PMO June 2014 by The Oncology Nurse

Unifying Oncologists & Pathologists

A Peer-Reviewed Journal June 2014 • Volume 3 • Number 4

PM O

BIOMARKERS • TARGETED THERAPIES • DIAGNOSTICS

Personalized Medicine in Oncology TM

IMMUNO-ONCOLOGY Immuno-Oncology Takes Center Stage at ASCO 2014...............................................Page 198

THE BIOMARKER Molecular Diversity of CLL..............................Page 202

INTERVIEW WITH THE INNOVATORS Implementing Global Healthcare: Partners In Health and the Rwandan Cancer Center Initiative. An Interview With Lawrence N. Shulman, MD, of Dana-Farber Cancer Institute.......................Page 206

PROSTATE CANCER Androgen Suppression in Castration-Resistant Prostate Cancer.................................................Page 212

VALUE-BASED CANCER CARE Personalizing Value-Based Medicine...........Page 220

THE LAST WORD PMO and the PMC – A Collaboration to Advance Precision Medicine. Introducing Dr Edward Abrahams, President of PMC, as the Author of The Last Word....................Page 238

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

The official publication of

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

WORLD CUTANEOUS MALIGNANCIES CONGRESS

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%).

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.

JUNE 2014

VOLUME 3, NUMBER 4

TABLE OF CONTENTS IMMUNO-ONCOLOGY

198

Immuno-Oncology Takes Center Stage at ASCO 2014

Highlights of exciting developments in a wide variety of tumor types for which novel immunotherapies may have value. THE BIOMARKER

202

Molecular Diversity of CLL

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

INTERVIEW WITH THE INNOVATORS

206

Implementing Global Healthcare: Partners In Health and the Rwandan Cancer Center Initiative. An Interview With Lawrence N. Shulman, MD, of Dana-Farber Cancer Institute PMO speaks with Dr Shulman about the awe-inspiring commitment to a global cancer care initiative that is taking place in Africa, Haiti, and other areas lacking basic care.

PROSTATE CANCER

212

Androgen Suppression in Castration-Resistant Prostate Cancer An in-depth look at androgen suppression in CRPC, including a comparison of androgen suppression strategies and information on new hormonal therapy agents.

VALUE-BASED CANCER CARE

220

Personalizing Value-Based Medicine

Aymen Elfiky, MD, MPH

Dr Elfiky explores the pursuit of value in current models of cancer care.

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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Personalized Medicine in Oncology

www.PersonalizedMedOnc.com

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

June 2014

Vol 3, No 4

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

JUNE 2014

VOLUME 3, NUMBER 4

TABLE OF CONTENTS

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

(Continued)

Global biomarkers Consortium Clinical Approaches

CONFERENCE COVERAGE

222

Important information from the Gastrointestinal Cancers Symposium, the Genitourinary Cancers Symposium, the National Comprehensive Cancer Network annual meeting, and the Society of Gynecologic Oncology annual meeting.

to Targeted Technologies

ASSOCIATION FOR VALUE-BASED CANCER CARE

228

Prospects for Personalization of Medicine Lie in Evidence Thresholds

AMERICAN ASSOCIATION FOR CANCER RESEARCH

230

The most compelling information from the 2014 annual meeting of the AACR.O

THE LAST WORD

238

PMO and the PMC – A Collaboration to Advance Precision Medicine. Introducing Dr Edward Abrahams, President of PMC, as the Author of The Last Word

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

Professional Experience of GBC Attendees 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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FROM THE

EDITOR-IN-CHIEF

Over the past decade, significant progress has been made in the management of multiple myeloma, including new standards of care and the development and approval of several novel, effective agents. Despite this progress, more work needs to be done and numerous questions remain regarding the application and interpretation of recent clinical advances. In this sixth annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this second issue, experts from Dana-Farber Cancer Institute answer questions related to the management of patients in the maintenance setting.

to learn more!

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

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

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

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

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

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Discussions in Personalized Treatment for Lymphoma: Do We Have Consensus? CONTRIBUTING FACULTY Chair Stephanie A. Gregory, MD

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

Sonali M. Smith, MD

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

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

2014 PROSPECTUS

Steve M. Horwitz, MD

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

Supported by an educational grant from Celgene Corporation

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

YEAR ANNIVER SARY

FIFTH ANNUAL

Navigation and Survivorship Conference SEPTEMBER 18-21, 2014 WALT DISNEY WORLD DOLPHIN HOTEL ORLANDO, FLORIDA

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EDITORIAL BOARD

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

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

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

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

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

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

Darren Sigal, MD Scripps Clinic Medical Group San Diego, California Breast Cancer Edith Perez, MD Mayo Clinic Jacksonville, Florida Hematologic Malignancies Gautam Borthakur, MD The University of Texas MD Anderson Cancer Center Houston, Texas Pathology David L. Rimm, MD, PhD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut Drug Development Igor Puzanov, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee Lung Cancer Vincent A. Miller, MD Foundation Medicine Cambridge, Massachusetts Predictive Modeling Michael Kattan, PhD Case Western Reserve University Cleveland, Ohio Gastrointestinal Cancer Eunice Kwak, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts Melanoma Doug Schwartzentruber, MD Indiana University Simon Cancer Center Indianapolis, Indiana

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Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona Mark S. Boguski, MD, PhD Harvard Medical School Boston, Massachusetts Gilberto Castro, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil Madeleine Duvic, MD The University of Texas MD Anderson Cancer Center Houston, Texas Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland Gregory Kalemkerian, MD University of Michigan Ann Arbor, Michigan Howard L. Kaufman, MD Rush University Chicago, Illinois Katie Kelley, MD UCSF School of Medicine San Francisco, California Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota

Nikhil C. Munshi, MD Dana-Farber Cancer Institute Boston, Massachusetts Steven O’Day, MD John Wayne Cancer Institute Santa Monica, California Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois Hope S. Rugo, MD University of California, San Francisco San Francisco, California Lee Schwartzberg, MD The West Clinic Memphis, Tennessee John Shaughnessy, PhD University of Arkansas for Medical Sciences Little Rock, Arkansas Lillie D. Shockney, RN, BS, MAS Johns Hopkins University Baltimore, Maryland Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida David Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee Moshe Talpaz, MD University of Michigan Medical Center Ann Arbor, Michigan Sheila D. Walcoff, JD Goldbug Strategies, LLC Rockville, Maryland Anas Younes, MD The University of Texas MD Anderson Cancer Center Houston, Texas

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

Personalized Medicine in Oncology

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June 2014

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WORLD CUTANEOUS MALIGNANCIES S CONGRESS

& ™

GLOBAL BIOMARKERS CONSORTIUM

™

Clinical Approaches to Targeted Technologi Technologies

™

CONFERENCE

THIRD ANNUAL October 29 - November 1, 2014 Marriott Marquis • San Francisco, California

CONFERENCE CHAIR World Cutaneous Malignancies Congress Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

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

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

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

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

www.cutaneousmalignancies.com

www.globalbiomarkersconsortium.com

LETTER TO OUR READERS

The Evolution of Personalized Medicine in Oncology To Our Reading Community,

I Sanjiv S. Agarwala, MD

t gives me great pleasure to present this issue of Personalized Medicine in Oncology (PMO). We constantly and thoroughly examine every aspect of our journal – appearance, readability, and, most importantly, editorial content. With input from our expert editorial board and our readership, we are always expanding and improving our content to bring you the information you need to continue growing in your knowledge of personalizing treatment for your patients.

You will see the results of our efforts in the following ways: • The Biomarker. Under the direction of our editorial board member and pathologist Dr Pranil Chandra, we introduced this department to discuss the identification of biomarkers in patients with cancer and the prognostic/predictive impact of that marker. • The Last Word. Beginning in the July/August issue of PMO, we are pleased to have Dr Edward Abrahams from the Personalized Medicine Coalition author this department. In this thought-provoking column, Dr Abrahams will provide insights on the hot topics surrounding personalized medicine. • QR codes. You will begin to notice more QR codes in our pages to conveniently bring you more information related to the topics presented. • Interview With the Innovators. The world of personalized medicine is a rapidly changing and ever-evolving state involving many stakeholders on the front lines of its creation: physicians, industry, researchers, patient advocates, and payers. PMO seeks out the leaders in these sectors and brings you their game-changing strategies, missions, and impact on personalized oncology care. We believe these features will greatly enrich your reading experience and enhance your knowledge of the world of personalized medicine. Please let us know what you think by e-mailing our editorial director at ksiyahian@the-lynx-group.com. We look forward to and welcome your feedback. Sincerely,

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

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Vol 3, No 4

Dear Physician Colleague... Your Support Is Critical

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

Lillie D. Shockney, RN, BS, MAS

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

Show continued support for your oncology nurse and patient navigator colleagues by referring them to join forces with me and more than 4500 of their colleagues. Recommend they become a member of AONN+ today so they may take advantage of our exclusive benefits and educational opportunities. Together we can increase our network and define the future of oncology navigation. Your colleagues will have an opportunity to: CONNECT with nurse navigators close to home, exchange practice tips, and get involved in community outreach initiatives that improve care in your region. ACCESS tools and resources for your patients and their caregivers through our members-only online resource center. SUBMIT ABSTRACTS AND PRESENT research findings, programs, and results with their navigation and survivorship care colleagues. GET INVOLVED in our community of nurse navigators; share best practices, clinical resources, and advocate for your patients and their profession. ACCESS COMPLIMENTARY SUBSCRIPTIONS to the Journal of Oncology Navigation & Survivorship ® (the official journal of AONN+), The Oncology Nurse-APN/PA®, and Personalized Medicine in Oncology ™ (digital version). OBTAIN CONTINUING EDUCATION through online courses, including navigation basics, implementing a survivorship program, community outreach, personalized medicine, tumor topic–specific programs, best practices, and many more. RECEIVE A $100 DISCOUNT on registration to the Fifth Annual AONN+ Conference at the Walt Disney World Dolphin Hotel in Orlando, Florida!

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

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IMMUNO-ONCOLOGY

Immuno-Oncology Takes Center Stage at ASCO 2014

ore than 250 abstracts that included the term “immunotherapy” or “immuno-oncology” were presented during the Annual Meeting of the American Society of Clinical Oncology (ASCO) in May 2014. Presentations at this year’s ASCO meeting featured the latest findings related to immuno-oncology agents, as well as their implications for oncologists and their patients with cancer. The following summaries highlight these exciting developments and illustrate the wide variety of tumor types for which novel immunotherapies may have value.

Blinatumomab in Relapsed/Refractory Acute Lymphoblastic Leukemia Although more than 80% of adults with acute lymphoblastic leukemia (ALL) respond to induction chemotherapy, up to 50% of these patients relapse with chemotherapy-resistant disease.1 Relapsed/refractory (r/r) ALL remains a significant clinical challenge.2 Like other immunotherapies, bispecific single-chain antibodies act using mechanisms that are independent from small-molecule therapeutics and conventional monoclonal antibodies.3 Blinatumomab, an investigational bispecific T-cell engaging antibody, directs cytotoxic T cells to target cells that express CD19, which is expressed in virtually all B-lineage ALL cells and throughout B-cell development.4 Topp and colleagues reported the efficacy and toxicity of blinatumomab in a large phase 2 study.5 This open-label, single-arm, multicenter study was conducted in patients with Philadelphia chromosome (Ph)-negative r/r ALL who had relapsed within 12 months of initial therapy. Blinatumomab was administered by continuous IV infusion for 4 weeks, followed by a 2-week “holiday” (6week cycle) for up to 5 cycles. The primary end point was complete remission (CR) or CR with partial hematological recovery (CRh) within the first 2 cycles. The study enrolled 189 r/r ALL patients with a median age of 39 years (range, 18-79). Compared with initial studies of blinatumomab, these patients had a higher burden of disease based on bone marrow blood count. Blinatumomab was given for a median of 2 cycles (range, 1-5). Among these 189 patients, the response rate (CR + CRh) to blinatumomab was 43%, with 80% of responses occurring within the first cycle. Median relapse-free survival (RFS) was 5.9 months, and median overall survival (OS) was 6.1 months. Responses were seen in all patient subgroups. Thirty-two of 81 patients who were eligible for stem cell transplant (40%) were able to undergo the procedure.

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The most frequent adverse events (AEs) associated with blinatumomab in r/r ALL, including pyrexia, headache, and febrile neutropenia, were consistent with prior trials. The most frequent grade ≥3 AEs were febrile neutropenia (25%), neutropenia (16%), and anemia (14%). Two percent of patients had grade ≥3 cytokine release syndrome. Twenty eight patients (15%) had grade 5 AEs. These fatal events were only observed in patients who did not respond to blinatumomab. Topp concluded that this phase 2 study confirms the antileukemic activity of single-agent blinatumomab in patients with Ph-negative r/r ALL. A randomized, open-label, phase 3 study of blinatumomab in this patient population is under way. The extent to which blinatumomab can serve as a bridge to transplant for patients with r/r B-cell ALL is of specific interest in future studies.

Nivolumab in Recurrent Metastatic Renal Cell Carcinoma The prognosis of patients with recurrent metastatic renal cell cancer (mRCC) remains poor, regardless of histology. Treatment options for these patients include surgical resection of localized metastatic disease, cytokine therapy, and targeted therapies such as mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF) inhibitors.6 None of these treatments has demonstrated extended survival or cure. A recent retrospective study of patients with mRCC who were treated with targeted therapy demonstrated OS medians that approached 3 years (range, 27-34 months).7 PD-L1 expression has been observed in most clear cell mRCC and is associated with unfavorable cancer-specific survival.8 To exploit this potential mechanism of tumor responsiveness, Motzer and colleagues conducted a phase 2 trial of nivolumab (NIV), an anti–PD-1 antibody, in metastatic RCC patients who had relapsed after treatment with agents targeting the VEGF pathway.9 In this trial, patients with clear cell mRCC who had received at least 1 agent that targeted the VEGF pathway and no more than 3 prior systemic therapies were randomized to NIV given at a dose of 0.3, 2, or 10 mg/kg every 3 weeks until disease progression or toxicity. The primary objective of the study was to evaluate progression-free survival (PFS). Secondary objectives included OS, objective response rate (ORR), and safety. Most of the 168 relapsed RCC patients who enrolled in this trial of NIV had received prior systemic therapy, including VEGFR inhibitors (98%), mTOR inhibitors (34%), and immunotherapy (24%). One-fourth (25%)

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were poor risk according to Memorial Sloan Kettering Cancer Center criteria. After at least 16 months of follow-up, median PFS ranged from 2.7 to 4.4 months and the ORR was 22%. Motzer noted that many responders in each of the NIV dosing cohorts continue to respond after 24 months or more. Median OS in the 2 higher-dose cohorts was approximately 25 months. Rates of grade 3/4 AEs were 17% or less for all doses of NIV. The most common grade 3/4 events varied among dosing cohorts. In the 10 mg/kg group, 2 patients experienced severe asthenia, while in the 3 mg/kg group, severe nausea and pruritis were noted in 2 patients each. No grade 3/4 pneumonitis was seen. In the NIV 0.3, 2, and 10 mg/kg cohorts, 3%, 17%, and 13% of patients discontinued due to treatment-related AEs, respectively. Motzer and colleagues concluded that the promising activity of NIV in heavily pretreated RCC warrants further evaluation. NIV is currently being compared with everolimus in a phase 3 trial as later-line therapy for RCC, as well as in a first-line trial in metastatic RCC combined with ipilimumab.

Adjuvant Ipilimumab for Patients With High-Risk Melanoma Management of patients with lymph node–positive (high-risk) stage III melanoma is a clinical challenge. In Europe, high-dose interferon alpha-2b is approved for use in this setting. In the United States, both high-dose interferon alpha-2b and pegylated interferon alpha-2b are approved for patients with high-risk stage III melanoma.10,11 Because these agents can be difficult for patients in light of adverse events and administration, alternative treatments are desired.12 Eggermont and colleagues presented final data from EORTC 18071, a randomized double-blind, placebocontrolled phase 3 study designed to assess the impact of ipilimumab (IPI), an anti–CTLA-4 antibody, on RFS.13 This study is the first to assess an immune checkpoint inhibitor in the adjuvant melanoma setting. A total of 951 patients with surgically treated stage III cutaneous melanoma were randomly assigned to receive IPI or placebo. None had received prior systemic therapy for melanoma. Patients had disease features that correlate with a high likelihood of melanoma recurrence, including positive lymph nodes. Patients receiving IPI were dosed at 10 mg/kg every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years. After median follow-up of 2.7 years, IPI reduced the relative risk of melanoma recurrence by 25% compared with placebo. The 3-year RFS rates were 47% and 35% in the IPI and placebo groups, respectively. Subgroup analysis showed a 33% reduction in relapse risk among

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stage III melanoma patients with microscopic disease in lymph nodes, and a 17% reduction in relapse risk among patients with macroscopic disease. In contrast, the EORTC 18991 trial that supported the approval of peg ylated interferon alpha-2b did not show a significant RFS benefit in patients with macroscopic disease.14 Side effects were observed with IPI, including 5 treatment-related deaths. Over half (52%) of patients discontinued IPI secondary to adverse events (AEs), most often during the first 12 to 16 weeks of treatment. AEs were consistent with those observed with IPI in the treatment of metastatic melanoma, and included colitis, endo crinopathies, and skin rash. Eggermont stated that these phase 3 data justify consideration of adjuvant use of IPI for patients with high-risk stage III melanoma. More study is needed to fully assess the balance of benefits and risks associated with IPI, including assessments of long-term toxicity and OS. An ongoing phase 3 study is comparing 2 different doses (3 mg/kg and 10 mg/kg) of adjuvant IPI with high-dose interferon.

More study is needed to fully assess the balance of benefits and risks associated with IPI, including assessments of long-term toxicity and overall survival. Concurrent Treatment of Advanced Melanoma With Ipilimumab and Nivolumab After demonstrating durable responses and improved OS, IPI has become a standard option in the management of advanced melanoma.15 In contrast to CTLA-4 antibodies, PD-1 and PD-L1 antibodies potentiate antitumor T-cell responses at a tumor-specific level.16 Sznol and colleagues conducted a large phase 1 study in which IPI and nivolumab (NIV), a PD-1 antibody, were administered concurrently to patients with advanced melanoma.17 In this study, 94 patients with inoperable stage III or IV melanoma who had received up to 3 prior systemic therapies received concurrent treatment with IPI + NIV in various dose schemes. Approximately half (53%) of patients who enrolled in this phase 1 trial had very advanced melanoma (stage M1c), and 55% had received no prior systemic treatments. Sznol reported that concurrent treatment with IPI + NIV produced an “unprecedented” median OS of approximately 3.5 years (40 months) for patients with advanced melanoma. These data are based on long-term follow-up of 53 patients who enrolled in the initial 4 concurrent-dosing cohorts. Median OS data were de-

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scribed as “nearly double” the OS findings of previous studies of either agent alone in advanced melanoma. Among the 53 patients, 41% responded to concurrent IPI + NIV, with CRs observed in 17%. Tumor shrinkage was described as rapid and extensive. Responses were also durable, with 18 of 22 responses (82%) ongoing at the time of analysis. Clinical responses were seen regardless of BRAF mutation status or PD-L1 status, and across all dose cohorts. The 1- and 2-year median OS rates were 85% and 79%, respectively, and the median OS was 40 months. In the cohort of patients receiving NIV 1 mg/kg + IPI 3 mg/kg, which is the approach being tested in an ongoing phase 2/3 trial, 1- and 2-year OS rates were 94% and 88%, respectively. Rates of AEs, including immune-related AEs, were higher than previously observed for IPI and NIV used as single agents, but these were characterized as manageable and reversible in almost all patients. Researchers continue to follow patients in 8 dosing cohorts of this phase 1 study. A separate, ongoing phase 3 study comparing IPI + NIV with NIV and IPI alone, and a phase 2 randomized study comparing IPI + NIV to IPI alone, have completed accrual.

MPDL3280A in Metastatic Bladder Cancer Metastatic transitional cell or urothelial bladder cancer (UBC) is associated with a grim prognosis and limited treatment options.18 Because many of these patients are elderly with comorbidities, management is not standardized.19 PD-L1 expression is prevalent in this disease and may protect UBC cells from immune-mediated destruction.20 Powles and colleagues presented results of a phase 1 study of MPDL3280A, a human anti–PD-L1 monoclonal antibody, in metastatic UBC.21 A total of 67 patients received MPDL3280A given at a dose of 15 mg/kg every 3 weeks for up to 1 year. The primary end point was ORR, including unconfirmed responses as assessed by RECIST 1.1. Most patients with UBC in this trial were male (72%), and the median age was 65 years. The majority had visceral metastases (75%), received prior cisplatin-based chemotherapy (79%), and progressed within 3 months of their prior treatment (42%). To date, the most common AEs related to treatment with MPDL3280A were decreased appetite, fatigue, nausea, pyrexia, and asthenia. Related grade 3/4 AEs occurred in 4% of patients. MPDL3280A was not associated with renal toxicity. No investigator-assessed immune-related AEs were observed. Sixty-five patients with UBC were evaluated for efficacy. ORR was higher in patients whose tumor highly expressed PD-L1 (52%) compared with those with low

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or no PD-L1 expression (11%). Sixteen of 17 responding patients continued to respond at the time of data cutoff. Powles noted that responders to MPDL3280A included UBC patients with visceral metastases at baseline. Powles and colleagues concluded that MPDL3280A has noteworthy activity in heavily pretreated patients with metastatic UBC. Biomarker analysis revealed pharmacodynamic markers, as well as markers of potential mechanisms of resistance to MPDL3280A therapy. u

References

1. Gökbuget N, Hoelzer D. Treatment of adult acute lymphoblastic leukemia. Semin Hematol. 2009;46:64-75. 2. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944-950. 3. Topp MS, Kufer P, Gökbuget N, et al. Targeted therapy with the T-cell–engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29:2493-2498. 4. Cooper LJ, Topp MS, Serrano LM, et al. T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B–lineage leukemia effect. Blood. 2003;101:1637-1644. 5. Topp MS, Goekbuget N, Stein AS, et al. Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL). J Clin Oncol. 2014; 32(suppl). Abstract 7005. 6. National Cancer Institute website. Renal Cell Cancer Treatment: PDQ. Stage IV and Recurrent Renal Cell Cancer. Updated February 21, 2014. www.cancer.gov/can certopics/pdq/treatment/renalcell/HealthProfessional/page8. Accessed June 1, 2014. 7. Kroeger N, Choueiri TK, Lee JL, et al. Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy. Eur Urol. 2014;65:1086-1092. 8. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. Cancer. 2005;104:2084-2091. 9. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma (mRCC): results of a randomized, dose-ranging phase II trial. J Clin Oncol. 2014;32(suppl). Abstract 5009. 10. Sylatron [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; December 2013. 11. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7-17. 12. Sabel MS, Sondak VK. Pros and cons of adjuvant interferon in the treatment of melanoma. Oncologist. 2003;8:451-458. 13. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Ipilimumab versus placebo after complete resection of stage III melanoma: initial efficacy and safety results from the EORTC 18071 phase III trial. J Clin Oncol. 2014;32(suppl). Abstract LBA9008. 14. Eggermont AM, Suciu S, Testori A, et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012;30:3810-3818. 15. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; December 2013. 16. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212. 17. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol. 2014;32(suppl). Abstract LBA9003. 18. National Cancer Institute website. Bladder Cancer Treatment: PDQ. General Information About Bladder Cancer. Updated February 21, 2014. www.cancer.gov/ cancertopics/pdq/treatment/bladder/HealthProfessional/page1. Accessed June 1, 2014. 19. National Cancer Institute website. Bladder Cancer Treatment: PDQ. Recurrent Bladder Cancer Treatment. Updated February 21, 2014. www.cancer.gov/cancertopics/pdq/treatment/bladder/HealthProfessional/page9. Accessed June 1, 2014. 20. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007;109:1499-1505. 21. Powles T, Vogelzang NJ, Fine GD, et al. Inhibition of PD-L1 by MPDL3280A and clinical activity in pts with metastatic urothelial bladder cancer (UBC). J Clin Oncol. 2014;32(suppl). Abstract 5011.

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Join Us in the Fight Against Metastatic Prostate Cancer Bavarian Nordic, Inc., which specializes in developing cancer immunotherapies, is exploring a targeted immunotherapy for prostate cancer. Our PROSPECT study is a global, randomized, double-blind, Phase 3 efficacy study of an investigational therapeutic cancer vaccine (PROSTVAC-VF) Âą GM-CSF in men with metastatic, castration-resistant prostate cancer (mCRPC).

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

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THE BIOMARKER

Molecular Diversity of CLL PMO is pleased to offer the department The Biomarker to discuss the identification of biomarkers in patients with cancer and the prognostic/predictive impact and clinical decision-making implications of that marker. Do you have a unique case to share with our reading community? Please submit your biomarker-driven cases to us at thebiomarker@the-lynx-group.com.

n the third installment of The Biomarker, we will be discussing the molecular diversity of chronic lymphocytic leukemia (CLL). This month, our guest author, Jason Gottwals, returns to highlight another intriguing case. Jason is the technical director of marketing and provides leadership to the Pranil K. Chandra, scientific training of our sales force at PathGroup. DO Our patient presented with leukocytosis via routine complete blood count and underwent a diagnostic bone marrow biopsy and ancillary studies as a follow-up to a peripheral blood study previously reported. Routine morphologic examination and flow cytometric analysis confirmed B-cell CLL. Conventional karyotyping demonstrated an interstiJason Gottwals tial deletion on the long arm of chromosome 14, in addition to trisomy 12. Fluorescence in situ hybridization (FISH) studies were negative for commonly seen B-cell abnormalities. Polymerase

The genomic signature identified indicates an aggressive clinical course and potential utility of targeted therapeutics that are available in an investigational context. chain reaction (PCR) molecular study for immunoglobulin variable heavy chain hypermutation was negative. These results placed the patient in an interPranil K. Chandra, DO, is Director, Molecular Pathology Services and Interim Medical Director, Clinical Pathology of PathGroup. Jason Gottwals is Director of Training & Technical Marketing at PathGroup.

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mediate to negative prognostic category. A next-generation sequencing (NGS) study was ordered to further delineate the prognosis of this patient and identify possible treatment approaches. The NGS study revealed 5 point mutations in this patient, including 2 ATM mutations, 2 KRAS mutations, and 1 PTPN11 mutation.

Multiple Pathway Interrogation in CLL â&#x20AC;&#x201C; ATM, KRAS, and PTPN11 The ATM protein is the principal activator of the p53 pathway in response to DNA double-strand breaks.1 Loss of ATM is a frequent event in sporadic lymphoid tumors, and it is generally recognized as a tumor suppressor gene.2,3 In contrast to familial cancer syndromes, ATM gene alterations in CLL cases fail to follow the postulated pathway of tumor suppressor gene inactivation, since most cases associated with a reduced ATM expression show biallelic ATM mutations with no detectable loss of heterozygosity.4 RAS genes encode a family of 21-kDa proteins that are central nodes in signaling networks of cell fate regulation in many tissue lineages.5 Different RAS genes are preferentially mutated in distinct tumor types, with KRAS mutations highly prevalent in common epithelial malignancies.6 KRAS mutations have recently been described in a small subset of CLL and are thought to be involved in posttherapeutic subclonal evolution.7 The protein encoded by PTPN11 is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known signaling molecules that regulate a variety of cellular processes, including cell growth, differentiation, mitotic cycle, and oncogenic transformation.8 PTPN11 mutations are a cause of Noonan syndrome and have been implicated in acute myeloid leukemia, juvenile myelomonocytic leukemia, and rarely in CLL, as noted in COSMIC (can cer.sanger.ac.uk). PTPN11 mutations have been known to cause activation of the RAS signaling pathway. In total, the genomic signature identified indicates an aggressive clinical course and potential utility of targeted therapeutics that are available in an investigational context. CLL: A Molecularly Diverse Disease With New Genomic Discoveries CLL, the most frequent leukemia in the Western world, is characterized by an extremely variable clinical course, with survivals ranging from 1 to more than 15 years.9 Currently, in addition to morphologic examination, a CLL workup in the hematopathology

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and molecular pathology laboratory consists of cytogenetic analysis, FISH testing, and a PCR-based test to look for somatic hypermutation of IGVH. Recent genomic studies in CLL have displayed a complex panorama of somatic mutations in various genes that have prognostic significance. In 2011, Puente and colleagues identified 46 somatic mutations in CLL, including 4 recurrent mutations in NOTCH1, XPO1, MYD88, and KLHL6 across 363 patients.10 Shortly thereafter, Doménech and colleagues performed an analysis of 301 select genes in 10 CLL patients with progressive disease and identified recurrent abnormalities in KRAS, SMARCA2, NFKBIE, and PRKD3, all of which play a role in B-cell receptor, NF-κB, and related signaling pathways.11 A review article published May 20, 2013, cites 13 genes as recurrent somatic mutations in CLL and highlights the challenge of integrating these mutations with the known prognostic variables mentioned above.12

Table Clinical Implications of CLL Genetics Diagnosis Prevalence (%)

Overall Survival (years)

Prevalence (%)

Overall Survival (years)

17p13 deletion

4-5

5-7

8-10

1.5-2

TP53 mutation

5-10

5-6

8-11

1.5-3

11q22/23 deletion

8-9

21-23

3-5

ATM mutation

10-15

7-8

NOTCH1 mutation

5-11

4-8

4.5

SF3B1 mutation

6-9

4-9

4.5

BIRC3 mutation

3.5

unknown

Trisomy 12

9.5

unknown

Aberration

Adapted from Foà R, Del Giudice I, Guarini A, et al. Clinical implications of the molecular genetics of chronic lymphocytic leukemia. Haematologica. 2013;98:675-685.

Molecular Diversity of CLL: Implications for Precision Oncology Integration of recurrently mutated genes into the clinical workup of CLL patients continues to evolve as new information is published. What is known to date is that the presence of a NOTCH1 mutation is associated with a shorter time to progression requiring therapy, a shorter overall survival, and is increased in patients who transform to diffuse large B-cell lymphoma.13 SF3B1 mutations have been associated with rapid disease progression and a decrease in overall survival14 and are also commonly seen in conjunction with del 11q, a known unfavorable prognostic marker.15 Importantly, Stilgenbauer and colleagues recently performed an analysis in the CLL-8 trial (NCT00281918) in which they looked at gene mutations and treatment outcome in CLL treated with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR). The presence of a NOTCH1 mutation in this analysis predicted for a lack of benefit to rituximab, and both TP53 and SF3B1 mutations were negatively correlated with progression-free survival during FCR therapy.16 Another recent discovery is the inactivating mutations of BIRC3 in fludarabine-refractory patients by Rossi and colleagues in 2012. BIRC3 is a regulator of the NF-κB pathway, and inactivation may play a role in refractoriness to purine analogs.17

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Conclusion The pathologic evaluation of CLL is evolving to integrate results from somatic mutation testing in a number of genes to inform prognostic and therapeutic decision making. CLL is a molecularly complex disease with genomic aberrations ranging from multiple point mutations, hypermutation of genomic regions, and gross cytogenetic abnormalities that are clinically significant. All of these factors require balanced

Integration of recurrently mutated genes into the clinical workup of CLL patients continues to evolve as new information is published. integration into treatment planning. Allogeneic stem cell transplantation is now a viable option for “poorrisk” CLL patients,18 and proper prognostic stratification is essential to guide current and future chemotherapeutics. The molecular aberrations identified in this case were important to inform prognostic and therapeutic decisions and show that as knowledge of genomic complexity expands, further refinement of risk will require comprehensive molecular oncology testing and a general understanding that each patient’s cancer is molecularly unique. u

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References

1. Austen B, Powell JE, Alvi A, et al. Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. Blood. 2005;106:3175-3182. 2. Gumy-Pause F, Wacker P, Sappino AP. ATM gene and lymphoid malignancies. Leukemia. 2004;18:238-242. 3. Derheimer FA, Kastan MB. Multiple roles of ATM in monitoring and maintaining DNA integrity. FEBS Lett. 2010;584:3675-3681. 4. Stankovic T, Weber P, Stewart G, et al. Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet. 1999;353:26-29. 5. Ward AF, Braun BS, Shannon KM. Targeting oncogenic Ras signaling in hematologic malignancies. Blood. 2012;120:3397-3406. 6. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007;7:295-308. 7. Landau DA, Carter SL, Stojanov P, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell. 2013;152:714-726. 8. National Center for Biotechnology Information. PTPN11 protein tyrosine phosphatase, non-receptor type 11 [Homo sapiens (human)]. www.ncbi.nlm.nih.gov/ gene?cmd=Retrieve&dopt=full_report&list_uids=5781. Accessed May 21, 2014. 9. Dal-Bo M, Bertoni F, Forconi F, et al. Intrinsic and extrinsic factors influencing the clinical course of B-cell chronic lymphocytic leukemia: prognostic markers with pathogenetic relevance. J Transl Med. 2009;7:76. 10. Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing identifies

recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475:101-105. 11. Doménech E, Gómez-López G, Gzlez-Peña D, et al. New mutations in chronic lymphocytic leukemia identified by target enrichment and deep sequencing. PLoS One. 2012;7:e38158. 12. Rampal R, Levine RL. Leveraging cancer genome information in hematologic malignancies. J Clin Oncol. 2013;31:1885-1892. 13. Fabbri G, Rasi S, Rossi D, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011;208:13891401. 14. Quesada V, Conde L, Villamor N, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet. 2011;44:47-52. 15. Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med. 2011;365:2497-2506. 16. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014;123:3247-3254. 17. Rossi D, Fangazio M, Rasi S, et al. Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. Blood. 2012;119:2854-2862. 18. Dreger P. Allotransplantation for chronic lymphocytic leukemia. Hematology Am Soc Hematol. 2009:602-609.

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Implementing Global Healthcare: Partners In Health and the Rwandan Cancer Center Initiative An Interview With Lawrence N. Shulman, MD, of Dana-Farber Cancer Institute

artners In Health (PIH) was founded in 1987 by Ophelia Dahl; Paul Farmer, MD, PhD; Jim Kim, MD, PhD; Todd McCormack; and Thomas J. White to deliver healthcare to residents of Haiti. In the 27 years since then, PIH has launched healthcare projects around the world. Its mission is to provide a preferential healthcare option Lawrence N. Shulman, MD for the poor. By establishing long-term relationships with sister organizations based in settings of poverty, PIH strives to achieve 2 overarching goals: to bring the benefits of modern medical science to those most in need of them and to serve as an antidote to despair.

PIH in Rwanda Rwanda was one of the world’s poorest countries even before the 1994 genocide devastated the nation and its fragile healthcare system. In 2005, as part of its rebuilding, the Rwandan government asked PIH to help strengthen the public health system in 2 underserved districts in the eastern province. Widespread poverty, limited access to care, and insufficient resources to address easily treatable diseases resulted in countless preventable deaths. With Rwandan sister organization Inshuti Mu Buzima (Kinyarwanda for “Partners In Health”), PIH has brought high-quality healthcare to 3 rural districts that previously had some of the country’s worst health outcomes. In addition to the 3 hospitals and 41 health centers throughout the districts of Burera, southern Kayonza, and Kirehe, the Butaro Cancer Center of Excellence opened in July 2012. The center

Dr Shulman received his MD from Harvard Medical School in 1975 and trained in hematology-oncology at Beth Israel Hospital in Boston. He is currently chief of staff and senior vice president for Medical Affairs at Dana-Farber Cancer Institute, where he is also director of the Center for Global Cancer Medicine. He is actively involved in clinical research in breast cancer.

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vastly improves Rwandans’ options for diagnosis and treatment and is the first of its kind to bring comprehensive cancer care to rural East Africa. At the Butaro Cancer Center, patients have access to screening, diagnostics (tissue procurement, pathology evaluation, and imaging), chemotherapy, surgery, patient follow-up, palliative care, mental health and social work services, and socioeconomic support such as food, transportation, home visits, and community health worker accompaniment. Patients needing radiation therapy (still unavailable in Rwanda) are referred to Mulago Hospital in Uganda. Cancer Center Features Include: • 24 beds for adult and pediatric cancer patients, plus 3 isolation rooms • A patient-centered design – each bed faces a beautiful view • Care from trained nurses who are mentored by visiting oncology nurses from Dana-Farber Cancer Institute (DFCI) • Care from general practitioner doctors with special training in oncology and Butaro-based internist and pediatric specialists • Support from oncology specialists from DFCI and Brigham and Women’s Hospital to provide mentorship and guidance

Catalyzing Lasting Change The center will also serve as the first facility to implement standardized cancer training and protocols developed in partnership with the Rwandan Ministry of Health. The center’s contributions to national cancer care will include: • Developing and implementing standardized national cancer protocols to improve the quality of patient care • Collaborating with national partners and colleagues to share experiences and strengthen strategies for procuring necessary equipment, consumables, and medications

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• Creating a comprehensive paper chart system and sophisticated electronic medical records to streamline care and reduce medical errors • Developing a database and indicators to facilitate monitoring and evaluation of diagnostic and treatment programs • Developing cancer training programs for nurses, doctors, medical and nursing students, medical residents, and pathology support

Partners The Butaro Cancer Center of Excellence is a critical element of Rwanda’s ambitious plan to strengthen cancer prevention, screening, and treatment on a national level. It was built and operates with support from a unique partnership brought together through the Clinton Global Initiative: the Rwandan Ministry of Health, PIH, DFCI, Brigham and Women’s Hospital, Boston Children’s Hospital, and the Jeff Gordon Children’s Foundation. Looking Forward Today, Rwanda is seen as a model for how resource-poor countries can recover from traumatic events,

PMO Dr Shulman, let me thank you in advance for sharing with us the remarkable work you are doing in Rwanda and elsewhere around the globe to bring modern cancer care to places that would appear to lack even the most basic requirements for practicing meaningful care. Can you begin by sharing with us the genesis of this initiative? Dr Shulman Certainly, my pleasure. I’ve worked with Paul Farmer and his organization, Partners In Health, for more than 2 decades. For many of those years, particularly in Haiti, when cancer patients would present to his facility, we’d figure out if we could treat them or not and do the best we could. In 2008 he and I agreed to develop cancer care infrastructures, primarily in Rwanda and Haiti, 2 of the sites where he already had established facilities. The work started first in Rwanda. We built a new hospital in northern Rwanda, Butaro Hospital, which opened in January 2011, and immediately went to work on developing a cancer infrastructure that included a pathology lab and the ability to obtain, prepare, and administer chemotherapy, and so on. That cancer center was dedicated by former President Bill Clinton, Chelsea Clinton, and the Minister of Health, Dr Agnes Binagwaho, in July 2012. It’s the most accessible cancer care in the entire country of Rwanda.

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and PIH is proud to be playing an ongoing role in this emerging global health success story. The development of the Butaro Cancer Center of Excellence is a manifestation of this partnership and a strong will to bring quality healthcare to those who have not had access. Personalized Medicine in Oncology is pleased to provide the following interview with our editorial board member, Dr Lawrence N. Shulman of Dana-Farber Cancer Institute. Dr Shulman works closely with PIH, where he is senior advisor in oncology, helping to lead the development of a structured cancer program for healthcare sites in Rwanda, Malawi, and Haiti. He was the previous cochair, with Dr Julio Frenk, dean of the Harvard School of Public Health, of the Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries, a Harvard-based, international task force committed to the improvement of cancer care worldwide. He provides an awe-inspiring look at the commitment to the global cancer care initiative that is taking place in Africa, Haiti, and several other areas lacking basic care. His work is emblematic of the altruism at the core of cancer care and is just part of a major, permanent initiative for the globalization of cancer care.

What we have found over the past year and a half since we opened is that people have come from all over the country and, in fact, neighboring countries as well, to receive cancer care at Butaro. We’ve seen over 1500 new cancer patients in that first year and a half. Over 80% of those patients come from outside of the district of the hospital, which demonstrates that we are providing cancer care for the entire country. Patients have come from east Congo, Uganda, Burundi, and other neighboring countries as well. We treat everybody free of charge and have increased our ability to make diagnoses and deliver care.

What we have found over the past year and a half since we opened is that people have come from all over the country and, in fact, neighboring countries as well. It’s a complicated process. We have a functioning pathology lab in the country that is supported by my pathology colleagues at the Brigham and Women’s Hospital. We have a telepathology system so that slides can be read remotely. We’re developing expertise in immu-

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nohistochemistry for breast cancer, including estrogen receptors and HER2 status. We’re developing in-country capabilities for molecular testing such as looking for the Philadelphia chromosome, the BCR-ABL translocation, which you need to diagnose chronic myelogenous leukemia [CML], and we’re able to obtain imatinib free of charge from the Max Foundation and Novartis. We’ve put a lot of pieces into place over the last 18 months, but we certainly continue to have challenges. It’s not easy to administer cancer therapy there. We’ve been fortunate to have Boston-based physicians from Dana-Farber, Brigham and Women’s Hospital, Massachusetts General Hospital, and Boston Children’s Hospital go for periods of time to provide care and train our colleagues there, and we’ve had Dana-Farber nurses on the ground in Butaro for most of the past 24 months. We’re beginning to fully flesh out the system. There are things that we don’t have that US physicians take for granted. We don’t have a CT scanner in our hospital. We can send patients to the capitol for CT scans, but it’s expensive and difficult. There’s no radiation therapy in the country. We send patients to Uganda for radiation, but that’s obviously a big undertaking. We are working with the Ministry of Health to try to establish a radiation facility in the country.

We’re beginning to fully flesh out the system. There are things that we don’t have that US physicians take for granted. We don’t have a CT scanner in our hospital. We have a research team in Rwanda, including a research assistant who’s collecting data. We have an electronic health record where the data are stored and also used as a database. We have several other researchers, medical students, and physicians who are there on fellowships. We all think that it’s critical that we look at several aspects of research. We need to better understand the demographics of cancer in Rwanda. There’s no reason to believe that demographics in Rwanda are the same as they are in the US. In almost every different geographic and ethnic population there are differences. We have an area that we refer to as implementation science; this is where we assess whether we are effectively and safely treating our cancer patients – that we are administering the therapies at full dose and on time, safely managing the toxicities, and recording what the outcomes are. Again, you can’t assume that if you treat a patient with Hodgkin lymphoma in Rwanda with the same 4 drugs we use in Boston that the outcomes will

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be the same, because there could be genomic differ ences of the cancers or germline polymorphisms that affect the efficacy and/or toxicities of the drugs. This summer we hope to begin to document the molecular biology of the cancers that we see there compared with the cancers that we see in the US. And even in the US, we know there are differences, for instance, in the breast cancer genomics in Caucasians versus African Americans. There are likely to be differences in the Rwandan population as well. The first cancer we’re going to look at is Wilms’ tumor, which is a childhood cancer of the kidney. In the US, Wilms’ tumor is a very rare, highly curable cancer. In Rwanda, for reasons that are unclear to us, it is the most common cancer we see in children. Acute lymphoblastic leukemia, the most common pediatric cancer in the US, is the second most common pediatric cancer in Rwanda. Our work in Haiti is a little bit further behind than it is in Rwanda. We just opened our new hospital in April 2013 and moved our cancer program in there in July 2013. We treat a lot of cancer patients in Haiti, but we don’t have the infrastructure set up as we do in Rwanda at this point. PMO One of the things that springs to mind is screening and identifying patients with cancer. It’s axiomatic in developed countries that the earlier the diagnosis, the better the chances for clinical success. How do you screen patients in a country that lacks anything remotely like our healthcare infrastructure? Dr Shulman The answer is, not much. There’s no breast cancer screening program, for instance. We’ve just started to do cervical cancer screening. There’s no prostate cancer screening. There’s no colon cancer screening. Part of the issue that you need to remember, I think, is that 24 months ago there was little access to cancer care in the country. Why would you screen anybody if you didn’t have the capacity to do a biopsy and make a diagnosis and treat them? The ability to treat cancer patients is a new thing in Rwanda, relatively speaking. The people and the country are just beginning to understand that cancer is a potentially curable disease. Rwanda is a small country. Word travels fast, and so people are bringing themselves in for care in increasing numbers. But we know from some research that we’ve done recently that if you look at a group of breast cancer patients, most of them had gone to a medical facility somewhere in the country with a breast complaint for some period of months before they finally found their way to our hospital. Healthcare providers didn’t appreciate the fact that they could send them to our hospital in Butaro for care. I think that’ll change with time. But one of the

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other issues is that Rwanda is a country of 11 million people, and as we strive to diagnose more patients at earlier stages of disease, we need to scale-up the capacity to evaluate and treat those patients. We still have work to do in this regard. This is going to be an iterative process. We have to build increased capacity to treat cancer. We have to educate the physicians, nurses, and laboratory technicians at other hospitals in the country, which we’re actively doing. We need to develop cancer programs in these other hospitals and begin to do screening for some basic diseases in the community health centers, including screening for breast cancer and cervical cancer at a minimum. These are the 2 most common diseases we see in adults: breast cancer first, and cervical cancer second. There are some things that we can’t explain. We see very little prostate cancer. My guess is that it exists, but men don’t come in for medical care, or they do come in and it’s not identified as the cause of their renal failure or their bone pain. There’s not general availability of PSA testing. What we’re seeing at our hospital is almost certainly the tip of the iceberg and largely at this point either referred from physicians in other hospitals or selfreferred, but generally not picked up as part of screening programs. PMO Has this scenario, this “tip of the iceberg” idea, impacted your strategic and tactical attack on cancer in Rwanda? Dr Shulman Yes. We recently had a Partners In Health–wide summit with the leaders from all their site programs – Rwanda, Haiti, Malawi, and other programs – in Boston last month where we spent 4 solid days reviewing all the programs, not just the cancer programs. We’re now starting to turn out data with patient outcomes. We are a year and a half into our program, and we’re starting to turn out data that are telling us exactly how patients have been treated – whether they’ve gotten their treatment on time, on schedule, and with manageable toxicity – and what their disease outcomes are. We already have some of those data; for instance, outcomes in CML treated with imatinib are excellent. All those patients have been determined to have the p210 BCR-ABL translocation, and they have all responded well to imatinib. Nobody’s been lost to follow-up, and I think 22 of the first 26 patients are still in hematologic remission. You have to look at those data. This is a research experiment. You need to prove what you can accomplish, how the patients do, what the compliance with care is, what the toxicities are, and what the tumor outcomes are. Those data are being continually gener-

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Dr Lawrence Shulman, Honorable Minister of Health Dr Agnes Binagwaho, Chelsea Clinton, former President Bill Clinton, Jeff Gordon, Dr Paul Farmer.

ated and updated, and that will give us a better idea of exactly what we have accomplished, where the gaps in care are, and where we can design changes in our care delivery model that might improve outcomes. PMO Addressing the problem of cancer in a country like Rwanda requires you to establish priorities. How would you describe the way in which you have set your priorities in bringing cancer care to Rwanda?

We have tried to prioritize the diseases in which we can make the greatest impact. Certainly all the childhood cancers are included. Dr Shulman We are not going to be able to provide all care for all patients immediately. You have to start somewhere, and we have started. Take the pathology system, for instance. We first started making tumor blocks and sending the blocks back to Boston to be cut, stained, and read. Then we made tumor blocks and did the cutting and the staining and sent the slides back to be read. And then we started doing the reading with the visiting pathologists there and have started utilizing telepathology. We’re currently doing a validation study to determine the accuracy of telepathology. That’s just a small example of the fact that it’s not an on/off light switch, it’s a developmental process. We have tried to prioritize the diseases in which we can make the greatest impact. Certainly all the childhood cancers are included. We have good support from

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Rwanda by the Numbers

Total population: 10,942,950 Life expectancy at birth: 56 years Child mortality: 76 per 1000 Maternal mortality: 476 per 100,000 live births Adult prevalence of HIV: 3% Prevalence of TB: 565 per 100,000 Population living on less than $1 a day: 44.9% Source: www.pih.org

The Unpleasant Truth • The World Health Organization expects 16 million new can-

cer cases worldwide by 2020, with 70% in developing countries such as Rwanda • More than 2.4 million cancer deaths could be avoided each year in developing countries by using prevention and treatment interventions that are affordable and available in rich countries • Developing countries account for almost 80% of the global cancer burden (loss from death and disability) but only 5% of global spending on cancer • In Rwanda, 3430 cancer cases were registered from 20072011; 320 were in children younger than 15. This doesn’t include the great number of cases that go undiagnosed and unreported Source: www.pih.org

our pediatric oncology colleagues in developing treatment protocols appropriate for Rwanda. It’s worth pointing out that for every disease we treat we have a written, agreed-upon, nationally approved approach from diagnostics to treatment. We need to be very thoughtful about the therapies that we are administering and be able to do it in a uniform way and therefore be able to capture the data in a meaningful way that tells us how we have done. PMO Personalized medicine is predicated on an enriched patient population, and it stands in contrast to the blockbuster drug era or “population-based” approach to cancer care. Is it possible to apply a personalized approach to cancer care in an underdeveloped country like Rwanda, or are you limited from using the full armamentarium to date of personalized medicine targeting techniques? Dr Shulman The answer is, it’s spotty. As I mentioned, we can get imatinib free of charge from the Max Foundation with the generosity of Novartis if we can prove the patient has the t(9;22) translocation in their CML cells or if they have a c-KIT mutation in gastrointestinal stromal tumors. That’s been incredibly generous on the part of Novartis and the Max Foundation

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and lifesaving for those patients. So that’s an example of success, if you will. We don’t have the second- and third-line TKI [tyrosine kinase inhibitor] drugs if the patient’s disease becomes resistant to imatinib; but so far, fortunately, that’s been a rare occurrence. PMO How receptive have patients been to your efforts, as exemplified by adherence to treatment, or just their overall receptivity to it? Dr Shulman They’re incredibly receptive and very grateful. They’re incredibly compliant. Their adherence to treatment and follow-up is very high. We almost never lose a patient to follow-up. With CML, for which they’re getting an oral drug, the only way you really can tell whether they’re taking it is by their hematologic parameters, which are excellent, so our assumption is that the patients are taking it as prescribed. Let me give you an example. A couple of years ago the government, the Ministry of Health, in Rwanda in a partnership with Merck vaccinated over 93% of the girls between the ages of 11 and 14 with HPV [human papillomavirus] vaccine. That’s well above what the vaccination rates are in the US. PMO What is the potential for wellness-based care in Rwanda and for continuing your efforts there? Dr Shulman There are a few things to think about. I’ve just mentioned that HPV vaccination has been very successful. That’s a risk-reducing strategy for cervical cancer. Smoking is a very low-prevalence problem there. Obesity essentially doesn’t exist in the country. PMO Have you established a model for replication in other third-world countries? Dr Shulman We have begun to publish our experience, but in conversations with my colleagues who work in Uganda or Kenya or Tanzania or Botswana, we learn that in all these different places, the challenges are different, and the approaches need to be tailored to overcome those specific challenges. I don’t think it’s a one-size-fits-all approach. We have a set of basic principles regarding the delivery of cancer care. For example, we deliver cancer care at Butaro without full-time oncologists on the ground. We have had full-time oncology nurses from DanaFarber there but not full-time oncologists. We conduct weekly phone calls during which Dana-Farber oncologists review all the patients under treatment, and we also have multiple exchanges during the week to support those caring for patients. One of the reasons I think this is such an important model is that if you look at the number of oncologists in the world – even if we were very aggressive about training more – how many will there be in 20 years?

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PMO Dr Shulman, we cannot thank you enough for bringing your experience to us. We wish you all success with this endeavor and look forward to hearing of news of your next center.

There are not going to be nearly enough oncologists to treat most of the cancer patients in the world. Developing different models of care, I think, is an important thing to do. PMO Is this concern stimulating the government of Rwanda to do more to bring oncologists into their country? Dr Shulman The Ministry of Health led by Dr Agnes Binagwaho is very strong, and with funding from the Clinton Global Initiative and the US government, we have a very broad program to increase healthcare capacity in Rwanda. Rwanda has other problems besides cancer: infectious disease, trauma from accidents, child/maternal mortality, and so on. They’re confronting all these areas of healthcare, and the government is proactive in trying to increase their capacity to address all these issues.

It’s worth pointing out that for every disease we treat we have a written, agreedupon, nationally approved approach from diagnostics to treatment. Dr Shulman It was my pleasure. I will be glad to share more with you in the future as we continue our efforts. I cannot emphasize enough that it is the extraordinary team I am privileged to work with that is making this happen. u

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Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

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Androgen Suppression in Castration-Resistant Prostate Cancer

rostate cancer is the most frequently diagnosed cancer in men other than skin cancer and is the second-leading cause of cancer death in men in the United States.1,2 An estimated 238,590 new cases of prostate cancer will have occurred in the United States during 2013, with an estimated 29,720 deaths1,2 Most patients have low-risk, clinically localized disease at diagnosis and can be treated effectively (or even cured) with prostatectomy (open, laparoscopic, or roboticassisted) and radiation therapy (external beam radiation or brachytherapy).1 However, 10% to 20% of patients are diagnosed with locally advanced or metastatic disease, and an additional 10% to 20% of patients diagnosed with localized disease will eventually develop metastases despite surgery and radiation.3,4

Prostate cancer deaths are typically the result of mCRPC, and historically the median survival for men with mCRPC has been less than 2 years. When prostate cancer progresses – marked by elevated levels of prostate-specific antigen (PSA), new metastases, and progression of existing metastases – despite confirmation of castrate levels of testosterone, it is referred to as castration-resistant prostate cancer (CRPC).5,6 A review characterizing the CRPC population revealed that 10% to 20% of patients develop CRPC within 5 years of follow-up.7 Prostate cancer deaths are typically the result of metastatic CRPC (mCRPC), and historically the median survival for men with mCRPC has been less than 2 years.8 The exact mechanism of transition from castration-sensitive prostate cancer to castrationresistant disease is not fully elucidated, but it is now understood that despite castrate levels of androgens, the androgen receptor (AR) remains active and continues to drive prostate cancer progression.9-13 In fact, in mCRPC, the AR remains hypersensitive to even low levels of androgen, increasing the stimulatory effects of testosterone and dihydrotestosterone (DHT).14-16 In addition, it has been shown that, in mCRPC, the tumor itself is an additional source of androgen.9,17

Androgen Deprivation Therapy Since the 1940s, when Huggins and colleagues

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demonstrated the responsiveness of prostate cancer to androgen deprivation, ie, that lowering serum testosterone levels by surgical castration or injection of estrogens induces a major regression of advanced prostate cancer and provides rapid relief from symptoms in patients with metastatic disease,18,19 the mainstay of treatment for advanced and metastatic prostate cancer has been androgen deprivation therapy (ADT; also known as androgen suppression therapy or hormonal therapy). In ADT, castration is accomplished either surgically by bilateral orchiectomy (surgical castration), or pharmacologically by the use of gonadotropin-releasing hormone (GnRH; also known as luteinizing hormone–releasing hormone [LHRH]) agonists, GnRH (or LHRH) antagonists, or antiandrogens – or their combination, which is referred to as combination (or maximal) androgen blockade (Table 1).2,3,20-25 Removal of the testicular source of androgens leads to a considerable decline in testosterone levels and induces a hypogonadal status, although a very low level of testosterone (known as the “castration level”) persists.25 Surgical castration is still considered the “gold standard” for ADT, against which all other treatments are rated, especially in Europe.25 In the United States, practice patterns favor GnRH agonists over orchiectomy because of their reversibility, ease of administration, and acceptability to patients.26 Results from a large retrospective study showed that external beam radiation therapy with ADT confers survival equal to that of radical prostatectomy in men with high-risk prostate cancer.27 ADT consistently results in a 90% to 95% reduction in circulating levels of testosterone.4 Synthesis of androgens outside the testes contributes to disease progression in CRPC. ADTs decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor; therefore, although the majority of patients with metastatic disease initially respond to hormonal therapy, almost all of them will eventually progress after an average of 14 to 24 months, despite maintenance of castrate serum testosterone levels <50 ng/mL.2,28-31

New Hormonal Therapy Agents Two new hormonal therapy agents targeting the AR pathway have recently been approved by the FDA for the treatment of patients with mCRPC: abiraterone acetate and enzalutamide (MDV3100) (Table 2).32,33

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Abiraterone Acetate The FDA approval of abiraterone acetate was based on the results of 2 randomized, placebo-controlled, multicenter phase 3 studies (Study 1 and Study 2) in patients who had mCRPC who were using a GnRH agonist or had been previously treated with orchiectomy. Patients with prior ketoconazole treatment for Table 1

prostate cancer and a history of adrenal gland or pituitary disorders were excluded from these trials.32 Study 1 enrolled 1195 patients with mCRPC who had received prior docetaxel chemotherapy. Results from a survival analysis conducted when 775 deaths (97% of the planned number of deaths for final analysis) were observed showed that overall survival was longer for

Comparison of Androgen Suppression Strategies21,24,25

Androgen Suppression Strategy

Examples

Advantages

Disadvantages

Orchiectomy (surgical castration)

• Open • Laparoscopic • Robotic-assisted

• Procedure is easy; can be performed as outpatient surgery • Provides definitive androgen ablation • Lowers testosterone levels immediately • Low long-term cost vs other forms of ADT • No problem with long-term compliance • For men who are concerned about their appearance after surgery, artificial silicone sacs that look much like testicles can be inserted into the scrotum

• Procedure is irreversible • Surgical complications are possible • Many men have trouble accepting the removal of their testicles • Psychological effects • Loss of libido • Impotence (occurs immediately and may improve over time) • Loss of muscle mass; weight gain • Hot flashes • Osteoporosis • Anemia • Increased risk of coronary heart disease and myocardial infarction • High short-term cost

Estrogens

• Conjugated estrogens • Treatment is reversible • Esterified estrogens • Low cost • Diethylstilbestrol (DES; • Oral administration no longer manufactured or marketed in the US)

GnRH agonists

• Goserelin • Histrelin • Leuprolide acetate • Buserelin

• Loss of libido • Impotence • Gynecomastia • Cardiovascular toxicity

• Treatment is reversible • Side effects comparable to surgi• Lower androgen levels comparacal castration (eg, impotence, hot ble to orchiectomy flashes, loss of libido) • Allow the testicles to remain in • At the start of treatment, testosplace, but the testicles will terone levels increase briefly beshrink over time, and they may fore falling to very low levels, reeven become too small to feel sulting in tumor flare reactions, • Temporary treatment is possible which can result in bone pain or • Tumor flare reactions may be paralysis in men whose cancer prevented by antiandrogens or has metastasized to the bone short-term estrogens at a low • While GnRH agonists stop the dose for several weeks testicles from making androgens, other cells in the body, including prostate cancer cells themselves, can still make small amounts of androgens, which may fuel cancer growth • Possible increased risk of diabetes and/or cardiovascular disease • High long-term cost

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Table 1

Comparison of Androgen Suppression Strategies21,24,25 continued

Androgen Suppression Strategy

Examples

Advantages

Disadvantages

GnRH receptor antagonist

• Degarelix

• Treatment is reversible • Anaphylaxis • Lower androgen levels compara- • Injection-site reactions (pain, ble to orchiectomy redness, and swelling) • Work like GnRH agonists but • Increased levels of serum liver reduce testosterone levels more enzymes quickly • Do not cause tumor flares • Temporary treatment is possible

Antiandrogens and androgen synthesis inhibitors

• Abiraterone acetate • Treatment is reversible • Enzalutamide (MDV3100) • Temporary, adjuvant, step-up, • Bicalutamide or intermittent therapy possible • Flutamide • Favorable tolerability profile; • Nilutamide preservation of sexual function • Cyproterone acetate is possible; may have fewer sex• Megestrol acetate ual side effects vs GnRH antag• Ketoconazole onists or orchiectomy; osteopo• Aminoglutethimide rosis occurs less frequently • Oral administration

Combined (maximal) ADT

• Combination of androgen deprivation (ie, orchiectomy or a GnRH agonist or antagonist) plus an antiandrogen

• High long-term cost • Gynecomastia, breast tenderness, hot flashes, loss of libido, impotence are possible • Hepatotoxicity; nausea; diarrhea • Noncompliance is possible • Less effective in patients with high tumor burden (metastatic disease)

• Suppression of both testicular • Combined side effects of both and adrenal androgens androgen deprivation and oral • Possible small survival advantage antiandrogens

ADT indicates androgen deprivation therapy; GnRH, gonadotropin-releasing hormone.

Table 2

Hormonal Therapy Agents Recently FDA Approved for the Treatment of mCRPC

Agent

Indication (Date of FDA Approval)

Mechanism of Action

Abiraterone acetate32

• Indicated in combination with prednisone for the treatment of patients with mCRPC (December 10, 2012) • Indicated for use in combination with prednisone for the treatment of patients with mCRPC who have received prior chemotherapy containing docetaxel (April 28, 2011)

• An androgen biosynthesis inhibitor that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17), an enzyme that is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis

Enzalutamide (MDV3100)33

• Indicated as monotherapy for the treatment of patients with mCRPC who have previously received docetaxel (August 31, 2012)

• An androgen receptor inhibitor

mCRCP indicates metastatic castration-resistant prostate cancer.

patients treated with abiraterone acetate than for those who received placebo (Figure 1).32 Study 2 enrolled 1088 patients with mCRPC who had not received prior cytotoxic chemotherapy. At the protocol-prespecified third interim analysis for overall survival, 37% of patients (200 of 546) treated with abiraterone acetate, compared with 43% of patients

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(234 of 542) treated with placebo, had died. As in Study 1, overall survival was longer with abiraterone acetate than with placebo (Figure 1).32 In both studies, abiraterone acetate was administered at a dose of 1000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. The most common adverse drug reactions (≥10%)

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50 Study 1

Study 2 Hazard Ratio (95% CI): 0.792 (0.655, 0.956)

35.3 30.1

30 Hazard Ratio (95% CI): 0.740 (0.638, 0.859)

15.8 11.2

Abiraterone Placebo Acetate (n=398) (n=797)

Abiraterone Placebo Acetate (n=542) (n=546)

Overall Survival of Patients Treated With Either Enzalutamide or Placebo (Intent-to-Treat Analysis)33,35

Figure 2 50

40 Median Survival (months)

Enzalutamide The FDA approval of enzalutamide was based on the results of a randomized, placebo-controlled, multicenter phase 3 study (AFFIRM) in 1199 patients with mCRPC who had received prior docetaxel-based therapy.33,35 The primary end point was overall survival. The prespecified interim analysis showed a statistically significant improvement in overall survival in patients in the enzalutamide group compared with those receiving placebo (Figure 2).33,35 The most common adverse drug reactions (≥5%) with enzalutamide were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flushes, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade ≥3 adverse reactions were reported among 47% of enzalutamide-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of enzalutamide-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% (n=7) of the enzalutamide-treated patients compared with 0% of the placebo-treated patients.33 Enzalutamide has also been investigated in prechemotherapy CRPC patients, including both metastatic and nonmetastatic disease in the PREVAIL trial, a randomized, double-blind, placebo-controlled phase-

Overall Survival of Patients Treated With Either Abiraterone Acetate or Placebo in Combination With Prednisone32

Figure 1

Median Survival (months)

reported in the 2 randomized studies that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flushes, diarrhea, vomiting, cough, hypertension, dysp nea, urinary tract infection, and contusion. The most common laboratory abnormalities (>20%) reported in the 2 randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.32 Coadministration of low-dose prednisone is necessary with abiraterone acetate to ameliorate hypertension, hypokalemia, and fluid overload resulting from mineralocorticoid excess induced by CYP17 inhibition.34 While coadministration of prednisone is manageable in patients with mCRPC, longer-term use in earlier disease phases could be problematic due to potential side effects (eg, diabetes, weight gain, Cushing syndrome, and osteoporosis).

Hazard Ratio (95% CI): 0.63 (0.53, 0.75)

18.4 13.6

Enzalutamide (n=800)

Placebo (n=399)

trial that included 1715 patients who had progressed following treatment with an LHRH analog only, as well as patients who had progressed following treatment with both an LHRH analog and an antiandrogen. The primary end points were radiographic progression-free and overall survival. Due to positive results in both end points (30% reduction in the risk of death, hazard ratio [HR] 0.70, P<.0001; 81% reduction in the risk of radiographic progression or death, HR 0.19, P<0001), the Independent Data Monitoring Committee recommended the study be stopped and patients treated with placebo be offered enzalutamide.36

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Table 3

Investigational Hormonal Therapy Agents in Development for the Treatment of CRPC37-40

Agent

Mechanism of Action

Phase of Development

Orteronel (TAK-700)37

• An androgen biosynthesis inhibitor that inhibits 17 α-hydroxylase/C17,20lyase (CYP17), an enzyme expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis

• A randomized, double-blind, • On July 25, 2013, a prespecified multicenter, global phase 3 interim analysis indicated that study (ELM-PC 5) is evaluating orteronel + prednisone would orteronel + prednisone vs placelikely not meet the primary end bo + prednisone in the treatpoint of improved overall surment of men with mCRPC that vival vs the control arm (HR had progressed during or follow0.894; P=.226) ing docetaxel-based therapy • The interim analysis did show an advantage for orteronel + prednisone for the secondary end point, radiographic progression-free survival, over the control arm (HR 0.755, P=.00029)

Galeterone (TOK-001)38,39

• Selectively inhibits CYP17 lyase to prevent testosterone synthesis, antagonizes testosterone binding to the AR, and degrades the AR protein

• A phase 2 study (ARMOR2) is • Results from a phase 1, under way in 4 distinct populadose-finding study (ARMOR1) tions of CRPC patients: 1) metin 49 patients showed that gaastatic treatment-naive patients; leterone was well tolerated with 2) nonmetastatic treatmentminimal side effects and naive patients; 3) patients who demonstrated clinical activity have progressed while taking in patients with CRPC abiraterone acetate; and 4) pa• Galeterone was reformulated tients who have progressed prior to the initiation of the while taking enzalutamide ARMOR2 clinical trial in order • The primary end points of the to increase the drug exposure study are reduction in PSA levand mitigate the effect of food els and safety on oral bioavailability. The • The secondary end points innew formulation has been clude tumor responses by shown to be unaffected by diet RECIST, levels of circulating and therefore can be taken tumor cells and markers of with or without food CYP17 lyase inhibition, and AR modulation

ARN-50940

• A novel AR antagonist that inhibits AR nuclear translocation and AR binding to androgen response elements and, unlike bicalutamide, does not exhibit agonist properties in the context of AR overexpression

• A phase 1/2 study is under way in patients with advanced CRPC (NCT01171898)

Comments

• Results from a phase 1 study in 30 patients with progressive CRPC showed PSA declines at 12 weeks (≥50% reduction from baseline) in 46.7% of patients • The most frequently reported adverse event was grade 1/2 fatigue (47%)

AR indicates androgen receptor; HR, hazard ratio; (m)CRPC, (metastatic) castration-resistant prostate cancer; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria In Solid Tumors.

Investigational ADT Agents for CRPC More recently, other drugs that act along the androgen signaling pathway, such as orteronel (TAK-700),37 galeterone (TOK-001),38,39 and ARN-509,40 have shown promise in clinical trials (Table 3).

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Complications Associated With Androgen Suppression Because a diagnosis of prostate cancer does not alter the life expectancy for most men (ie, most men diagnosed with prostate cancer will die of something other

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Table 4

ADT-Induced Complications26,42-47

Complication

Comments

Management Strategies

Cardiovascular disease and stroke

• In a population-based cohort of patients with newly diag• Preventive measures, such as statin theranosed prostate cancer, combination therapy with GnRH agpy, antihypertensive therapy, and aspirin onists and antiandrogens was associated with a significant (unless contraindicated) are advised46 increase in the risk of coronary heart disease (OR, 4.35; • Lifestyle changes: increased exercise and 95% CI, 1.94-9.75), stroke (OR, 3.57; 95% CI, 1.44-8.86), normalization of body mass index46 incident heart failure (OR, 3.19; 95% CI, 1.10-9.27), and hospitalized heart failure (OR, 3.39; 95% CI, 1.07-10.70) compared with nonuse of these drugs42 • In a population-based cohort (N=22,310) of patients with prostate cancer followed for a mean of 3.9 years, current users of GnRH agonists (adjusted RR, 1.18; 95% CI, 1.001.39), oral antiandrogens (adjusted RR, 1.47; 95% CI, 1.082.01), and those who underwent bilateral orchiectomy (adjusted RR, 1.77; 95% CI, 1.25-2.39) were at an increased risk of stroke/TIA compared with nonusers of ADT43 • A systematic review of the literature revealed that men who underwent ADT had a 17% increase in cardiovascularrelated mortality compared with men who did not undergo ADT (HR, 1.17; 95% CI, 1.07-1.29)44 • Another literature review found that the increased risk of serious cardiovascular disease becomes evident within months of beginning ADT45

Metabolic syndrome and diabetes

• An analysis of 73,196 men with prostate cancer followed for a median of 4.55 years showed that GnRH agonist treatment is associated with a greater incidence of diabetes (HR, 1.44; P<.001)26 • An analysis of another database of nearly 20,000 men treated with either bilateral orchiectomies or 6 months or more of GnRH agonist therapy showed a statistically significant ADT-associated elevation in the risk for diabetes compared with men with prostate cancer who were not treated with ADT (HR, 1.16; 95% CI, 1.11-1.21)26

• Metformin plus lifestyle intervention, including dietary advice and regular aerobic exercise46 • Lifestyle changes: increased exercise and normalization of body mass index26,46

Bone disease

• Results from a systematic review of the literature showed that men who underwent ADT for prostate cancer had a significantly increased risk of overall fracture of 23% (relative risk, 1.23; 95% CI, 1.10-1.38) compared with men who had prostate cancer but did not undergo ADT44

• Lifestyle changes: increased exercise, calcium and vitamin D supplementation, cessation of smoking, decreased alcohol consumption, and normalization of body mass index46 • Bisphosphonates (eg, pamidronate, zoledronic acid, alendronate, and risedronate)26,46 • Selective estrogen receptor modulators (eg, raloxifene, toremifene)26,46 • Denosumab increases lumbar spine, hip, and radius bone mass density and also reduces the risk of vertebral fractures in men receiving ADT for nonmetastatic prostate cancer46,47

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Table 4

ADT-Induced Complications26,42-47 continued

Complication

Comments

Management Strategies

Vasomotor flushing (hot flashes)

• Affecting up to 80% of men on ADT, one of the most bothersome side effects is hot flashes. A loss of negative feedback in hypothalamic noradrenaline production as a result of sex hormones resets the hypothalamic thermoregulatory center, leading to vasomotor flushing46

• Progestational agents such as megestrol acetate and medroxyprogesterone acetate46 • Selective serotonin and serotonin norepinephrine reuptake inhibitors, such as sertraline, venlafaxine, paroxetine, and fluvoxamine46 • Gabapentin, an antiseizure agent46

Fatigue

• Occurs in approximately 43% of men receiving long-term ADT46

• Muscle strengthening (resistance) and aerobic exercise46

Sexual dysfunction

• Erectile dysfunction and a decrease in libido are troubling side effects that occur secondary to lack of testosterone46

• Parenteral estrogen therapy (eg, transdermal estradiol patches or gel) and psychological intervention for sexual sequelae46

Anemia

• ADT leads to anemia in as many as 90% of patients46

• Nutrient deficiencies such as iron and vitamin B12/folate should be appropriately addressed by oral or parenteral supplementation46 • In patients with severe anemia, metastatic cancer, and a limited bone marrow reserve, regular blood transfusions may be the only effective measure46 • Erythropoietin-stimulating agents46

ADT indicates androgen deprivation therapy; GnRH, gonadotropin-releasing hormone; HR, hazard ratio; OR, odds ratio; RR, rate ratio; TIA, transient ischemic attack.

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than their cancer), the benefits of ADT must be weighed against ADT-related adverse effects that are a consequence of the induced sex steroid deficiency.26,41 ADT has been shown to cause weight gain, decreased lean muscle mass, and increased fat mass leading to insulin resistance and diabetes; increased cholesterol and triglycerides leading to cardiovascular disease; and loss of bone mineral density causing osteoporosis and increased fracture risk.26,41 Men commencing ADT should be counseled about and be carefully monitored for these and other ADT-induced complications, which include vasomotor flushing (hot flashes), sexual dysfunction (loss of libido, impotence), fatigue, and anemia (Table 4).26,42-47

mCRPC initially respond to hormonal therapy, almost all of them will eventually progress. In addition, ADT is associated with a number of side effects, including vasomotor flushing, sexual dysfunction, fatigue, anemia, and metabolic complications, as well as effects on cardiovascular health and bone density. Therefore, clinicians should consider comorbidities and functional status of patients before initiating ADT, and the risk-benefit ratio related to ADT must be assessed for each individual patient – keeping in mind that the best way of preventing side effects is to use ADT only when it is absolutely indicated.46 u

Conclusion For more than 70 years, the benefits of androgen deprivation in the management of CRPC have been recognized. Two new hormonal therapy agents (abir aterone acetate and enzalutamide) have recently been granted FDA approval for the treatment of patients with CRPC, and additional hormonal therapy agents are under investigation in clinical trials. However, although the majority of patients with

References

Personalized Medicine in Oncology

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castration resistant prostate cancer (CRPC) docetaxel resistant. Cancer Biol Ther. 2012;13:1001-1008. 7. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65:1180-1192. 8. Cookson MS, Roth BJ, Dahm P, et al. Castration-resistant prostate cancer: AUA Guideline. J Urol. 2013;190:429-438. www.auanet.org/common/pdf/education/clini cal-guidance/Castration-Resistant-Prostate-Cancer.pdf. Accessed August 31, 2013. 9. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447-4454. 10. Mohler JL, Titus MA, Bai S, et al. Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res. 2011;71:1486-1496. 11. Reid AH, Attard G, Barrie E, et al. CYP17 inhibition as a hormonal strategy for prostate cancer. Nat Clin Pract Urol. 2008;5:610-620. 12. Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol. 2009;10:981-991. 13. Yuan X, Balk SP. Mechanisms mediating androgen receptor reactivation after castration. Urol Oncol. 2009;27:36-41. 14. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33-39. 15. Pienta KJ, Bradley D. Mechanisms underlying the development of androgenindependent prostate cancer. Clin Cancer Res. 2006;12:1665-1671. 16. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68:6407-6415. 17. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66:2815-2825. 18. Huggins C, Hodges CV. Studies on prostatic cancer, I: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-297. 19. Huggins C, Stevens RE Jr, Hodges CV. Studies on prostatic cancer, II: the effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43:209-223. 20. Nandha R. Abiraterone acetate: a novel drug for castration-resistant prostate carcinoma. J Postgrad Med. 2012;58:203-206. 21. National Cancer Institute. Prostate Cancer Treatment (PDQ). Bethesda, MD: National Cancer Institute; 2013. www.cancer.gov/cancertopics/pdq/treatment/prostate/ HealthProfessional. Updated November 19, 2013. Accessed September 1, 2013. 22. Wirth MP, Hakenberg OW, Froehner M. Antiandrogens in the treatment of prostate cancer. Eur Urol. 2007;51:306-313. 23. Sridhar SS, Freedland SJ, Gleave ME, et al. Castration-resistant prostate cancer: from new pathophysiology to new treatment. Eur Urol. 2014;65:289-299. 24. American Cancer Society. Hormone (androgen deprivation) therapy for prostate cancer. www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-hormone-therapy. Updated March 2013. Accessed September 1, 2013. 25. Heidenreich A, Bastian PJ, Bellmunt J, et al. Guidelines on Prostate Cancer. Arnheim, The Netherlands: European Association of Urology; 2013. www.uroweb.org/gls/pdf/09_ Prostate_Cancer_LR.pdf. Updated March 2013. Accessed September 3, 2013. 26. Saylor PJ, Smith MR. Adverse effects of androgen deprivation therapy: defining the problem and promoting health among men with prostate cancer. J Natl Compr Canc Netw. 2010;8:211-223. 27. Boorjian SA, Karnes RJ, Viterbo R, et al. Long-term survival after radical pros-

tatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer. Cancer. 2011;117:2883-2891. 28. Lam JS, Leppert JT, Vemulapalli SN, et al. Secondary hormonal therapy for advanced prostate cancer. J Urol. 2006;175:27-34. 29. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med. 1998;339:1036-1042. 30. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321:419-424. 31. Fitzpatrick JM, Anderson J, Sternberg CN, et al. Optimizing treatment for men with advanced prostate cancer: expert recommendations and the multidisciplinary approach. Crit Rev Oncol Hematol. 2008;68(suppl 1):S9-S22. 32. Zytiga [package insert]. Horsham, PA: Janssen Biotech, Inc; 2013. 33. Xtandi [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2012. 34. de Bono JS, Logothetis CJ, Molina A, et al; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005. 35. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197. 36. Medivation and Astellas announce the phase 3 PREVAIL trial of enzalutamide meets both co-primary endpoints of overall survival and radiographic progression-free survival in chemotherapy-naive patients with advanced prostate cancer [press release]. San Francisco, CA, and Tokyo, Japan: Marketwired; October 22, 2013. http://investors. medivation.com/releasedetail.cfm?ReleaseID=798880. Accessed January 3, 2014. 37. Takeda announces unblinding of phase 3 study of orteronel in patients with metastatic, castration-resistant prostate cancer that progressed post-chemotherapy based on interim analysis [press release]. Osaka, Japan, and Cambridge, MA: Takeda Pharmaceutical Co Ltd; July 26, 2013. www.takeda.com/news/2013/20130726_5894. html. Accessed September 11, 2013. 38. Tokai Pharmaceuticals. About galeterone (TOK-001): three distinct mechanisms of action. www.tokaipharma.com/programs-tok-001.php. Accessed September 12, 2013. 39. Tokai Pharmaceuticals. About galeterone: ARMOR. http://tokaipharma.com/ programs-armor.php. Accessed October 18, 2013. 40. Rathkopf DE, Morris MJ, Fox JJ, et al. Phase I study of ARN-509, a novel antiÂ androgen, in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2013;31:3525-3530. 41. Grossmann M, Zajac JD. Androgen deprivation therapy in men with prostate cancer: how should the side effects be monitored and treated? Clin Endocrinol (Oxf). 2011;74:289-293. 42. MartĂn-Merino E, Johansson S, Morris T, et al. Androgen deprivation therapy and the risk of coronary heart disease and heart failure in patients with prostate cancer: a nested case-control study in UK primary care. Drug Saf. 2011;34:1061-1077. 43. Azoulay L, Yin H, Benayoun S, et al. Androgen-deprivation therapy and the risk of stroke in patients with prostate cancer. Eur Urol. 2011;60:1244-1250. 44. Taylor LG, Canfield SE, Du XL. Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer. Cancer. 2009;115:2388-2399. 45. Kintzel PE, Chase SL, Schultz LM, et al. Increased risk of metabolic syndrome, diabetes mellitus, and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer. Pharmacotherapy. 2008;28:1511-1522. 46. Ahmadi H, Daneshmand S. Androgen deprivation therapy: evidence-based management of side effects. BJU Int. 2013;111:543-548. 47. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379:39-46.

COMMENTARY

What are the experts saying about Androgen Suppression in CRPC? Scan these codes* to read commentaries by Dr Winston Tan of Mayo Clinic and Dr Judd W. Moul of Duke University

Dr Winston Tan

Dr Judd W. Moul

*To view these commentaries, download a QR code scanner app on your smart phone, or visit our website at www.PersonalizedMedOnc.com

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Personalizing Value-Based Medicine Aymen Elfiky, MD, MPH

he multidimensionality of health for an individual is best captured by the World Health Organization’s definition of health as “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.”1 With respect to oncology, sophisticated advances in molecular biology and technology continue to better facilitate the management of cancer as a chronic, albeit complex, health condition. Nonetheless, for early-stage and terminally ill cancer patients alike, extended longevity has also prompted a growing focus on the parallel dimensions of heath included above. As cancer is the second leading cause of death in the United States,2 cancer care delivery is consistently at the center of debates over the affordability of healthcare. The continually rising costs, ironically effected in part by progress of new expensive diagnostic and therapeutic paradigms, have increasingly been impacting health systems across the country. It is within this continually evolving cancer care landscape that the concept of value-based care has been taking center stage.

Sophisticated advances in molecular biology and technology continue to better facilitate the management of cancer as a chronic, albeit complex, health condition. To date, the pursuit of value, defined as patient outcomes per dollar spent,3 has been characterized by various management and policy efforts that aim to reduce medical errors, minimize practice variation through use of clinical guidelines, and facilitate information exchange between providers. Not surprisingly, despite the providers and institutional leaders who define and ultimately operationalize care delivery, this compliance-based approach to delivery of value-based care has not consistently translated to institutional cost containment or patient outcome benefits. A clinical process-based view of cancer care delivery helps to shed light on the shortcomings of this approach. Specifically, Dr Elfiky is an Instructor in the Department of Medicine at Harvard Medical School as well as an Instructor in Medical Oncology at the Dana-Farber Cancer Institute.

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viewing care delivery organizations as complex adaptive systems4-6 with networked stakeholders that typify the practice and delivery of cancer care, a value-based approach must fundamentally eschew the rigid machine-like view to instead account for the perspectives and interdependent roles of the institution, provider, patient, and payer. This restructured systems view is of paramount importance to cancer care given the technology-driven and -enabled role of the patient and caregiver. The quest for value within cancer care can be seen as prompting a return to the fundamentals of what is “health” and what is the mission of any healthcare organization that purports to achieve it. Within a complex adaptive system, cancer care necessarily must account for patients and caregivers as individual agents in pursuit of parallel dimensions of health, whose needs are networked with the series of interventions enabled by organizations, implemented by providers, and reimbursed by payers. In a system anchored by the care of cancer patients, “health” is enabled by a range of interventions such as curative surgery, palliative chemotherapy, access to novel trials, and survivorship care. Thus, the need of individual patients varies depending on where they are in their disease pathway and trajectory. As such, the patients’ health state provides the context for the other system agents and requires them to coevolve to achieve health outcomes. As reasoned by Porter, “since value depends on results, not inputs, value in health care is measured by the outcomes achieved, not the volume of services delivered, and shifting focus from volume to value is a central challenge.”3 Successful commitment to achieving value centered on quality of care from the patient’s point of view requires a nimble system willing and capable of adapting and re-engineering practice processes. Building on the above point of outcome measurement, the next issue becomes defining and capturing specific patient-derived outcomes within clinical scenarios. Considering the spectrum of care and outcome issues from localized to advanced cancer states, it is clear that certain outcomes become prioritized relative to others based on disease and patient characteristics. Considering prostate cancer as an example, the quality-of-life metrics that characterize patients with localized disease may include degree of incontinence and erectile dysfunction. In contrast, patients with advanced-stage disease are invariably concerned with outcomes of survival, pain control, and toxicity man-

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agement of systemic treatments that they may be receiving. For any given institution or practice to successfully capture and accommodate these varying needs depends on baseline conditions, the adaptive reserve, and the cultural view toward personal and organizational change.7 In most practices, however, there is no consensus or existing infrastructure for consistent capture of patient-specific outcomes. In the same vein, payers do not have any requirements for such outcome measurements. Ultimately, this lack of definition and capture acts as a barrier to incentivize preferred practices. Importantly, given that many point-of-care decisions by providers, especially when dealing with advanced cancer patients, are based on patient-defined considerations, the value of these decisions is not often captured in their compliance or lack thereof with guidelines or pathways, but instead the specific patient outcome for which each decision was undertaken. By extension, consistent evaluation of outcomes then provides a backdrop against which to assess cost utilization, which defines value.3,8 A useful framework to characterize outcomes of relevance to patients for any given medical condition, including specific cancer diagnoses, is to use the 3-tiered “outcome hierarchy” defined by Porter and Teisberg9: • Tier 1 involves the health status achieved, eg, performance status, pain levels, and mortality • Tier 2 outcomes relate to the care cycle and processes, eg, hospital readmission • Tier 3 outcomes relate to the sustainability of health, eg, psychosocial services for survivorship An example that helps to illustrate the use and impact of outcome measures in healthcare practice is the Integrated Healthcare Association’s overseeing of the California Pay-for-Performance (P4P) plan. It is a large physician-incentive program representing 8 health plans representing 10 million insured people.10 Operationally, the program collects data on a common measure set that captures practice outcomes of about 35,000 physicians in 221 practices.11 The success of the program was reflected in 87% of clinics improving their ratings by an average of 5.3% and a 65% improvement in patient experience. In contrast to existing fee-forservice systems, which do not integrate quality of care, the P4P program highlighted the incremental cost benefits realized when patients’ outcomes were shown to be improving.12 Notably, a similar attempt in the United Kingdom using the Quality and Outcomes Framework did not show a similar benefit precisely because cases were being inadequately related to patients’ outcomes.13 This account offers a cautionary lesson that achieving value using outcomes-based measures re-

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quires a proper infrastructure to collect and analyze outcomes. Fundamentally, these outcomes are normalized to reflect the differences and nuances of a particular specialty as well as the patient populations in each specialty. Naturally, care offered to advanced-stage

As cancer is the second leading cause of death in the United States, cancer care delivery is consistently at the center of debates over the affordability of healthcare. cancer patients is more complex; however, this complexity underscores the opportunity for impact across the various outcome tiers above. Given the discussion points above, the action point that will naturally facilitate the migration toward value- based oncology practice is to equip practices with an infrastructure designed to capture standardized and structured data reflecting disease-specific outcomes. The variables used should be a natural reflection of patients’ goals of care viewed within the context of their physical, mental, and social condition. Ultimately, the individual and collective findings can be used to drive performance improvement and transparency. Insomuch that an outcomes-focused infrastructure represents an innovation at multiple levels, its adoption is driven by institutional culture and reflected at point of service. This adoption, in turn, reaffirms true dedication to the patient writ large. u

References

1. Preamble to the Constitution of the World Health Organization as adopted by the International Health Conference, New York, 19-22 June, 1946; signed on 22 July 1946 by the representatives of 61 States (Official Records of the World Health Organization, no. 2, p. 100) and entered into force on 7 April 1948. 2. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9-29. 3. Porter ME. What is value in healthcare? N Engl J Med. 2010;363:2477-2481. 4. Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academy Press; 2000. 5. Plsek PE, Greenhalgh T. The challenge of complexity in health care. BMJ. 2001;323:625-628. 6. Sweeney K, Griffiths F, eds. Complexity and Healthcare: An Introduction. London: Radcliffe Medical Press; 2002. 7. Nutting PA, Crabtree BF, Miller WL, et al. Journey to the patient-centered medical home: a qualitative analysis of the experiences of practices in the National Demonstration Project. Ann Fam Med. 2010;8(suppl 1):S45-S56. 8. Porter ME. Defining and introducing value in health care. In: Evidence-Based Medicine and the Changing Nature of Health Care: 2007 IOM Annual Meeting Summary. Washington, DC: National Academies Press; 2008:161-172. 9. Porter ME, Teisberg EO. Redefining Health Care: Creating Value-Based Competition on Results. Boston, MA: Harvard Business School Press; 2006:86-87. 10. Integrated Healthcare Association. Pay for Performance. www.iha.org/perfor mance_measurement.html. Accessed April 30, 2014. 11. Ezziane Z. Pathways and complexity of innovation in health care. http://pub. bsalut.net/jhiic/vol3/iss1/2/. Accessed April 30, 2014. 12. Maynard A. The powers and pitfalls of payment for performance. Health Econ. 2012;21:3-12. 13. Fleetcroft R, Cookson R. Do the incentive payments in the new NHS contract for primary care reflect likely population health gains? J Health Serv Res Policy. 2006;11:27-31.

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2014 GASTROINTESTINAL CANCERS SYMPOSIUM

Bevacizumab Improves Survival in Patients With Metastatic Colorectal Cancer

n routine patient care, adding bevacizumab to standard FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan) improves progression-free survival (PFS) and overall survival (OS) in patients with metastatic colo rectal cancer (mCRC), according to data presented at the 2014 Gastrointestinal Cancers Symposium. “There is consistent benefit in terms of PFS and a more substantial advantage in terms of 1-, 2-, and 3-year survival rates with the addition of bevacizumab to FOLFIRI,” said lead investigator Jean A. Maroun, MD, professor of medicine, University of Ottawa, and medical oncologist, Ottawa Hospital Cancer Centre, Ontario, Canada.

“There is consistent benefit in terms of PFS and a more substantial advantage in terms of 1-, 2-, and 3-year survival rates with the addition of bevacizumab to FOLFIRI.” – Jean A. Maroun, MD Bevacizumab plus FOLFIRI has become the standard of care for the first-line treatment of mCRC, but few data exist about its utilization and effectiveness in the community. Maroun and colleagues therefore looked at the outcomes of 470 patients with mCRC receiving standard first-line treatment with FOLFIRI alone or with FOLFIRI plus bevacizumab who were treated at the Ottawa Hospital Cancer Centre from January 2004 through August 2010.

Colorectal Cancer by the Numbers • Of tumors that affect both sexes, CRC is the second leading cause of cancer-related deaths in the United States

• CRC is the third most common cancer in both sexes • In 2010, 131,607 Americans were diagnosed with CRC • In 2010, 52,045 Americans died of CRC • The estimated number of CRC cases in 2013 was 142,820 • The estimated deaths related to CRC in 2013 was 50,830 • The rate of new cases of CRC in the United States is 20.8% for

people aged 55 to 64 years, 24% for those aged 65 to 74 years, and 24.1% for those aged 75 to 84 years • After age 84 years, the risk for CRC decreases significantly Sources: www.cdc.gov/cancer/colorectal/statistics/index.htm; http://seer.cancer.gov/statfacts/html/colorect.html.

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A total of 176 patients (37%) received FOLFIRI plus bevacizumab, and 294 (63%) received FOLFIRI alone – 127 before bevacizumab became available and 167 after. At the start of FOLFIRI therapy, the baseline characteristics were not significantly different between the 3 groups: the median age was 61 to 64 years, although a greater proportion of patients receiving bevacizumab were women compared with patients receiving FOLFIRI alone. “Patients treated with FOLFIRI plus bevacizumab received more cycles of chemotherapy but with more dose adjustments,” said Maroun. Patients receiving FOLFIRI plus bevacizumab completed 3579 cycles of chemotherapy, compared with 2404 cycles completed by the 167 patients who received FOLFIRI alone after bevacizumab was available, and 1606 cycles completed by the 127 patients who received FOLFIRI before bevacizumab became available. Patients receiving FOLFIRI alone had a median of 16 cycles before bevacizumab became available and 13 cycles after. Patients receiving FOLFIRI plus bevacizumab had a median of 14 cycles of FOLFIRI and a median of 15 cycles of bevacizumab. Overall, ≥1 FOLFIRI dose adjustments were made in 78% of patients, with a median of 6 cycles to the first adjustment; 49% of patients had their first adjustment during the first 3 cycles. Bevacizumab was placed on hold in 95 patients (54%): once in 35% of the patients, and twice in 25% of the patients. The median time off bev acizumab was 37 days. The dose intensity across the 3 groups was approximately 76%. Adverse events were responsible for at least 1 dose adjustment in 146 patients (83%) receiving FOLFIRI plus bevacizumab and in 215 (73%) receiving FOLFIRI alone. The median PFS was 17 months with FOLFIRI plus bevacizumab. In patients receiving FOLFIRI before bevacizumab availability, the median PFS was 13 months, and in those receiving it after the availability of bevaciz umab, it was 14 months. Over 3 years, OS rates in the 3 groups (FOLFIRI plus bevacizumab, FOLFIRI alone before bevacizumab availability, and FOLFIRI alone after the availability of bevacizumab) were 90%, 77%, and 78%, respectively, at 1 year; 67%, 49%, and 56%, respectively, at 2 years; and 54%, 31%, and 44%, respectively, at 3 years. At the time of data cutoff, there was an insufficient number of events to estimate median OS, said Maroun. u

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2014 GENITOURINARY CANCERS SYMPOSIUM

Phi Index Can Select Patients With Prostate Cancer for Active Surveillance

new tool called the Prostate Health Index (phi) can identify which patients with favorable-risk prostate cancer can safely be managed with active surveillance and which patients will probably require treatment. The phi index is relatively low tech and is calculated using 3 serum measurements: prostate-specific antigen (PSA), free/total PSA, and a measurement called [-2]proPSA. A preliminary study of the phi index in the active surveillance setting showed that it provided a more accurate estimate of the course of illness than PSA or free/ total PSA. The study was reported at the 2014 Genitourinary Cancers Symposium. “This is a new method for identifying which patients assigned to watchful waiting will need treatment. There are many patients who don’t need treatment even 10 years after diagnosis,” said lead investigator Andrew Eichholz, MD, of the Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. Eichholz explained that phi is starting to be used in the prebiopsy setting in the United States. Although he is quite enthusiastic about the applicability of phi in the active surveillance setting, he said, “It is not ready for prime time. The phi index needs to be validated. We are the first group to study it [in this setting], and another group is also studying it. If it is validated, it could change the way we manage these patients.” The investigators sought to determine the predictive value of phi in a retrospective study based on frozen blood samples collected at diagnosis from 370 patients a median of 11.4 years ago. The patients had stage T1/T2 cancer, Gleason scores of ≤3 + 4, and a PSA of <15 ng/mL. Patients were monitored with PSA testing every 6 months and repeat biopsy every 2 years. Treatment was

indicated for patients with a PSA velocity of >1 ng/mL annually or a Gleason score of ≥4 + 3 on repeat biopsy. A total of 115 patients started treatment after a median of 11.4 years. Phi was significantly associated with the time to treatment (P<.001). The test results were grouped into quartiles according to phi. The investigators determined that the cutoff point for phi was <31.4 for the lowest-risk quartile and >58.5 for the highest-risk quartile. Among the lowest-risk patients, the test predicted that 95% would not need therapy within 5 years from diagnosis, whereas among the highest-risk patients, 54% would require treatment within 5 years.

“This is a new method for identifying which patients assigned to watchful waiting will need treatment. There are many patients who don’t need treatment even 10 years after diagnosis.” – Andrew Eichholz, MD After 10 years, 37% of the patients still did not require treatment, and approximately 20% needed treatment within 2 years of diagnosis. “If phi is validated in this setting, it will be a useful tool for discussions with patients,” Eichholz stated. Phi received premarketing approval from the FDA in June 2012 for use in men (not diagnosed with prostate cancer) with a PSA in the range of 4 ng/mL to 10 ng/mL. At that time, a multicenter study showed that phi reduced unnecessary biopsies by 31%. The phi assay kit is marketed by Beckman Coulter. u

THIRD ANNUAL CONFERENCE

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies

™

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

www.regonline.com/GBC2014

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2014 NCCN CONFERENCE

Updated NCCN Guidelines for Non-Hodgkin Lymphoma Note Controversy Related to B-Cell Disease Management Cell of Origin May Soon Influence Treatment Decisions

he updated guidelines from the National Comprehensive Cancer Network (NCCN) for the management of non-Hodgkin lymphoma (NHL) include new strategies in the management of diffuse large B-cell lymphoma (DLBCL) and new guidelines for T-cell lymphoproliferative disorders. The updates were presented by Andrew D. Zelenetz, MD, PhD, vice chair, medical informatics, department of medicine, Memorial Sloan Kettering Cancer Center, New York, at the 2014 NCCN Conference.

The new guidelines for induction therapy for stage I or stage II nonbulky DLBCL no longer distinguish between risk factors that are present and those that are not present. The guidance for primary mediastinal B-cell lymphoma (PMBL) states that optimal first-line therapy is more controversial than for other subtypes of NHL and includes the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, plus rituximab) regimen; and R-CHOP followed by the ICE (ifosfamide, carboplatin, and etoposide) regimen. The coexpression of the MYC protein and the BCL2 protein predicts poor outcomes for a group of patients with DLBCL. This “double hit” by immunohistochemistry represents approximately 30% of patients. There is no evidence-based standard of care for patients with this MYC/BCL2 coexpression lymphoma, who “really need to go on prospective clinical trials,” said Zelenetz. Dose-adjusted EPOCH-R, although effective at improving survival in patients with MYC-positive DLBCL, needs to be validated as a treatment for this subgroup of patients with DLBCL. The new guidelines for induction therapy for stage I or stage II nonbulky DLBCL no longer distinguish between risk factors that are present and those that are not present, because there is no evidence to support a

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differential management of patients with favorable or unfavorable risk factors, Zelenetz said, even though patients with such risk factors have worse outcomes.

PMBL: 3 Treatment Options Produce Excellent Outcomes Currently, 3 treatment options are included in the guidelines for the management of patients with PMBL: • R-CHOP followed by radiation therapy • Dose-adjusted EPOCH-R with optional radiation • R-CHOP for 4 cycles, followed by ICE, with optional radiation In a 2013 study by Dunleavy and colleagues, dose-adjusted EPOCH-R without radiation therapy was associated with an event-free survival of 100% over a median of 3 years of follow-up in 16 patients involved in a retrospective analysis. The 51 patients in the prospective cohort had an event-free survival of 93% over 5 years. Of note, dose-adjusted EPOCH-R had no significant impact on cardiac function. “I would argue that with a total of 67 patients, we need more data before we call this the standard of care,” said Zelenetz. “Given the demographics of this disease with high incidence in young women, avoidance of radiation is preferred,” he said. Hence, avoiding radiation is an option. “R-mini-CHOP” an Option in Older Patients In patients aged >80 years with comorbidities, “R-mini-CHOP” has been added as a treatment option for patients with DLBCL. This regimen consists of dose-attenuated rituximab (375 mg/m2), a reduced dose of cyclophosphamide (400 mg/m2), halving of the usual doxorubicin dose (25 mg/m2), and a 1-mg flat dose of vincristine, as was established in a prospective study by Ballester and colleagues in their evaluation of 150 patients aged >80 years with DLBCL. Therapy Based on Cell of Origin In the not-too-distant future, the cell of origin may influence the treatment choice. In this respect, the more promising results have been achieved with non– germinal center B-cell lymphoma (non-GCB), Zele-

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netz noted, discussing several specific examples in this setting. • Lenalidomide plus R-CHOP ameliorates the negative effect of the non-GCB phenotype and is well tolerated, including in elderly patients • Ibrutinib has shown clinically meaningful response rates in relapsed or refractory non-GCB, which is consistent with an essential role of B-cell receptor signaling in this subtype of disease • Bortezomib added to R-CHOP has also had success in early studies in the treatment of non-GCB DLBCL and is now under investigation in 3 largescale randomized trials for this purpose • The sequence of R-CHOP and ICE may be a more cost-effective way to achieve these same results in non-GCB tumors, Zelenetz said.

What’s New in T-Cell Lymphoma? Two new guidelines in T-cell lymphoma have been constructed for primary cutaneous CD30+ lympho proliferative disorders and large granular lymphocytic leukemia. For the lymphomatoid papulosis subtype of primary cutaneous CD30+ lymphoproliferative disorders, the primary treatment depends on the extent of the disease. Observation is preferred for asymptomatic patients with limited lesions, with the option to use topical steroids or phototherapy. For patients with extensive lesions or who have symptoms, weekly methotrexate, phototherapy, systemic retinoids, topical steroids, and topical nitrogen mustard are options. For patients with primary cutaneous anaplastic large-cell lymphoma (ALCL), surgical excision with or

RepRints

without radiation therapy is considered primary therapy for patients with solitary or grouped ALCL lesions. Weekly methotrexate, radiation therapy, systemic retinoids, observation (if asymptomatic), or interferon alpha-2b are options for primary therapy for patients with multifocal ALCL lesions.

“I would argue that with a total of 67 patients, we need more data before we call this the standard of care. Given the demographics of this disease with high incidence in young women, avoidance of radiation is preferred.” – Andrew D. Zelenetz, MD, PhD For patients with T-cell large granular lymphocytic leukemia, the most common indications are cytopenias. If patients with indolent disease are asymptomatic, the recommended management strategy is obser vation. The preference for symptomatic patients is enrollment into a clinical trial, “but many things work,” said Zelenetz. Immunosuppressive therapy with methotrexate or cyclophosphamide, or cyclosporine A without steroids, all have reasonable activity. Persistence is crucial when using cyclosporine A, Zelenetz said, because responses may not be observed for several weeks. u

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BREAST CANCER

New Molecular Test to Monitor Breast Cancer Recurrence by Sequencing Circulating Tumor Cells

genomic test to sequence the circulating tumor cells (CTCs) from whole blood, ClearID Breast Cancer from Cynvenio Biosystems, is now available commercially to molecularly monitor for breast cancer recurrence. The test uses a standard blood draw from which DNA from tumor cells is isolated and interrogated using next-generation sequencing tools to determine the presence of cancer-associated DNA mutations.

“It is a great way to detect the metastatic process because that’s what these tumor cells in blood are responsible for. We’re going to give doctors an ability with the same blood draw to also monitor estrogen receptor status, progesterone receptor status, as well as human epidermal growth factor receptor 2.” – André de Fusco The CLIA-certified laboratory at Cynvenio has a validated protocol to recover CTCs and evaluate them for the presence of more than 4500 single point genetic mutations. According to André de Fusco, chief executive officer and director of Cynvenio, the ClearID test is useful for patients with breast cancer who are at high risk for disease recurrence after treatment because CTCs reflect the underlying biology of the disease process. “It is a great way to detect the metastatic process, because that’s what these tumor cells in blood are responsible for,” de Fusco said. The ClearID test evaluates blood samples for elevat-

ed numbers of cells that are phenotypically characterized as CTCs. When elevated, the CTCs are examined for the presence of somatic mutations that are not found in the germline sequence. “These data can provide additional insight into the molecular character of disease, and do so with a very stringent analytical specificity due to the multiple biomarkers involved in the test and the evaluation of the CTC genome for somatic mutations,” according to the company. Physicians who send in a blood sample using the patient sample kit receive a comprehensive report of actionable genomic alterations plus associated treatments for each alteration found. The fixed sample is stable for 96 hours without refrigeration. This platform to enumerate and isolate CTCs has been patented. The test, which can identify mutations present in as few as 1% of CTCs, is designed to be a “blood to readout” solution, with reports available in 3 to 10 days, said de Fusco. It offers the opportunity for longitudinal monitoring to track the disease course. “We’re going to give doctors an ability with the same blood draw to also monitor estrogen receptor status, progesterone receptor status, as well as human epidermal growth factor receptor 2,” de Fusco said. “In one single test, they’ll have pretty much everything they need to look at breast cancer. In the metastatic patient, they’re going to be interested in estrogen receptor and progesterone receptor status, but they may also want to know if there’s a PIK3CA mutation in an unresponsive patient in the third line of therapy.” The advanced genomic reporting contains not only the cancer-associated mutations identified but also the targeted treatments – both those approved by the FDA and those currently in clinical trials – to which the mutation is sensitive, as well as advice on off-label treatments. “The doctor doesn’t have to be a genetic oncologist to know what to do,” said de Fusco. u

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2014 SOCIETY OF GYNECOLOGIC ONCOLOGY ANNUAL MEETING

PARP Inhibitor Active in Recurrent BRCAPositive Ovarian Cancer

he PARP inhibitor veliparib demonstrated activity in relapsed/refractory BRCA-mutated ovarian cancer, according to results from a phase 2 trial conducted by the Gynecologic Oncology Group. Almost one-fourth of 50 evaluable patients had objective responses, including 2 patients with complete responses. Additionally, about half of the patients had stable disease of 16 weeks or longer. Median progression-free survival was 8.1 months among patients who had received as many as 3 prior systemic regimens, according to Robert L. Coleman, MD, at the Society of Gynecologic Oncology annual meeting in Tampa, FL. “Veliparib demonstrated activity in both platinum-sensitive and platinum-resistant disease,” said Coleman, professor of gynecologic oncology and reproductive medicine at MD Anderson Cancer Center in Houston, TX. “A criticism of PARP inhibitors is that they are not active in patients who have developed resistance to other therapies. These results indicate that veliparib has activity in some of the patients, who generally have few remaining treatment options.” Laboratory studies suggested targeting of the DNArepair defect in BRCA-mutant tumors had potential as a therapeutic strategy. In contrast to some other PARP inhibitors in development, veliparib blocks both isomers of the enzyme. The small-molecule inhibitor demonstrated efficacy across several preclinical models of tumors, including ovarian cancer. Coleman reported data from a nonrandomized, open-label trial involving patients with germline BRCA mutations. Investigators enrolled patients who had BRCA1/2-deficient epithelial ovarian, fallopian tube, or primary peritoneal cancers. The patients had received from 1 to 3 prior regimens. All patients received veliparib at a dose of 400 mg bid, and treatment continued until disease progression, development of unacceptable toxicity, or voluntary withdrawal from the study. The statistical design of the trial specified a response rate ≥25% for continuing clinical investigation. Of the 50 patients included in the analysis of safety and efficacy, 8 remain in the study. A majority of the patients (58%) were 40 to 59 years

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of age, and an additional 30% were 60 to 69 years of age. Two-thirds of the patients had performance status 0 and the rest had performance status 1. More than 80% of the patients had high-grade serous tumors. Treatment history consisted of 1 prior regimen in 14 patients (28%), 2 in 18 patients Robert L. (36%), and 3 in 18 patients (36%). All but 4 Coleman, MD patients had received radiotherapy, all but 3 had exposure to immunotherapy, and only 1 patient had not undergone debulking surgery. A majority of the patients (30; 60%) had platinum-resistant disease, which investigators defined as a platinum-free interval <6 months. Three-fourths of the patients had BRCA1-mutant tumors, and 12 had founder mutations, which were BRCA1 in 8 patients and BRCA2 in 4 patients.

Patients received veliparib at 400 mg bid, and treatment continued until disease progression, development of unacceptable toxicity, or voluntary withdrawal from study. Hematologic adverse events were generally mild, as 1 patient had grade 3 neutropenia and 1 patient had grade 4 thrombocytopenia. The most common nonhematologic adverse events were nausea (42 of 50 patients) and other gastrointestinal adverse events (32 patients). No patient had grade 4 nonhematologic events, and grade 3 events consisted of 2 cases of nausea and 1 case related to metabolism/ nutrition. Coleman reported that 11 patients had confirmed partial responses and 2 had confirmed complete responses, resulting in an overall response rate of 26%, which met the predefined criteria for continuing clinical evaluation of veliparib. Response assessment was ongoing in 6 patients, some of whom had unconfirmed responses. A similar proportion of patients with platinum-sensitive and platinum-resistant disease derived benefit from treatment with veliparib. u

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Prospects for Personalization of Medicine Lie in Evidence Thresholds

lthough targeted drug development and testing is clearly transforming medicine, resistance to greater uptake of personalized medicine includes a shift in the evidence threshold in personalized testing and drawbacks to the delivery system, including the cost of tests, said Peter Bach, MD, at Peter Bach, MD the Fourth Annual Conference of the Association for Value-Based Cancer Care. The traditional cancer treatment has an established taxonomy, with the treatment based on an established test and disease characteristics (eg, HER2 amplification and breast cancer). Insurers then work around the lack of specific coding for the test. In the case of breast cancer, UnitedHealthcare instituted a program whereby the results of HER2 testing had to be communicated before trastuzumab treatment would be covered.

The tests are opening up a Pandora’s box in treatment in that any mutation found anywhere could become justification for a trial of treatment. The action on the test was stopped until the test results were known, not before the test was performed, said Bach, director of the Center for Health Policy and Outcomes, Memorial Sloan Kettering Cancer Center, New York City. “That matters, and it also matters as we move towards this place where the tests themselves will be expensive. If you put the barricade after the test, then it’s going to have a different effect on utilization than if you do it before.” The paradigm for cancer drug development, approval, and labeling may eventually change from one based on the organ site of the cancer, the cancer stage, and the cell type to mutation status or biologic pathway. “As we move forward, the FDA has been heavy-handed about saying that we’re going to live in a new age of paired diagnostics,” he said. Crizotinib was the prototype for this model, with the test codeveloped with the pharmaceutical manufacturer within the context of a clinical trial. According to Bach, however, the age of paired diagnostics may already be over, as the number of re-

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quired tests and tissue samples becomes cumbersome. “We’re going to rapidly need to do too many assays and look for too many different mutations in any particular organ type for us to stick with a paired paradigm,” he said. “I think testing for multiple mutations at the same time in the tumor is where we’re going to end up.”

Building of Evidence An evidence shift is taking place around personalized testing. The first trend is an evolution in recognizing that not all tests are equivalent. HER2 testing errors occur in about 20% of samples, resulting in misclassification of patients. In addition, there are many flavors of alterations with similar biologic activity (ie, base pair substitutions, deletions, copy number alterations, etc), not simply the alteration that was studied. It is also clear that there is no gold standard in test development. The targets and compounds number in the hundreds. Tests themselves are becoming a cost center, sometimes running into the thousands of dollars. “Payers are noticing the costs of these tests, and they’re trying to figure out what the standard should be for them,” said Bach. The tests are opening up a Pandora’s box in treatment in that any mutation found anywhere could become justification for a trial of treatment. “There is a fear that it’s going to lead to wild experimentation without the capture of data, and I think that’s a legitimate one,” he said. Insurers also have operational challenges, he said. Insurers generally cover tests under fairly simple rules that can be administered, such as obtaining a HER2 assay in a patient with breast cancer. But the new multigene tests themselves are complex, as are the clinical scenarios (ie, first, second, or third line of therapy; the indication for the agent being considered; the results of other tests). It is not clear that oncologists will know how to respond to the coming barrage of information. The appropriate evidence standard remains open, said Bach. Moving from a test result to improved outcome should be one standard, he argued. The evidence for off-label uses of agents should go beyond supposition, but randomized controlled trials are not feasible for every possibility. “We’re probably headed for a case series kind of approach,” he said.

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Pricing trends also a problem

MAY 6-9, 2014

The FDA often approves comFigure Pricing Trends Also a Problem pounds under accelerated approval based on single-arm studies with surrogate end points – essentially case series. Imatinib, for example, was approved with evidence of cytogenetic changes on sequential case series, and ceritinib was approved AVBCC LEADERSHIP on the basis of response in a FOURTHrate ANNUAL CONFERENCE Burt Zweigenhaft, BS President and CEO single-arm trial. Disease registries OncoMed such as those used by Medicare for coverage under evidence development are also fundamentally case Craig K. Deligdish, MD Hematologist/Oncologist series, he said.Loews Hollywood Hotel Oncology Resource Networks “The essential of [case Los features Angeles, California series/registries] are that they are sequential,” said Bach. “There’s no HELD IN PARTNERSHIP WITH Gary M. Owens, MD President cherry picking; they enroll all comGary Owens Associates ers.” They capture high-quality data with deep follow-up, with no bias www.regonline.com/avbcc2014 introduced from loss to follow-up or end point evaluation triggered by clinical events. Outcomes otherwise CONFERENCE CO-CHAIRS must be known from historical data. PROGRAM DIRECTOR Lillie D. Shockney, RN, BS, MAS Until evidence is built correctly, YEAR University Distinguished Service the default stance will be very conAssociate Professor of Breast Cancer Departments of Surgery and Oncology servative. “We have shown ourAdministrative Director, The Johns Hopkins Breast Center selves to be somewhat aggressive Administrative Director, Johns Hopkins Cancer about pushing the ANNUAL envelope for Survivorship Programs FIFTH Associate Professor, JHU School of Medicine using expensive therapies when they Departments of Surgery, Oncology & Gynecology and Obstetrics are not indicated, so the default is approval increasing exponentially over the years. Associate Professor, JHU School of Nursing MD the resistance of 2 opposing forces,” he said. “Any issue we haveBaltimore, with off-label use of drugs that are Pricing trends are also a problem, with monthly targeted is going toSharon get worse as the go higher,” Gentry, RN, MSN, prices AOCN, CBCN Walt Disney World Hotel Breast Health Navigator and median costs of cancer drugs at the Dolphin time of FDA he said. u Derrick L. Davis Forsyth Regional

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CDK 4/6 Inhibitor Slows Progression of Metastatic Breast Cancer

albociclib, an inhibitor of cyclin-dependent kinase (CDK) 4/6, demonstrated “striking” activity when combined with conventional hormone therapy for patients with metastatic breast cancer, according to the results from an open-label phase 2 trial. Patients who received palbociclib in addiRichard S. Finn, tion to letrozole had a median progression-free MD survival (PFS) of 20.2 months compared with 10.2 months for patients who received letrozole alone as first-line therapy. The positive outcome is due to a combination of better patient selection and better therapy, said Richard S. Finn, MD, assistant professor of medicine, University of California, Los Angeles.

“Palbociclib is very specific and efficient in blocking CDK 4/6, which results in less toxicity.” – Richard S. Finn, MD “Two prominent reasons for this success are that we identified a subtype of breast cancer – hormone receptor–positive, HER2-negative – most likely to respond to the therapy, and we had a much improved second-generation inhibitor of CDK 4/6,” said Finn. “Palbociclib is very specific and efficient in blocking CDK 4/6, which results in less toxicity.” The outcome of the randomized, phase 2 trial left a major question unanswered: why patients chosen on the basis of estrogen receptor (ER) positivity had better PFS with palbociclib than those selected for ER positivity and CDK 4/6 expression. Invited discussant José Baselga, MD, PhD, physician-in-chief, Memorial Sloan Kettering Cancer Center, New York City, said that confirmation of the “strikingly positive” results in phase 3 studies could make palbociclib a new therapeutic standard for patients with advanced ER-positive breast cancer. Baselga also cautioned that positive phase 2 results do not always translate into positive phase 3 trials, singling out the PARP inhibitor iniparib as a prime example. Finn reported findings from a trial conducted in 2 phases involving biomarker-selected patients. Investigators in the multicenter trial first evaluated the combi nation of palbociclib and letrozole in patients with

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ER-positive breast cancer. During the second phase, patients were chosen on the basis of having ER-positive tumors that also expressed CDK 4/6.

Study Details The trial involved a total of 165 women with previously untreated metastatic breast cancer. During the first phase, 66 patients with ER-positive breast cancer were randomized to receive letrozole with or without palbociclib. During the second phase, investigators randomized 99 patients with ER-positive, CDK 4/6–positive breast cancer to the same 2 treatment regimens. The primary end point was PFS, and the 10-month differential in favor of the palbociclib regimen resulted from combining the PFS results from the 2 phases. During the first phase, the combination led to a median PFS of 26.7 months compared with 5.8 months with letrozole alone. In the second part of the trial, patients chosen on the basis of both biomarkers had a median PFS of 18.1 months with letrozole plus palbociclib compared with 11.1 months for letrozole alone. The reason for the apparent disconnect between PFS benefit and biomarker status was not clear, said Finn. He noted that patient selection could have focused on other potential biomarkers. Preclinical studies showed that response to palbociclib in ER-positive breast cancer was associated with overexpression of cyclin D1 and retinoblastoma protein, as well as downregulation of p16. The use of a different biomarker or biomarker profile to select patients might have led to different results. Another possible explanation is that ER positivity is the key factor in response to the CDK 4/6 inhibitor, Finn added. Overall survival did not differ significantly between the treatment groups: 37.5 months with palbociclib and 33.3 months with letrozole alone. However, Finn pointed out that survival data are immature and will continue to be analyzed. In general, palbociclib was well tolerated. The most frequently reported adverse events in patients treated with letrozole plus palbociclib were neutropenia, leukopenia, fatigue, and anemia. Adverse events were mostly grade 1/2 in severity, with the exception of grade 3/4 neutropenia, which occurred in more than 50% of patients who received palbociclib (grade 3 in 48% of patients). Phase 3 trials of palbociclib have already begun, one of which is evaluating the CDK 4/6 inhibitor with letrozole and the other in combination with fulvestrant. u

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Multitargeted Kinase Inhibitor Shows Promising Results for Breast Cancer Subgroup HER2+/HR– Breast Cancer Subtype Identified as Biomarker Signature for Neratinib Use

multitargeted kinase inhibitor met criteria for a phase 3 clinical trial in breast cancer after statistical modeling of clinical data showed a high probability of success versus standard therapy for patients with HER2-positive/hormone receptor (HR)-negative (HER2+/HR–) disease. Neoadjuvant treatment with paclitaxel plus neratinib (followed by doxorubicin plus cyclophosphamide) led to an estimated pathologic complete response (pCR) rate of 56% compared with 33% for paclitaxel paired with trastuzumab and followed by doxorubicin plus cyclophosphamide. Statistical modeling showed that the neratinib combination had a 95% probability of demonstrating superiority to paclitaxel plus trastuzumab, and a 79% likelihood of success in a phase 3 clinical trial of patients with HER2+/HR– breast cancer, as reported at the 2014 American Association for Cancer Research annual meeting. “The adaptive trial identified a biomarker signature for neratinib, and neratinib has graduated in the HER2+/ HR– signature,” said John W. Park, MD, professor of clinical medicine, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center. “Based on these results, neratinib is under consideration for phase 3 testing in the neoadjuvant population.” The results came from the ongoing I-SPY 2 trial, which uses a combination of adaptive randomization and Bayesian modeling to match a breast cancer therapy with the subgroup of patients most likely to benefit. The strategy is designed to provide results in a short period of time, and with as few patients as possible. Neratinib is an irreversible pan-ErbB/HER2 inhibitor. According to Park, I-SPY 2 has 6 experimental regimens under investigation. The HER2+/HR– breast cancer subtype was 1 of 10 biomarker signatures evaluated in the trial. The signatures are derived from combinations of HER2 status, HR status, and results from the MammaPrint gene expression assay. Patients with early breast cancer are randomized to the experimental or control arm. Response data are incorporated into the statistical model, which “learns” from the information and narrows the biomarker signature to patients most likely to respond to the experimental arm.

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As tumor signatures unlikely to benefit from the experimental therapy are excluded, randomization continues in the remaining signatures, a process known as adaptive randomization. Because of confounding by the randomization process, estimated response rates are calculated for each signature, said Park. The phase 2 clinical trial has 3 principal end John W. Park, MD points: estimated pCR, probability that the experimental regimen is superior to the current standard, and predicted probability of success. To receive consideration for phase 3 evaluation, a treatment regimen must achieve a 95% probability of superiority and an 85% probability of success versus standard care in a trial of 300 patients whose breast cancer has the signature identified in the phase 2 trial.

“The adaptive trial identified a biomarker signature for neratinib, and neratinib has graduated in the HER2+/HR– signature.” – John W. Park, MD Park reported data from 115 patients treated with neratinib and 78 patients receiving standard care. On the basis of the results, the statistical model yielded an estimated pCR of 56% for the neratinib regimen and 33% for the standard regimen. The regimen met the 85% probability threshold for a phase 3 trial, but the recent addition of new data decreased the probability to 79%, said Park. The principal toxicity issue with neratinib was severe diarrhea (grade 3/4), which occurred in 39% of patients who received the drug compared with 4% of patients in the control arm. Early in the trial, investigators modified supportive care for diarrhea and initiated the prophylactic use of loperamide. The changes appeared to reduce problem diarrhea, said Park. Cardiac toxicity was not a problem in the neratinib arm or in the control arm. Discontinuation resulting from toxicity occurred more often with neratinib, whereas disease progression was a more common cause of discontinuation in the control arm. u

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PD-L1 Expression a Potential Biomarker for Response to Immunotherapy With MK-3475

Patients With Melanoma and With NSCLC Investigated in 2 Studies

wo studies, one in melanoma and one in non–small cell lung cancer (NSCLC), presented at the 2014 American Association for Cancer Research annual meeting attempted to correlate response to the PD-1 inhibitor MK-3475 with the biomarker PD-1 ligand (PD-L1). The hope is that the level of Adil I. Daud, MD PD-L1 expression will be a biomarker for the selection of patients for treatment with this new agent. The first study suggests that PD-L1 expression may become a marker for determining which patients with melanoma will benefit most from MK-3475, and the second study indicates that PD-L1 is a robust predictor of response and outcome in patients with NSCLC treated with this drug. Ongoing studies are looking for additional evidence.

“We found a major difference in the response rates between patients with PD-L1–positive and PD-L1–negative tumors treated with MK-3475.” – Adil I. Daud, MD MK-3475 is an investigational potent antibody that inhibits PD-1. This immunotherapy is designed to restore the ability of the immune system to recognize and target cancer cells by selectively achieving dual blockade of the PD-1 ligands PD-L1 and PD-L2.

Melanoma Results The first study involved patients with melanoma, and the results were presented by lead investigator Adil I. Daud, MD, codirector of the Melanoma Center at the University of California, San Francisco (UCSF) and director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center. “We found a major difference in the response rates between patients with PD-L1–positive and PD-L1–negative tumors treated with MK-3475,” said Daud. “This is the largest data set yet, to my knowledge, looking at

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PD-L1 expression in tumors from melanoma patients treated with PD-1 inhibitors.” In this study, 195 patients with advanced melanoma had a mandatory biopsy and were then treated with 1 of 3 doses of MK-3475 for 12 weeks, after which response was assessed; responders continued receiving treatment until disease progression, and nonresponders discontinued the study. Patients treated previously with ipilimumab had no restriction on previous therapies; ipilimumab-naive patients could have had up to 2 previous therapies. Among 125 evaluable patients, 89 (71%) were positive for PD-L1 expression and 36 (29%) were negative. In unselected patients, the response rate was 40%. Among PD-L1–positive patients, the response rate was 49% versus 13% among PD-L1–negative patients (P=.007). The responses were durable in both groups, Daud said. Progression-free survival (PFS) curves also showed major differences between PD-L1–positive and PD-L1– negative patients. The median PFS was 10.6 months in PD-L1–positive patients versus 2.9 months in PD-L1– negative patients (P=.051). The overall survival data are not mature. In patients with PD-L1–positive melanoma tumors who received MK-3475, the overall response rate (ORR) was 46%, compared with 17% in patients without PD-L1 expression. After 6 months of therapy with MK-3475, 64% of the patients with PD-L1–positive tumors had no disease progression, compared with 34% of those with PD-L1–negative tumors. Similarly, 86% of patients with PD-L1–positive tumors were alive after 12 months, compared with 72% of patients with PD-L1–negative tumors. When discussing the study at a press briefing, Daud emphasized that these were preliminary results, and more data are needed to verify the utility of PD-L1 as a biomarker for treatment with MK-3475 in patients with advanced melanoma, saying, “Because we saw durable responses in PD-L1–negative patients, the clinical utility of selecting patients for treatment with MK-3475 based on PD-L1 expression is not clear in advanced melanoma.” Data from ongoing studies may indeed provide additional information on the relationship between PD-L1 expression and response to MK-3475. The FDA has

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assigned a priority review for the manufacturer’s application for the licensing of MK-3475 (now known as pembrolizumab) for the treatment of patients with advanced melanoma, with a final FDA decision expected in October 2014.

NSCLC Results A second presentation from an early-phase study showed that PD-L1 expression of >50% was predictive of response to MK-3475 in patients with NSCLC. These findings were also based on an analysis of a training set of 146 patients from the ongoing phase 1 study and were reported by Leena Gandhi, MD, PhD, thoracic oncologist, Dana-Farber Cancer Institute, Boston, MA. The ORR for PD-L1–positive and PD-L1–negative groups was 19%. However, strong positivity (>50% expression) clearly differentiated responders from nonresponders. Approximately 25% of the cohort was PD-L1– positive using this cutoff. The median PFS was 14.1 weeks in the PD-L1–positive patients versus 9.3 weeks in the PD-L1–negative or weakly positive patients. Overall survival times were 9.3 months versus 7.3 months, respectively, which were not statistically significant. “PFS was markedly improved in those with strong PD-L1 staining, and responses were durable. We expect

that these median and final PFS rates may change over time. As with melanoma, there is no statistically significant difference in survival at this point, but we do see a trend favoring PD-L1 positivity,” Gandhi said.

“PFS was markedly improved in those with strong PD-L1 staining, and responses were durable. We expect that these median and final PFS rates may change over time.” – Leena Gandhi, MD, PhD Ongoing studies will analyze more patients in the phase 1 study, and there is an ongoing randomized study of 2 mg/kg MK-3475 versus 10 mg docetaxel in patients with NSCLC. MK-3475 is also being evaluated as a single agent and in combination with other drugs in patients with multiple solid tumors and hematologic malignancies. A major problem with this effort is that the tests for PD-L1 expression are not standardized. Several tests for PD-L1 expression are being developed by pharmaceutical companies, and they differ in many aspects, including set points for positivity and reagents. u

FGFR Inhibitor Shows Promising Anticancer Activity

nhibition of fibroblast growth factor receptors (FGFRs) 1, 2, 3, and 4 is showing promise in the treatment of cancers driven by FGFR alterations, especially bladder cancer and lung cancer, according to phase 1 studies presented at the 2014 American Association for Cancer Research annual meeting. A phase 1 study, singled out for attention at an official press conference, showed that the investigational pan-FGFR inhibitor BGJ398 had activity against different types of solid tumors, including bladder cancer. The most notable side effect of this drug is hyperphosphatemia, an on-target effect that is manageable by dose interruptions, schedule adjustments, and phosphate-lowering medications. “The primary purpose of this first-in-human clinical trial of BGJ398 was to look at tolerability. However, we restricted enrollment only to patients with FGFR ge-

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netic alterations in their tumors, because we believed that these patients would have the greatest chance of benefiting from the drug,” said Lecia V. Sequist, MD, MPH, associate professor of medicine, Harvard Medical School, and assistant physician, Massachusetts General Hospital, Boston. Sequist said that she and her colleagues Lecia V. Sequist, were especially encouraged by the activity MD, MPH seen in bladder cancer, “for which there are few treatment options.” “This study clearly demonstrates the value of a personalized approach to cancer therapy with a targeted agent by showing that patients with FGFR genetic abnormalities can respond to an FGFR inhibitor,” Sequist said. The study enrolled 107 patients with lung cancer, breast cancer, cholangiocarcinoma, or urothelial cell

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bladder cancer. Of those patients, 43 were treated in the dose-escalation phase of the trial. Three groups were treated in the expansion phase: squamous cell lung cancer treated daily, and 2 other groups with various cancers (one group was treated continuously daily,

“This study clearly demonstrates the value of a personalized approach to cancer therapy with a targeted agent.” – Lecia V. Sequist, MD, MPH and the other group was treated for 3 weeks on and 1 week off). The 125-mg daily dose was identified as the maximum tolerated dose. The 3-weeks-on/1-week-off schedule demonstrated an improved safety profile and is the schedule that will go forward for phase 2 testing. Tumor shrinkage was observed in patients treated at doses of ≥100 mg daily in the dose-escalation phase, as

well as among patients in all 3 expansion arms. Tumor shrinkage was observed in various cancer types, most notably in 5 of 6 patients with bladder cancer who had an FGFR3 mutation. Anticancer activity was also observed in patients with squamous cell lung cancer, squamous cell head and neck cancer, breast cancer, and cholangiocarcinoma. Sequist said that the lung cancer data will be presented at the 2014 American Society of Clinical Oncology meeting. Lessons learned from this phase 1 study and others include the need for proactive management to reduce hyperphosphatemia. A number of phase 2 studies are ongoing or are planned, and correlative studies of specific FGFR genetic alterations will be included. Another abstract presented at the meeting focused on a similar drug under development – a pan-FGFR inhibitor called JNJ-42756493. The study had a similar design, similar responses, and similar adverse events – mainly hyperphosphatemia. The 9-mg daily dose was identified as the maximum tolerated dose going forward in phase 2 trials. u

Simple Blood Test Predicts Response to Enzalutamide in Patients With Prostate Cancer

esults from a preliminary study from a highly respected group of researchers suggest that a simple blood test for the androgen receptor splice variant-7 (AR-V7) in the AR gene can identify men with castrate-resistant prostate cancer (CRPC) who will not respond to enzalutamide. If these results are confirmed in a larger population, the test could help differentiate whether patients would benefit from this drug, avoid unnecessary costs, and allow patients to move on to an effective drug. The data were presented for the first time at the 2014 American Association for Cancer Research annual meeting. “AR-V7 is detectable in circulating T cells in a subset of CRPC patients and seems to predict resistance to enzalutamide. We believe these data have immediate clinical implications in that we can steer patients who test positive for this splice variant away from enzalutamide and offer them chemotherapy and radiation,” said Emmanuel S. Antonarakis, MD, assistant professor of oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD. “Further, the availability of a blood biomarker

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for AR-V7 could fuel the development of novel AR therapies,” Antonarakis added. The use of enzalutamide for CRPC in the pre docetaxel space is off-label. However, approval for this indication may be forthcoming. Currently, 3 other therapies are approved for this indication: abiraterone plus prednisone, radium-223, and sipuleucel-T. “Even though enzalutamide is considered a very effective drug for some patients, about 20% of patients do not respond,” Antonarakis said. He noted that many potential reasons for resistance to the drug have been proposed, but he and his team have focused on splice variants of the AR gene. “Our studies suggest that AR-V7 is the most important variant related to resistance to enzalutamide,” Antonarakis said. A 2-part assay was used to detect AR-V7 in circulating T cells: the Dana Test Prostate Cancer Select and the AdnaTest ProstateCancer Select kits. The study enrolled 31 men with CRPC who were planning to initiate treatment with enzalutamide. Circulating T-cell samples were provided at baseline, time of response, and time of resistance. The data presented by

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Antonarakis were derived from baseline circulating T-cell samples. Of the 31 patients, 12 (39%) had detectable AR-V7 in their circulating T cells. Among patients previously treated with abiraterone, the risk of detectable AR-V7 increased to 55%, whereas it was detectable in only 9% of abiraterone-naive patients. According to the RECIST, no tumor shrinkage was seen in any patient with detectable AR-V7. Every patient who had a prostate-specific antigen (PSA) response was wild-type for AR-V7, whereas only 1 of the patients with detectable AR-V7 had a PSA response. The presence of detectable AR-V7 was associated with a 7-fold risk of PSA progression and an 8.5-fold risk of clinical progression.

A multivariate analysis identified 3 factors associated with lack of response: detectable AR-V7, baseline PSA level, and previous abiraterone treatment. The 2

“AR-V7 is detectable in circulating T cells in a subset of CRPC patients and seems to predict resistance to enzalutamide.” – Emmanuel S. Antonarakis, MD factors associated with progression-free survival were the presence of AR-V7 and previous treatment with abiraterone. u

Potential New Approach to Treatment of Melanoma

reliminary results suggest that an investigational antibody-drug conjugate called DEDN6526A has activity against melanoma, including cutaneous, mucosal, and ocular melanoma, which is considered difficult to treat. The new drug comes on the heels of trastuzumab emtansine, the first antibody-drug conjugate approved by the FDA for the treatment of breast cancer. The conjugate links an antibody to a toxic chemotherapy that remains inactive until the antibody recognizes a protein on the surface of cancer cells and releases its toxic “payload” into the cancer cells. This is one of the first clinical trials to test an antibody-drug conjugate for the treatment of melanoma, explained Jeffrey R. Infante, MD, director, drug development program, Sarah Cannon Research Institute, Nashville, TN. “We are encouraged by the initial responses. DEDN6526A is well tolerated and, more important, benefits a substantial proportion of patients. It is particularly promising to see clinical activity in patients with mucosal, as well as ocular, melanoma, and we hope that patients who enroll in the ongoing expansion phase of the trial gain similar benefit,” Infante told attendees at the 2014 American Association for Cancer Research annual meeting. Infante presented the results of the dose-escalation phase of the first-in-human phase 1 trial of this new therapy. The antibody recognizes the endothelin B receptor (ETBR), which Infante estimates is elevated in

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approximately 50% of melanomas; the toxic chemotherapy is monomethyl auristatin E (MMAE). When DEDN6526A is administered to a patient, the antibody attaches to ETBR on the cancer cell surface, and MMAE is released to kill the melanoma cells. Infante said that he and his coinvestigators are still working on a reliable assay to measure ETBR Jeffrey R. Infante, MD levels to get a more precise handle on how this drug works. “We need a companion diagnostic to go along with this drug to identify patients who express ETBR. We are working on it,” Infante noted.

“These are exciting results because there are not that many examples of antibodydrug conjugates that work.” – Thomas J. Lynch, Jr, MD The dose-escalation phase included 28 patients with metastatic or unresectable melanoma (17 with cutaneous melanoma, 8 with ocular melanoma, and 3 with mucosal melanoma). Patients were given DEDN6526A every 3 weeks; the maximum tolerated dose was determined as 2.4 mg/kg every 3 weeks, and this is the dose

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being tested in the expansion phase of the trial. Adverse events thought to be drug-related included fatigue, chills, alopecia, sensory neuropathy, decreased appetite, headache, nausea, and vomiting. Neutropenia was the most frequent grade 3 adverse event. Infusionrelated reactions were also observed, but these were reduced with steroid premedication. Among 19 patients in the dose-escalation phase who received ≥1.8 mg/kg of DEDN6526A, clinical benefit was observed in 12 patients; 2 patients with cutaneous melanoma and 2 with mucosal melanoma had confirmed partial responses. Of the remaining 8 patients, 5 with cutaneous melanoma, 2 with ocular melanoma, and 1 with mucosal melanoma had stable disease for 6 months or longer. In some cases, disease was stable for a prolonged period. Infante said that 1

patient has been stable and in the study for 2 years. Infante emphasized that this was an unselected population. It may be that responses will be even better once a companion diagnostic can identify patients with elevated expression of ETBR. An expansion cohort of an additional 24 patients with melanoma is now being studied. Thomas J. Lynch, Jr, MD, director, Yale Cancer Center, New Haven, CT, commented on this study. “These are exciting results because there are not that many examples of antibody-drug conjugates that work. The demonstration of clinical response is important. This was not an enriched population, and we still don’t know the biomarker, but if a test is developed to identify responders, then this may turn out to be a new approach to treatment of patients with melanoma,” Lynch stated. u

Highest Response Rate to Date With a ThirdLine VEGF Inhibitor, Pazopanib, in Metastatic Renal Cell Carcinoma

lmost 50% of patients with metastatic renal cell carcinoma (mRCC) had objective responses to third-line treatment with the angiogenesis inhibitor pazopanib, according to the results from a small clinical trial reported at the 2014 American Association for Cancer Research annual Sumanta K. Pal, meeting. MD Overall, 12 of 28 patients achieved objective responses (including 1 complete response), and another patient had an unconfirmed partial response. In the subgroup of responding patients, the duration of response to pazopanib exceeded the duration of previous responses in a majority of cases.

“This is the highest objective response rate observed to date in a trial of third-line therapy for metastatic renal cell carcinoma.” – Sumanta K. Pal, MD The cohort had a median progression-free survival of 16.5 months, a “remarkable” clinical outcome for such a heavily pretreated group of patients, said principal inves-

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tigator Sumanta K. Pal, MD, assistant professor of medical oncology and therapeutics research, City of Hope, Duarte, CA. “This is the highest objective response rate observed to date in a trial of third-line therapy for metastatic renal cell carcinoma,” said Pal. “Equally unprecedented is the median progression-free survival, which is remarkable for this group of patients.” Pazopanib, a multitargeted tyrosine kinase inhibitor, is approved for the treatment of advanced RRC. Previous studies of the agent included a phase 3 trial in patients who were refractory to cytokine therapy or were treatment naive. No previous trial had determined pazopanib’s activity in the third-line setting or examined temporal changes in molecular profile during therapy.

Study Details Pal and colleagues evaluated pazopanib’s third-line potential for mRCC in a well-defined group of previously treated patients. They performed a phase 3, single-arm trial involving patients whose disease had progressed after 2 previous systemic regimens, 1 of which had to be an inhibitor of vascular endothelial growth factor (VEGF). Other eligibility criteria included ECOG performance status of 0 to 2, and clear cell histology.

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The primary outcome was response rate, and the trial was statistically powered to detect a 23% overall response rate, defined as “clinically encouraging.” Investigators also examined immunologic markers associated with treatment failure or success. Patients received pazopanib 800 mg daily on 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or death. None of the patients enrolled in the study had goodrisk characteristics. Approximately 60% had intermediate-risk features, and about 40% had poor-risk features. Overall, 23 of the 28 patients received anti-VEGF therapy as first-line treatment, and the most frequently used second-line therapy was the mTOR inhibitor class. Some of the patients received anti-VEGF therapy as first- and second-line therapy. The median duration of previous anti-VEGF therapy was 4 months.

In addition to the 13 patients who had responses (including the 1 unconfirmed response), 9 had stable disease, resulting in a clinical benefit rate of 78%. After a median follow-up of 17.1 months, the median overall survival had yet to be reached. Biomarker analysis showed that response was associated with lower levels of hepatocyte growth factor, VEGF, interleukin (IL)-8, IL-6, and soluble IL-2 receptor (P<.05 for each analysis). The most frequently reported adverse event was hypertension (93%, all grades), which was grade 3/4 in 50% of the cases. Blood pressure was manageable with antihypertensive medications, and no patient stopped treatment because of uncontrolled blood pressure. In addition, 14% of patients had grade 3 proteinuria. The most frequently reported laboratory abnormalities were hyponatremia and elevated creatinine. u

Sanjiv S. Agarwala, MD

THIRD ANNUAL CONFERENCE

Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

WORLD CUTANEOUS MALIGNANCIES CONGRESS

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OCT. 29 - OCT. 31, 2014

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GBC CONFERENCE CHAIRS Jorge E. Cortes, MD

WORLD THIRD ANNUAL CONFERENCE CUTANEOUS GLOBAL BIOMARKERS MALIGNANCIES CONSORTIUM Clinical Approaches to Targeted Technologies CONGRESS TM

Roy S. Herbst, MD, PhD

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OCT. 31 - NOV. 1, 2014

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Marriott Marquis San Francisco • San Francisco, California WCMC GBC2014RegisterToday_21214

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THE LAST WORD

PMO and the PMC – A Collaboration to Advance Precision Medicine Introducing Dr Edward Abrahams, President of PMC, as the Author of The Last Word Kristin Siyahian

ince the inception of Personalized Medicine in Oncology (PMO), we have offered the department The Last Word in which we sum up thoughts on various overriding themes in the world of personalized medicine. In this thought-provoking column we have discussed the impact on oncology care of various forces in our culture – from Edward Abrahams, PhD the Affordable Care Act to a star’s decision to proceed with double mastectomy. Also during our publishing tenure, we have established a partnership with the Personalized Medicine Coalition (PMC). PMC exists for many of the same reasons as PMO – personalized medicine will (and is) changing the way drugs are developed and medicine is

The mission of PMC is to build a foundation for the advancement of personalized medicine as a viable solution to the challenges of efficacy, safety, and cost. prescribed. The use of new breakthrough methods of molecular analysis to better manage a patient’s disease or predisposition to a disease will transform medicine. Yet the regulatory and financial systems that will support personalized medicine are not yet in place. While PMO exists to educate readers about the advances in personalized medicine that will improve patient care, the mission of PMC is to build a foundation for the advancement of personalized medicine as a viable solution to the challenges of efficacy, safety, and cost. To this end, PMC was launched in 2004 to educate the public and policymakers and to promote new ways

of thinking about healthcare. Today, PMC represents a broad spectrum of more than 225 innovator, academic, industry, patient, provider, and payer communities, as they seek to advance the understanding and adoption of personalized medicine concepts and products for the benefit of patients. As a part of our partnership, we are pleased to have the president of the PMC, Edward Abrahams, PhD, as the new author of The Last Word. By way of background, prior to serving as president of the PMC, Dr Abrahams was executive director of the Pennsylvania Biotechnology Association, where he spearheaded the successful effort that led to the Commonwealth of Pennsylvania’s investment of $200 million to commercialize biotechnology in the state. Earlier he had been assistant vice president for federal relations at the University of Pennsylvania and held a senior administrative position at Brown University. Dr Abrahams worked for 7 years for the US Congress, including as a legislative assistant to Senator Lloyd Bentsen, an economist for the Joint Economic Committee under the chairmanship of Representative Lee Hamilton, and as an American Association for the Advancement of Science Congressional Fellow for Representative Edward J. Markey. The author of numerous essays, Dr Abrahams serves on the editorial board of Personalized Medicine. He has also taught history and public policy at Brown University and the University of Pennsylvania. The next issue of PMO will feature Dr Abrahams’ inaugural column, in which he will present an overview of PMC’s signature and soon-to-be-launched document, The Case for Personalized Medicine (4th edition). All of us at PMO are looking forward to Dr Abrahams’ contributions to this department and are confident they will be of great interest to our readers. u

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October 29-31, 2014

Marriott Marquis • San Francisco, CA

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PM O

Interview With the Innovators A PMO Exclusive Series The world of personalized medicine is a rapidly changing, ever-evolving state involving many stakeholders on the front lines of its creation: physicians, industry, researchers, patient advocates, and payers. PMO seeks out the leaders in these sectors and brings you their game-changing strategies, missions, and impact on personalizing oncology care. To view Interview With the Innovators, or to nominate an interviewee, visit us at

www.personalizedmedonc.com

PMO Interviewees include:

Lawrence M. Weiss MD, Clarient Diagnostic Services, Inc. Inno111313

Edith Perez, MD Mayo Clinic

Kimberly Popovits Genomic Health

Edward Abrahams, PhD Personalized Medicine Coalition

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