patients with advanced prostate cancer receiving ADT. After multivariate analysis and censor for false discovery rates of 0.10 or more, 2 of the 4 TRMT11tagged SNPs (rs1268121 and rs6900796) were found to be associated with time to ADT failure.47 Fraga et al studied variants of hypoxia-inducible factor 1 alpha (HIF1A), which regulates cellular response to hypoxia and induces cancer progression, in 754 prostate cancer patients. Results showed that patients who carried the HIF1A +1722 T-allele had an increased risk for developing resistance to ADT after multivariate analysis (odds ratio [OR] 6.0; P=.001) and for developing distant metastasis (OR 2.0; P=.027).48 Conclusion Prostate cancer usually has heterogeneity in the cells that comprise the tumor. Although many biomarkers have been studied, none has been validated in a prospective fashion. In the genomic era, with the assistance of high-throughput sequencing and data management, more genetic variants could be discovered and incorporated into the prognostic/predictive model along with traditional biomarkers. So far, there is no biomarkerguided strategy for advanced prostate cancer treatment except up-front ADT. Data suggest that lower GS cancers tend to express more AR and thus may be associated with better outcomes from hormone manipulation.

Higher GS cancers tend to express lower AR and are thus less amenable to a good outcome. This is consistent

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with the outcome strictly based on the biology/morphology of the disease. This is substantiated by the recently reported ECOG-3805 trial by Sweeney et al that demonstrated a significant survival advantage to applying docetaxel up-front with ADT in hormone-sensitive metastatic prostate cancer when compared with ADT alone (HR 0.61; median OS 57.6 vs 44 months; P=.0003).49 There is an unmet need to develop strategies to identify the tumors that would respond to first-line and second-line hormonal manipulations for long periods. This would also allow for the appropriate early use of cytotoxic agents in the other group of patients. The aggressive cancer cells tend to be of Gleason grades 4 and 5 pattern and the unusual histologies per the available data. Despite that knowledge, there is a lack of enthusiasm to apply cytotoxic chemotherapies up-front in those patients with high-grade disease, especially when the tumor volume is low. If high-grade elements could be eliminated by early application of cytotoxic agents in the adjuvant or neoadjuvant setting, we could see higher rates of cures in this disease in the near future. u

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14. Nakada SY, di Santâ&#x20AC;&#x2122;Agnese PA, Moynes RA, et al. The androgen receptor status of neuroendocrine cells in human benign and malignant prostatic tissue. Cancer Res. 1993;53:1967-1970.

15. Oosterlinck W, Mattelaer J, Derde MP, et al. Prognostic factors in advanced prostatic carcinoma treated with total androgen blockade. Flutamide with orchiectomy or with LHRH analogues. A Belgian multicentric study of 546 patients. Acta Urol Belg. 1995;63:1-9.

16. Hussain M, Tangen CM, Higano C, et al. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT0162). J Clin Oncol. 2006;24:3984-3990.

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17. Sasaki T, Onishi T, Hoshina A. Nadir PSA level and time to PSA nadir following primary androgen deprivation therapy are the early survival predictors for prostate cancer patients with bone metastasis. Prostate Cancer Prostatic Dis. 2011;14:248252.

18. Choueiri TK, Xie W, D’Amico AV, et al. Time to prostate-specific antigen nadir independently predicts overall survival in patients who have metastatic hormone-sensitive prostate cancer treated with androgen-deprivation therapy. Cancer.

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19. Tomioka S, Shimbo M, Amiya Y, et al. Outcome of patients with hormonerefractory prostate cancer: prognostic significance of prostate-specific antigendoubling time and nadir prostate-specific antigen. Jpn J Clin Oncol. 2008;38:36-42.

20. Kwak C, Jeong SJ, Park MS, et al. Prognostic significance of the nadir prostate specific antigen level after hormone therapy for prostate cancer. J Urol. 2002;168:9951000.

21. Morote J, Esquena S, Abascal JM, et al. Usefulness of prostate-specific antigen nadir as predictor of androgen-independent progression of metastatic prostate cancer. Int J Biol Markers. 2005;20:209-216.

22. Sciarra A, Cattarino S, Gentilucci A, et al. Predictors for response to intermittent androgen deprivation (IAD) in prostate cancer cases with biochemical progression after surgery. Urol Oncol. 2013;31:607-614.

23. Hori S, Jabbar T, Kachroo N, et al. Outcomes and predictive factors for biochemical relapse following primary androgen deprivation therapy in men with bone scan negative prostate cancer. J Cancer Res Clin Oncol. 2011;137:235-241.

24. Perachino M, Cavalli V, Bravi F. Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: prognostic significance? BJU Int. 2010;105:648-651.

25. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol.

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26. van der Sluis TM, Vis AN, van Moorselaar RJ, et al. Intraprostatic testosterone and dihydrotestosterone. Part I: concentrations and methods of determination in men with benign prostatic hyperplasia and prostate cancer. BJU Int. 2012;109:176-182.

27. van der Sluis TM, Meuleman EJ, van Moorselaar RJ, et al. Intraprostatic testosterone and dihydrotestosterone. Part II: concentrations after androgen hormonal manipulation in men with benign prostatic hyperplasia and prostate cancer. BJU Int. 2012;109:183-188.

28. Komiya A, Yasuda K, Watanabe A, et al. The prognostic significance of loss of the androgen receptor and neuroendocrine differentiation in prostate biopsy specimens among castration-resistant prostate cancer patients. Mol Clin Oncol.

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29. Takeda H, Akakura K, Masai M, et al. Androgen receptor content of prostate carcinoma cells estimated by immunohistochemistry is related to prognosis of patients with stage D2 prostate carcinoma. Cancer. 1996;77:934-940.

30. Trachtenberg J, Walsh PC. Correlation of prostatic nuclear androgen receptor content with duration of response and survival following hormonal therapy in advanced prostatic cancer. J Urol. 1982;127:466-471.

31. Sun T, Lee GS, Werner L, et al. Inherited variations in AR, ESR1, and ESR2 genes are not associated with prostate cancer aggressiveness or with efficacy of androgen deprivation therapy. Cancer Epidemiol Biomarkers Prev. 2010;19:1871-1878.

32. Koivisto P, Kononen J, Palmberg C, et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 1997;57:314-319.

33. Koivisto P, Hyytinen E, Palmberg C, et al. Analysis of genetic changes underlying local recurrence of prostate carcinoma during androgen deprivation therapy. Am J Pathol. 1995;147:1608-1614.

34. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34-45.

35. Steinkamp MP, O’Mahony OA, Brogley M, et al. Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res. 2009;69:4434-4442.

36. Culig Z, Hobisch A, Cronauer MV, et al. Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endocrinol. 1993;7:1541-1550.

37. Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25:276-308.

38. Huang CN, Huang SP, Pao JB, et al. Genetic polymorphisms in androgen receptor-binding sites predict survival in prostate cancer patients receiving androgen-deprivation therapy. Ann Oncol. 2012;23:707-713.

39. Bao BY, Pao JB, Huang CN, et al. Significant associations of prostate cancer susceptibility variants with survival in patients treated with androgen-deprivation therapy. Int J Cancer. 2012;130:876-884.

40. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:1028-1038.

41. de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer.

Clin Cancer Res. 2008;14:6302-6309.

42. Okegawa T, Nutahara K, Higashihara E. Immunomagnetic quantification of circulating tumor cells as a prognostic factor of androgen deprivation responsiveness in patients with hormone naive metastatic prostate cancer. J Urol. 2008;180:13421347.

43. Goodman OB Jr, Symanowski JT, Loudyi A, et al. Circulating tumor cells as a predictive biomarker in patients with hormone-sensitive prostate cancer. Clin Genitourin Cancer. 2011;9:31-38.

44. Evans MJ, Smith-Jones PM, Wongvipat J, et al. Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen. Proc Natl Acad Sci U S A. 2011;108:95789582.

45. Miyamoto DT, Lee RJ, Stott SL, et al. Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer. Cancer Discov.

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46. Yang M, Xie W, Mostaghel E, et al. SLCO2B1 and SLCO1B3 may determine time to progression for patients receiving androgen deprivation therapy for prostate cancer. J Clin Oncol. 2011;29:2565-2573.

47. Kohli M, Riska SM, Mahoney DW, et al. Germline predictors of androgen deprivation therapy response in advanced prostate cancer. Mayo Clin Proc.

2012;87:240-246.

48. Fraga A, Ribeiro R, Príncipe P, et al. The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration. Eur J Cancer. 2014;50:359-365.

49. Sweeney C, Chen Y-H, Carducci MA, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): an ECOG-led phase III randomized trial. J Clin Oncol. 2014;32(suppl). Abstract LBA2.

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RG- 24.0.0.15 Rev2 1/14

CONTINUING EDUCATION

Faculty Perspectives

OCTOBER 2014 • VOLUME 5 • NUMBER 1

™

Latest Treatment Advances for Individualized Care of Breast Cancer

PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale

OVERVIEW Every day, exciting advances are being made in the field of cancer research and treatment, due to a better understanding of cancer initiation, progression, and response to treatment. In addition, significant technical achievements continue to be made in bioinformatics and genome/proteome analysis, markedly expanding available treatment options and the ability to tailor therapy to individual patients. This trend toward personalized cancer care was reflected in numerous posters and presentations at 2 recent international oncology meetings—the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) and the 39th European Society for Medical Oncology (ESMO) Congress. This 4-part Faculty Perspectives™ series will provide readers with summaries of pivotal emerging data from ASCO and ESMO 2014 as well as expert perspectives on the application of the data to daily patient care. The first issue will focus on the latest advances in the treatment of breast cancer, with subsequent issues covering the topics of non-small-cell lung cancer, metastatic melanoma, and colorectal cancer.

Associate Director, Content Strategy & Development John Welz Director, Quality Control Barbara Marino

FACULTY

Quality Control Assistant Theresa Salerno

Lisa A. Carey, MD Physician-in-Chief, North Carolina Cancer Hospital Chief, Division of Hematology-Oncology UNC School of Medicine Preyer Distinguished Professor in Breast Cancer Research Medical Director, UNC Breast Center Lineberger Cancer Center University of North Carolina Chapel Hill, NC

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Lillie D. Shockney, RN, BS, MAS University Distinguished Service Associate Professor of Breast Cancer Johns Hopkins University School of Medicine Baltimore, MD

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Supported by an educational grant from Boehringer Ingelheim.

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FACULTY PERSPECTIVES Target Audience This activity is directed toward medical and surgical oncologists, advanced practice oncology nurses, research nurses, and clinical oncology pharmacists involved in the personalized management of patients with solid tumors, and interested in the use of molecular biomarkers to help optimize patient care.

Statement of Need/Program Overview The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the management of patients with solid tumors.

Educational Objectives After completing this activity, the participant should be better able to: • Assess emerging data from ASCO 2014 and ESMO 2014 on the discovery of molecular biomarkers and their impact on the management of patients with solid tumors • Discuss the advances from ASCO 2014 and ESMO 2014 on the personalized therapy for patients with solid tumors • Outline the practical aspects of integrating molecular biomarkers and emerging targeted agents into everyday clinical practice in the personalized treatment of cancer patients Faculty Lisa A. Carey, MD Physician-in-Chief, North Carolina Cancer Hospital Chief, Division of Hematology-Oncology, UNC School of Medicine Preyer Distinguished Professor in Breast Cancer Research Medical Director, UNC Breast Center Lineberger Cancer Center, University of North Carolina Chapel Hill, NC Lillie D. Shockney, RN, BS, MAS University Distinguished Service Associate Professor of Breast Cancer Johns Hopkins University School of Medicine, Baltimore, MD Atheer A. Kaddis, PharmD Senior Vice President, Managed Markets/Clinical Services Diplomat Specialty Pharmacy, Flint, MI Term of Offering Estimated time to complete activity: 1.0 hour Date of initial release: October 15, 2014 Valid for CME/CPE/CE credit through: October 15, 2015 Physician Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Center of Excellence Media, LLC. Global is accredited by the ACCME to provide continuing medical education for physicians.

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The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity: Name of Faculty or Presenter Lisa A. Carey, MD Lillie D. Shockney, RN, BS, MAS Atheer A. Kaddis, PharmD

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The Accreditation Council for Pharmacy Education (ACPE) learners must also provide their NABP number and date of birth through the application for credit in order to receive credit. Global Education Group will submit ACPE learners’ information to CPE Monitor where credit will be issued.

Reported Financial Relationship Nothing to disclose Nothing to disclose Nothing to disclose

The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/

Updates from ASCO 2014 and ESMO 2014 INTRODUCTION The 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) was held in Chicago, Illinois, May 30–June 3, 2014, and the 39th European Society for Medical Oncology (ESMO) Congress was held in Madrid, Spain, September 26–30, 2014. Both meetings brought together thousands of oncology professionals from a wide range of specialties. This supplement will address important topics in breast cancer (BC) treatment presented at these meetings. Lisa A. Carey, MD, of the University of North Carolina School of Medicine and UNC Breast Center; Lillie D. Shockney, RN, BS, MAS, of Johns Hopkins University School of Medicine; and Atheer A. Kaddis, PharmD, of Diplomat Specialty Pharmacy, after reviewing the presented data, provide their key take-home messages for community oncology practices.

Weekly Paclitaxel and Trastuzumab With or Without Lapatinib: Gene Expression Signatures At ASCO 2014, Carey and colleagues presented results from Cancer and Leukemia Group B (CALGB) 40601, a neoadjuvant phase 3 trial that evaluated weekly paclitaxel and trastuzumab with or without lapatinib in 305 patients with stage II–III human epidermal growth factor receptor 2 (HER2)positive BC.1 Patients were randomly assigned to receive 16 weeks of preoperative paclitaxel and trastuzumab; paclitaxel, trastuzumab, and lapatinib; or paclitaxel and lapatinib, and were observed for pathologic complete response (pCR). Previous results showed that the addition of lapatinib did not statistically significantly impact pCR,2 but did show that response to chemotherapy and HER2 targeting varied by molecular subtype. In the present study, the investigators used mRNA sequencing to determine gene expression in 271 pretherapy samples and in 136 matched posttherapy samples. The investigators found that HER2-positive disease is molecularly heterogeneous: 30%

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were the Luminal A intrinsic subtype, 31% Luminal B, 31% HER2-Enriched, 5% Basal-Like, 2% Normal-Like, and 1% Claudin-Low. The pCR rates varied significantly according to subtype: pCR was 34% for Luminal A; 36% for Luminal B; 36% for Basal-Like; and 70% for HER2-Enriched (P<.0001).

Gene expression studies also showed that several other variables in addition to treatment significantly and independently affected pCR, including immune cells, proliferation, and having a p53 mutation. The investigators concluded that with pCR rates in excess of 70% in the HER2-Enriched samples with paclitaxel and trastuzumab alone, dual HER2-targeting or more aggressive chemotherapy may be unnecessary in that biologic subtype.1 Perspectives I am obviously biased about this abstract, but I think it is a seminal study for several reasons. First, it was designed to answer clinical and correlative

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CONTINUING EDUCATION questions simultaneously, and second, simultaneous examination showed that while treatment mattered in HER2-positive BC, it only mattered a little, and that equally important were biologic considerations such as intrinsic subtype (the HER2-Enriched subtype had double the pCR rates regardless of treatment arm) and microenvironment (expression of immune cells significantly and independently influenced pCR). These findings should be replicated in other datasets, but if confirmed, they suggest that we may be able to identify tumors with an excellent outcome with minimal chemotherapy and single HER2 targeting.

-Lisa A. Carey, MD This is valuable research using epigenetics to help guide decisions about which genes need to be targeted and with what systemic agent in order to increase the likelihood of the best pathologic response to treatment.

Recognizing that patients with these stages of BC and prognostic factors are at increased risk of recurrence, such results provide optimism for the longevity of these patients. Incorporating the risk of recurrence into the drug selection provides added information about what combination of drugs may produce the best results.

-Lillie D. Shockney, RN, BS, MAS As we have observed in clinical trials, including those in BC, genetic subtypes can play a major role in treatment efficacy. However, results from this clinical trial demonstrated that the addition of the oral oncolytic lapatinib does not improve pCR rates, compared with trastuzumab and paclitaxel alone, for the most common biologic subtypes. Not only is this consistent with past results, it also provides value in that it may spare some patients unnecessary added therapies that may not improve outcomes.

-Atheer A. Kaddis, PharmD

Neoadjuvant Lapatinib Plus Trastuzumab for Early Breast Cancer in Patients With PIK3CA Mutations At ESMO 2014, Guarneri and colleagues presented results from CherLOB, a study that included 121 patients with HER2-positive early-stage BC who were randomly assigned to neoadjuvant anthracycline-/taxane-based chemotherapy plus trastuzumab, lapatinib, or both.3 PIK3CA mutations were evaluated in 106 of the 121 patients, in an effort to evaluate the correlation of PIK3CA mutational status with pCR. Exon 9 and exon 20 PIK3CA mutations were evaluated on formalin-fixed paraffin-embedded core biopsies using pyrosequencing. The researchers also conducted an event-based pooled analysis of several trials (NeoALTTO and GeparSixto) that reported pCR events according to PIK3CA mutation status.

Results showed that 22 (20.8%) of the 106 evaluable patients in CherLOB had a PIK3CA mutation. Rates of pCR in both CherLOB and the pooled analysis were similar between patients who had wild-type PIK3CA (33.3%) and those who had a PIK3CA mutation (22.7%). However, patients with wild-type PIK3CA who had received trastuzumab plus lapatinib were more likely to achieve pCR compared with those who had a PIK3CA mutation (48.5% vs 12.5%; P=.06). The researchers concluded that the increased activity of the dual anti-HER2 blockade of trastuzumab plus lapatinib appears to be limited to tumors that do not have PIK3CA mutations.3 Perspectives This is another interesting study that suggests that fundamental features of the tumor are as important as the drugs we give in determining responsiveness. In this case, the presence of activating mutations in PIK3CA, which has long been known to interact with HER2 signaling, conferred resistance to HER2 targeting. Given the high cost of dual HER2 targeting, identifying those tumors likely to truly benefit is crucial.

-Lisa A. Carey, MD In the past, we had limited prognostic information when assessing patients with early-stage BC, such as grade and estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor status. However, we have now entered an age of personalized medicine, and our prognostic tools continue to evolve. I think this is evidenced by results of the CherLOB study,

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which reinforce the value of using genetic information from BC cells to tailor treatment more effectively.

-Lillie D. Shockney, RN, BS, MAS

Genomic Analysis of Immune Function Genes and Clinical Outcomes Results from the North Central Cancer Treatment Group N9831 adjuvant trastuzumab trial were presented by Perez and colleagues at ASCO 2014.4 Because 20% to 25% of patients with HER2-positive BC relapse after adjuvant trastuzumab, the investigators used a genomic approach (whole-genome DASLÂŽ technology) to identify genes associated with relapse-free survival (RFS) among 1282 patients enrolled in the trial. They used Cox proportional hazard ratios (HRs) to determine the association between genes and RFS for 433 patients who received chemotherapy alone and 849 patients who received chemotherapy plus trastuzumab.

Ten of 13 significantly enriched biological processes associated with increased RFS (P<.01) were linked to immune functions, and these 10 processes defined a cohort of 87 immune function genes. Patients with immune-enriched tumors based on the 87 genes had a more favorable outcome when given trastuzumab (HR, 0.36; P<.0001). Patients whose tumors were not immune enriched had similar outcomes regardless of whether or not they were treated with trastuzumab (HR, 0.99; P=.91). Among patients who received chemotherapy alone, enriched immune function was not associated with increased RFS (HR, 1.01; P =.96). The investigators concluded that improved RFS after treatment with adjuvant trastuzumab may be associated with a heightened state of immunological function, and may indicate a significant biological process linked to the efficacy of HER2-targeted therapy, provide a method of predicting relapse probability after treatment with adjuvant trastuzumab, and lead to a discovery of possible routes of therapeutic enhancement.4 Perspectives In N9831, which is one of the seminal adjuvant trastuzumab trials, the benefit of trastuzumab was driven by those tumors with high immune function expression. This is now the third cooperative group trial to find that the immune microenvironment is a key contributor to response to HER2 targeting; the others are the CALGB 40601 trial,1 which examined immune signatures, and the FinHER trial,5 which examined tumor-infiltrating lymphocytes.

-Lisa A. Carey, MD Science has finally reached a critical juncture in which immunological function can be identified and targeted. As shown in N9831, this may indicate a significant biological process linked to the efficacy of HER2targeted therapy and provide a method of predicting relapse probability after treatment with adjuvant trastuzumab. This is an excellent example of personalized medicine, targeting the genomic behavior of the tumors.

-Lillie D. Shockney, RN, BS, MAS This clinical trial evaluated the impact of specific gene targeting in patients with immune function enrichment. Adding an immune targeting agent such as trastuzumab to chemotherapy for such patients provided higher RFS than chemotherapy alone. This demonstrates the importance of genetic testing and suggests that appropriate targeting with current therapies may lead to better outcomes for patients with BC. -Atheer A. Kaddis, PharmD

Women Who Choose Mastectomy for Early-Stage Breast Cancer Overestimate Their Risk Covelli and colleagues reported at ASCO 2014 on results of their study that sought to understand why mastectomy rates have been increasing.6 They conducted a grounded-theory qualitative study to examine the surgeonâ&#x20AC;&#x2122;s practice and the patientâ&#x20AC;&#x2122;s decision-making that led to a choice for unilateral mastectomy (UM) and/or contralateral prophylactic mastectomy (CPM).

The study population consisted of 45 surgeons across Ontario, Canada, and 29 female patients in Toronto who were eligible for breast-conserving thera-

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FACULTY PERSPECTIVES py but opted for UM with or without CPM. The investigators collected data through semistructured interviews and used constant comparative analysis to identify key ideas. Results showed a desire for control to be the motivation behind the patients’ decision; the women believed they could improve their outcomes by undergoing more extensive surgery. Surgeons described breast-conserving therapy and UM as equivalent treatment options for early-stage BC but frequently recommended the breast-conserving option and discouraged CPM as there is no evidence of survival advantage. Despite surgeon recommendations, women often initiated a request for UM plus CPM, and their requests for CPM appeared to be most influenced by their personal experiences with family and friends and not their surgical consultation.

Previous negative experience with BC led the women to overestimate their risk of recurrence, contralateral cancer, and subsequent mortality; thus, women chose UM plus CPM to ensure they would “never go through this again.” Although they remained confident in their choice, many women interviewed continued to experience pain and issues with cosmesis and body image after UM with or without CPM. The investigators recommend more education, including exposure to other patients’ postoperative concerns, to assist in decision-making.6 Perspectives This study reinforces the emerging finding that fear, rather than information, drives some women’s decision for mastectomy over breast conservation. Although mastectomy may be a reasonable choice for some, it is a morbid procedure, and it is important that patients are fully informed about the risk of local recurrence as well as complications of therapy for both mastectomy and breast conservation.

-Lisa A. Carey, MD This research confirms that although there may not be a clinical reason (eg, increased survival rates) for having CPM, patients with early BC still seek it out for peace of mind, as well as for desired cosmetic results. Body image is an important quality-of-life factor that should not be ignored.

Providing more education about the facts associated with doing prophylactic surgery of this kind and what outcomes the patient might expect, and comparing these to the desired outcomes, are important in the decision-making process. When a patient inquires about CPM, surgeons should engage in a more specific discussion as to what exactly is the driving force for this being requested. This will help ensure that a patient is not requesting it for a reason that such surgery will not provide—improved survival.

-Lillie D. Shockney, RN, BS, MAS

Impact of Physicians on Cancer Screening Despite the success of cancer screening in reducing morbidity and mortality, participation remains suboptimal. At ASCO 2014, Chen and Cheung reported on results of a study designed to characterize the frequency of breast, colorectal, cervical, and prostate cancer screening in a US population–based setting of 7327 patients of average risk; describe the clinical factors associated with screening uptake; and examine the effect of patient contact with their physicians and the quality of these interactions in modifying screening behavior.7 The investigators developed a scoring system, based on patientreported patterns of care, to characterize the quality of patients’ interactions with physicians. Results showed screening rates to be suboptimal in each of the cancer cohorts (Table 1). Patients of advanced age, those with a family history of any cancer, high-income earners, those who visited their physicians frequently, and those who rated their interactions with their physicians highly were generally more likely to undergo screening. Although quality of the physician was a stronger predictor of screening than frequency of physician contact, the odds of screening were greatest for patients who indicated both frequent and high-quality interactions with their physicians. The investigators concluded that interventions to improve both of these provider-related factors may improve cancer screening rates.7

Cancer screening rate (%)

Breast Cancer (n=1696)

Colorectal Cancer (n=2377)

Cervical Cancer (n=2240)

Prostate Cancer (n=1014)

72

69

76

61

Characteristics associated with cancer screening (odds ratio) Advanced age

0.99

1.05a

0.96

1.06

Family history

1.26

1.17

1.10

1.82a

High income

1.08

1.22a

1.18a

1.22a

Frequent visits with physician

1.41

1.36

1.06

1.39a

Good interactions with physician

1.87

1.27

1.67

1.19

a

a a

a a

a

P<.05.

a

suggest that healthy behaviors are augmented in patients who are being cared for regularly in the healthcare system. While one explanation may be that these patients were more aware of screening needs because of their interactions with physicians, another equally plausible explanation may be that their screening behavior and their interaction with physicians are both separately reflective of healthy behavior. Not surprisingly, those with exposure to cancer risk directly through a family member were also more likely to undergo screening themselves.

-Lisa A. Carey, MD The quality of the physician, as rated by the patient, plays a significant role in whether cancer screening is pursued after a visit. Although the frequency of the visits also carried weight, combining both quality and frequency seems to be the most likely way to encourage patients to follow through with the screenings they need. Often, when a patient is visiting his or her doctor, it is for an acute illness. The majority of the time spent with the doctor during that visit is dedicated to determining the cause of that illness and providing appropriate treatment. Providers need to remember that every encounter with their patient is an opportunity to provide personalized care and to discuss overall healthcare needs, including cancer screening and monitoring tests.

-Lillie D. Shockney, RN, BS, MAS

Confidence in Efficacy of Cancer Screening in Vulnerable Versus Nonvulnerable Populations Since 2005, EDIFICE surveys have been conducted every 3 years to characterize behavior related to recommended, organized breast and colorectal cancer screening services. In the present study, Eisinger and colleagues focused on levels of confidence in screening efficacy for cancer locations for which only opportunistic screening is available, and presented their results at ASCO 2014 comparing vulnerable and nonvulnerable populations.8 They conducted phone interviews with 1600 individuals between the ages of 40 and 75 years, using the method of quotas, and assessed opinions on efficacy of cancer screening for 8 anatomic locations. The investigators analyzed data according to a validated vulnerability score. Results showed that for cancer locations with no organized screening services, the level of confidence in screening efficacy was high, and significantly higher in vulnerable than in nonvulnerable populations (Figure 1a). Organized screening programs resulted in similarly high levels of confidence in the 2 populations (Figure 1b).

The investigators concluded that their results showed an excess of confidence in the efficacy of cancer screening, especially by vulnerable populations. They believe that individuals may allow themselves greater exposure to known risk factors because they feel protected by screening (a phenomenon termed “moral hazard”).8 Perspectives

Perspectives These results mirror those from studies in non-cancer populations that

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Table 1. Cancer Screening Rates and Odds Ratios for Patients More Likely to Undergo Screening7

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Both vulnerable (in this case defined as patients with unhealthy habits or behaviors) and nonvulnerable populations have equally high confidence

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Figure 1a. Level of confidence in screening efficacy for cancer locations with no organized screening programs8 180

Nonvulnerable population Vulnerable population

160

Patients (%)

140 120

78% P<.05

100

60%

56%

80

48%

52%

63%

59%

60 40

27%

85%

69%

67%

20 0

34% Lung Cancer

Leukemia

Gastric Cancer Liver Cancer

Esophageal Central Nervous Cancer System Cancers

Figure 1b. Level of confidence in screening efficacy for cancer locations with organized screening programs8 250

Patients (%)

200 150

Nonvulnerable population Vulnerable population

96%

94%

95%

92%

Breast Cancer

Colorectal Cancer

100 50 0

Perspectives

in known screening for breast and colon cancer, but a high proportion of the vulnerable population also believes that screening for diseases for which we do not have validated tools is effective. This may reflect irrational exuberance, or a lack of health literacy resulting in both incorrect beliefs regarding screening tools and unhealthy habits. Either way, it is a problem.

-Lisa A. Carey, MD This research study points out the need for more consumer education regarding the purpose of specific types of cancer screenings. Breast cancer screening using mammography can be misinterpreted by a patient as being in some way a form of protection from the disease when the goal is early detection. On the flip side, colonoscopies can prevent colorectal cancer by identification and removal of colon polyps. In recognition of the higher risk of developing cancer among vulnerable populations, there is a need for more education regarding risk factors for various types of cancer and promotion of healthier lifestyle behaviors to help reduce risk.

Clinicians as well as community outreach workers need to take advantage of every patient and consumer encounter to correct the myths and reinforce the facts.

-Lillie D. Shockney, RN, BS, MAS

Adjuvant Exemestane Plus Ovarian Function Suppression Compared With Tamoxifen Plus Ovarian Function Suppression in Premenopausal Women With Hormone Receptor–Positive Breast Cancer Adjuvant endocrine therapy with aromatase inhibitors (AIs) compared with tamoxifen has previously been shown to improve outcomes in postmenopausal women with hormone receptor–positive BC. At ASCO 2014,

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Pagani and colleagues presented the results of the Tamoxifen and Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT).9 These phase 3 trials were designed to examine whether adjuvant AI therapy improved outcomes in premenopausal women with hormone receptor–positive BC treated with ovarian function suppression (OFS) and to determine the value of OFS in women who remain premenopausal and are eligible for adjuvant tamoxifen therapy. Between the years 2003 and 2011, the 2 trials collectively enrolled 5738 premenopausal women with hormone receptor– positive early-stage BC (TEXT, n=2672; SOFT, n=3066). In TEXT, patients were randomly assigned within 12 weeks of surgery to 5 years of exemestane plus OFS or tamoxifen plus OFS. Chemotherapy was optional and concurrent with OFS. In SOFT, patients were randomly assigned to 5 years of exemestane plus OFS, tamoxifen plus OFS, or tamoxifen alone, either within 12 weeks of surgery if no chemotherapy was planned, or within 8 months of completing neoadjuvant or adjuvant chemotherapy. OFS was accomplished by a choice of 5 years of triptorelin, oophorectomy, or ovarian irradiation. The primary end point of the joint analysis was disease-free survival (DFS).

After a median follow-up of 5.7 years, 514 (11%) DFS events were found in the intention-to-treat population comparing exemestane plus OFS (n=2346) versus tamoxifen plus OFS (n=2344). Patients who were given exemestane plus OFS had a significantly reduced risk of recurrence (HR, 0.72; 95% confidence interval [CI], 0.60–0.86; P=.0002) compared with those given tamoxifen plus OFS, with results showing a 5-year DFS rate of 91.1% versus 87.3%. The investigators found similar reductions for secondary end points of BC-free interval (HR, 0.66; 95% CI, 0.55–0.80), rate of freedom from BC at 5 years (92.8% vs 88.8%), and distant recurrence-free interval (HR, 0.78; 95% CI, 0.62–0.97). However, no reduction in overall survival (OS) with exemestane plus OFS was seen at this early follow-up (HR=1.14; 95% CI, 0.86–1.51). Grade 3/4 adverse events (AEs) were reported in 31% of patients given exemestane plus OFS and in 29% of patients given tamoxifen plus OFS.9

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The combined analysis from SOFT and TEXT found that in premenopausal women, it was better to give ovarian suppression plus an AI than ovarian suppression plus tamoxifen. This differed from the results of the ABCSG-12 study,10 in which there was a survival disadvantage to the AI arm. There are potential methodologic reasons for the discrepancy; regardless, the question that has not yet been answered is the extent to which either of these approaches improves outcome over tamoxifen alone. Clearly, there are quality-of-life and comorbidity complications related to premature loss of ovarian function. We hope that this question will be answered at the San Antonio Breast Cancer Symposium in December 2014.

-Lisa A. Carey, MD New information regarding the management of hormone receptor–positive BC is being generated with considerable speed now that clinical trials that required 5 years of treatment have concluded. This study showed that those patients given exemestane plus OFS had a significantly reduced risk of recurrence. It is, however, important to remember that AEs from OFS as well as from hormonal drugs impact the quality of life for this patient population, making it more difficult for some to adhere to these treatment guidelines. Minimizing side effects needs to be part of the treatment planning process.

-Lillie D. Shockney, RN, BS, MAS These results demonstrate again the advantages of AIs plus OFS over the use of tamoxifen plus OFS. Aromatase inhibition has become the standard of care as adjuvant endocrine therapy for premenopausal patients with BC. The risk of AEs is similar to those we have seen with tamoxifen.

-Atheer A. Kaddis, PharmD

First-Line Pertuzumab, Trastuzumab, and Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer At ESMO 2014, Swain and colleagues discussed final results from the

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FACULTY PERSPECTIVES CLEOPATRA trial, in which 808 patients with HER2-positive metastatic BC (MBC) were randomly assigned to either first-line placebo/trastuzumab/ docetaxel or pertuzumab/trastuzumab/docetaxel.11 The primary end point of the study was progression-free survival (PFS) (independently assessed).

Secondary end points included PFS (investigator-assessed), objective response rate, safety, and OS. An interim analysis previously reported in May 2011 showed that pertuzumab increased PFS significantly; by the second interim analysis in May 2012, OS had also improved to a statistically significant, clinically meaningful degree. In July 2012, patients in the placebo arm were offered the chance to cross over to pertuzumab.

After a median follow-up of 50 months, OS was shown to be 56.5 months for patients in the pertuzumab arm, compared with 40.8 months in the placebo arm (HR, 0.68; P=.0002). PFS was 18.7 months in the pertuzumab arm compared with 12.4 months in the placebo arm (HR, 0.68; P<.0001). The median time spent on study treatment was 17.4 months for patients in the pertuzumab arm compared with 11.4 months for those in the placebo arm.

Side effects experienced by patients in the pertuzumab arm included diarrhea, rash, mucosal inflammation, pruritus, dry skin, and muscle spasm.

Longer follow-up did not lead to new safety concerns and no evidence of cumulative or late toxicity was observed. The cardiac safety profile was also maintained in the long term.

The researchers asserted that the median OS of 56.5 months is unprecedented in first-line treatment of MBC and confirms that a pertuzumabcontaining regimen is now the standard of care in this setting.11 Perspective This study established the role of pertuzumab added to trastuzumab and a taxane in the first-line setting for metastatic HER2-positive disease, and this update on survival lends even more support to this approach.

The 6-month improvement in PFS is impressive alone, but a nearly 1.5-year improvement in OS is unprecedented. In part, this spectacular finding may reflect the study population, in whom access to HER2-targeted drugs outside of the trial was limited, but it remains a highly positive trial in favor of dual HER2 targeting.

-Lisa A. Carey, MD

Trastuzumab Alone, Trastuzumab Plus Lapatinib, and Trastuzumab Followed by Lapatinib At ASCO 2014, Piccart-Gebhart and colleagues presented results from the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial, a multicenter, randomized, phase 3 trial that compared 3 oral lapatinib-containing regimens with trastuzumab in the adjuvant treatment of women with HER2-positive early-stage BC.12 Each regimen was given for 1 year. A total of 8381 patients were randomly assigned between June 2007 and July 2011 to treatment with lapatinib plus trastuzumab, trastuzumab followed by lapatinib, or trastuzumab alone. The trial originally consisted of a fourth arm of lapatinib alone, but that arm was discontinued in August 2011 due to futility. HER2-targeted therapy was given after chemotherapy was completed in 4613 patients; concurrently with a taxane following anthracycline in 3337 patients; or concurrently with a nonanthracycline, platinum-containing regimen in 431 patients. The primary end point was invasive DFS. The investigators tested lapatinib plus trastuzumab versus trastuzumab alone for superiority and trastuzumab followed by lapatinib versus trastuzumab alone for noninferiority.

Among the total number of patients, 40% were node-negative and 57% were hormone receptor–positive. After a median follow-up of 4.5 years and 555 DFS events, results showed no significant difference between lapatinib plus trastuzumab versus trastuzumab alone (HR for DFS, 0.84; 97.5% CI, 0.70–1.02; P=.048; 4-year DFS rate, 88% vs 86%). The HR was 0.93 (97.5% CI, 0.76–1.13; noninferiority P=.04; 4-year DFS rate, 87% vs 86%) for patients given trastuzumab followed by lapatinib versus trastuzumab alone.

Diarrhea (75% vs 20%), rash (55% vs 20%), and hepatobiliary AEs (23% vs 16%) occurred more frequently in patients given lapatinib plus trastuzumab versus those given trastuzumab alone. The investigators pointed out that the results were unexpected given the success of the NeoALTTO trial, which

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showed that the combined use of lapatinib and trastuzumab doubled the pCR rate compared with trastuzumab alone.13 Perspectives Some, but not all, neoadjuvant studies have suggested that dual HER-2 targeting improves pCR compared with single HER-2 targeting. The ALTTO study tested the adjuvant use of lapatinib added to trastuzumab-based therapy, and results suggest that dual targeting with lapatinib is unlikely to markedly improve outcomes, at least in this overall good-risk population.

Identifying patients for whom less is needed (versus more) is a key question in HER-2 positive BC; the role of pertuzumab added to trastuzumab will be addressed by the ongoing APHINITY trial.14 For now, chemotherapy plus trastuzumab remains the adjuvant best option.

-Lisa A. Carey, MD In this study, there were some surprising (and perhaps disappointing) results associated with the AEs that patients experienced in the trastuzumab followed by lapatinib arm. Therefore, risks and benefits need to be weighed carefully given that the benefits can be great (doubled complete response rate); but the side effects can be severe (eg, 75% diarrhea, 55% rash, 23% hepatobiliary AEs).

-Lillie D. Shockney, RN, BS, MAS These results point to a need for additional clinical trials to determine the true benefit of lapatinib plus trastuzumab. Interestingly, the outcomes in this trial were different than those reported in a previous study using the same regimen.15 Given that the incidence of AEs was much higher with the addition of lapatinib, this will be an important question to answer.

-Atheer A. Kaddis, PharmD

Neoadjuvant Treatment in HER2-Positive Breast Cancer: Docetaxel Plus Lapatinib, Trastuzumab, or Both, Followed by an AnthracyclineBased Regimen Results from the randomized, phase 2 European Organisation for Research and Treatment of Cancer (EORTC) 10054 study were presented at ESMO 2014 by Bonnefoi and colleagues.16 Previous neoadjuvant trials using a double HER2 blockade of lapatinib and trastuzumab along with paclitaxel-containing chemotherapy regimens have shown high toxicity, which the researchers hypothesized may have been due to a specific interaction between paclitaxel and lapatinib. Therefore, the objective of EORTC 10054 was to assess the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab. The trial enrolled 128 patients with stage IIA–IIIC HER2positive BC from October 2010 to January 2013. Patients received 6 cycles of chemotherapy every 3 weeks (3 cycles of docetaxel followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide). During the first 3 cycles, patients were randomly assigned to receive lapatinib (arm A, n=22), trastuzumab (arm B, n=52), or trastuzumab and lapatinib (arm C, n=48). The primary end point was pCR. Secondary end points included safety and toxicity. Arm A closed because of futility in June 2012.

Results showed that when pCR was defined as absence of invasive cancer in the breast, it was achieved in 45.5% of patients in arm A, 51.9% in arm B, and 60.4% in arm C. When pCR was defined more strictly as absence of invasive cancer in the breast and lymph nodes, it was achieved in 38.1%, 51.9%, and 56.3%, respectively. Grade 3/4 toxicities experienced included febrile neutropenia in 23%, 15%, and 10% in arms A, B, and C, respectively; diarrhea in 9%, 2%, and 18%, respectively; other infection in 9%, 4%, and 8%, respectively; and liver enzyme alteration in 0%, 4%, and 10%, respectively. Dose reductions were required in 36%, 13%, and 48% of patients in arms A, B, and C, respectively.16 Perspectives This study joins the legions of neoadjuvant trials demonstrating that the addition of lapatinib to trastuzumab-based therapy modestly augments pathologic response, but at a cost of side effects regardless of which taxane you use. Like others, they found that the impact on response of

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CONTINUING EDUCATION adding lapatinib was far greater in the hormone receptor–negative subset. Efforts to define the group within HER2-positive BC who will derive real benefit from more aggressive approaches is key.

-Lisa A. Carey, MD AEs that disrupt activities of daily living must be factored into the discussion of treatment options for BC. Some patients cannot tolerate certain toxicities, especially if they interfere with the ability to continue working, which may be necessary to pay medical bills and maintain insurance benefits. Financial concerns can be a barrier to optimal treatment, and out-of-pocket expenses must be discussed between patients and the healthcare team. There may be resources that can help to offset some of this burden; however, these must be investigated up front. Nurse navigators can play an important role by meeting with a financial counselor to calculate treatment-related expenses and help patients explore their options.

-Lillie D. Shockney, RN, BS, MAS

Docetaxel Weekly Versus Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Chemotherapy for Elderly Patients With Early-Stage Breast Cancer Perrone and colleagues presented final results at ESMO 2014 from the randomized, phase 3 study ELDA (Elderly Breast Cancer—Docetaxel in Adjuvant Treatment), which evaluated whether weekly docetaxel in elderly patients with early-stage BC was more effective than cyclophosphamide, methotrexate, and fluorouracil (CMF).17 Patients were eligible for study inclusion if they were between the ages of 65 and 79 years and had metastatic nodes or an average to high risk of recurrence.

A total of 302 patients were randomly assigned between July 2003 and April 2011 to either weekly docetaxel or CMF, both administered every 4 weeks and given for 4 cycles to ER-positive patients and for 6 cycles to patients who were ER-negative. After chemotherapy, patients who were ER-positive received endocrine treatment and those who were HER2-positive received trastuzumab. The most frequent comorbidities were hypertension, arthropathy, osteoporosis, and controlled diabetes. Median follow-up was 5.5 years.

The HR for DFS for those who received weekly docetaxel versus CMF was 1.20 (95% CI, 0.82–1.75; P=.35); the HR for death was 1.23 (95% CI, 0.73–2.07; P=.42). Multivariable analysis showed similar results.

Patients who received weekly docetaxel experienced worse quality of life in terms of emesis, appetite loss, diarrhea, impaired body image, diminished future perspective, hair loss, allergy, fatigue, dysgeusia, abdominal pain, neuropathy, and cardiac and skin toxicity. Patients who received CMF experienced worse hematologic toxicity, mucositis, and nausea. The researchers concluded that weekly docetaxel was not more effective than CMF and resulted in worse quality of life and greater toxicity. They stated that CMF remains the standard of care for elderly patients with early-stage BC.17 Perspectives Older patients with high-risk tumors need polychemotherapy. This is the second trial to demonstrate that standard approaches to adjuvant therapy should be used, regardless of age (CALGB 49907, which compared capecitabine alone vs standard first-generation regimens, was the first).

The fact is, physiologic age is probably more important to consider in determining treatment than chronologic age, but our tools for assessing this are still undeveloped.

-Lisa A. Carey, MD An important issue to consider is whether any of these patients were candidates for Oncotype DX™. If they were, I think it would be important to utilize this tool to determine whether chemotherapy would truly be beneficial. In this elderly cohort of patients, it is not unusual to see a high incidence of comorbidities, which can be exacerbated by certain therapies. It makes us reflect back on the Hippocratic Oath—Do no harm.

-Lillie D. Shockney, RN, BS, MAS

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Maintenance Bevacizumab With or Without Capecitabine After Initial First-Line Bevacizumab Plus Docetaxel for HER2-Negative Breast Cancer At ESMO 2014, Gligorov and colleagues presented results from the open-label, randomized phase 3 IMELDA trial, which examined whether the addition of capecitabine to maintenance bevacizumab after initial treatment with bevacizumab and docetaxel would improve PFS.18 Patients with HER2-negative MBC, an Eastern Cooperative Oncology Group score less than 2, and no prior chemotherapy for mBC were eligible for study inclusion. A total of 284 patients were enrolled between June 2009 and March 2011 (at which point enrollment was prematurely terminated).

Patients who had had 3 to 6 cycles of bevacizumab and docetaxel and who had not experienced disease progression (n=185, 65%) were then randomly assigned to bevacizumab alone (n=94) or bevacizumab plus capecitabine (n=91), until disease progression. The primary end point was PFS from randomization; secondary end points included response rate, OS, safety, and quality of life. Median follow-up ranged from 30.4 months for the bevacizumab group to 31.6 months for the bevacizumab plus capecitabine group.

Results showed median PFS to be 4.3 months for the patients who received bevacizumab alone compared with 11.9 months (HR, 0.38; 95% CI, 0.27– 0.55; P<.001) for patients who received bevacizumab plus capecitabine.

Median OS was 23.7 months for the bevacizumab-alone group compared with 39 months (HR, 0.43; 95% CI, 0.26–0.69; P<.001) for the bevacizumab plus capecitabine group. AEs of grade 3 or higher, including hand-foot syndrome, hypertension, proteinuria, and gastroenteritis, were experienced by 30% of the patients who received bevacizumab and 52% of those who received the bevacizumab-capecitabine combination.18 Perspectives The results of this trial could be interpreted to show that the combination of bevacizumab plus capecitabine is a good—and relatively well-tolerated—regimen in the metastatic setting, which has been demonstrated in the past. However, skeptics may point out that the contribution of bevacizumab is unclear; this could just reflect the activity of capecitabine, which is an effective second-line drug. From a practical standpoint, I also would not advocate for taking the approach used in this trial of stopping 1 cytotoxic regimen that is working in order to start a completely different cytotoxic regimen.

-Lisa A. Carey, MD In this trial, not only was there an improvement in PFS of 7.6 months, but OS was increased by greater than 15 months. That is a long time for a patient with BC to survive and enjoy additional time with her family.

What may be a barrier to treatment in the future, however, relates to the increased cost of drugs, which will be shared by the patient and her insurance company. Deductibles and copayments will continue to climb, and patients with metastatic disease do not want to leave financial debt for their family to pay after they are gone, especially if it is related to their cancer treatment. This means thoughtful discussions are needed among the family members as well as between the patient and the oncology team.

-Lillie D. Shockney, RN, BS, MAS

Luteinizing Hormone–Releasing Hormone Analog During Chemotherapy in Early-Stage, Hormone Receptor–Negative Breast Cancer At ASCO 2014, Moore and colleagues presented results from the Prevention of Early Menopause Study (POEMS), a phase 3 trial coordinated by the Southwest Oncology Group that evaluated whether luteinizing hormone–releasing hormone (LHRH) analog administration with chemotherapy for early-stage BC would reduce premature ovarian failure (POF).19 The study population consisted of 257 premenopausal patients younger than 50 years with stage I–IIIA ER/PR-negative BC. Patients were randomly assigned to receive standard cyclophosphamide-containing chemotherapy with or without monthly goserelin, beginning 1 week before the first dose of chemotherapy. The primary end point was 2-year POF (defined as amenorrhea for the prior 6 months and postmenopausal level of follicle-stimulating hormone

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FACULTY PERSPECTIVES [FSH]). Other end points included pregnancies and survival. Results showed POF rates were 22% among patients who received standard treatment and 8% among those who received goserelin (odds ratio [OR], 0.36; 95% CI, 0.11–1.14; P=.08 on adjusted analysis). A sensitivity analysis that defined 2-year POF more liberally (as either amenorrhea or elevated FSH) showed POF rates to be 45% among those receiving standard treatment and 20% in those who received goserelin (OR, 0.29; 95% CI, 0.12–0.70; P=.006). There were 13 pregnancies among the patients who received standard treatment and 22 among those who received goserelin (OR, 2.22; 95% CI, 1.00–4.92; P=.05). Patients who received goserelin experienced better rates of DFS and OS compared with those who received standard treatment (HR, 0.49; 95% CI, 0.24–0.97; P=.04 and HR, 0.43; 95% CI, 0.18–1.00; P=.05, respectively).19 Perspectives Premature ovarian failure and infertility are major issues for young patients with BC. This study examined an LHRH agonist given concurrently with chemotherapy in hormone receptor–negative BC and found that patients treated with this regimen were more likely to maintain ovarian function and to successfully become pregnant. This is a reasonable option for this cohort of women; however, it should not be generalized to the hormone receptor–positive group given the possibility of an interaction between the endocrine therapy and the chemotherapy.

-Lisa A. Carey, MD Preservation of fertility is a priority to many premenopausal women diagnosed with BC. Consideration regarding this life goal needs to be acknowledged and incorporated in the treatment planning process whenever feasible. This study provides a new treatment option to enable this to happen, which is associated with DFS and OS benefits.

-Lillie D. Shockney, RN, BS, MAS This clinical trial demonstrated a novel use for the LHRH agonist goserelin.

Given in hormone receptor–negative, early-stage BC, this agent can help to preserve ovarian function in patients receiving chemotherapy, with some patients even achieving successful pregnancies. Disease-free survival and OS were also better in patients who received goserelin.

-Atheer A. Kaddis, PharmD

Zoledronic Acid Every 4 Weeks Versus Every 12 Weeks in Women With Bone Metastases From Breast Cancer OPTIMIZE-2 was a phase 3, prospective, randomized, double-blind, multicenter study that examined the efficacy and safety of continued zoledronic acid every 4 weeks compared with every 12 weeks in women with bone metastases from BC. The objective was to determine whether zoledronic acid given every 12 weeks was noninferior to zoledronic acid given every 4 weeks in patients who previously received monthly intravenous bisphosphonate therapy for at least 1 year (approximately 9 or more doses of zoledronic acid or pamidronate during the first 10–15 months of therapy). Hortobagyi and colleagues discussed the results at ASCO 2014.20 A total of 403 patients were randomly assigned to a schedule of zoledronic acid every 4 weeks (n=200) or every 12 weeks with placebo given between doses (n=203), for 1 year. The primary end point was the proportion of patients with at least 1 skeletal-related event (SRE). Secondary end points included time to first SRE, skeletal morbidity rate (SMR), bone pain score, change in bone turnover markers, and safety.

The investigators found an SRE rate of 22% for patients in the 4-week group and 23.2% in the 12-week group, demonstrating noninferiority of zoledronic acid administered every 12 weeks compared with every 4 weeks.

The 2 groups experienced similar time to first on-study SRE (HR, 1.06; 95% CI, 0.70–1.60; P=.79); mean SMRs were also similar (0.46 vs 0.50, respectively; P=.85). Changes in bone turnover markers and incidence of treatment-emergent AEs were also similar in the 2 groups. The 4-week group experienced more renal treatment-emergent AEs than the 12-week group (9.6% vs 7.9%), and 2 cases of osteonecrosis of the jaw were found in the 4-week group.20

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Perspectives The optimal schedule and duration of bisphosphonate treatment in MBC is uncertain. This study, which examined women after 1 year of monthly administration, found that it appears safe to change at that point to every-third-month administration. This is a very appealing finding from a practical and toxicity standpoint. Denosumab has some benefits in outcome and toxicity over zoledronic acid, but now zoledronic acid has the benefit of a far more tolerable schedule to consider.

-Lisa A. Carey, MD This is a good example of how research is able to validate that more treatment does not necessarily mean better treatment, enabling patients to receive zoledronic acid every 12 weeks instead of every 4 weeks with approximately the same clinical outcomes for those with stage IV BC that has metastasized to the bone.

-Lillie D. Shockney, RN, BS, MAS The results of this trial are important not only for patients and providers, but for payers as well, since less frequent administration of zoledronic acid may result in less cost while still achieving similar clinical results compared with administration every 4 weeks.

-Atheer A. Kaddis, PharmD

50 YEARS OF ADVANCES IN BREAST CANCER TREATMENT: WHAT WE HAVE LEARNED AND THE CHALLENGES AHEAD

At ASCO 2014, Harold Burstein, MD, PhD, discussed the evolution of BC treatment over the past 50 years as well as where treatment is headed.21 Therapies for the disease have progressed from an era in which the focus was on local treatment only to one in which local and systemic therapy is the standard. Almost all patients today, he said, will receive adjuvant therapy. In years past, treatment was stage-centered, whereas now it has become tumor-centered; the biological features of the tumor determine therapy.

Evolution of Treatment The advantages of effective (neo)adjuvant systemic therapy are many.

When given preoperatively, this includes locally advanced BCs becoming “operable”; downstaging a tumor to permit breast-conserving surgery; diminishing the need for axillary dissection and enabling sentinel node biopsy; reducing local recurrence after breast-conserving surgery; facilitating radiotherapy survival benefit; and improving survival after local–regional recurrence.

Whether given pre- or postoperatively, systemic therapy used in stage I–III BC improves both distant and local RFS and OS. Similar, although less impressive, advances are seen with prolonged survival in the metastatic setting, particularly for hormone receptor–positive and HER2-positive BC. The 3 Strands of Therapy Three strands of therapy have developed, the first consisting of adjuvant chemotherapy. The confounding factors that have existed for the past 40 years, Dr Burstein said, including age, menopausal status, differences in the biologic behavior of the tumor, modest treatment effects, short- and longterm follow-up, and concern over possible late side effects, have since been sorted out through robust trials with many patients, collaborative research, long-term follow-up, and careful correlative/translational science. In the end, dozens of trials and tens of thousands of patients have demonstrated the efficacy of anthracycline-based chemotherapy over CMF-based chemotherapy and taxane-based regimens over nontaxane-based regimens.

Endocrine therapy comprises the second strand of therapy. The benefit of tamoxifen was eventually found to correlate with ER status, with research confirming that it was not beneficial for women who were ER-negative but clearly valuable for women who were ER-positive. Although tamoxifen treatment longer than 5 years was not believed to be of benefit about 15 years ago, trials since have shown up to 10 years of tamoxifen to be beneficial in some patients. Trials that compared 5 years of tamoxifen with new approaches showed that incorporating an AI lowered the risk of recurrence in postmenopausal women who were ER-positive, and this is now part of the standard regimen for postmenopausal women with early-stage BC. The final strand of therapy involves the protein known as HER2, which is

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CONTINUING EDUCATION

Table 2. Adjuvant Treatment for Breast Cancer21 HER2-Negative

HER2-Positive

ER-Negative

ER-Positive

Chemotherapy

Endocrine therapy (eg, tamoxifen, AI) ± chemotherapy

Chemotherapy + trastuzumab

Endocrine therapy + chemotherapy + trastuzumab

AI indicates aromatase inhibitor; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2.

Table 3. Simplified Guideline-Based Care21 Breast Cancer Subtype

Preferred Non-anthracycline Regimen

Preferred Adjuvant Chemotherapy Regimen

• HER2-negative • ER-positive • Triple-negative

Anthracycline (doxorubicin/ cyclophosphamide) followed by taxane (paclitaxel)

Docetaxel/ cyclophosphamide

HER2-positive

Anthracycline (doxorubicin/ cyclophosphamide) followed by taxane (paclitaxel) and trastuzumab

Docetaxel/carboplatin/ trastuzumab

ER indicates estrogen receptor; HER2, human epidermal growth factor receptor 2.

associated with about 15% to 20% of BCs and is now recognized as an adverse prognostic factor. The discovery of HER2 led to a revolution in cancer diagnostics and therapeutics, paving the way for high-quality testing for HER2 and leading to the discovery of trastuzumab, which has altered the natural history of HER2-positive BC and has been one of the great successes of medical oncology in the past 25 years.

Adjuvant Chemotherapy: Yes or No? The decision to administer adjuvant chemotherapy to a patient has typically been a difficult one. Because there has been a shift from a stage- and risk-informed process to a tumor biology–driven process, however, treatment today can be guided by the general classification of patients as ER-negative or ER-positive, and HER2-negative or HER2-positive (Table 2).21 Pre- and perimenopausal women may choose tamoxifen for initial endocrine therapy, then for extended therapy remain on tamoxifen or switch to an AI (if they are postmenopausal). Postmenopausal women may choose an AI or tamoxifen for initial and extended therapy.

For women with early-stage BC, CMF-based regimens have been replaced by anthracycline-based regimens, which in turn have given way to taxaneand anthracycline-based regimens (regardless of age, stage, grade, or ER status). Best evidence supports the idea that women should receive both anthracyclines and taxanes for treating higher-risk BC. Simplified guideline-based care, as summarized by Dr Burstein, can be seen in Table 3.21 Challenges That Lie Ahead: The Genomic Era, Improving on Good Prognoses, Evolving Healthcare, and Metastatic Disease The many challenges that remain ahead include mainstreaming genomic medicine, identifying hereditary and acquired mutations, and reconciling discordant stage and biology findings.

Significant inroads have been made in sequencing vast numbers of BCs, and many mutations have been identified, but incidence is rare, and the more common mutations have been difficult to target with a drug, according to Dr Burstein. Among critical mutations that should be targeted include BRCA3, “although,” he said, “at this point it does not appear to exist,” and triple-negative BC, for which a biologically based redefinition of the syndrome is badly needed.

The most vexing challenge, however, is the persistent problem of discordance between anatomic stage and biologic risk. For example, should chemotherapy be given for a 3-mm triple-negative cancer? Or for a 4-cm lobular

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cancer affecting 3 or more lymph nodes and having a recurrence score of 8?

“At these extremes,” Dr Burstein said, “most of our clinical data break down, although that doesn’t stop these types of patients from being treated.” Results of a recent multicenter, open-label study of paclitaxel and trastuzumab for small, HER2-positive BCs showed a very low risk of recurrence (2% per 4 years of follow-up).

Improving on a good prognosis, caring for patients in the new healthcare marketplace, and metastatic disease are more of the challenges that remain on the horizon. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 study was conducted in the 1990s, and from that trial, 3 things were learned: 1. The outcomes were the same with pre- or postoperative treatment.

2. Among patients who required a mastectomy at baseline, 27% converted to breast-conserving surgery.

3. Those women with a pCR had a more favorable long-term prognosis.

“Alas, I am not sure that the field has radically transformed itself in the 20 years since this study,” Dr Burstein said. “Can we successfully develop and use NSABP B-18 as a model for drug discovery, for acceleration of treatment for early-stage BC, or to tailor or adapt treatment based on response?”

Additionally, the evolving changes in healthcare delivery in the United States present opportunities and challenges for BC care, namely value-based care; integrated, streamlined care across the spectrum of health, disease/treatment, and survivorship; guideline-driven care; and concerns about access to specialists and costs that need to be addressed.

Finally, Dr Burstein concluded, although great strides have been made in the past 50 years with regard to metastatic disease and undoubtedly will continue to be made, “fundamentally we do not have the tools we need.” Patients with MBC are typically given 4 or 5 lines of chemotherapy, and improvements have been seen in quality and longevity. But, he said, “we need the next big thing.”21 Perspectives Dr Burstein beautifully highlights the evolution of BC systemic therapy and the pivot from a single-minded focus on anatomic extent of disease to a perspective that incorporates both anatomy and biology. The explosion of our understanding of cancer pathophysiology has had real clinical benefits. Endocrine therapy now includes multiple active agents and drugs designed to circumvent resistance to anti-estrogen approaches. Similarly, we have 4 approved HER2-targeted agents and effective dual- and single-targeted approaches. However, triple-negative BC remains a thorny clinical problem. Although we have improved cure rates in early-stage triple-negative disease, systemic therapy remains limited to cytotoxics; we have not yet identified a targeted therapy for this entity.

-Lisa A. Carey, MD Great strides have been made in the field of diagnosing and treating BC. We have transitioned over time from the poison, slash, and burn methods to more innovative ways that include the timing of phases of treatment, with more neoadjuvant chemotherapy being performed, to also launching into an epigenetic field of treatment, which is likely where the future lies. There are now more surgical options, better reconstruction methods, improved chemotherapy regimens, and less harsh radiation treatments today. We have seen a decline in the death rate as a result of earlier diagnosis and better treatments; however, for those battling stage IV BC, more needs to be done. Quality of life is now on the radar screen, whereas 50 years ago, the only measure of success was survival.

Personalized medicine is a blossoming field, with epigenetic treatments becoming the new wave of systemic therapies for the future.

-Lillie D. Shockney, RN, BS, MAS

References 1. Carey LA, Barry WT, Pitcher B, et al. Gene expression signatures in pre- and post-therapy specimens from CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapitinib for HER2-positive breast cancer. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 506.

2. Carey LA, Berry DA, Ollila D, et al. Clinical and translational results of CALGB 40601: a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib

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FACULTY PERSPECTIVES for HER2-positive breast cancer. J Clin Oncol (ASCO Annual Meeting Abstracts). 2013;31 (suppl):Abstract 500.

3. Guarneri V, Dieci M, Carbognin L, et al. Activity of neoadjuvant lapatinib plus trastuzumab for early breast cancer according to PIK3CA mutations: pathological complete response rate in the CherLOB study and pooled analysis of randomized trials. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract 2540.

4. Perez EA, Thompson EA, Anderson SK, et al. Association of genomic analysis of immune function genes and clinical outcome in the NCCTG (Alliance) N9831 adjuvant trastuzumab trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl): Abstract 509.

5. Loi S, Michiels S, Lambrechts D, et al. Tumor PIK3CA mutations, lymphocyte infiltration, and recurrence-free survival (RFS) in early breast cancer (BC): Results from the FinHER trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 507.

6. Covelli AM, Baxter NN, Fitch M, et al. Why women are choosing mastectomy: influences beyond the surgeon. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl): Abstract 1094.

7. Chen L, Cheung WY. A population-based analysis of the impact of physicians on cancer screening. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 1572.

8. Eisinger F, Morère J-F, Touboul C, et al. Vulnerable populations and overconfidence in cancer screening. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 1574.

9. Pagani O, Regan MM, Walley B, et al. Randomized comparison of adjuvant aromatase inhibitor exemestane plus ovarian function suppression (OFS) vs tamoxifen plus OFS in premenopausal women with hormone receptor-positive early breast cancer: joint analysis of IBCSG TEXT and SOFT trials. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32 (suppl):Abstract LBA1.

10. Pfeiler G, Königsberg R, Fesl C, et al. Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. J Clin Oncol. 2011;29:2653-2659.

11. Swain S, Kim S, Cortes J, et al. Final overall survival analysis from the CLEOPATRA study of first-line pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4): Abstract 3500_PR. 12. Piccart-Gebhart M, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone, trastuzumab alone, their sequence, or their combination in the adju-

vant treatment of HER2-positive early breast cancer. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract LBA4.

13. de Azambuja E, Holmes AP, Piccart-Gebhart M, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomized, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014;15:1137-1146.

14. ClinicalTrials.gov. A study of pertuzumab in addition to chemotherapy and Herceptin (trastuzumab) as adjuvant therapy in patients with HER2-positive primary breast cancer. http://clinicaltrials.gov/show/NCT01358877. Accessed October 6, 2014.

15. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial.

Lancet. 2012;379:633-640.

16. Bonnefoi H, Jacot W, Saghatchian M, et al. Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline based chemotherapy in HER2positive breast cancer: results of the randomized phase II EORTC 10054 study. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract 2530.

17. Perrone F, Nuzzo F, Di Rella F, et al. Weekly docetaxel vs CMF as adjuvant chemotherapy for elderly early breast cancer patients: final results from the randomised phase 3 ELDA trial.

Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract 2560.

18. Gligorov J, Doval D, Bines J, et al. Efficacy and safety of maintenance bevacizumab with or without capecitabine after initial first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer: IMELDA randomised phase III trial. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract 3520.

19. Moore HCF, Unger JM, Phillips K-A, et al. Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy to reduce ovarian failure in early-stage, hormone receptor–negative breast cancer: an international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract LBA505.

20. Hortobagyi GN, Lipton A, Chew HK, et al. Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: results of the OPTIMIZE-2 trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014; 32(suppl):Abstract LBA9500.

21. Burstein H. 50 years of advances in breast cancer treatment: what have we learned? Where are we going? Presented at: 2014 ASCO Annual Meeting; May 30–June 3, 2014; Chicago, IL. http://meetinglibrary.asco.org/presentationBySession/6472/1280?media=vm. Accessed October 3, 2014.

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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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The Third Annual World Cutaneous Malignancies Congress The Third Annual World Cutaneous Malignancies Congress (WCMC) will take place in San Francisco, California, on October 29-31, 2014. The WCMC is 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. The following abstracts will be presented at the meeting.

CATEGORY I: Epidemiology and risk factors A Study of Basal Cell Carcinoma in South Asians for Risk Factor and Clinicopathological Characterization – A Hospital-Based Study Sumir Kumar,1 B. B. Mahajan,1 Sandeep Kaur,1 Amarbir Singh1 GGS Medical College & Hospital, Faridkot, Punjab, India

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Objectives: Basal cell carcinoma (BCC) is the most common cutaneous malignancy worldwide. Methods: A hospital-based study was conducted in Punjab, North India, from 2011-2013. All patients visiting skin department with suspected lesions underwent history, examination and histopathological confirmation. The results were analyzed using appropriate statistical tests. Results: Total of 36 confirmed cases were seen from 2011-2013. The disease had predilection for females (63.9%) and elderly (47.2% of cases aged 61-80 years) with mean ± SD age being 60.9 ± 14.2 years (65.92 ± 14.35 years for males and 57.96 ± 13.54 years for females). Mean duration of disease was 4.7 years (range being 5 months to 15 years). Majority of patients were rural (69.4%) and illiterate (80.6%). Though there was statistically significantly higher sun exposure in males compared to females (P value being .000), BCC was more common in females, explainable by intermittent sun exposure (during household work in the open kitchens) in women. There was also seen a statistically significant association between long duration of disease and illiteracy (χ2 value = 6.95 and P value = .01) and also, duration with size of lesion (evaluated using χ2 test with P value equal to .004). Majority of patients (88.9%) had a single lesion. Head and neck region was involved in 97.2% of cases, nose being the most common site (50%), with nodular/noduloulcerative morphology in 77.8% of cases. Pigmentation was evident in 22.2% of cases clinically. Nodular variety was the most common histopathological variant (77.8%).

Conclusion: This study highlights a paradoxically increasing trend of BCC with female preponderance, preferential involvement of nose and higher percentage of pigmentation in Indians. It is more common in rural and agriculturebased populations. Major risk factors include intermittent rather than constant UV exposure, cultural and lifestyle changes, cosmetic indifference, arsenic and pesticides, improved clinical and diagnostic skills. The increasing cancer burden calls for the need of national screening program. The data collected in this study would serve as a reference for future research and development of preventive strategies.

CATEGORY II: Molecular biology and pathogenesis – implications for therapy Rituximab-Induced Oral Squamous Cell Carcinoma in a Patient With Pemphigus Vulgaris: Consequence or Coincidence?

Sumir Kumar,1 Nidhi Kamra,1 Amarbir Singh,1 B. B. Mahajan1 1 GGS Medical College & Hospital, Faridkot, Punjab, India

Objectives: 1. To assess the association between use of intra-lesional rituximab and development of oral squamous cell carcinoma. 2. To determine the risk of development of oral squamous cell carcinoma in patients with pemphigus

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CATEGORY II: Molecular biology and pathogenesis â&#x20AC;&#x201C; implications for therapy vulgaris. Methods: Detailed history and clinical examination was done of a 55-year-old man who had presented with a complaint of ulceration over right lateral border of tongue. He was a known case of pemphigus vulgaris diagnosed 4 years back. He was administered intra-lesional injections of rituximab for his recalcitrant oral lesions present over buccal mucosa and base of the tongue 6 months back. But bolt out of blue he developed oral squamous cell carcinoma with complete resolution of other lesions of pemphigus in oral mucosa. On examination, a single ulcero-indurative lesion was present on the right lateral border of tongue. Routine as well as specific investigations including histopathology and DIF were done. The literature regarding risk of malignancy with rituximab and pemphigus vulgaris was reviewed. Results: Histopathology confirmed the diagnosis of oral squamous cell carcinoma and DIF findings for pemphigus were negative. As per the literature reviewed, most common adverse effect reported with rituximab was infusion-related reactions and those related to immunosuppression. Only few studies evaluated the risk of malignancies with rituximab. The time interval between development of malignancy with rituximab was quoted as 5 months in one of the articles with cutaneous squamous cell carcinoma being the most common malignancy. Role of various desmoglein molecules has been proposed in oral squamous cell carcinoma, and decrease in levels of desmoglein-3 molecule has been suggested to be associated with development of poorly differentiated carcinoma. Conclusion: Though development of SCC might have been the consequence of use of intra-lesional rituximab, with no randomized trials establishing risk of malignancies in pemphigus, it might have been just a mere coincidence. Thus this case serves as a lightning bolt to constitute randomized controlled trials to constitute a good quality evidence for the safe and cautious use of rituximab in pemphigus.

CATEGORY III: Current treatment guidelines and challenges Primary Vulvovaginal Melanoma. A Twelve-Year Multidisciplinary Team Experience

G. Moreno,1 J. Hurren,2 D. McCormick,3 B. Hughes1 Dermatology Department, St Maryâ&#x20AC;&#x2122;s Hospital, Portsmouth, UK; 2Plastics/Surgical Oncology Department, Queen Alexandra Hospital, Portsmouth, UK; 3Histopathology Department, Queen Alexandra Hospital, Portsmouth, UK 1

Introduction: Vulvovaginal melanoma is a rare skin malignancy with poor prognosis. Early diagnosis and surgical treatment provide the best chance of cure. Close monitoring is essential to recognise early possible recurrences. Objective: We aim to present our experience with diagnosis, treatment and outcome with an emphasis on close monitoring aided by serial medical photography. Methods: A retrospective review of medical and pathology records was conducted and data extracted for analysis. Demographics, clinicopathological and treatment data with overall survival were recorded.

Clinical photography (when available) was reviewed. The revised 2002 AJCC classification was used to determine the stage of disease. Results: Between 2002 and 2014, eleven cases of primary vulvovaginal melanoma were identified.

Mean age at diagnosis was 65.8 years (range 41-88). Mean time from onset of symptoms to presentation was 6.5 months (1.5-12). Signs and symptoms included dyspigmentation, itch, pain, discharge, ulceration, and bleeding.

Medical photography was obtained in 5/11 patients. A mean Breslow depth of 3.2 mm was noted in invasive tumours. Wide local excision was the preferred treatment, while radical surgery was performed in 4/11 to control locally advanced disease. Sentinel lymph node biopsy was performed in 1 patient. Radiation and chemotherapy were largely reserved for palliation of symptoms. Conclusion: Early detection and close monitoring of premalignant lesions can be assisted by serial photography. We have set up this as the standard of care for any vulval and low vaginal melanocytic lesion.

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CATEGORY III: Current treatment guidelines and challenges Preliminary Results of a Proof-of-Concept Trial of Intratumoral (IT) Administration of Glucopyranosyl Lipid Adjuvant (GLA), a Toll-Like Receptor-4 (TLR-4) Agonist, in Patients With Merkel Cell Carcinoma (MCC) Shailender Bhatia,1 Dafina Ibrani,1 Olga Afanasiev,1 Natalie Vandeven,1 David Byrd,1 Upendra Parvathaneni,1 Michael Donahue,1 Frank J. Hsu,2 Barry Storer,1 David Koelle,1 Paul Nghiem1 1 University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA; 2Immune Design, Seattle, WA

Background: MCC is an aggressive skin cancer with limited therapeutic options. Despite persistent expression of the non-self Merkel cell polyomavirus (MCPyV) proteins, MCC tumors are able to evade the immune surveillance mechanisms through multiple interrelated mechanisms: down-regulation of MHC class I expression, strikingly sparse IT infiltrates of T cells, and immune exhaustion of infiltrating T-lymphocytes (TIL). Therapeutic immune modulation of the MCC tumor microenvironment using IT injections of GLA, a synthetic TLR-4 agonist, may overcome these evasion mechanisms via immune responses against the tumor antigens. Objectives: This proof-of-concept trial (NCT02035657) is a single center study to test the safety, clinical efficacy and immunologic effects of IT administration of GLA in MCC patients (pts). Methods: 10 MCC pts will be enrolled to receive multiple IT injections into a superficial injectable tumor. Pts with localized MCC (cohort A) may receive 1 cycle of GLA injections (on days 1, 8) followed by definitive surgery and/or radiation therapy (RT) starting during week 4; pts with distant metastatic disease (cohort B) may receive multiple cycles of GLA injections (days 1, 8, 22) every 6 weeks (up to 4 cycles, may be in conjunction with RT). Serial tumor biopsies and peripheral blood samples will be collected in all pts at baseline and posttreatment. Results: Four pts have been enrolled to date (2 in each cohort). Treatment has been tolerated well with no grade 3/4 or serious adverse events (AEs). Treatment-related AEs have all been grade 1 (inflammation, pain and bruising at the injection site), except transient grade 2 inflammation at the injected inguinal lymph node in patient 002 (in cohort A), who interestingly also had a pathologic complete remission of the involved node after only 2 GLA injections. Both pts in cohort A successfully completed definitive therapy without any delays. Both pts in cohort B successfully completed cycle 1 but had progressive disease at the first restaging evaluation. We identified MCPyV-specific CD8 T cells isolated from TIL and peripheral blood, and correlative immune studies tracking these cells in terms of frequency and functional status are in progress. Conclusion: Preliminary results indicate that IT immunotherapy with GLA injections in MCC patients is tolerated well and may induce antitumor responses. Updated clinical and correlative results will be presented at the meeting.

CATEGORY V: Ongoing pivotal clinical trials A Phase 2, Randomized, Double-Blind Study of Sonidegib (LDE225) in Patients (pts) With Advanced Basal Cell Carcinoma (BCC): BOLT 12-Month Update

Michael Migden,1 Alexander Guminski,2 Ralf Gutzmer,3 Luc Dirix,4 Karl Lewis,5 Patrick Combemale,6 Robert Herd,7 Sven Gogov,8 Tingting Yi,9 Manisha Mone,9 Ragini Kudchadkar,10 Uwe Trefzer,11 John Lear,12 Dalila Sellami,9 Reinhard Dummer13 1 The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Royal North Shore Hospital, St Leonards, New South Wales, Australia; 3Medizinische Hochschule Hannover, Hannover, Germany; 4Sint-Augustinus Ziekenhuis, Antwerp, Belgium; 5University of Colorado Cancer Center, Aurora, CO, USA; 6Centre Leon Bérard, Lyon, France; 7 Glasgow Royal Infirmary, Glasgow, UK; 8Novartis Pharma AG, Basel, Switzerland; 9Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 10Moffitt Cancer Center, Tampa, FL, USA; 11Dermatologikum Berlin, Berlin, Germany; 12 Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; 13UniversitätsSpital Zürich – Skin Cancer Center University Hospital, Zürich, Switzerland Hedgehog (Hh) signaling, aberrantly activated in ≥95% of BCCs, is blocked by sonidegib, a selective smoothened inhibitor. BOLT, a study of 2 dosages of sonidegib in pts with advanced BCC (NCT01327053), met its primary end point of objective response rate (ORR) ≥30% (locally advanced BCC [LaBCC] and metastatic BCC [mBCC] combined) in both arms using data collected up to 6 mo after the last pt randomization (cutoff, Jun 28, 2013; median

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CATEGORY V: Ongoing pivotal clinical trials follow-up, 13.9 mo; Migden, ASCO 2014). Pts with LaBCC (n=194), not amenable to curative surgery or radiation, or mBCC (n=36) were randomized 1:2 to receive sonidegib 200 or 800 mg daily. ORR (complete response [CR] or partial response [PR]), CR rate, time to tumor response (TTR), duration of response (DOR), and progression-free survival (PFS) were assessed according to modified RECIST (LaBCC) or RECIST v1.1 (mBCC). Efficacy and safety data up to 12 mo after the last pt randomization (cutoff, Dec 31, 2013; median follow-up, 20.0 mo) are reported.

Median duration of exposure was 11.0 (200 mg) and 6.6 (800 mg) mo. ORRs (95% CI) per central review for 200 vs 800 mg were 57.6% (44.8%-69.7%; n=66) vs 43.8% (35.0%-52.8%; n=128) for LaBCC and 7.7% (0.2%-36.0%; n=13) vs 17.4% (5.0%-38.8%; n=23) for mBCC. Respective ORRs (95% CI) per investigator review were 71.2% (58.7%-81.7%; n=66) vs 57.8% (48.8%-66.5%; n=128) and 23.1% (5.0%-53.8%; n=13) vs 34.8% (16.4%-57.3%; n=23). Remaining data are per investigator. Disease control (CR + PR + stable disease) rates for 200 vs 800 mg were 92.4% vs 85.9% (LaBCC) and 84.6% vs 82.6% (mBCC). Median TTR (95% CI) for 200 vs 800 mg was 2.5 (1.9-3.7) vs 1.9 (1.4-2.0) mo for LaBCC and 1.0 (0.9-3.7) vs 2.7 (1.0-5.6) mo for mBCC. Median DOR (95% CI) was 20.2 (not estimable [NE]; 200 mg) and 19.8 (15.7-20.5; 800 mg) mo for LaBCC and 17.7 (NE; 200 mg) and 10.2 (NE; 800 mg) mo for mBCC. Median PFS (95% CI) was 22.0 (NE; 200 mg) and 21.5 (NE; 800 mg) mo for LaBCC and 13.1 (9.2-18.6; 200 mg) and 14.3 (11.1-20.2; 800 mg) mo for mBCC. The safety findings remained consistent with longer follow-up. Adverse events (AEs) were manageable; the most common AEs (any grade; 200/800 mg) included muscle spasms (52%/69%), alopecia (49%/57%), dysgeusia (41%/60%), and nausea (35%/47%). An additional 6 mo of follow-up provides further evidence that sonidegib treatment leads to meaningful disease control, with sustained DOR and prolonged PFS in pts with advanced BCC. The 200-mg dose had a more favorable benefit-risk profile.

BRIM8: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Vemurafenib Adjuvant Therapy in Patients With Surgically Resected, Cutaneous BRAF-Mutant Melanoma at High Risk for Recurrence (NCT01667419)

Grant R. Goodman,1 Dirk Schadendorf,2 Michele Maio,3 Mario Mandalà,4 Betty J. Nelson,1 Karl D Lewis5 1 Genentech, Inc, South San Francisco, California, USA; 2University Hospital Essen, Essen, Germany; 3Papa Giovanni XXIII Hospital, Bergamo, Italy; 4University Hospital, Siena, Italy; 5University of Colorado, Denver, Aurora, Colorado, USA Approximately 50% of melanomas have a mutation in the BRAF gene. The oral BRAF inhibitor vemurafenib has shown meaningful clinical benefit in BRAF V600–mutated, locally advanced/unresectable or metastatic melanoma.

For patients with resected melanoma, interferon α-2b is the only widely approved adjuvant therapy; however, its use is limited by modest improvement in disease recurrence and high incidence of severe adverse effects that lead to treatment discontinuation in up to one-third of patients. BRIM8 is a phase 3, international, multicenter, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of adjuvant vemurafenib therapy. Patients ≥18 years with completely resected, histologically confirmed, stage IIC or III BRAF V600 mutation–positive (as detected by the cobas® BRAF V600 Mutation Test [Roche Molecular Diagnostics]) melanoma of cutaneous origin are eligible. Patients without evidence of regional lymph node involvement must undergo sentinel lymph node biopsy, and those with evidence of regional or sentinel lymph node involvement must undergo complete regional lymphadenectomy. Patients with a history of systemic therapy for treatment or prevention of melanoma are ineligible. Two cohorts (C) will enroll 725 patients: C1, 500 patients with stage IIC, IIIA (nodal metastasis >1 mm in diameter), or IIIB cutaneous melanoma; C2, 225 patients with stage IIIC cutaneous melanoma. Patients will be randomized 1:1 to receive vemurafenib (960 mg bid) or placebo for 52 weeks, with randomization stratified by stage and region (C1) or by region alone (C2). Primary efficacy outcome measure is investigator-assessed disease-free survival. Secondary efficacy outcome measures include overall and distant metastasis-free survival. Safety, pharmacokinetic, and patient-reported outcomes will also be assessed.

Reused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting.

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CATEGORY V: Ongoing pivotal clinical trials NEMO: A Phase 3 Trial of Binimetinib (MEK162) Versus Dacarbazine in Patients With Advanced NRAS-Mutant Melanoma Who Are Untreated or Have Progressed After Any Number of Immunotherapy Regimens

Reinhard Dummer,1 Paolo A. Ascierto,2 Georgina V. Long,3 Dirk Schadendorf,4 Ana Arance,5 Petr Arenberger,6 Lev Demidov,7 Ralf Gutzmer,8 Mario Mandalà,9 Michele Maio,10 Frank Meiss,11 Piotr Rutkowski,12 Pascal Wolter,13 Naoya Yamazaki,14 Ernesto Wasserman,15 James Ford,15 Marine Weill,15 Keith Flaherty16 1 University Hospital Zurich, Zurich, Switzerland; 2Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; 3Melanoma Institute Australia and The University of Sydney, Sydney, Australia; 4University Hospital Essen, Essen, Germany; 5Hospital Clínic, Barcelona, Spain; 6Charles University, 3rd Medical Faculty, Prague, Czech Republic; 7N. N. Blokhin Russian Cancer Research Center, Moscow, Russia; 8Hannover Skin Cancer Center, Hannover Medical School, Hannover, Germany; 9Papa Giovanni XXIII Hospital, Bergamo, Italy; 10University Hospital of Siena, Siena, Italy; 11Freiburg University Medical Center, Freiburg, Germany; 12Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; 13University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium; 14National Cancer Center Hospital, Tokyo, Japan; 15 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 16Massachusetts General Hospital, Boston, MA, USA. Background: The tumors of patients with melanoma often harbor mutations in the mitogen-activated protein kinase-signaling pathway family members BRAF or NRAS. Mutations in the NRAS gene are observed in about 20% of melanoma cases. Compared with BRAF-mutant and wild-type disease, NRAS-mutant melanoma has been associated with increased proliferation, thicker primary tumors, higher rates of brain metastasis, and poorer prognosis. In a large retrospective analysis (n=677), NRAS mutations were shown to be independently predictive of poor survival in patients with cutaneous melanoma (Jakob et al, 2011). There are no approved targeted therapies specifically for NRAS-mutant melanoma, and treatments are currently limited to chemotherapy and/or immunotherapy in this patient subset. Binimetinib (MEK162) is a potent and selective inhibitor of MEK1/2 that has demonstrated promising phase 2 clinical activity in NRAS-mutant melanoma. Here we describe the “NRAS mElanoma and MEK inhibitOr” (NEMO) trial, an ongoing phase 3 study designed to compare the efficacy of binimetinib vs dacarbazine in patients with metastatic NRAS-mutant melanoma (NCT01763164). Trial Design: The NEMO trial is a 2-arm, open-label, 2:1 randomized trial comparing binimetinib vs dacarbazine in patients with metastatic NRAS-mutant melanoma. Eligible patients must have advanced unresectable or metastatic cutaneous melanoma or melanoma of unknown primary origin with a documented NRAS Q61 mutation (by central molecular screening) that was previously untreated or has progressed after any number of immunotherapy regimens. Patients are stratified by stage, performance status, and prior immunotherapy. The primary end point of the study is progression-free survival, and secondary end points include overall survival, overall response, disease control rate, safety, and quality of life. Patients receive oral binimetinib at 45 mg twice daily or dacarbazine dosed intravenously at 1000 mg/m2 once every 3 weeks. The phase 3 NEMO trial is designed to enroll 393 patients and is currently recruiting patients at more than 150 centers worldwide. The overall study design, eligibility criteria, methodology, and end points of this trial will be presented.

CATEGORY VI: Targeted therapy Safety and Efficacy of Vismodegib in Patients With Basal Cell Carcinoma Nevus Syndrome: Analysis of the ERIVANCE BCC and Expanded Access Studies

Anne L.S. Chang,1 Sarah T. Arron,2 Michael R. Migden,3 James A. Solomon,4-6 Simon Yoo,7 Bann-Mo Day,8 Edward McKenna,8 Aleksandar Sekulic9 1 Stanford University, Redwood City, California, USA; 2University of California, San Francisco, San Francisco, California, USA; 3The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 4Ameriderm Research, Ormond Beach, Florida, USA; 5University of Central Florida, Orlando, Florida, USA; 6University of Illinois, Urbana, Illinois, USA; 7 Northwestern University, Chicago, Illinois, USA; 8Genentech, Inc, South San Francisco, California, USA; 9Mayo Clinic, Scottsdale, Arizona, USA

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CATEGORY VI: Targeted therapy Background: Aberrant activation of the Hedgehog pathway (HhP) is a key driver in the pathogenesis of basal cell carcinoma (BCC), including patients (pts) with BCC nevus syndrome (BCCNS). Vismodegib (VISMO), the first HhP inhibitor to be FDA approved, represents a new treatment option for pts with advanced (a) BCC, including local advanced (laBCC) or metastatic (mBCC) disease. VISMO is indicated for pts with aBCC that has recurred after surgery or who are not candidates for surgery and radiation. We present the efficacy and safety of VISMO in BCCNS pts with aBCC across 2 trials – ERIVANCE BCC trial and the expanded access study (EAS). Methods: ERIVANCE BCC and EAS enrolled pts with aBCC. The EAS was terminated early upon FDA approval of VISMO. All pts received oral VISMO 150 mg daily until disease progression or intolerable toxicity. Response in both studies for mBCC pts was evaluated using RECIST v1.0. Response for laBCC pts was evaluated by a novel composite end point in ERIVANCE BCC and by RECIST v1.0 in the EAS. Response was assessed every 8 wks in ERIVANCE BCC and every 8-16 wks in the EAS. Safety assessments (NCI-CTCAE v3.0) were performed monthly in both trials. BCCNS diagnosis was based on medical history at enrollment. Due to described differences in response assessment/schedule, pts with BCCNS were not pooled across trials. Analytic cohorts for BCCNS and sporadic aBCC were created within each trial for comparison using descriptive statistical methods. Results: 22/0 and 12/7 BCCNS pts (laBCC/mBCC) were enrolled in ERIVANCE BCC and EAS, respectively. Baseline characteristics included median age (47/52 years), female sex (45%/50%), ECOG PS 0-1 (100%/100%), prior surgery (96%/100%), prior radiotherapy (5%/8%), and prior systemic therapy (23%/17%). Median treatment durations were 10.5 and 5 months, respectively, and similar to treatment duration of sporadic aBCC pts within each trial. Best objective response rate (BORR) (investigator assessed) in laBCC cohorts was 81% (17/21 pts) in ERIVANCE BCC and 33% (4/12 pts) in EAS. The BORR for the sporadic laBCC cohort was 50% in both studies. No BCCNS pts with mBCC were enrolled in ERIVANCE BCC. BORR in the EAS mBCC cohort was 50% (3/6 pts) compared with 46% and 27% in sporadic mBCC cohorts in ERIVANCE BCC and EAS, respectively. Most frequent adverse events (AEs) included alopecia (86%/58%), muscle spasms (77%/63%), weight decrease (68%/5%), and dysgeusia (59%/74%). 9 (41%) and 2 (16%) pts had grade ≥3 AEs in each study, respectively. Incidence and severity of AEs were comparable with the sporadic aBCC cohort of both trials. Conclusion: VISMO demonstrated clinical activity across analytic cohorts and studies. Observed variability (ORR and AEs) across cohorts is likely due to small sample size, differences in response criteria, assessment schedule, treatment duration, and length of follow-up. The safety profile of VISMO was similar between pts with BCCNS and pts with sporadic aBCC.

Safety and Efficacy of Vismodegib in Elderly Patients: Analysis of the ERIVANCE BCC and Expanded Access Studies

Anne L.S. Chang,1 Karl Lewis,2 Sarah T. Arron,3 Michael R. Migden,4 James A. Solomon,5-7 Simon Yoo,8 Bann-Mo Day,9 Edward McKenna,9 Aleksandar Sekulic10 1 Stanford University, Redwood City, California, USA; 2University of Colorado Cancer Center, Aurora, Colorado, USA; 3 University of California, San Francisco, San Francisco, California, USA; 4The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 5Ameriderm Research, Ormond Beach, Florida, USA; 6University of Central Florida, Orlando, Florida, USA; 7University of Illinois, Urbana, Illinois, USA; 8Northwestern University, Chicago, Illinois, USA; 9 Genentech, Inc, South San Francisco, California, USA; 10Mayo Clinic, Scottsdale, Arizona, USA Methods: ERIVANCE BCC and EAS enrolled pts with laBCC or mBCC. The EAS was terminated early upon FDA approval of VISMO. All pts received oral VISMO 150 mg daily until disease progression/intolerable toxicity. Safety assessments (NCI-CTCAE v3.0) were performed monthly in both trials. Efficacy assessment was (1) RECIST v1.0 for mBCC in both studies, (2) novel composite end point for laBCC in ERIVANCE BCC and by RECIST v1.0 for laBCC in EAS. Response assessments were performed every 8 weeks in ERIVANCE BCC and every 8-16 weeks in EAS. Because of differences in treatment duration and response assessment, data were not pooled across trials. Analytic cohorts for pts aged <65 and ≥65 years were created within each trial for comparison using descriptive statistical methods. Background: Aberrant activation of the Hedgehog pathway (HhP) is a key driver in the pathogenesis of basal cell carcinoma (BCC). Vismodegib (VISMO), the first HhP inhibitor to be FDA approved, is a new treatment option for patients (pts) with advanced (a) BCC and is indicated for pts with aBCC (including locally advanced [la]

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CATEGORY VI: Targeted therapy or metastatic [m] disease) that has recurred after surgery or who are not candidates for surgery and radiation. BCC, particularly aBCC, are prevalent among the elderly. We present analyses of the safety and efficacy of VISMO in pts aged ≥65 years vs pts <65 years across 2 trials – ERIVANCE BCC trial and the expanded access study (EAS). Results: 104 aBCC pts were enrolled in ERIVANCE BCC (33 mBCC/71 laBCC) and 119 aBCC pts were enrolled in the EAS (57 mBCC/62 laBCC). ERIVANCE BCC included 57 pts <65 years and 47 pts ≥65 years. The EAS included 66 pts <65 years and 53 pts ≥65 years. Of laBCC pts aged <65 vs ≥65 years in ERIVANCE BCC, 45% vs 46% were female.

In the EAS, 43% vs 15% were female. Of the mBCC pts aged <65 vs ≥65 years in ERIVANCE BCC, 26% vs 29% were female. In the EAS, 26% vs 15% were female. Median treatment durations in aBCC pts aged <65 and ≥65 years were 10.2 and 9.2 months in ERIVANCE BCC, respectively, and 5.4 and 5.5 months in EAS, respectively. The most frequent adverse events (AEs) in aBCC pts aged <65 vs ≥65 years in ERIVANCE BCC and the EAS, respectively, were muscle spasms (72% vs 64%/71% vs 70%), dysgeusia (51% vs 51%/73% vs 70%), and alopecia (75% vs 49%/61% vs 55%). Grade 3-5 AEs in aBCC pts aged <65 vs ≥65 years occurred in 35% vs 51% in ERIVANCE BCC and 21% vs 25% in EAS, respectively. Similarly, AEs leading to treatment discontinuation occurred in 11% vs 15% and 2% vs 11% of aBCC pts aged <65 vs ≥65 years, respectively. Best objective response rates (BORRs) by investigator (INV) assessment were 73% and 47% in laBCC pts aged <65 years and 47% and 46% in laBCC pts aged ≥65 years in ERIVANCE BCC and EAS, respectively. BORRs by INV assessment were 53% and 29% in mBCC pts aged <65 years and 36% and 33% in mBCC pts aged ≥65 years in ERIVANCE BCC and EAS, respectively. Conclusion: VISMO demonstrated similar safety profiles and clinical activity in pts <65 and ≥65 years across both studies.

Treatment of Basal Cell Carcinoma With Oral Vismodegib Preceding Mohs Micrographic Surgery Excision: Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study (NCT01898598)

Abel Torres,1 Jean Tang,2 Sarah Arron,3 Michael Migden,4 Clay Cockerell,5 Steve Lee,6 Edward McKenna,6 Diana Chen6 Loma Linda University Medical Center, Loma Linda, California, USA; 2Stanford University Medical Center, Redwood City, California, USA; 3University of California, San Francisco, San Francisco, California, USA; 4University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 5University of Texas Southwestern Medical Center, Dallas, Texas, USA; 6 Genentech, Inc, South San Francisco, California, USA 1

Background: Basal cell carcinoma (BCC) is the most common malignancy in the United States. Almost all sporadic BCCs have mutations in the Hedgehog (Hh) signaling pathway. Vismodegib is an oral Hh pathway inhibitor approved by the FDA for the treatment of adults with metastatic BCC, or with locally advanced BCC that has recurred following surgery, or who are not candidates for surgery or radiation therapy. Treatment goals for operable BCC focus on complete tumor removal and minimization of functional and aesthetic defects. Mohs micrographic surgery (MMS) represents the most definitive treatment method for BCC, with visualization of the entire surgical margin ensuring complete tumor removal with maximal preservation of surrounding tissue. Clinical studies have demonstrated that vismodegib is safe and effective in shrinking the majority of locally advanced BCC tumors; however, it is unknown whether vismodegib may be used as an adjunct to surgery and if discontiguous subclinical tumor (skip areas) remains following treatment.

This study will enroll patients whose target BCC may be excised by MMS to evaluate whether vismodegib can safely and effectively be used before surgery to shrink tumors and reduce the surgical defect size. Methods: The trial will consist of a 12-week study drug treatment period followed by MMS within 2 weeks of the last study drug treatment, postsurgical follow-up visits to assess for recurrence, and a 52-week follow-up period for safety after the final dose of study drug. Men and women at least 18 years of age with an untreated, biopsy-confirmed target BCC at least 50 mm2 and less than 2.0 cm in diameter will be enrolled. Patients will be randomly assigned 2:1 to receive once-daily oral vismodegib or placebo and stratified at randomization by presence or absence of morpheaform/infiltrative BCC subtype. Computer-aided planimetry of the entire original tumor area will be used to measure expected and actual surgical defect areas.

After the Mohs surgeon has established clear margins, MMS tissue specimens will be submitted to an independent dermatopathologist for determination of skip areas. The primary objective will be to compare the efficacy of vismodegib to placebo as adjunctive presurgical treatment before MMS, as assessed by the percentage change in expected surgical defect area at the MMS excision. Secondary objectives will include an assessment of the actual tumor-free excision area, presence/absence of skip areas, and safety. An interim analysis will be performed when the first 38 patients have completed the MMS visit or withdrawn early. The study is currently open at 19 sites.

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CATEGORY VI: Targeted therapy Hedgehog Pathway Inhibition With Sonidegib (LDE225) in Patients With Advanced Basal Cell Carcinoma

Reinhard Dummer,1 Ralf Gutzmer,2 Michael Migden,3 Martin Kaatz,4 Carmen Loquai,5 Alex Stratigos,6 Hans-Joachim Schulze,7 Ruth Plummer,8 Celine Pallaud,9 Sven Gogov,9 Mahtab Marker,10 Manisha Mone,10 Anne Lynn S. Chang,11 Frank Cornélis,12 John Lear,13 Dalila Sellami,10 Alexander Guminski14 1 UniversitätsSpital Zürich – Skin Cancer Center University Hospital, Zürich, Switzerland; 2Medizinische Hochschule Hannover, Hannover, Germany; 3University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 4SRH Wald-Klinikum Gera GmbH, University Hospital Jena, Gera, Germany; 5University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany; 6Andreas Sygros Hospital, University of Athens, Athens, Greece; 7Fachklinik Hornheide, Münster, Germany; 8Northern Centre for Cancer Care, Freeman Hospital, Newcastle Upon Tyne, UK; 9Novartis Pharma AG, Basel, Switzerland; 10Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; 11Stanford University School of Medicine, Redwood City, California, USA; 12Cliniques Universitaires Saint-Luc, Bruxelles, Belgium; 13Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; 14Royal North Shore Hospital, St Leonards, New South Wales, Australia The Hedgehog (Hh) pathway is aberrantly activated in ≥95% of basal cell carcinomas (BCCs); expression of GLI1 is a marker for Hh pathway activation. Sonidegib, which blocks Hh signaling by inhibiting smoothened, provided meaningful disease control in patients (pts) with advanced BCC in a phase 2 study (BOLT; NCT01327053). Associations of GLI1 levels with clinical outcomes are presented here. Pts with locally advanced BCC (LaBCC) not amenable to curative surgery or radiotherapy (n=194) or metastatic BCC (mBCC; n=36) were randomized 1:2 to receive sonidegib 200 or 800 mg once daily. Clinical response was assessed by central review using modified RECIST (LaBCC) or RECIST 1.1 (mBCC). Exploratory analyses were performed, including assessment of GLI1 levels in tumor samples (137 LaBCC; 13 mBCC) at baseline (BL), wk 9, and wk 17 by qRT-PCR; tumor presence in samples was confirmed prior to GLI1 analyses. GLI1 levels were reduced from BL at wk 9 and 17 with both sonidegib doses (Table). With adjustments for dose, BCC subtype, and multiple testing, similar GLI1 BL levels and decreases from BL at wk 9 and 17 were seen for LaBCC (aggressive and nonaggressive) and mBCC. At wk 17, reductions from BL in GLI1 levels were seen with both doses in pts with disease control (complete or partial response [CR or PR] or stable disease [SD]).

Among pts with greater GLI1 inhibition from BL at wk 17, those in the 800-mg group appeared to have a higher risk of grade ≥2 creatine kinase elevation than those in the 200-mg group. Sonidegib substantially reduced GLI1 levels in pts with advanced BCC, with similar results across doses, time points, and BCC subtypes. Pts with disease control showed GLI1 reductions from BL; 1 pt with progressive disease (PD) had increased GLI1 from BL. This supports the potential of sonidegib as an option for treating advanced BCC. Sonidegib 200 mg

Sonidegib 800 mg

Median GLI1 % Change (95% CI)

Parameter

Na

Na

Time pointb BL Wk 9 Wk 17

67 55 48

–91.07 (–95.26, –86.89)c –93.75 (–97.08, –90.41)c

83 63 50

Best overall response (wk 17)e CR PR SD PD Unknown

1 23 21 1 2

–99.47 –90.79 (–95.49, –64.40) –96.58 (–98.13, –76.51) +10.19 –94.24 (–99.83, –88.66)

0 26 15 0 9

Median GLI1 % Change (95% CI)

–96.16 (–97.85, –94.48)c,d –96.02 (–98.09, –93.95)c,d

–96.96 (–98.80, –85.84) –96.07 (–99.31, –62.11) –91.81 (–97.48, –34.72)

Pts with valid biomarker samples; bLongitudinal analysis of GLI1 changes; cP<.0001 vs BL; dP>.05 vs 200 mg, with adjustment for multiple testing; eSummary statistics of GLI1 changes at wk 17.

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CATEGORY VI: Targeted therapy Quality of Life With Sonidegib (LDE225) Treatment in Patients With Advanced Basal Cell Carcinoma

Alexander Guminski,1 Michael Migden,2 Ralf Gutzmer,3 Karl Lewis,4 Luc Dirix,5 Ragini Kudchadkar,6 Robert Herd,7 Sven Gogov,8 Tingting Yi,9 Keiko Higuchi,9 Patrick Combemale,10 Uwe Trefzer,11 John Lear,12 Dalila Sellami,9 Reinhard Dummer13 1 Royal North Shore Hospital, St Leonards, New South Wales, Australia; 2The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 3Medizinische Hochschule Hannover, Hannover, Germany; 4University of Colorado Cancer Center, Aurora, Colorado, USA; 5Sint-Augustinus Ziekenhuis, Antwerp, Belgium; 6Moffitt Cancer Center, Tampa, Florida, USA; 7 Glasgow Royal Infirmary, Glasgow, United Kingdom; 8Novartis Pharma AG, Basel, Switzerland; 9Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; 10Centre Leon Bérard, Lyon, France; 11Dermatologikum Berlin, Berlin, Germany; 12Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; 13UniversitätsSpital Zürich – Skin Cancer Center University Hospital, Zürich, Switzerland Advanced basal cell carcinoma (BCC) can lead to reduced quality of life (QOL) in patients (pts) due to morbidity and disfigurement. The Hedgehog (Hh) pathway is aberrantly activated in ≥95% of BCCs; sonidegib blocks the Hh pathway via inhibition of smoothened. In a phase 2 study of sonidegib (BOLT; NCT01327053), meaningful disease control was achieved in pts with advanced BCC. The impact on pt-reported QOL is presented here. Pts with locally advanced BCC (LaBCC) not amenable to curative surgery or radiotherapy (n=194) or metastatic BCC (mBCC; n=36) were randomized in a 1:2 ratio to receive sonidegib 200 or 800 mg daily. Assessment of QOL was based on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (C30) and the associated Head and Neck Cancer module (H&N35). Prespecified subscales included physical functioning, social functioning, pain, and fatigue for C30 and trouble with social contact, head and neck pain, and weight loss for H&N35. C30 and H&N35 were completed at baseline (BL) and ≥1 post-BL time by 89% and 90% of pts, respectively. In a majority of pts, scores were maintained or improved compared with BL with both sonidegib doses in LaBCC and mBCC. With 200 mg, improvement in C30 scores was seen in pts (LaBCC, mBCC) for physical functioning (36%, 69%), social functioning (26%, 38%), pain (31%, 46%), and fatigue (38%, 46%); in additional pts, scores were maintained for physical functioning (48%, 23%), social functioning (66%, 46%), pain (59%, 54%), and fatigue (43%, 46%). Improvement in H&N35 scores was seen for trouble with social contact (43%, 31%), head and neck pain (18%, 23%), and weight loss (16%, 17%); scores were maintained in additional pts for trouble with social contact (47%, 54%), head and neck pain (78%, 69%), and weight loss (84%, 67%). In general, maintenance of scores in each scale was observed through week 73 with both doses in a descriptive analysis of mean scores. Median time (mo) to deterioration (>10-point worsening without subsequent improvement) with 200 mg was 13.7 for fatigue, 16.6 for weight loss, and not estimable (NE) for other scales; with 800 mg, median time (mo) to deterioration was 11.1 for physical functioning, 11.3 for social functioning, 5.6 for fatigue, 16.5 for weight loss, and NE for other scales. In summary, pts treated with sonidegib had maintenance or improvement in QOL, supporting the treatment effect observed in the BOLT study and good tolerability of sonidegib.

Longitudinal Safety Modeling and Simulation for Optimization of Vismodegib Treatment Interruption in a Phase 2 Study of Operable Basal Cell Carcinoma

Howard Sofen,1 Tong Lu,2 Ivor Caro,2 Jin Jin2 UCLA School of Medicine, Los Angeles, California, USA; 2Genentech, Inc, South San Francisco, California, USA

1

Background: Vismodegib (VISMO), the first FDA-approved Hedgehog pathway inhibitor, is indicated for adults with metastatic or locally advanced basal cell carcinoma (BCC) that has recurred after surgery or who are not candidates for surgery and radiation; it provides a new treatment option for patients (pts) with advanced BCC. Most common adverse drug reactions (ADRs) (>30%) included muscle spasms, alopecia, dysgeusia, weight loss, fatigue, and nausea.

To explore the effect of VISMO treatment interruption/discontinuation (I/D) on the ADRs including muscle spasms and dysgeusia/ageusia, we used longitudinally ordered categorical models in a phase 2 study with varying treatment durations and follow-up in pts with operable BCC. Methods: Pts received VISMO (150 mg QD): cohort (C)1, 12

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CATEGORY VI: Targeted therapy weeks (wks); C2, 12 wks with 24 wks observation (obs); or C3, 8 wks with 4 wks obs then 8 wks. Individual pharmacokinetic (PK) profiles for unbound VISMO were predicted based on a previous population PK model incorporating individual covariates and used in this PK/AE analysis in NONMEM (Laplacian method). Results: 24 pts enrolled in C1, 25 in C2, and 25 in C3. 24 pts in each cohort reported any adverse events, the most frequently reported (>30% in any individual cohort) including: C1, muscle spasms (19 pts; 79%), ageusia (10 pts; 42%), dysgeusia (9 pts; 38%), and alopecia (8 pts; 33%); C2, muscle spasms (19 pts; 76%), alopecia (17 pts; 68%), and dysgeusia (13 pts; 52%); C3, muscle spasms (18 pts; 72%), alopecia (18 pts; 72%), and dysgeusia (15 pts; 60%). The median duration of AEs was approximately 20 days for muscle spasm and 35 days for dysgeusia/ageusia. Simulations showed that after 12 wks of VISMO, 6 wks of I/D could lead to complete resolution of all grades of muscle spasm in 80% of pts and 4 wks of I/D could lead to significant improvement without grade ≥2 muscle spasms in 95% of pts. For dysgeusia/ageusia, a 12-wk I/D could lead to complete resolution of all grades of dysgeusia/ageusia in 80% of pts, and a 6-wk I/D could lead to a significant improvement without grade ≥2 dysgeusia/ageusia in 95% of pts. Conclusion: Longitudinal PK/PD modeling indicates that 4 to 6 wks and 6 to 12 wks of treatment I/D may lead to significant improvement and complete resolution of ADRs typically associated with VISMO, respectively. Such data may enable the optimization of VISMO treatment interruption.

CATEGORY VII: Emerging translational data – impact on future therapy High-Dose (HD) IL-2 Immunotherapy for Metastatic Melanoma (mM) in the Era of Checkpoint Inhibitors and Targeted Therapies: Analysis of the PROCLAIM 2007-2012 National Registry

Gregory A. Daniels,1 Michael K. Wong,2 Howard L. Kaufman,3 David F. McDermott,4 Michael A. Morse,5 Sandra Aung6 1 University of California, San Diego; 2University of Southern California; 3Rutgers Cancer Center; 4Beth Israel Hospital; 5 Duke University Medical Center; 6Prometheus Laboratories Inc.

Background: HD IL-2 has been reported to have an overall response rate (ORR) for mM of 16% and a median OS of 11.4 months (Atkins, 1999); however, the studies that led to its regulatory approval are >15 years old and were performed in an era predating checkpoint inhibition and targeted therapies. Methods: The PROCLAIMSM registry (www.proclaimregistry.com), an HD IL-2 observational database currently with over 38 participating sites, consists of a retrospective cohort (treated 2007-2012) informing an ongoing prospective cohort (>650 patients). We report on the retrospective mM subjects (n=170, 13 sites) with survival status determined as of April 2014 and a median follow-up of 37 months. Sites were encouraged to enroll patients sequentially. Inclusion criteria required that patients have received at least 1 dose of HD IL-2. Results: The ORR for mM in the database, 16%, was similar to the historical rates. All 170 subjects were accounted for, 117 were deceased and 53 were known to be alive. Median OS (mOS) for all patients was 20 months, for patients with complete response (CR) mOS was not reached, for patients with partial response (PR), stable disease (SD), and progressive disease (PD) the mOS was 36.8, 33.3, and 15 months, respectively (Figure 1). The median time on therapy (mTOT) was 1 month (Figure 2), with response typically determined 6-8 weeks after treatment. Comparison of patients who received HD IL-2 as 1st or 2nd line (n=128 and 42, respectively) showed no significant difference in OS between these patients. No deaths due to IL-2–related toxicity were reported in the retrospective cohort. Conclusion: The PROCLAIM registry documents an improvement in OS for patients treated with HD IL-2 as compared to the historical reference standards. Response to HD IL-2 traditionally defined as CR or PR, according to these data, should also include SD, which can be very durable. The observation that 1st and 2nd line HD IL-2 possessed similar OS raises intriguing hypotheses about the sequencing of immunotherapy and targeted therapy in mM and the utility of IL-2 as a salvage option – all of which are currently under examination in the prospective database.

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CATEGORY VII: Emerging translational data – impact on future therapy Continued from page 403

Fig. Fig. 11 Survival Survival bby y RResponse esponse RRate ate

CR, n=7, mOS=NR PR, n=19, mOS=36.8 SD, n=30, mOS=33.3

PD, n=102, mOS = 15.0

0

12

24

36

48

60

72

0.5

Alive, n=117, mTOT=2.6 months (0.5-14) Deceased, n=53, mTOT=0.8 months (0.07-9.2)

0.4

Overall mTOT=0.97 months

0.3 0.2 0.1 0.0

84

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Percent of Survival

Proportion Proportion ofof Patients Patients

0.6

Percent Survival

100 90 80 70 60 50 40 30 20 10 0

Fig. 22 M Median Fig. edian TTime ime oon n TTherapy herapy

Time Since First Dose of IL-2,

Median Time on Therapy (mTOT),

Time Since Months First Dose of IL-2, Months

Median Time Months on Therapy (mTOT), Months

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SCIENTIFIC CONFERENCES 2014-2015

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

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

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

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

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

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

PMO LIVE ABSTRACTS

The Third Annual PMO Live: A Global Biomarkers Consortium Initiative The Third Annual PMO Live: A Global Biomarkers Consortium Initiative (formerly known as Global Biomarkers Consortium) will take place in San Francisco, California, on October 31 â&#x20AC;&#x201C; November 1, 2014. PMO Live is the only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting. The following abstracts will be presented at the meeting.

CATEGORY I: Epidemiology and risk factors Computed Tomography (CT) and Chest X-Ray (CXR) Screening for Lung Cancer: End Points, Outcomes, and Population-Based Screening

Gary M. Strauss,1,2 Lorenzo Dominioni3 1 Tufts University School of Medicine, Boston, Massachusetts, USA; 2Tufts Medical Center, Boston, Massachusetts, USA; 3 University of Insubria, Varese, Italy Background: The National Lung Screening Trial (NLST) generated excitement by demonstrating that CT screening reduces lung cancer mortality in comparison to CXR screening. In randomized population trials (RPTs) on cancer screening, disease-specific mortality is assumed to provide an unbiased measure of screening effectiveness. This is based upon the assumption that randomization produces comparison groups with equal probability of death from the target cancer unless the intervention reduces risk. However, this assumption has been violated in numerous RPTs, leading to uncertainty about the effectiveness of screening for numerous cancers. Objectives of this analysis are to assess whether the mortality end point provided an unbiased measure of screening efficacy in the Mayo Lung Project (MLP) and NLST, the most influential RPTs on CXR and CT screening, respectively. Methods: In MLP, following a normal prevalence CXR, 9192 smokers were randomized to an experimental group (EG) undergoing CXR and cytology every 4 months for 6 years followed by 3 years of observation, or to a control group (CG) observed for 9 years. Controls were advised to undergo annual CXR. In NLST, 53,454 current/former smokers were randomized to EG undergoing annual CT screening or to CG undergoing annual CXR. Participants underwent prevalence screening followed by 2 annual incidence screens. Results: In MLP, nonâ&#x20AC;&#x201C;small cell lung carcinoma (NSCLC) mortality was 13% higher (P=.48), although survival was far superior to EG (P=.0095). NSCLC incidence was 37% higher in EG (P=.0098), leading to the hypothesis that overdiagnosis was responsible for the mortality/survival discrepancy. However, MLP data are inconsistent with overdiagnosis. Randomization failure was responsible for higher NSCLC incidence in EG, confounding the ability of mortality to reflect CXR screening efficacy. Indeed, survival, not mortality, provided an unbiased surrogate for cure in MLP. In NLST, there was a significant 20% lung cancer mortality reduction in EG (P=.0022).

There was also a significant increase in lung cancer incidence in this group (P=.0067). Because CT is more sensitive than CXR, higher incidence of lung cancer is predictable based upon lead time and length biases, and possibly overdiagnosis. However, incidence of the most virulent lung cancers, including small cell lung cancer and NSCLC not otherwise specified, was 16% lower in EG (P=.046). These differences suggest imbalances in randomization. Conclusion: In NLST, lower incidence of lethal lung cancer subtypes in EG predicts for lower lung cancer mortality, independent of CT screening efficacy. Accordingly, lower lung cancer mortality in EG does not provide an unbiased measure of CT screening efficacy. Notwithstanding, stage and case fatality differences support that CT is superior to CXR screening. Population-based screening is mandatory to reduce the global burden of lung cancer mortality among the 1.3 billion cigarette smokers on our planet. CXR screening is a viable option in regions where cost is likely to preclude widespread CT screening.

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CATEGORY II: Molecular biology and pathogenesis – implications for therapy Predictive Molecular Analysis of Regional Lymph Node Metastasis in Melanoma: First Steps to Elimination of Sentinel Lymph Node Biopsy

Collins J,1 George K,2 Stafford C,1 Edenfield J,3 Schammel C,4 Horton S,4 Trocha S5 1 Medical University of South Carolina, Charleston, South Carolina, USA; 2Furman University, Greenville, South Carolina, USA; 3Institute for Translational Oncologic Research, Greenville Health System, Greenville, South Carolina, USA; 4 Pathology Associates, Greenville, South Carolina, USA; 5Greenville Health System, Greenville, South Carolina, USA The incidence of melanoma worldwide has steadily been increasing for decades. Although clinicopathologic and histopathologic characteristics are generally successful in characterizing and classifying melanoma, molecular biomarkers offer a more conclusive prognosis and the opportunity for individualized treatment. We used exome sequencing to identify molecular markers associated with positive lymph nodes in patients with T2 and T3 melanomas (1-4 mm).

Our study population included 9 patients with metastatic melanoma to the lymph nodes, and 9 patients with melanoma localized to the primary tumor site and corresponding SLNBx negative nodes. The 2 cohorts were statistically identical as shown by a one-sided t test comparing the 2 groups on the basis of age (P=.17), race (P=.18), Breslow depth (P=.14), Clark level (P=.33), host response (P=.17), ulceration (P=.50), satellite nodules (P=.17), lymphovascular invasion (P=.50), and mitotic activity (P=.09). Only PIK3CA showed a statistically significant difference (P=.03) between the 2 cohorts. Further analysis using classification and regression tree (CART) analysis was conducted. Of the patients that were PIK3CA positive (n=6), 5 were SLN positive (83%); furthermore, a lack of mutation in the NRAS gene guaranteed that our PIK3CA-positive patients would end up as SLN-positive patients (100%). Interestingly, the only patient that was PIK3CA positive and SLN negative was also NRAS positive (100%). For the rest of our cohort that was PIK3CA negative (n=14), all the patients with a mutation in the ERBB4 gene (n=3) were SLN negative. Of patients that were PIK3CA and ERBB4 negative (n=11), 7 were TP53 negative (63.3%). Of these patients, there was a 71.5% chance that they would be SLN negative. The other 4 patients as yet unaccounted for in the cohort were TP53 positive. Of those 4, only 1 was SMAD4 positive and was SLN negative. Those patients that were TP53 positive and SMAD4 negative (n=3) were all SLN positive. In the emerging world of personalized medicine utilizing molecular evaluation and now in combination with powerful statistical analyses, we demonstrate an exciting first step in the new era of evaluation of metastatic potential in melanoma. While evaluation of lymph node metastases in melanoma, shown to be the most important prognostic indicator, is typically dominated by surgical excision of a sentinel node, utilizing molecular analyses, it may be possible to apply surgery only to those who will benefit from the risk. While this pilot study shows the possibility of creating a predictive model for metastatic potential, a larger patient population is necessary to generalize the model.

CATEGORY VII: Emerging translational data – impact on future therapy Next-Generation Sequencing Demonstrates Association Between Tumor Suppressor Gene Aberrations and Poor Outcome in Patients With Cancer

Maria Schwaederle,1 Gregory A. Daniels,1 David E. Piccioni,1 Paul T. Fanta,1 Richard B. Schwab,1 Kelly A. Shimabukuro,1 Barbara A. Parker,1 Razelle Kurzrock1 1 Center for Personalized Cancer Therapy, and Division of Hematology and Oncology, UCSD Moores Cancer Center, La Jolla, California, USA Background and Objectives: Next-generation sequencing is advancing at a breathtaking pace and is transforming patient care by allowing physicians to customize and match treatment to their patients’ tumor alterations. Genomic aberrations may be important because they predict response to therapy or because they are prognostic. Our primary objective was to study the association between key molecular alterations and outcome parameters. Methods: This was a retrospective, correlative and exploratory study that integrated clinicopathology and clinical outcomes of 392 patients seen at the UC San Diego Moores Cancer Center (October 2012 to April 2014) that had clinical grade molecular testing performed (next-generation sequencing of 236 cancer-related genes). Potential associations

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CATEGORY VII: Emerging translational data â&#x20AC;&#x201C; impact on future therapy between clinical characteristics and outcome parameters (overall survival [OS]), time to metastasis/ recurrence, and best progression-free survival (PFS) were examined. The Kaplan-Meier method and Cox regression models were used for our analysis, and results were subjected to internal validation using a resampling method (bootstrap analysis). Results: In a multivariable analysis (Cox regression model), the parameters that were statistically associated with a poorer OS were the presence of metastasis at diagnosis (P=.014), gastrointestinal histology (P<.0001), PTEN (P<.0001), and CDKN2A alterations (P=.0001). The variables associated with a shorter time to metastasis/recurrence were gastrointestinal histology (P=.004), APC (P=.008), PTEN (P=.026), and TP53 (P=.044) alterations. The analysis of best PFS demonstrated that, in our population, TP53 (P=.003) and PTEN (P=.034) alterations were independent predictors of a shorter best PFS; the type of treatment was also associated with best PFS (P=.039) (with hormonal therapy having a better outcome), as was a personalized treatment approach (matching at least one abnormality in a patient molecular profile to a cognate targeted drug) (P=.046).

Conclusion: Our study demonstrated that anomalies in several tumor suppressor genes, including TP53, PTEN, CDKN2A, and APC had a negative prognostic association in our patients.

Cyclin Alterations in Diverse Cancers: Outcome and Coamplification Network

Maria Schwaederle,1 Gregory A. Daniels,1 David E. Piccioni,1 Paul T. Fanta,1 Richard B. Schwab,1 Kelly A. Shimabukuro,1 Barbara A. Parker,1 Razelle Kurzrock1 1 Center for Personalized Cancer Therapy, and Division of Hematology and Oncology, UCSD Moores Cancer Center, La Jolla, California, USA Background and Objectives: Cyclin genes are key regulatory components of the cell cycle. Importantly, there are several potent targeted agents in development that can impact them. Our primary objective was to examine the biological implications and clinical and outcome associations of cyclin gene (CCN) alterations in diverse malignancies. Methods: This was a correlative study that integrated clinicopathology and clinical outcomes of 392 patients seen at the UC San Diego Moores Cancer Center (October 2012 to April 2014) that had clinical-grade, next-generation sequencing performed (about 236 cancer-related genes were assessed). Clinical characteristics as well as outcome parameters (best progression-free survival [PFS]), time to metastasis/recurrence, metastatic sites, and overall survival (OS) were compared for patients harboring cyclin alterations versus not. Correlations with other molecular alterations were also studied. Results: CCN alterations were found in 13% of our population (50/392; all were amplifications) and were associated with breast cancer (P<.0001) and a higher median number of alterations (median, 8 vs 3 alterations, P<.0001). A multiple logistic regression analysis showed that patients with CCN amplifications had more liver metastases (P=.046). Harboring a cyclin amplification was not associated with OS, time to metastasis/recurrence, nor with the best PFS. In a Cox regression model, gastrointestinal histology, PTEN, and CDK alterations had a significant association with poorer overall survival. CCN amplifications correlated with alterations in FGF/FGFR family genes as well as in MET and ARFRP1 (all P<.05). An extended correlation study shed light on a network of coamplifications influenced in part by genes that were localized on the same amplicons. Conclusion: CCN amplifications are common across cancers and had distinctive biological associations: correlation with higher numbers of aberrations, and with liver metastases, as well as with abnormalities in FGF/FGFR, MET, and ARFRP1 genes. Customized combinations targeting the cyclin pathway as well as the extended coamplification network may be necessary in order to address resistance mechanisms.

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Novel Treatment-Specific Genetic Marker on the Horizon

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ne of the areas of personalized medicine that has signaled a new era is the development of genetic signatures that can be used to select therapy that is likely to be effective in separate disease sites: for example, Oncotype DX for breast and colon cancer and MammaPrint for breast cancer. These are considered disease-specific signatures.

By contrast, until now, no treatment-specific genetic signatures have been available, but that is about to change, according to the physician who spearheaded development of the first radiation-specific genetic signature.

At the recent 2014 Annual Meeting of ASTRO, Personalized Medicine in Oncology caught up with Javier F. Torres-Roca, MD, a radiation oncologist at the Moffitt Cancer Center in Tampa, FL. Torres-Roca said, “Fifty percent of all cancer patients receive radiation as part of their cancer therapy, and thus the development of a radiation-specific signature is critical. We are the only group that has developed a radiation-specific gene expression signature. This 10-gene signature is a radiation therapy–specific biomarker that predicts response and outcome. This marker is not predictive with other treatments.”

The signature is called the radiosensitivity index (RSI, commercial name InterveneXRT) and consists of the following genes: Oncogenes: cABL, P65/RelA Inflammatory response: STAT1, IRF1 Transport/ubiquitination: SUMO1, PKC Cell cycle: PAK2, HDAC, c-JUN, AR “RSI-good or -low” patients are deemed radiosensitive, and those found to be “RSI-poor or -high” are considered radiation resistant when correlating the signature with outcomes such as overall survival, disease-free survival, locoregional recurrence, and response.

Torres-Roca said that there have been 4 publications on the development and initial validation of the radiation-specific signature. At the 2014 ASTRO meeting, 10 presentations and 1 panel discussion focused on the second phase of validation in outcomes with breast, lung, pancreatic, prostate, and brain cancer, as well as metastatic colorectal cancer. These abstracts (2463, 2224, 2615, 1246, 2649, 2899, 3633, 3916, 1420, 1031, and 2873) can be found at www. astro.org.

“We show that if patients are not receiving radia-

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tion therapy, there is no difference between resistant and sensitive patients [to a specific treatment]. But if they are undergoing radiation therapy, sensitive patients [according to the genetic signature] do better, and those who are nonsensitive have a worse outcome.

We have tested outcomes that include overall survival in glioblastoma, relapse-free survival in breast cancer, locoregional recurrence in breast cancer and head and neck cancer, disease-free survival in lung cancer, response in metastatic colorectal cancer, response in rectal and esophageal cancer, and distant metastases in prostate cancer.”

The signature took 11 years to develop, Torres-Roca said. First the researchers trained the signature to predict cell survival after radiation in cancer lines. The final signature was tested in more than 15,000 tumor samples and correlated with clinical outcomes in 2000 samples across disease sites that are treated with radiation, he explained.

The final signature was tested in more than 15,000 tumor samples and correlated with clinical outcomes in 2000 samples.

He believes the signature will be clinically actionable – showing that higher doses of radiation may be needed in resistant patients [according to the signature] and lower radiation doses in sensitive patients.

“If the test is done before treatment, it will be clinically actionable. You may be able to avoid radiotherapy if a patient is unlikely to benefit. Treating patients inappropriately is very expensive. There is a lot of imprecision in the decisions we make in radiation oncology. We need better tools, and this is one tool we can use in radiation oncology. This signature gives us the opportunity to optimize radiation delivery and dosing,” he said.

Torres-Roca and his colleague Steven Eschrich, PhD, also from Moffitt, have founded a company called CvergenX that holds the exclusive commercial license to the genetic signature.

A commercial assay based on the signature is being developed in a joint venture with CvergenX, the National Cancer Institute, Moffitt Cancer Center, and the Asan Medical Center in Korea. u

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Combo of BRAF and MEK Inhibitors Improves Survival in Advanced Melanoma

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ombination therapy with a BRAF and a MEK inhibitor improves outcomes in advanced BRAF-positive melanoma, according to 2 phase 3 studies presented at the 2014 ESMO Congress. These studies support the hypothesis that inhibition of both BRAF Grant McArthur, and MEK will improve survival in melanoma MD, PhD by overcoming the mechanism of acquired resistance to vemurafenib, which is thought to be reactivation of cell growth through MEK. In the CoBRIM study, first-line treatment of advanced melanoma with the combination of vemurafenib + cobimetinib (not approved by the FDA) improved progression-free survival (PFS) and overall response rate (ORR) versus vemurafenib alone. In the COMBI-v study, the FDA-approved combination of dabrafenib + trametinib improved overall survival (OS) compared with vemurafenib alone.

Median investigator-assessed PFS was 6.2 months for the vemurafenib arm versus 9.9 months for the combination arm, a highly statistically significant difference.

CoBRIM Study CoBRIM was a phase 3, double-blind, placebo-controlled study of vemurafenib/cobimetinib versus vemurafenib alone in previously untreated BRAF V600 mutation–positive metastatic melanoma. The study ran­ domized 495 patients to either arm in a 1:1 ratio, with the primary end point of PFS. “This study is very important, as it shows that using 2 drugs together to turn off 2 individual proteins [BRAF and MEK] that interact and bind to each other in the cell gives improved results for patients. This is a fundamental concept that could have far-reaching consequences for how we treat many cancers,” said lead author Grant McArthur, MD, PhD, head of the Cancer Therapeutics Program at the Peter MacCallum Cancer Centre, Melbourne, Australia.

Median investigator-assessed PFS was 6.2 months for the vemurafenib arm versus 9.9 months for the combination arm, a highly statistically significant difference (P<.0001) representing a 49% reduction in risk of progression or death for the combination therapy arm.

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ORR was significantly better with the combination therapy: 68% versus 45%; complete response (CR) rates were 10% versus 4%, respectively. An interim OS analysis suggested that the risk of death would be reduced by 35% in patients who received both drugs versus those who received vemurafenib + placebo (P<.05).

The combination was tolerable, MacArthur said, with a manageable adverse event profile consistent with previous reports. Gastrointestinal events were more common with the combination, and these were mostly grade 1 and manageable with medication and dose reduction. Photosensitivity was also more common on the combination therapy. Hyperkeratosis was significantly lower with the combination, because MEK inhibition reduces this side effect of vemurafenib, MacArthur explained. Creatine phosphokinase level was increased with the combination, but other adverse events were similar in the 2 arms.

“This study provides clear definitive evidence that cobimetinib combined with vemurafenib results in improved progression-free survival and increased overall response rates. The preliminary overall survival is promising, and the combination was tolerable, consistent with previous trials of this combination,” MacArthur stated. “We anticipate that the combination of a BRAF and MEK inhibitor will become a new standard treatment for advanced BRAF-mutant melanoma.”

COMBI-v Study COMBI-v is an ongoing open-label phase 3 study of BRAF V600–mutated advanced melanoma in treatment-naive patients randomized to receive the combination of dabrafenib + vemurafenib (MEK inhibitor and BRAF inhibitor). The study enrolled 704 patients with advanced or metastatic melanoma and good performance status. In COMBI-v, brain metastases were allowed, but only if treated and stable for at least 12 weeks.

The combination therapy reduced the risk of death by 31%, according to a preplanned interim OS analysis presented at ESMO 2014. Median OS is not yet reached in the combination arm and was 17.2 months in the vemurafenib-alone arm (P=.005).

“These results further corroborate the early preclinical data that more complete blockade of the MAP kinase pathway delays the emergence of resistance, translating into longer survival for our patients,” said lead author Caroline Robert, MD, head of the Dermatology Unit at the Institut Gustave Roussy, Paris, France.

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Because of the excellent results at the interim analysis, the study was stopped early and patients originally randomized to the vemurafenib arm were allowed to cross over to combination treatment. The analysis Robert presented was the interim analysis, which is now considered the final analysis, she said.

Additionally, the combination reduced the risk of disease progression by 44% versus vemurafenib monotherapy. Median PFS was 11.4 months for the combination versus 7.3 months for vemurafenib (P<.001). ORR was 64% versus 51%, respectively, a significant difference of 13% (P<.001). CR was 13% versus 8%, respectively,

and partial response was 51% versus 44%, respectively.

Duration of response was almost twice as long for the combination arm: 13.8 months versus 7.5 months.

The rate of adverse events was similar in the 2 arms.

The combination was associated with increased incidence of pyrexia and decrease in left ventricular ejection fraction compared with vemurafenib alone, while the incidence of cutaneous malignancies, hyperproliferative cutaneous events, and photosensitivity was much lower in the combination arm.

“Both of these trials of combination therapy go in the same direction,” Robert commented. u

Nivolumab: Impressive Responses in Melanoma

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mmunotherapy marches on showing continued progress in treating advanced melanoma. At the recent ESMO 2014 Congress, first reports from a phase 3 study showed that the monoclonal anti–PD-1 antibody nivolumab achieved superior responses and longer duration of response compared with standard chemotherapy in the second- or third-line treatment of patients whose melanoma progressed on treatment with ipilimumab.

“Patients who progress on previous treatment have limited options. In this study, nivolumab had impressive responses and duration of response, and these data suggest that the drug can prolong progression-free survival (PFS) and overall survival (OS), but the data are not yet mature,” said lead author Jeffrey Weber, MD, PhD, director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at the Moffitt Cancer Center, Tampa, FL. Like ipilimumab, the first immunotherapy to be approved for treatment of advanced melanoma, nivolu­mab is a PD-1–blocking antibody, referred to as a “check­point inhibitor,” because it releases a brake placed on the immune system by the tumor itself. Once the brake is released, the immune system goes into action mounting an antitumor response and shrinking the tumor.

This is the first phase 3 trial of nivolumab in melanoma patients with progressive disease despite treatment with ipilimumab. The study randomized 405 patients with unresectable melanoma in a 2:1 ratio to intravenous nivolumab 3 mg/kg versus investigator’s choice of chemotherapy (ICC). Patients were treated until disease progression or unacceptable toxicity.

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Weber explained that the control arm was designed to accommodate differences in preferred chemotherapy regimens between North America and Europe (carboplatin/paclitaxel or dacarbazine, respectively).

The patients were stratified prospectively according to expression of Jeffrey Weber, MD, PhD PD-L1, a potential biomarker for response, BRAF status, and best overall response to prior anti–CTLA-4 (ipilimumab). Thirty percent had BRAF mutations and had previously received a BRAF inhibitor.

Overall response rate (ORR) was 32% for nivolumab versus 11% with ICC using a RECIST definition. Ninety-five percent of responses (36 of 38) were ongoing in the nivolumab arm at the time of the analysis, and me-

Nivolumab is a PD-1–blocking antibody, referred to as a “checkpoint inhibitor,” because it releases a brake placed on the immune system by the tumor itself. dian duration of response in that arm had not yet been reached at the time of ESMO 2014. Median duration of response in the ICC arm was 3.6 months.

No deaths were attributed to study drug toxicity.

One patient in the nivolumab group experienced grade 5 hypoxia, possibly pneumonitis, and this cause of death was classified as “other” rather than “study drug

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toxicity,” Weber said.

PFS and OS will be reported when the data are more mature.

The company has filed for FDA approval in the United States, and the drug has breakthrough status. A similar drug, pembrolizumab, received FDA approval for melanoma based on less robust response data than those seen in the nivolumab trial (ie, 22% ORR), Weber said.

A course of treatment with ipilimumab is estimated at $120,000. If nivolumab is approved, the cost is likely to be at least as high.

“This appears to be the death knell of chemotherapy, at least in second and third line. I hate using chemotherapy in melanoma, and I hope this study puts to rest that it should be used as a comparator arm in clinical trials. In the US, you won’t be able to do this anymore,” Weber said in a separate interview.

Discussion Formal discussant of this trial, Ignacio Melero, MD, Pamplona, Spain, called this “very exciting clinical data with impressive responses. I am disappointed that the survival data are not available yet.”

He said that the study included patients with brain metastases, and he is looking forward to hearing the specific outcome in that subgroup as well as in the 50% of patients who were PD-L1 positive.

“We will learn a lot [about potential biomarkers] when we get correlative data from this trial,” he said.

He mentioned that pembrolizumab is also showing good responses in melanoma. “The treatment of melanoma is changing,” Melero said.

“If a patient is BRAF wild type, treatment is with chemotherapy or ipilimumab or a clinical trial. With BRAF-mutated melanoma, it is more entangled. Patients have the option of targeted therapy or immunotherapy. The trend is to move anti–PD-1 agents up front and get rid of chemotherapy. It is important to study immunotherapy combinations, but we need good biomarkers,” he stated.

“I believe that melanoma treatment with anti–PD-1 will be the tip of the iceberg. Many other indications for this treatment are emerging, including lung cancer, head and neck cancer, and bladder cancer,” Melero said.

“My main conclusion is that immunotherapy in cancer is no longer an exotic task,” he said. u

Record-Breaking Survival in HER2 Metastatic Breast Cancer

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inal results of the CLEOPATRA trial show that dual HER2 blockade with the combination of pertuzumab and trastuzumab plus chemotherapy extended overall survival (OS) by almost 16 months compared with trastuzu­ mab plus chemotherapy in patients with HER2-positive metastatic breast cancer. This Sandra Swain, should become the new standard of care for metMD astatic HER2-positive disease, according to investigators.

“The final results of CLEOPATRA show that the addition of pertuzumab to standard therapy [trastuz­­u­mab plus docetaxel] significantly improved overall survival by 15.7 months. I am so pleased to present these results.

The 56.5-month median overall survival is unprecedented for this indication. This study confirms the pertuzumab/trastuzumab regimen as standard of care for first-line therapy in patients with HER2-positive metastatic breast cancer,” stated lead investigator Sandra Swain, MD, MedStar Washington Hospital Center, Washington, DC.

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These findings confirm interim results reported 2 years ago, she said. “Two monoclonal antibodies that bind at different sites of the HER2 receptor, used together, not sequentially, extended survival,” she told listeners at the 2014 ESMO Congress.

CLEOPATRA enrolled 808 patients with centrally confirmed HER2-positive metastatic breast cancer from 204 centers in 25 countries. Patients were randomized to treatment with placebo + trastuzumab + docetaxel versus pertuzumab + trastuzumab + docetaxel. Docetaxel was given for at least 6 cycles (median number, 8) and both monoclonal antibodies were given until disease progression.

The final OS analysis was presented after a median follow-up of 50 months. “This is 20 months longer than the last interim analysis,” Swain noted.

Median OS was 56.5 months for the dual combination arm versus 40.8 months for those treated with trastuzumab + docetaxel, representing a highly statistically significant 32% increase in the risk of survival (P=.0002).

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“This change of 15.7 months [favoring dual HER2 blockade] has changed things for HER2-positive patients.

I have never seen a survival benefit of this magnitude in metastatic HER2-positive breast cancer,” she said.

The OS improvement was in the context of a 6.3month improvement in progression-free survival (PFS) reported in the updated final analysis. “PFS was significantly improved in the interim analyses [6.1-month improvement] and in the final analysis. This shows that in this blinded study, PFS was a good surrogate for OS,” Swain continued.

There was concern that the combination of 2 monoclonal antibodies would lead to additional toxicities. In this study, rash, mucositis, and diarrhea were increased in the pertuzumab-containing arm compared with trastuzumab + docetaxel.

There was no increase in cardiac toxicities with dual HER2 blockade. Asymptomatic declines in left ventricular ejection fraction were actually less with the combination (6.1% vs 7.4%), and symptomatic left ventricular dysfunction was reported in 1.5% and 1.8%, respectively. These decreases in heart function were

reversible in 88% of patients in the combination arm, she said.

“The median overall survival data presented by Dr Swain here at ESMO 2014 with pertuzumab and trastuzumab–based therapy in patients with HER2-positive metastatic breast cancer is remarkable. This is one of

CLEOPATRA enrolled 808 patients with centrally confirmed HER2-positive metastatic breast cancer from 204 centers in 25 countries. the biggest steps toward making this disease a chronic condition in the near future,” said Javier Cortés, MD, director of the Breast Cancer Program at Vall d’Hebron Institute of Oncology in Barcelona, Spain. Cortés was a coauthor of the CLEOPATRA report.

“We should consider this as standard of care for our patients. I can see no reason to justify the use of trastuzumab without pertuzumab,” he added. u

Interview With the Innovators An exclusive PMO series

Personalized Medicine in Oncology™ is pleased to offer insightful interviews with leaders in oncology about their approach to personalized medicine.

To watch our interviews, visit www.PersonalizedMedOnc.com/videolibrary

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HER2-Derived Vaccine Cuts Recurrences in High-Risk Breast Cancer

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vaccine derived from the GP2 peptide was safe and reduced the rate of breast cancer recurrence in women with high-risk breast cancer in a phase 2 clinical trial. The vaccine was particularly effective in reducing recurrence in women with HER2 overexpression, reported Elizabeth Mittendorf, MD, PhD, at the 2014 ASCO Breast Cancer Symposium.

The vaccine is delivered in the adjuvant setting after completion of standard of care therapy, including trastuzumab where appropriate, along with the immunoadjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) to help stimulate an immune response.

“Peptide vaccines have the benefit of being easy to construct and manufacture on a large scale, they’re inexpensive, and very importantly, they are ‘off the shelf’ therapy,” said Mittendorf, associate professor of surgical oncology at the University of Texas MD Anderson Cancer Center, Houston.

The vaccine series consisted of 6 monthly intradermal inoculations (primary series) followed by 4 boosters administered every 6 months.

GP2 is a HER2-derived HLA-A2+ restricted immunogenetic peptide designed to stimulate CD8+ cytotoxic T lymphocytes to recognize breast cancer cells with HER2 expression (IHC 1+, 2+, or 3+), said Erika Schneble, DO, coinvestigator and a general surgery resident, San Antonio Military Medical Center.

In the multicenter phase 2 trial, 180 women with HLA-A2+, node-positive or high-risk node-negative breast cancer with any level of HER2 expression rendered disease-free with standard of care therapy were randomized to receive GP2 plus GM-CSF or GM-CSF alone. The vaccine series consisted of 6 monthly intradermal inoculations (primary series) followed by 4 boosters administered every 6 months. HER2 overex-

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pression was present in 57% of vaccinated recipients and 55% of controls.

Only 1 grade 3 local and systemic toxicity was reported in the vaccine group. “The toxicities are mostly grade 1 local and systemic toxicities that match the control arm, suggesting that these toxicities are due to just the immunoadjuvant GM-CSF,” said Schneble.

About 70% of patients in each arm had grade 1 local toxicities. Seventy percent in the GM-CSF–alone arm and 60% in the vaccine plus GM-CSF arm had grade 1 systemic toxicity.

Disease-free survival (DFS) was analyzed on an intention-to-treat (ITT) basis and in a population that excluded those who had a recurrence before their primary vaccination series was completed and those who developed a second nonbreast malignancy. Two patients experienced early recurrence and 6 developed a second malignancy.

After a median follow-up of 34 months, the ITT analysis showed a DFS rate of 88% among GP2 vaccine recipients and 81% in the control group, for a nonsignificant 37% relative risk reduction in the vaccine group (P=.428). Excluding the patients who had a recurrence during their primary vaccination series or developed a second malignancy, the DFS rate was 94% in the vaccine recipients versus 85% in the controls, a nonsignificant 57% reduction in risk of recurrence (P=.168).

“After completion of the primary vaccine series, there have been no recurrences in the HER2 3+ population,” said Schneble. “This suggests a possible synergy with trastuzumab. All 3+ patients received trastuzumab as their standard of care therapy.”

Concurrent use of trastuzumab and the GP2 vaccine may address the early recurrences, Mittendorf said. A phase 1 trial of concurrent use showed the combination to be safe, with no increase in local or systemic toxicity.

A phase 2 trial looking at combination immunotherapy with trastuzumab and a CD8+ T-cell–eliciting vaccine in high-risk HER2-positive breast cancer will begin enrolling patients. u

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LH-RH Agonist Preserves Fertility When Added to Chemotherapy in Younger Breast Cancer Patients

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second study adds to the body of evidence that adding a luteinizing hormone-releasing hormone (LH-RH) analog to chemotherapy as treatment for breast cancer increases a younger woman’s likelihood of resuming menses and becoming pregnant. The new data, presented at the 2014 ASCO Breast Cancer Symposium, come from a long-term follow-up of the phase 3 clinical study known as PROMISE-GIM6. They come on the heels of another study called POEMS, presented earlier this year, in which the rate of premature ovarian failure was reduced by 70% at 2 years by the addition of an LH-RH agonist to chemotherapy for the treatment of breast cancer.

Current guidelines from ASCO and ESMO consider the use of LH-RH analogs to preserve fertility in women with breast cancer as experimental. “With the POEMS trial and this updated analysis of PROMISE-GIM6, both ASCO and ESMO should consider updating their recommendations and consider LH-RH agonists as a strategy to preserve ovarian function and fertility,” said Matteo Lambertini, MD, who presented the long-term follow-up of PROMISE-GIM6 here.

Initial (1-year) results of PROMISE-GIM6 (JAMA. 2011;306:269-276) demonstrated that temporary suppression of ovarian function using the LH-RH analog triptorelin during chemotherapy reduced the occurrence of early menopause and increased the pregnancy rate in young women with early-stage breast cancer compared with women treated with chemotherapy alone. (The POEMS study used goserelin instead of triptorelin.)

The open-label, multicenter, parallel study included 281 premenopausal women with early-stage breast cancer who were candidates for neoadjuvant or adjuvant chemotherapy. They were randomized to chemotherapy alone or chemotherapy plus triptorelin 3.75 mg intramuscularly every 4 weeks starting at least 1 week before chemotherapy and continued for the duration of chemotherapy. About 80% of the patients in each arm had hormone receptor (HR)-positive disease. More than 90% of patients received anthracyline-based or anthracycline- and taxane-based chemotherapy.

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tion of menstrual activity and postmenopausal levels of both follicle-stimulating hormone and estradiol 1 year after the end of chemotherapy.

Over a median follow-up of 7.3 years, 8 pregnancies and 5 live births occurred in the chemotherapy plus triptorelin arm compared with 3 pregnancies and 3 live births in the chemotherapy-alone arm. The 5-year cumulative incidence estimate of menstrual resumption at any time was 72.6% in the chemotherapy plus triptorelin arm compared with 64.0% in the chemotherapyalone arm (P=.071). Although the difference was not significant, the trend toward an improvement in resumption of menses is consistent with the finding in POEMS, said Lambertini, an oncology fellow at San Martino-IST in Genoa, Italy.

Disease control or survival was not adversely affect-

Current guidelines from ASCO and ESMO consider the use of LH-RH analogs to preserve fertility in women with breast cancer as experimental. ed by triptorelin. The 5-year disease-free survival was 80.5% in the chemotherapy plus triptorelin arm and 83.7% in the chemotherapy-alone arm (P=.519). An exploratory multivariate analysis adjusted for baseline disease stage and HR status “importantly showed no difference in disease-free survival between the 2 treatment arms,” Lambertini said. An exploratory subgroup analysis showed no significant interaction between HR status and disease-free survival.

An LH-RH agonist during chemotherapy can be considered to preserve fertility in women with estrogen receptor–negative disease, given the lack of apparent risk, said Hope Rugo, MD, professor of medicine, division of hematology and oncology, University of California, San Francisco. However, it is not a substitute for established methods of fertility preservation such as ovarian stimulation and cryopreservation of embryos and oocytes. u

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In melanoma…

A T CELL IS ONLY AS EFFECTIVE AS THE ANTIGEN THAT ACTIVATES IT1 T cell

Dendritic cell

Tumor-derived antigens (TDAs) set the immune system in motion by priming and activating T cells. Once released, TDAs are processed by dendritic cells and subsequently presented to T cells, initiating an adaptive immune response.1-3 Learn more at

MelanomaAntigens.com

References: 1. Kaufman HL, Disis ML. J Clin Invest. 2004;113:664-667. 2. Klebanoff CA, Gattinoni L, Restifo NP. Immunol Rev. 2006;211:214-224. 3. den Boer AT, van Mierlo GJD, Fransen MF, Melief CJM, Offringa R, Toes REM. J Immunol.

2004;172:6074-6079. ©2014 Amgen Inc. All rights reserved. 8/14 USA-678-100568