PMO April 2014

A Peer-Reviewed Journal

April 2014 • Volume 3 • Number 2

PM O

BIOMARKERS • IMMUNOTHERAPY • TARGETED THERAPIES • DIAGNOSTICS

Personalized Medicine in Oncology TM

THE BIOMARKER

NEW

KIT Genetic Mutation in a Melanoma Patient.............................................................Page 82

AML CASE STUDY Molecular Profiling in Acute Myeloid Leukemia.........................................................Page 86

INTERVIEW WITH THE INNOVATORS Empowering the Practice of Personalized Medicine: The Evolving Role of Pathology in Cancer Diagnostics. An Interview With Pranil K. Chandra, DO ......................................Page 88

HEMATOLOGIC MALIGNANCIES CME Faculty Perspectives. Advances in the Treatment of Hematologic Malignancies..........................Page 92

NEW ASCO RECOMMENDATION ASCO Proposes New Model for Reimbursement

by Medicare for Cancer Care.......................Page 106

THE LAST WORD The Affordable Care Act and Cancer Patients – Winners and Losers in an Unsteady GLOBAL BIOMARKERS Paradigm Shift…...........................................Page 121

CONSORTIUM Clinical Approaches to Targeted Technologies ™

The official publication of

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

WORLD CUTANEOUS MALIGNANCIES CONGRESS

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

WORLD CUTANEOUS

In partnership with

™

n tio a dic n I L TC P ine L d 2n

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

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

RECHARGE THE POSSIBILITIES

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

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

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

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

www.istodax.com

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

15% ~60% 25%

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

9.2 months

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

1.8 months a

(~2 cycles) median time to Objective Response

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

APRIL 2014

VOLUME 3, NUMBER 2

TABLE OF CONTENTS THE BIOMARKER

82

KIT Genetic Mutation in a Melanoma Patient

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.

AML CASE STUDY

86

Molecular Profiling in Acute Myeloid Leukemia

A case presented by Mark J. Levis, MD, PhD, associate professor, Department of

Oncology, Medicine, and Pharmacology, Sidney Kimmel Comprehensive Cancer

Center, Johns Hopkins University, at the recent Global Biomarkers Consortium annual conference.

INTERVIEW WITH THE INNOVATORS

88

Empowering the Practice of Personalized Medicine: The Evolving Role of Pathology in Cancer Diagnostics. An Interview With Pranil K. Chandra, DO PMO speaks with Dr Pranil K. Chandra of PathGroup about the changing role of the pathologist in personalizing care, the responsiveness of pathology as a discipline to cancer care needs, and the future goals of PathGroup.

HEMATOLOGIC MALIGNANCIES CME

92 Faculty Perspectives. Advances in the Treatment of Hematologic Malignancies

Paul Richardson, MD; Stephanie A. Gregory, MD; Ruben A. Mesa, MD, FACP;

Susan M. O’Brien, MD EDITORIAL

104

Family With a Risk of Cancer Tries to Change Its Destiny Bonnie Rochman

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

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

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PUBLISHING STAFF Senior Vice President/Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Group Director, Sales & Marketing John W. Hennessy jhennessy2@the-lynx-group.com Publisher Russell Hennessy rhennessy@the-lynx-group.com Editorial 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 Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Jackie Luma Deanna Martinez IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Green Hill Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-656-7935 fax: 732-656-7938

April 2014

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Vol 3, No 2

Now enrolling Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial.

Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

NCT#01889186 Reference: ClinicalTrials.gov.

@ 2013 Genentech USA, Inc. All rights reserved. BIO0001961500 Printed in USA.

To learn more about this study, please visit www.ClinicalTrials.gov.

APRIL 2014

VOLUME 3, NUMBER 2

T

TABLE OF CONTENTS

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

(Continued)

Global biomarkers Consortium Clinical Approaches

NEW ASCO RECOMMENDATION

106

ASCO Proposes New Model for Reimbursement by Medicare for Cancer Care

TM

The American Society of Clinical Oncology (ASCO) has proposed a radical new model for the reimbursement of oncology services under Medicare, with the new paradigm consisting of incentives for oncologists to emphasize quality rather than quantity of care as the greater good to the bottom line.

NATIONAL CANCER INSTITUTE

107 NCI Pilot Trial to Assess Value of Genetic Sequencing for Improving Patient Outcomes AMERICAN SOCIETY OF HEMATOLOGY

108

Important information from the American Society of Hematology annual meetingOF

to Targeted Technologies

TM

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

GENITOURINARY AND GASTROINTESTINAL CANCERS SYMPOSIA

114

Important information from the GU and GI Cancers Symposia

THE LAST WORD

121

T he Affordable Care Act and Cancer Patients – Winners and Losers in an Unsteady Paradigm Shift

Kip Piper, MA, FACHE, talks about the impact of the ACA on oncologists and the patients they treat.

Professional Experience of GBC Attendees 26.7%

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

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

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

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

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Vol 3, No 2

SCIENTIFIC CONFERENCES 2014-2015:

Pancreatic Cancer: Innovations in Research and Treatment Co-Chairpersons: Dafna Bar-Sagi, David A. Tuveson, Christine Iacobuzio-Donahue, Alec Kimmelman, and Andrew M. Lowy May 18-21, 2014 New Orleans, LA AACR Precision Medicine Series Drug Sensitivity and Resistance: Improving Cancer Therapy Co-Chairpersons: Gideon Bollag, Elaine Mardis, Gordon Mills, and David Solit June 18-21, 2014 Orlando, FL 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 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 Hematological Malignancies: Translating Discoveries to Novel Therapies Co-Chairpersons: Kenneth C. Anderson, Scott Armstrong, Riccardo Dalla-Favera, and Margaret Shipp 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 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 Tumor Immunology Co-Chairpersons: Robert H. Vonderheide, Nina Bhardwaj, Stanley Riddell, and Cynthia L. Sears December 1-4, 2014 Orlando, FL San Antonio Breast Cancer Symposium December 9-13, 2014 San Antonio, TX AACR Annual Meeting 2015 Program Committee Chairperson: Lewis C. Cantley April 18-22, 2015 Philadelphia, PA Advances in Brain Cancer Research Co-Chairpersons: Eric C. Holland, Franziska Michor, Martine F. Roussel, and Michael D. Taylor May 27-30, 2015 • Washington, DC Metabolism and Cancer Co-Chairpersons: Ralph J. DeBerardinis, David M. Sabatini, and Almut Schultze June 7-10, 2015 Bellevue, WA

EDITORIAL BOARD

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

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

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

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

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

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

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

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

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

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

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Dear Physician Colleague...

Your Support Is Critical

5

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

Lillie D. Shockney, RN, BS, MAS

5

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

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

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

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

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

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

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LETTER TO OUR READERS

The Value of Personalized Medicine in Oncology Dear Colleague,

P Greg Kalemkerian, MD

ersonalized Medicine in Oncology (PMO) organizes the vastly complex forces of personalized medicine into an approachable model of cancer care:

• Identifying the genetic mutations and biological derangements that drive tumors • Translating genomics, proteomics, and metabolomics into real-world clinical strategies • Anticipating payers’ increasing demands for prior authorization of biological therapy • Interviewing healthcare visionaries in the medical, managed care, and policy sectors • Assessing the biological pipeline and its impact on transforming survival expectations

In short, PMO is the practicing oncologists’ survival guide for translating targeted, personalized cancer care from clinical trials to clinical practice. Our goal is to bring clarity to providers on making the transition from conventional to personalized cancer care.

The gratifying potential of personalized medicine is only attainable if it The gratifying potential of is understood by providers. With many new therapies being so rapidly developed, it is challenging for practicing oncologists to keep pace and personalized medicine to discern the true, clinically relevant advances within the field. We is only attainable if it is thank our readers and supporters because, as a community, we sustain the momentum of personalized cancer care, making it possible to sit back understood by providers. every now and then to take stock of the impact that novel therapies are having on the lives of our patients. We have come a long way in just a few short years, but there are many hurdles yet to overcome, and PMO will continue to serve as our guide to optimizing personalized medical care within our practices.

It is our sincere wish that this journal helps you achieve a new level in providing personalized care to your patients.

Sincerely,

Greg Kalemkerian, MD University of Michigan PMO Board Member

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OFFICIAL WEBSITE FOR

LynxCME is the new home of COEXM activities CONTINUING EDUCATION 6th Annual

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MAY 2013 • VOLUME 6 • NUMBER 2

CONSIDERATIONS in

Multiple Myeloma

™

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

LETTER

FROM THE

EDITOR-IN-CHIEF

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

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

to learn more!

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

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

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

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

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

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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.

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YEAR ANNIVER SARY

FIFTH ANNUAL

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

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Scan Here to Register To use 2D barcodes: Visit the app store to download a QR Code reader for your smartphone

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THE BIOMARKER

KIT Genetic Mutation in a Melanoma Patient PMO is pleased to offer the department â&#x20AC;&#x153;The Biomarkerâ&#x20AC;? 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.

W

elcome to The Biomarker column!

As you know, the field of oncology and pathology is dramatically changing from a diagnostic and treatment paradigm that was based largely on microscopic characteristics to one that integrates genomic alterations, also known as biomarkers, Pranil K. Chandra, to drive clinical management decisions. In each issue of PMO, we will be discussing the DO clinical implications of biomarkers in molecular pathology and oncology practice and will cover a broad range of established and emerging biomarkers.

Briefly about myself, I am a molecular oncologic pathologist with board certifications in anatomic pathology, clinical pathology, hematopathology, and molecular pathology. As part of my clinical duties, I evaluate tumor samples for the presence of genomic aberrations

Alterations in KIT have been observed in a number of malignancies and lead to constitutive activation and/or dysregulation of downstream molecular pathways. (or biomarkers) and condense this information down to clinically actionable decision points that summarize the diagnostic, prognostic, and therapeutic utility of the changes. I recently signed out a case of a metastatic melanoma that harbored a DNA point mutation in a very druggable gene. This alteration was not a BRAF V600E but rather a KIT V559G point mutation in exon 11.

Pranil K. Chandra, DO, is Director, Molecular Pathology Services and Interim Medical Director, Clinical Pathology of PathGroup.

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KIT in Molecular Oncologic Pathology Practice The KIT gene is located on the long arm of chromosome 4 and encodes for a transmembrane receptor tyrosine kinase protein (also known as CD117), which is expressed by interstitial cells of Cajal, hematopoietic precursors, mast cells, as well as melanocytes. Alterations in KIT have been observed in a number of malignancies and lead to constitutive activation and/or dysregulation of downstream molecular pathways including PIK3, JAK/STAT, and MAPK.1 Genomic aberrations in KIT have diagnostic, prognostic, and therapeutic value across a wide spectrum of malignancies, and these changes can be assessed by a variety of technologies. The presence of a certain type of KIT mutation (D816V), traditionally assessed by polymerase chain reactionâ&#x20AC;&#x201C;based methods, is a major required diagnostic criteria for systemic mastocytosis.2 The overexpression of the KIT protein by immunohistochemistry is critical to help pathologists arrive at a diagnosis of gastrointestinal stromal tumor.3 Certain mutations in KIT predict for response to small molecular inhibitor therapy such as imatinib, and KIT genotyping is now recommended in National Comprehensive Cancer Network guidelines.4 In certain acute myeloid leukemias with translocations involving core binding factor proteins, the presence of a KIT mutation predicts for an aggressive clinical course.5,6 Because of its protean utility, KIT evaluation is becoming incorporated into larger, multiplex molecular panels performed utilizing modern techniques, such as next-generation sequencing (NGS).

Melanoma: A Heterogeneous Disease on a Molecular Level We most commonly equate metastatic melanomas as harboring a BRAF V600E mutation because of widespread literature delineating its utility and prominent implications for FDA-approved targeted therapy.7 However, it is important to know that melanoma is a very heterogeneous disease on a molecular biologic level. There is a growing list of actionable genomic aberrations in melanomas that have diagnostic, prognostic, and therapeutic relevance.8 It is also intriguing that cutaneous melanomas have a different molecular biology compared with uveal melanomas, the latter being observed to more frequently harbor alterations in GNAQ and GNA11 genes.9 In fact, a metastatic melanoma with a GNAQ or GNA11 mutation should prompt a thorough evaluation to rule out a uveal primary. In addition, preclinical models have shown po-

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ity, and a median overall survival of equally relevant functionally. Many KIT 15 months.13 At the 2009 International mutations identified in melanoma have Melanoma Congress held in Boston, MA, not previously reported and are THEbeen BIOMARKER Hodi, et al provided an interim report on present only in individual cases, suga study led by the Dana-Farber Cancer gesting that some mutations represent Institute, revealing a 25 percent RECIST passenger mutations rather than true (Response Evaluation Criteria In Solid driver alterations. Interestingly, all Tumors) response rate in the 20 evalu- six responses in the MSKCC study ocable patients treated. All five curredKinase in tumors with L576P or K642E Schematic Representation of responses the KIT Tyrosine Receptor and Mutations

KIT Exon Number

Associated Protein Domain

Exon 9 (n = 3/48; 6%)

Extracellular Domain

N463S (n = 1) G466E (n = 1) G466R (n = 1)

Juxtamembrane Domain

Y553C (n = 1) E554K (n = 2) W557R (n = 2) V559A (n = 1) V559C (n = 1) V559G (n = 1) V560D (n = 2) Y570H (n = 1) L576P (n = 11)

Exon 11 (n = 22/48; 46%)

Exon 13 (n = 9/48; 19%)

Exon 17 (n = 5/48; 10%)

Exon 18 (n = 9/48; 19%)

N-terminal

KIT Mutation

Proximal Kinase Domain

K642E (n = 4) L647F (n = 1) G648D (n = 2) I653T (n = 1) V654A (n = 1)

Distal Kinase Domain

L813P (n = 1) K818Q (n = 1) D820Y (n = 1) N822K (n = 1) N822Y (n = 1)

Distal Kinase Domain

A829P (n = 1) L831P (n = 1) P838L (n = 1) S840I (n = 1) Y846C (n = 1) S850G (n = 1) V852I (n = 1) L859P (n = 1) L862P (n = 1)

teria, we may be better able to identify those patients who will benefit from imatinib. Only those tumors truly dependent upon a constitutively active KIT signaling pathway will likely be susceptible to KIT inhibition, and the development of biomarkers permitting the reliable identification of these KITdriven tumors is critical.

Frequency

Extracellular Domain

Juxtamembrane Domain Proximal Kinase Domain

Distal Kinase Domain

C-terminal

This diagram shows the distribution and frequency of mutations observed in a phase 2 trial of imatinib in patients Figure 1. Schematic representation of the KIT tyrosine kinase receptor and mutation frequency with melanoma harboring a mutation or amplification of KIT. Five immunoglobulin-like domains are located shows domain the distribution and frequency of mutations observed in aligand. phase IIThe trialjuxtamembrane of imatinib in patients with melanoma inThis the diagram extracellular and serve as the binding site for the KIT autoinhibitory harboring a mutation or amplifi cation of KIT. Five immunoglobulin-like domains are located in the extracellular domain and serve as domain serves to maintain the kinase domains in an inhibited state unless the receptor is bound by ligand. the binding site for the KIT ligand. The juxtamembrane autoinhibitory domain serves to maintain the kinase domains in an inhibited Reprinted from THE MELANOMA LETTER, courtesy of The Skin Cancer Foundation. state unless the receptor is bound by ligand.12

tential benefit with MEK inhibitors in melanoma cell lines harboring GNAQ mutations.10 NRAS mutations can also be seen in 15% to 20% of melanomas, most commonly in neoplasms arising in the background of sun-damaged skin.11 These mutations are known to render melanomas unresponsive to BRAF inhibitors, and early data suggest that MEK inhibitors either alone or as combination therapy may yield success.12

KIT in Melanoma: Implications for Precision Oncology KIT mutations were first reported in 2005 and are present in a small subpopulation of melanoma patients.

Mutations in KIT are generally mutually exclusive with other driver mutations, including NRAS, BRAF, and GNAQ. Typically, KIT mutations are found in melano-

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mas that arise in 10% to 20% of acral, mucosal, and sun-damaged sites.13 This particular mutation was located on exon 11 in the juxtamembrane domain and is known to render the tumor responsive to targeted therapy. Currently, there is no FDA-approved therapy available for melanoma with KIT mutations, but there are a number of published case studies as well as phase 2 clinical trials that have shown complete or partial tumor response to therapies such as imatinib in melanomas harboring mutations in exon 11 of KIT.14-19 Reports have also demonstrated efficacy with other targeted therapies such as dasatinib used singly or in combination.16,20 In addition, there are clinical trials enrolling patients with metastatic melanoma with KIT mutations (available at www.clinicaltrials.gov). Alternatively, consideration may be given to off-label use of

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THE BIOMARKER

targeted therapy with appropriate patient education and consent; however, this latter approach may be fraught with reimbursement challenges in the near term. While we have seen great success with targeted therapy in melanoma, it is important to temper our excitement as the vast majority of patients treated with these agents go on to develop resistance. Mechanisms for resistance are being elucidated on a molecular biologic level and include acquired mutations in the

Melanomas are heterogeneous on a molecular level and can frequently harbor genomic aberrations that may predict for response to targeted therapy.

NRAS gene as well as KIT amplification.19 Over time, it will become standard of care to comprehensively assess for the presence of alterations in genes such as BRAF, GNAQ, NRAS, KIT, and PDGFR-alpha21 at once to both predict for response to therapy and to monitor for potential resistance.

Conclusion Melanomas are heterogeneous on a molecular level and can frequently harbor genomic aberrations that may predict for response to targeted therapy. Mutations in the KIT gene are most commonly seen in a subset of melanomas and predict for response to therapies that are FDA approved for other cancers. Clinical management decisions in melanoma patients with such druggable aberrations, such as KIT mutations, should be grounded on implementing strategies that involve use of targeted therapy. Further work, however, is needed to better refine our ability to predict for therapeutic response and elucidate mechanisms of treatment resistance. In this regard, comprehensive molecular tumor profiling with technologies such as NGS in advanced

melanomas holds the promise to empower oncologists and other treating clinicians with information to make scientifically driven therapeutic management decisions.

This will in turn decrease costs and improve outcomes in patients afflicted with this aggressive disease. u

References

1. My Cancer Genome. www.mycancergenome.org/content/disease/melanoma/ kit/109. Accessed March 11, 2014.

2. Valent P, Horny H-P, Li CY, et al. Mastocytosis (mast cell disease). In: Jaffe ES, Harris NL, Stein H, et al, eds. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissue. Lyon, France: IARC Press; 2001:291-302.

3. Loughrey MB, Trivett M, Beshay V, et al. KIT immunohistochemistry and mutation status in gastrointestinal stromal tumours (GISTs) evaluated for treatment with imatinib. Histopathology. 2006;49:52-65.

4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Soft Tissue Sarcoma. Version 1.2014. www.nccn.org/ professionals/physician_gls/f_guidelines.asp#sarcoma. Accessed March 10, 2014.

5. Paschka P, Marcucci G, Ruppert AS, et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol. 2006;24:3904-3911.

6. Cairoli R, Beghini A, Grillo G, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood. 2006;107:3463-3468.

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

8. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135-2147.

9. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363:2191-2199.

10. Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599-602.

11. Ball NJ, Yohn JJ, Morelli JG, et al. Ras mutations in human melanoma: a marker of malignant progression. J Invest Dermatol. 1994;102:285-290.

12. Grimaldi AM, Simeone E, Ascierto PA. The role of MEK inhibitors in the treatment of metastatic melanoma. Curr Opin Oncol. 2014;26:196-203.

13. Curtin JA, Busam K, Pinkel D, et al. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24:4340-4346.

14. Hodi FS, Friedlander P, Corless CL, et al. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol. 2008;26:2046-2051.

15. Lutzky J, Bauer J, Bastian BC. Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. Pigment Cell Melanoma Res. 2008;21:492-493.

16. Woodman SE, Trent JC, Stemke-Hale K, et al. Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Mol Cancer Ther. 2009;8:2079-2085.

17. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305:2327-2334.

18. Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol. 2011;29:2904-2909.

19. Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31:3182-3190.

20. Postow MA, Carvajal RD. Therapeutic implications of KIT in melanoma. Cancer J. 2012;18:137-141.

21. Dai J, Kong Y, Si L, et al. Large-scale analysis of PDGFRA mutations in melanomas and evaluation of their sensitivity to tyrosine kinase inhibitors imatinib and crenolanib. Clin Cancer Res. 2013;19:6935-6942.

COMMENTARY Scan this code* to watch Dr Sanjiv Agarwala comment on this edition of The Biomarker: KIT Genetic Mutation in a Melanoma Patient. *To view this video, download a QR code scanner app on your smartphone, or visit our website at www.PersonalizedMedOnc.com.

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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

AML CASE STUDY

Case Study: Molecular Profiling in Acute Myeloid Leukemia At the 2013 conference of the Global Biomarkers Consortium, which took place October 4-6, 2013, in Boston, MA, Mark J. Levis, MD, PhD, associate professor, Department of Oncology, Medicine, and Pharmacology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, discussed the use of personalizing therapy in the management of acute myeloid leukemia.

A

cute myeloid leukemia (AML) can be divided functionally into as many as 8 categories that are molecularly defined. AML with an FLT3 internal tandem duplication (FLT3 ITD) mutation is an

“An investigational PCR technique, called tandem duplication PCR (TD-PCR), can detect the presence of an FLT3 ITD mutation with a high level of sensitivity and specificity.”

– Mark J. Levis, MD, PhD aggressive hematologic malignancy with a poor prognosis. It represents approximately 25% of patients with Table

Allogeneic Transplant for FLT3 ITD AML No. of Patients

Benefit for Transplant?

United Kingdom

283

No

Germany/ Austria

164

Yes

Study

Study Type

Location

Gale et al, 2005

Multiinstitutional

Schlenk et Multial, 2008 institutional DeZern et al, 2011

Single institution

USA

31

Yes

Lin et al, 2013

Single institution

Taiwan

34

Yes

Laboure et al, 2012

Single institution

France

24

Yes

Brunet et al, 2012

Multiinstitutional

International

120

Yes

AML indicates acute myeloid leukemia; ITD, internal tandem duplication.

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newly diagnosed AML, said Mark J. Levis, MD, PhD. ITD mutations typically result from the insertion of a duplicated sequence of a portion of the juxtamembrane region of the FLT3 wild-type gene. Polymerase chain reaction (PCR)-based molecular diagnostic DNA testing using inward-facing primers that flank the juxtamembrane domain of FLT3 is the standard technique to detect FLT3 ITD mutations.

Case: Woman With FLT3 ITD AML A 33-year-old woman with fatigue presents with a white blood cell count of 59,470 and 94% blasts. Her molecular profile was thus: normal cytogenetics, no chromosome rearrangement alterations by fluorescence in situ hybridization, no NPM1 mutation, normal CCAT/enhancer binding protein-alpha, and FLT3 ITD mutation by standard technique (90 base pairs for ITD, 0.69 allelic ratio).

She was treated with cytarabine/daunorubicin (7 + 3) as induction therapy. Her counts recovered, but with 10% blasts in the marrow. High-dose cytarabine was administered as salvage therapy, and a complete remission was achieved. There was no FLT3 mutation detectable in complete remission 1.

A high FLT3 mutant to wild-type ratio predicts a high risk of relapse in AML patients with the FLT3 ITD mutation (Figure). At Johns Hopkins, virtually all AML patients with FLT3 ITD mutations are offered allogeneic transplantation following several series showing improved outcomes in FLT3 ITD–positive disease (Table), said Levis.

The patient was consolidated with allogeneic transplant. The FLT3 ITD mutation was undetectable by conventional assay.

Detecting the FLT3 ITD mutation with the standard PCR assay has a limit of detection of approximately 1 in 100 cells. Many patients with FLT3 ITD AML ultimately relapse with FLT3-mutated disease after transplant, but the FLT3 mutation is still not detectable by standard PCR assay because the burden of disease is lower than the detection threshold of the assay.

“An investigational PCR technique, called tandem duplication PCR (TD-PCR), can detect the presence of an FLT3 ITD mutation with a high level of sensitivity and specificity,” said Levis.

TD-PCR uses outward-facing, overlapping primers within the expected region of mutation to im-

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Figure. FLT3 Mutant to Wild-Type Ratio: High Mutant Ratio Predicts Poor Prognosis

High

FLT3/ITD FLT3/ITD Hemizygous

Relapse

Survival

Inter.

Hemizygous

Low

Years

Months

CALGB:*

German SHG:†

CALGB indicates Cancer and Leukemia Group B; SHG, Suddeutsche Hamosblastosgruppe (CML Study Group). = Cancer and Leukemia group B; SHG = Suddeutsche Hamosblastosgruppe (CML Study Group) *Whitman SP, et al. CancerCALGB Res. 2001;61:7233-7239.

Thiede C, et al. Blood. 2002;99:4326-­‐4335. † Thiede C, et al. Blood. 2002;99:4326-4335.

Whitman SP, et al. Cancer Res. 2001;61:7233-­‐7239.

prove the limit of detection of leukemia cells in a background of wild-type cells. The limit of detection of the TD-PCR assay approaches a single mutant molecule.

TD-PCR assay posttransplant showed minimal residual disease. The patient was enrolled on a protocol for an FLT3 inhibitor (sorafenib) as maintenance therapy because of her high risk of relapse.

Sorafenib has shown high activity in FLT3 ITD– positive relapsed AML. The patient was maintained on sorafenib therapy for 12 months, during which time the FLT3 mutation remained detectable.

Unfortunately, the woman developed gastrointestinal intolerance to sorafenib, and it was discontinued. She relapsed within 30 days of discontinuing sorafenib. Her AML molecular profile at relapse was FLT3 ITD positive (90 base pairs ITD, 0.8 allelic ratio).

Examination of drug pharmacokinetics shows a 20-fold variation in sorafenib levels between patients,

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said Levis. “In retrospect, she was probably overdosed at 400 mg,” he said. “We may have been able to lower the dose and maintain the target inhibition.”

FLT3 tyrosine kinase inhibitors are close to approval as maintenance therapy, and isocitrate dehydrogenase inhibitors are in the pipeline.

Conclusion Molecular profiling is now essential to manage AML, as the number of tools to treat the disease is expanding, including cytarabine/daunorubicin, allogeneic transplant, all-trans retinoic acid, arsenic, and hypomethylating agents. FLT3 tyrosine kinase inhibitors are close to approval as maintenance therapy, and isocitrate dehydrogenase inhibitors are in the pipeline. u

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

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INTERVIEW WITH THE INNOVATORS

Empowering the Practice of Personalized Medicine: The Evolving Role of Pathology in Cancer Diagnostics An Interview With Pranil K. Chandra, DO

P

athGroup is a diagnostic and clinical service company providing comprehensive anatomic, clinical, and molecular pathology services. They are committed to providing diagnostic expertise, precision technologies, and innovative services to give physicians and their patients personalized inforPranil K. Chandra, mation for targeted therapies that lead to the best possible patient outcomes.

DO PathGroup works with individual and contract research partners in developing platforms for improved molecular intelligence. Their molecular diagnostics facility includes a dedicated Clinical Laboratory Improvement Amendments–validated laboratory and a full menu of molecular testing options. Through their collaboration with GenoSpace and Thomson Reuters,

they offer their new assay PathGroup SmartGenomics Next-Generation Sequencing (NGS), providing information on genes, gene variants and their therapeutic implications, and place diverse real-time data into clinically actionable context for oncologists and researchers. Further, PathGroup SmartGenomics NGS provides a decision support tool for identifying not only potential treatments and clinical trial opportunities for patients but also elucidation on why previous therapies may have failed and forward-looking intelligence on new therapeutic agent targets.

PMO had the pleasure of speaking with Dr Pranil K. Chandra at PathGroup about the changing role of the pathologist in personalizing care, the responsiveness of pathology as a discipline to cancer care needs, and the future goals of PathGroup.

PMO The practicing oncologists who read Personalized Medicine in Oncology are constantly learning about innovations in personalized medicine techniques and how to implement them into their practices. From that perspective, it is useful to provide optimal clarity about

Dr Chandra Pathology is undergoing a transformative change, especially in cancer diagnostics. Integrating molecular information into our testing is now critical to provide information to our clinicians that yield diagnostic, prognostic, and/or therapeutic utility. As the director of molecular pathology services at PathGroup, I provide clinical and administrative leadership to our molecular operations that deliver comprehensive and world-class molecular testing to our clients and empower the practice of personalized, precision medicine. The literature now clearly shows that these efforts add value, lead to better patient outcomes, and decreased healthcare costs and burden. In fact, information from pathology laboratories drives more than twothirds of clinical management decisions and accounts for less than 5% of total healthcare costs.

PMO PathGroup’s capabilities – consisting of laboratory work, oncology diagnostics, specialized PathGroup applications and technologies – are too extensive to cover in 1 interview. What areas would you like to focus on to provide practicing oncologists insights into the role of pathology in galvanizing personalized medicine in cancer care, and what are some significant advances that you would like to describe?

Information from pathology laboratories drives more than two-thirds of clinical management decisions and accounts for less than 5% of total healthcare costs. how pathology and hematopathology help drive the spread and adoption of personalized medicine in oncology. Could you please describe the role of pathology laboratory services and your mission at PathGroup in this iterative progression of personalized medicine?

Pranil K. Chandra, DO, is Director, Molecular Pathology Services and Interim Medical Director, Clinical Pathology of PathGroup.

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Dr Chandra We have invested in both NGS and array comparative genomic hybridization to maximize the likelihood of identifying actionable genomic alterations and being mindful of the resulting immense amount of genomic data that will be produced. Through our partnership with GenoSpace and Thomson Reuters, we have developed customized tools that allow clinical genomicists in our molecular pathology practice to interpret genomic changes based on what exists in regularly curated genomic knowledge databases in a robust and scalable fashion. These tools allow us to distill the findings to clinically actionable decision points and produce molecular reports that are educational, lucid, and interactive.

PMO How can practicing oncologists retain a working knowledge of innovations in pathology amidst the growth of personalized medicine on the pathology laboratory front?

Dr Chandra It is becoming increasingly difficult to keep up with the rapid advances in genomic medicine and molecular oncology. To address this, we have recently launched an interactive physician portal that functions to educate community-based oncologists on the latest developments in precision oncology and to support scientifically driven clinical decision making.

We have also developed online tools and webinars, which are available to physicians and healthcare providers both internal and external to our organization.

PMO What has been your focus or mission for making pathology responsive to cancer care needs?

Dr Chandra The division of molecular pathology services has 3 main goals for 2014. The first is to establish a national reputation for our efforts. We continue to form strategic partnerships and engage in projects that build a quality reputation and brand in molecular testing, which we promote as “SmartGenomics.” SmartGenomics testing includes advanced molecular tumor profiling such as NGS and/or microarray. The second is to overlay these cutting-edge and advanced onco­ genomic diagnostic tools in a manner that allows a comprehensive and complementary analysis of cancer tissue. At times certain genomic aberrations may be missed by one technology, and this entails utilizing additional tests in a responsible fashion. Protein overexpression is a prime example that may require a test known as immunohistochemistry to be utilized in conjunction with NGS and cytogenomic microarray (aCGH). The third is to build an infrastructure to efficiently manage the enormous amount of genomic information that will result from our testing and both aggregate and integrate those findings in a lucid summary report. This is the reason for our partnership with GenoSpace and Thomson Reuters.

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Pranil K. Chandra, DO (l), Director, Molecular Pathology Services, and James Prescott, PhD (r), Scientific Director, Molecular Diagnostics Services, for PathGroup’s precision oncology program in Nashville, TN.

A PathGroup Molecular Diagnostics Services technician prepares samples for molecular testing.

PMO Can you elaborate on the partnership between PathGroup, GenoSpace, and Thomson Reuters?

Dr Chandra GenoSpace has helped us develop cutting-edge tools to interpret genomic changes and produce a state-of-the-art, dynamic molecular pathology report. Thomson Reuters is an industry leader in providing life science information. Thomson Reuters also has a rapidly growing presence in personalized medicine and has a burgeoning role in the development and maintenance of genomic knowledge databases. As pathologists and laboratory professionals, we are in the business of generating an enormous amount of valuable

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Pranil K. Chandra, DO, PathGroup’s Director, Molecular Pathology Services, reviews slides to determine sufficient tumor burden as part of the quality assurance process to ensure high quality and quantity of tumor is present for molecular analysis. Molecular results are interpreted in the appropriate clinical and morphologic context utilizing sophisticated bioinformatics tools developed in partnership with GenoSpace and Thomson Reuters.

information. Therefore, the partnership with GenoSpace and Thomson Reuters is a powerful one, bolstered by complementary synergies across and between our respective organizations.

PMO What are your customers’ chief priorities, and how have you focused your energies to meet them?

Molecular testing is not reimbursed at a level that is commensurate with the resources and expertise required to deliver the testing...

Dr Chandra We have been laser focused on achieving industry-leading turnaround times to deliver testing results for the most timely patient management and therapeutic intervention and have put in place numerous operational efficiencies to facilitate this. Having

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timely results is imperative to help our clients manage cancer patients.

PMO How large is PathGroup relative to other pathology laboratory firms?

Dr Chandra PathGroup is composed of more than 70 pathologists and 1000 employees and is one of the largest privately owned pathology laboratories in the country. We are based in Nashville, TN, and provide comprehensive anatomic, clinical, and genomic services to more than 90 hospitals and 2000 physician offices in the country. Our size and structure allow us to provide the most sophisticated testing for our clients while maintaining a direct and personalized relationship. Over the past few years, PathGroup has experienced significant and rapid growth, and through it, we’ve continued to achieve optimal efficiencies and maintain a “team-based” culture of innovation.

In 2012, we performed more than 5 million laboratory tests.

PMO Are there any particular impediments to pathology laboratory diagnostics arising from different healthcare sectors: clinical, research, payer coverage, and/or government policy?

Dr Chandra Currently, molecular testing is not reimbursed at a level that is commensurate with the resources and expertise required to deliver the testing or the immense value brought to the healthcare system.

Given the enormous excitement behind personalized medicine, hopefully this will change in the near future.

Equally important is the responsibility to make sure we oversee and utilize the right tests at the right time.

PMO Conversely, are there examples of these healthcare sectors assisting in advances in pathology, bringing about new efficiencies servicing oncologists and their patients’ needs?

Dr Chandra All stakeholders involved in genomic testing need to build the infrastructure to manage the data. There are a number of bioinformatics companies that are facilitating efficient management of genomic information. We feel that GenoSpace is an emerging leader in this field and is poised to be a significant national player.

PMO What changes in these sectors’ systems and policies would you like to see?

Dr Chandra We need to gravitate toward a policy that focuses on reimbursement derived by the value brought to the healthcare system, which can be determined by a number of factors including outcome and decreased costs.

PMO What systems changes are dealing with inconsistency in biomarker validation? What progress has occurred over the past 5 years?

Dr Chandra There has been a general explosion in

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genomic discoveries and uptake in the appropriate utilization of molecular testing that has largely been due to an unprecedented rate of publications that implicate new biomarkers and others that continue to establish clinical utility.

PMO Are there any inherent factors impeding further progress?

Dr Chandra Standardization of molecular testing is very important to ensure that the data produced by one organization can be reproduced by another. The second is education of various stakeholders on the value of molecular testing. These are both enormous infrastructural efforts required to drive the progress of precision oncology.

PMO What are the most significant unmet needs for oncologists and patients that PathGroup has worked on, and is working on, to meet?

Dr Chandra Delivery of academic-caliber molecular testing to community-based physicians and oncologists. Approximately 80% of cancer patients are cared for in the community. Our organization is striving to bring the best and most comprehensive oncology testing to them.

PMO Finally, what is on the horizon at PathGroup?

Dr Chandra We are expanding our precision oncology offering to focus on tests that lead to actionable decisions. To this end, we will be bringing up 20

to 30 tests in the next 1 to 2 years. Some of these include single-gene tests that have prognostic or therapeutic impact in the management of cancer patients.

Others are more expansive and include analysis of multiplex panels of genes at once through NSG and/

Standardization of molecular testing is very important to ensure that the data produced by one organization can be reproduced by another. or aCGH. We have recently released a 75+ gene panel that uncovers genomic aberrations across a wide spectrum of hematologic disorders with high sensitivity and industry-leading turnaround time. This test will be complemented with aCGH to look for copy number alterations (amplification, deletions, and genomic instability) to maximize the number of actionable genomic aberrations identified, which should lead to increased therapeutic options including clinical trials, decreased healthcare costs, and improved patient outcomes.

PMO Thank you so much for your time today.

Dr Chandra My pleasure. u

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EDITORIAL

Family With a Risk of Cancer Tries to Change Its Destiny A Controversial Procedure Lets Couples Select Embryos Free of a Genetic Mutation

By Bonnie Rochman

T

o shield any future children from the fear she harbors of getting breast cancer, Katie Dowdy underwent a controversial procedure to select embryos of hers that were free of a genetic mutation linked to the disease.

Deciding to have the procedure, called preimplantation genetic diagnosis, or PGD, wasn’t easy, says Ms. Dowdy. Her husband initially “worried about playing God,” she says. “I thought, if I could have a healthy baby who doesn’t have to worry about the same thing I did, why wouldn’t I?” says the 34-year-old, who hasn’t had cancer. The couple, who live in Castle Pines, Colo., now have two young girls, both born using PGD. Preimplantation genetic diagnosis has long been available during IVF, or in vitro fertilization, to eliminate the risk of passing on severe disorders such as spinal muscular atrophy and cystic fibrosis. Now, fertility clinics say they are seeing a small but increasing number of women choosing PGD to avoid giving birth to children who carry mutations in the BRCA genes, which increase the risk for breast and other cancers.

“It’s on the rise because more people are becoming aware that there’s a genetic component to breast cancer,” says Mark Hughes, founder of Genesis Genetics, in

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Plymouth, Mich., which offers reproductive-geneticsdiagnosis services to fertility clinics nationwide.

Critics fear genetically vetting embryos can be used to create so-called designer babies. Embryos with the gene mutation may be discarded, which some critics also oppose. Gender selection is one form of embryo-testing that stirs ethical questions. Some clinics will agree to select for a specific sex only for health reasons – to avoid a disease such as hemophilia, for example, which typically is passed only to boys. Opponents of PGD for breast cancer also say that having a BRCA-gene mutation doesn’t mean a person will necessarily get the disease and that there are options for detecting and treating the cancer.

A parent with a mutation on the BRCA1 or BRCA2 genes has a 50-50 chance of transmitting it to the next generation. Between 45% and 65% of women with the mutations are expected to be diagnosed with breast cancer by age 70, according to the National Cancer Institute. That compares with about 12% of women in the general population.

BRCA mutations, which also increase the risk for ovarian, prostate and other cancers in men and women, are relatively rare, accounting for 5% to 10% of all breast cancers. Some women undergo prophylactic mastectomy to reduce their chances of getting the disease.

In Ms. Dowdy’s family, the specter of breast cancer hovers. Her paternal grandmother died in 1979, five months before Ms. Dowdy was born. Several of her grandmother’s sisters also got breast cancer. Ms. Dowdy’s father had a genetic test and found he had inherited the BRCA1 mutation. When she was 27, a test showed Ms. Dowdy also had the mutation.

After her aunt, who shares the same mutation, had a prophylactic mastectomy, Ms. Dowdy researched her options and learned about PGD. Ms. Dowdy says she and her husband had struggled to conceive. Figuring they would need fertility assistance, also doing PGD to avoid passing on the BRCA mutation seemed like an obvious precaution.

The PGD process begins with standard IVF. After two weeks of hormonal stimulation, eggs are retrieved, fertilized and left to multiply for five days. Then a laboratory

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Predict to Prevent Preimplantation genetic diagnosis, or PGD, tests an embryo for a genetic disorder it is at risk of inheriting from the parents. Here are some diseases for which PGD is used: Cystic fibrosis Hemophilia Huntington’s disease Marfan syndrome Muscular dystrophy Thalassemia Tay-Sachs Spinal muscular atrophy Sickle cell anemia Source: NYU Fertility Center. scrutinizes several cells, looking for gene mutations. The analysis isn’t believed to harm the embryo. Embryos without BRCA mutations are earmarked for transfer into a woman’s uterus.

Two of Ms. Dowdy’s seven embryos were BRCA-mutation free. Both were transferred to her uterus. One implanted and grew to become a daughter, Reagan, born in 2010. Ms. Dowdy and her husband opted for PGD again to conceive another child, Mackenzie, born in March 2013.

Only recently have some doctors started discussing PGD with women who have a breast-cancer mutation.

More often, BRCA-positive women learn about the procedure on their own. “We write about it in our newsletter and we’ve done webinars on it, but not everyone knows about it,” says Sue Friedman, executive director of Force, a nonprofit patient-support group focused on hereditary breast and ovarian cancers.

For women who have no trouble conceiving, the choice to do PGD involves the added hassle of fertility treatment. PGD can add about $6,000 to the price of IVF, which runs at least $10,000, depending on the clinic, plus thousands of dollars more for medications.

Some patients say “My grandma had it, my aunt had it, my mom had it. I want to stop this train.” Others have the attitude that if my baby turns out like me, so be it.

“It’s by no means 100% [of eligible women] who are choosing to do it,” says William Schoolcraft, medical director of the Colorado Center for Reproductive Medicine in Lone Tree, Colo., and Ms. Dowdy’s doctor. Dr. Schoolcraft says he has done about 10 PGD procedures to eliminate a BRCA mutation in the past three years.

He has heard some patients say “My grandma had it, my aunt had it, my mom had it. I want to stop this train.”

Others have the attitude that if my baby turns out like me, so be it.

Even after an embryo selected through PGD is successfully implanted, some doctors recommend an amniocentesis or another prenatal test called CVS to make sure there isn’t a BRCA-gene mutation.

“You have to think of it from the perspective of a woman whose life has been turned upside down by breast cancer and the guilt associated with choosing to have a baby that could have those same problems,” says James Grifo, director of the Division of Reproductive Endocrinology and Infertility at NYU Fertility Center. u Reprinted by permission of The Wall Street Journal, Copyright © 2014 Dow Jones & Company, Inc. All Rights Reserved Worldwide. License number 3335561341430.

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NEW ASCO RECOMMENDATION

ASCO Proposes New Model for Reimbursement

by Medicare for Cancer Care

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he American Society of Clinical Oncology (ASCO) has proposed a radical new model for the reimbursement of oncology services under Medicare, with the new paradigm consisting of incentives for oncologists to emphasize quality rather than quantity of care as the greater good to the bottom line.

“This payment reform proposal represents a real shift in the way oncologists would be reimbursed,” said ASCO President Clifford A. Hudis, MD, chief, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York. “ASCO is offering a new and different perspective on how oncologists should be compensated that recognizes their expertise as well as the care and services they are providing to patients.”

“The appeal of this proposed model is that by incentivizing high-quality, high-value patient care – patients win, oncologists win, and ultimately the American people will win with a stable, sensible, sustainable healthcare system.”

– Anupama Kurup Acheson, MD The proposed reform is part 5 of a 5-part series of ASCO communications intended to educate its membership on how Medicare reimbursement is currently configured, on ideas for moving away from the fee-forservice (FFS) model, and on the proposal itself.

The proposal, as put forth by ASCO’s Payment Reform Working Group, began with a (seemingly) simple question: “If we could build a logical Medicare model for oncology reimbursement from scratch, what would it look like?” The simple answer is, in brief, put quality of care first. How to do that requires a few more details, with 5 recommendations in particular: New patient payment. A single reimbursement is proposed for the time required to evaluate a new patient.

This would eliminate Current Procedural Terminology (CPT)-based evaluation and management payments but would retain payment for FFS diagnostic testing.

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Treatment month payment. After the patient begins treatment, the practice would receive a single monthly payment for all treatment-related activities (eg, chemotherapy administration, therapeutic injections and infusions, hydration services, etc). This compensation would replace all current CPT-based payments.

Four different levels of payment are proposed for the monthly reimbursement. This would account for the differing treatment needs of individuals within a practice population resulting from comorbidities, performance status, complications related to the proposed treatment plan, and so on.

Nontreatment month payment. This payment is proposed for circumstances in which a patient does not receive treatment during a particular month because of treatment complication or other medical circumstance.

For this nontreatment month, 2 levels of payment are proposed – 1) a higher amount for months immediately after the end of treatment, and 2) a lower amount for patients undergoing long-term monitoring.

Transition of treatment payment. This payment is made when a patient begins a new line of therapy or ends treatment without an intention to continue. The idea is to compensate (in a lump sum) for the additional time involved in treatment planning and patient education.

Again, 2 payment levels are recommended, with higher payments for a patient who has a recurrence while off treatment.

Continued FFS payment for some CPT codes. Some activities would retain current CPT code–based payments, such as laboratory tests, bone marrow biopsies, and the use of portable pumps.

The criteria for determining payment levels within each component of the proposal would be standardized

by Medicare.

“The appeal of this proposed model,” said ASCO Clinical Practice Committee chair Anupama Kurup Acheson, MD, medical oncologist, Providence Cancer Center Oncology and Hematology Care Clinic, Portland, OR, “is that by incentivizing high-quality, high-value patient care – patients win, oncologists win, and ultimately the American people will win with a stable, sensible, sustainable healthcare system.”

Improving the State of the Art: Whatever It Takes Under the proposed model, oncology practices will receive additional payments for participation in improvement-of-care initiatives. The initiatives include

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performance on instruments measuring quality of care, adherence to value-based treatment pathways, conservation of resources (ie, minimizing emergency department visits and avoidable hospitalizations resulting from complications of treatment), and participation in clinical trials.

“Oncologists are already integrating many of these best practices in their day-to-day work,” said ASCO Clinical Practice Committee past chair Jeffery C. Ward, MD, medical oncologist, Swedish Cancer Institute, Seattle, WA. “However, the current system does not recognize, incentivize, or reimburse for these critical components to high-quality cancer care.”

That said, Dr Ward and colleagues are not married to any single approach to payment reform. For example, just days after the above proposal went public, ASCO, in collaboration with the Community Oncology Alliance,

announced that they had achieved “a unified set of principles” intended to guide the organizations’ respective efforts to achieve payment reform in oncology.

“This payment reform proposal represents a real shift in the way oncologists would be reimbursed.”

– Clifford A. Hudis, MD Going forward, such intraorganizational cooperation is key, stated Dr Acheson. “If we do not work together to develop a solution for oncology reimbursement, then it will be forced upon us. We’ve seen the consequences that can bring – let’s get this done.” u

M-PACT TRIAL

NCI Pilot Trial to Assess Value of Genetic Sequencing for Improving Patient Outcomes

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he National Cancer Institute (NCI) has launched a clinical trial to determine whether selecting therapies based on genetic mutations can improve outcomes in patients with metastatic solid tumors.

Molecular Profiling based Assignment of Cancer Therapeutics (M-PACT) is one of the first randomized trials to assess if using genetic mutation as the basis for treatment selection can improve the rate and duration of response in patients with advanced-stage solid tumors.

A second goal is to see if the use of genetic sequencing can identify a subpopulation of patients who could benefit from specific targeted treatment, which would help to expedite drug development for these patients based on their genetic profile, and could lead to smaller clinical trials and reduce cost and time of drug development.

“Patients will have their tumors genetically screened, and if a predefined mutation is found, they will receive treatment with targeted agents,” said Shivaani Kummar, MD, head of NCI’s Developmental Therapeutics Clinic and the trial’s principal investigator. “What we don’t know, however, is whether using this approach to assign targeted treatments is really effective at providing clinical benefit to patients, as most tumors have

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multiple mutations, and it’s not always clear which mutation to target and which agent is most likely to provide maximal benefit.”

“Most tumors have multiple mutations, and it’s not always clear which mutation to target and which agent is most likely to provide maximal benefit.”

– Shivaani Kummar, MD The M-PACT trial is designed to determine whether patients with mutations that have been shown in the laboratory to affect drug effectiveness will benefit from a specific targeted therapy, and if this approach results in better outcomes.

The NCI is now screening hundreds of people to select 180 patients with advanced refractory solid tumors based on their genetic profile. u National Cancer Institute Press Release; January 30, 2014.

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ASH 2013

Clinical Practice Guidelines Should Include Patient’s Preferences

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linicians want to provide excellent patient care without having to appraise every new study in their field, but producing the “authoritative, instructive resource for most clinical scenarios” is not as straightforward as it would seem, according to David Garcia, MD, professor, University of Washington School of Medicine in Seattle.

At a special symposium on quality care and clinical practice guidelines during ASH, Garcia discussed the

Proposals for Guideline Developers • Minimize conflicts of interest but still harness the expertise held

by “conflicted” individuals; this can be controlled by limiting the power of those with conflicts of interest • Focus on patient-important outcomes • Consider trade-offs from the patient’s perspective • Maintain transparency regarding the evidence and methods used to create the guideline and any possible conflicts of interest • Provide key recommendations in synthesis form that can be used at the bedside: a summary, checklist, algorithm – with strength clearly labeled – From David Garcia, MD, professor, University of Washington School of Medicine

challenges of guideline development and emphasized the need to include the preferences of patients, whose lives are impacted by these guidelines.

“Our job is to apply evidence and guideline recommendations within the context of individual patient prefer­ ences and values, and these can never be predicted or accounted for by people writing the guidelines,” he said.

Consider the Patients The best guidelines are based on “strong evidence,” and the proper ingredients of a “strong recommendation” are 2-fold: the inclusion of high-quality evidence that proves the impact on important clinical outcomes, as opposed to surrogate outcomes that may not matter to the patient; and the demonstration that any risks associated with the intervention are clearly outweighed by benefits, he said.

“These seem obvious, but as physicians we may not always predict accurately what the patient sees as being worthwhile in terms of the risks they are willing to accept for the benefits we can offer,” Garcia said.

Future guideline writers need to focus on patient-important (not surrogate) outcomes whenever possible, he suggested, and to be equipped with better knowledge about how patients view the trade-offs associated with treatment options. u

Choosing Wisely Initiative Aims to Lower Cost, Improve Quality of Care

T

o improve the quality of care in hematology, and to eliminate waste and reduce costs, ASH has embraced the Choosing Wisely initiative of the American Board of Internal Medicine Foundation.

The Institute of Medicine estimated that in 2009, some $750 billion was wasted in healthcare, of which $210 billion was spent on unnecessary healthcare services across all specialties, according to Lisa Hicks, MD, University of Toronto and St. Michael’s Hospital, Toronto, Canada, and chair of the ASH Choosing Wisely Task Force.

“If we could redirect even a fraction of this to real people with real unmet healthcare needs, think of the

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good that we can do,” she said.

Mark Crowther, MD, McMaster University in Hamilton, Canada, added, “The landscape in quality improvement is changing” as reimbursement is being tied to outcome measures, quality, and maintenance of certification. “With the initiation of the Affordable Care Act and onwards, clinical practice based on quality management will become more and more important,” he suggested.

The evidence-based recommendations were developed after a careful review of data by the ASH task force, followed by input from ASH members. The goal was to initiate conversation within the hematologic

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community about quality of care in hematologic malignancies and other disorders. The dominant principle of these recommendations was to avoid harm, while also taking into account evidence, cost, frequency, and scope of practice.

At a press briefing during ASH, members of the task force described the recommendations, which primarily targeted unnecessary treatments and testing.

“We need to take a step back and decide whether the tests and procedures we order are truly necessary,” Hicks said. “We need a conversation about cost and value.”

Five Recommendations The 5 items named by the task force represent an important step in trimming waste and reducing harm to patients with hematologic malignancies and other blood-related conditions. They are: 1. Limit the use of CT scans in asymptomatic patients following curative-intent treatment for aggressive lymphoma.

In this common malignancy, treatment with chemotherapy and radiotherapy carries the expectation of cure, “but the question is how best to monitor these patients,” said Joseph Connors, MD, University of British Columbia, Vancouver, Canada.

“It is intuitively appealing to hover over these patients to detect recurrences as soon as possible, but at the end of the day hovering can be counterproductive if the tests themselves are harmful. Use of CT scanning and whole body scanning can be reduced and eliminated a short time after treatment,” he said.

Connors noted that unnecessary scans are associated not only with physical harm (ie, radiation exposure) and psychological harm (ie, anxiety) but also economic harm. He estimated that the new recommendation could save the healthcare system in North America $1 billion over 10 years.

2. Avoid the routine use of inferior vena cava (IVC) filters in patients with acute venous thromboembolism (VTE).

“IVC filters are costly, can cause harm, and do not have a strong evidence base,” said Mark Crowther, MD, McMaster University, Hamilton, Canada. He noted that acute VTE is the main indication for IVC filters, and some lesser indications may be reasonable – such as some cases of pulmonary embolism. Retrievable filters are recommended over permanent filters, with removal of the filter when the risk of pulmonary embolism has resolved and/or when anticoagulation can be safely resumed.

Crowther estimated that only 10% of the 250,000

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IVC filters inserted each year in the United States are currently being used appropriately.

3. Do not transfuse more than the minimum number of red blood cell (RBC) units necessary to relieve symptoms of anemia or to return a patient to safe hemoglobin range (7-8 g/dL in stable noncardiac inpatients).

Clinical trials of RBC transfusion have demonstrated that liberal transfusion strategies do not improve outcomes compared with the use of less blood, ie, a reduction from the 10 g/dL range to the range of 7 to 8 g/dL. “Using more generates higher costs and exposes patients to adverse effects,” said Jeffrey Carson, MD, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. “Avoid the routine use of 2 units of RBC if 1 is sufficient,” he recommended.

4. Clinicians should not test for thrombophilia in adults with VTE occurring in the setting of major transient risk factors such as surgery, trauma, or prolonged immobility.

“Thrombophilia testing is costly and harmful if the duration of anticoagulation is inappropriately prolonged or incorrectly labeled as thrombophilic,” according to John Heit, MD, Mayo Clinic, Rochester, MN. This recommendation for testing does not change management occurring in the setting of certain factors for which it is known to be important.

5. Do not administer plasma or prothrombin complex concentrates for nonemergent reversal of vitamin K antagonists (ie, outside the setting of major bleeding, intracranial hemorrhage, or anticipated surgery).

“Many people are on coumadin for stroke prevention, and there may be a need to reverse the effect of that drug as well as a tendency to accomplish this as quickly as possible with plasma or prothrombin complex concentrates. However, there is little evidence that this benefits the patient, and it is adequate to hold the next dose of coumadin or administer vitamin K instead,” said Robert Weinstein, MD, University of Massachusetts Medical School, Worcester, who added that the use of unnecessary blood products also exposes patients to unnecessary potential harm.

“Results of multiple audits suggest that 30% of the 4 million units used each year are given inappropriately.

That’s a lot of plasma,” Weinstein noted, estimating that up to 200 unnecessary deaths could be avoided each year in the United States if this recommendation was followed. u

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Readmission Following Stem Cell Transplant Decreases Survival

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nfection and fever without a source are the most common causes of readmission following allogeneic hematopoietic stem cell transplantation (HSCT), and being readmitted within 30 days of discharge is associated with a lower 5-year overall survival rate, according to Laura Spring, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA. “A better understanding of the risk factors for readmission in the transplant population will allow for more transitional care and clinical resources to be focused on the highest-risk patients,” said Spring. The United States spent $17.5 billion on readmissions among Medicare beneficiaries in 2010, she noted.

The 30-day readmission rate was examined in addition to the readmission rate at day 100, a traditional assessment point in transplantation readmission rate.

The retrospective review included 495 patients receiving myeloablative conditioning (MAC) and 602 patients receiving reduced-intensity conditioning (RIC) HSCT at Dana-Farber Cancer Institute and Brigham and Women’s Hospital. The 30-day readmission rate was examined in addition to the readmission rate at day 100, a traditional assessment point in transplantation readmission rate.

Following transplantation in the MAC group, the 30-day readmission rate was 26.3% and the day 100 readmission rate was 39.2%. The 30-day readmission rate for RIC was 17.4% and the day 100 rate was 30.7%.

“In both groups, the most frequent reasons for readmission were documented infection, fever without a source, and graft-versus-host disease,” Spring said. Infection was the reason for readmission in approximately 25%, fever in about 19%, and graft-versus-host disease in 15.1% (RIC) and 17.9% (MAC).

Readmission Variables A multivariate logistic regression model of the probability of being readmitted within 30 days following discharge or by day 100 following transplant was used to examine various disease transplant and sociodemographic variables.

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In the RIC group, active disease at the time of transplant was found to be a significant risk factor for readmission both by day 30 following discharge (P=.005) and by day 100 following transplant (P=.0001).

Transplant variables included donor status, type of stem cell product, and infection during the index transplant.

In the ablative group, infection during index admission was a significant risk factor for readmission by day 100 (odds ratio [OR] 1.9; P=.0006).

For the RIC group, a mismatched donor (OR 2.4; P=.029) and infection during index admission (OR 5.8; P<.0001) were significant risk factors for readmission both by day 30 following discharge and by day 100 (donor, OR 2.1; P=.030; infection, OR 4.8; P<.0001).

Among the MAC group, Hispanic/Latino ethnicity was a significant risk factor for readmission by day 100 (OR 4.6; P=.013). For the RIC group, nonprivate insurance was a risk factor at day 30 (OR 1.8; P=.025) and by day 100 (OR 1.6; P=.029).

Decreased Survival With Readmission Univariate analysis demonstrated that being readmitted in either group was associated with decreased survival.

In a landmark analysis of patients who survived beyond the studied time points, the 5-year overall survival for patients readmitted within 30 days of discharge from the index HSCT in the MAC group was 42%, compared with 56% among patients not readmitted.

Similarly, corresponding overall survival in the RIC group was 26% versus 50%.

The 5-year overall survival for those readmitted by day 100 following HSCT in the MAC group was 52% versus 61% among patients not readmitted, and in the RIC group, the corresponding OS was 26% compared with 57%.

“After adjusting for age, donor type, and disease risk index, a multivariate analysis confirmed the association between readmission and lower overall survival,” said Spring. In the multivariate analysis, the risk of death at 5 years was 58% higher in the MAC group with 30-day readmission (P=.0018) and 32.5% higher with readmission within 100 days (P=.068). In the RIC group, 30-day readmission increased the risk of 5-year mortality by 68% (P=.0002), and readmission within 100 days increased it by more than 2-fold (P≤.0001). u

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Peripheral T-Cell Lymphoma Represents High Clinical Burden, Resource Utilization, and Costs

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eripheral T-cell lymphoma (PTCL) is associated with high resource utilization rates and high overall costs, according to a multicenter study. Hospitalizations, in particular, represent a major clinical and economic burden, leading to a need for the development of treatments requiring lower resource utilization with better PTCL management.

Michele H. Potashman, PhD, of the Takeda Oncology Company, Cambridge, MA, and colleagues studied 1000 patients with PTCL identified by ICD-9 diagnosis codes over the period from October 1, 2007, through June 30, 2011. Truven MarketScan data for commercially insured and Medicare supplemental patients were used to retrospectively identify unique PTCL patients. This database comprises medical and pharmaceutical claims for >100 million unique patients across the United States.

All patients were required to have at least 6 months of continuous enrollment before and 12 months of continuous enrollment after their index date.

Mean patient age was 56 years, 58% were male, and all patients had a higher frequency of comorbidities (mean Charlson Comorbidity Index of 1.72 vs 0.39 for the control group).

The control group (n=5000) included randomly selected non-PTCL patients and was considered to represent the average insured patient population from the US payer perspective, according to the authors.

The study calculated healthcare costs per month, measured and annualized to provide average yearly costs.

Healthcare costs included hospitalizations, pharmacy services, office visits, emergency room visits, hospice stays, stem cell transplant, and other patient-related costs such as laboratory procedures, blood transfusions, and radiology procedures.

Higher Annual Costs “On an average annual basis, PTCL patients were hospitalized more often and experienced a longer length of stay compared with matched controls,” noted Potashman. “In addition, PTCL patients had higher utilization of office visits, pharmacy services, emergency room visits, and hospice care.”

The most common diagnosis codes associated with hospitalization were fever, fatigue, dizziness, dyspnea, chest pain, cough, and other chest symptoms.

Overall, PTCL patients incurred much higher average annual costs compared with matched controls ($75,934.08 vs $4,660.64), driven mainly by hospitalizations (32.2% of overall costs) and pharmacy services (19.6% of overall costs). Fifty percent of PTCL patients compared with 13.8% of controls had hospitalizations.

Emergency room visits were almost twice as frequent in the PTCL patients (47.0% vs 25.0%).

The mean cost of hospitalization per patient was $24,417 in the PTCL patients versus $1058 for controls (P<.0001).

Some 11.4% of PTCL patients had stem cell transplant compared with none of the controls. Mean cost per transplant patient in the PTCL cohort for a first stem cell transplant was $126,093.58.

The most common diagnosis codes associated with hospitalization were fever, fatigue, dizziness, dyspnea, chest pain, cough, and other chest symptoms. u

Surveillance Scanning in Transformed Indolent Lymphoma Is of Limited Clinical Benefit

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n patients with transformed indolent lymphoma (TrIL) who achieve a complete metabolic remission, surveillance PET/CT scans are of limited clinical benefit.

In a retrospective analysis of patients with TrIL man-

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aged at a single institution, “all subclinical relapses were low-grade histology and therefore of limited clinical benefit, as such patients rarely merit further therapy based on imaging findings alone,” said lead investigator Chan Y. Cheah, MD.

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The finding builds on prior evidence that surveillance scans after achievement of complete remission in patients with aggressive lymphoma do not lead to improved outcomes, he said.

Fifty-five patients with TrIL treated at Peter MacCallum Cancer Centre, East Melbourne, Australia, who achieved complete metabolic remission after primary therapy and who had subsequent surveillance PET/CT scans, were included in the analysis. During the time the patients in the study were managed, departmental protocol had recommended 6-monthly scans for patients in complete metabolic remission for the first 2 years, then annually until 5 years after completion of therapy, if there was intention to intervene on detection of subclinical relapse.

PET/CT scans and reports were reviewed and classified as either positive, negative, or indeterminate for relapsed lymphoma. True-positive results required either biopsy confirmation or unequivocal scan progression. A false-positive scan was refuted by a negative biopsy or no progression within 6 months. A negative scan was interpreted as negative for relapsed lymphoma: true negatives had no clinical relapse, and false negatives manifest relapse within 3 months from the date of the negative scan.

Of 180 surveillance PET/CT scans, there were 153 true negatives, 4 false positives, 1 false negative, 7 indeterminate, and 15 true positives. Considering indeterminate scans as false positives, the specificity of PET/CT for

detecting relapse was 93%, sensitivity was 93%, positive predictive value was 54%, and negative predictive value was 99%.

The high negative predictive value is reassuring but comes at a cost of radiation exposure, use of healthcare resources, and unnecessary biopsies, said Cheah, a hematology fellow at Peter MacCallum Cancer Centre.

After a median follow-up of 34 months, the actuarial 3-year progression-free and overall survival were 77% and 88%, respectively. “We were unable to find any prognostic factors besides age older than 60 years to isolate a subset of particular patients in whom a surveillance strategy could be focused,” he said.

“When patients relapsed with large cell disease, they typically presented with symptoms first. If they relapsed with indolent disease, they didn’t necessarily have symptoms,” said Cheah.

Sixteen patients experienced disease relapse; 7 were subclinical and 9 were suspected on the basis of clinical symptoms. Although 5% of scans in the first 2 years detected a subclinical relapse, all of these were shown to be low-grade lymphoma either clinically or by biopsy. All diffuse large B-cell lymphoma relapses, in contrast, were accompanied by clinical symptoms.

“Picking up patients that didn’t have symptoms didn’t change management,” he said. “If they didn’t have symptoms, they didn’t warrant treatment anyway.” PET/CT should therefore be reserved for evaluation of suspected relapse only, he said. u

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Switching From IV to Subcutaneous Rituximab Saves Staff Time and Money

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he efficiency of rituximab administration and the cost associated with administration can be improved by switching from IV to subcutaneous (SC) administration. Such a switch led to a substantial reduction in patient chair time and in active healthcare professional (HCP) time, said Christof Wiesner, PhD, MPH. Rituximab is the standard treatment for indolent non-Hodgkin lymphoma (iNHL), currently administered

by IV infusion. Results from studies in follicular lymphoma showed that a fixed-dose SC formulation of rituximab shortened administration time without compromising efficacy or safety compared with an IV infusion.

Wiesner and colleagues conducted a multinational, prospective, observational time and motion study in which the possible resource benefits of switching from rituximab IV to SC administration were investigated.

The data for rituximab SC injections were collected alongside the MABCUTE trial, which is exploring maintenance therapy with SC rituximab in patients with relapsed or refractory iNHL, while data for rituximab IV infusions were collected in a real-world setting in 23 centers in Italy, Russia, Slovenia, United Kingdom (UK), Spain, France, Austria, and Brazil.

Trained observers recorded both the time during which HCPs were actively completing prespecified tasks (using a stopwatch) and the patient chair time (based on length of time between patients entering and exiting chairs).

“We found time savings from the patient’s perspective in the range of 50% to 80%, which is pretty impressive, but we also have savings in the active healthcare professional time...pharmacists and nurses, in the range of 40% going up to 50%,” said Wiesner, from the Market Access Department at Genentech, South San Francisco, CA. The difference in mean active HCP time saved by

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switching from rituximab IV to rituximab SC ranged from 7.3 minutes (Austria) to 30.9 minutes (UK). The proportionate reduction in mean HCP time ranged from 28% (Spain) to 59% (Russia).

The mean time saved in the treatment room ranged from 28% (Spain) to 59% (Russia). Over the course of the first year of treatment (8 induction and 3 maintenance sessions), the estimated reduction in total HCP time associated with the switch ranged from 1.2 hours in Austria to 5.1 hours in the UK. The estimated chair time saved per patient for the first year of treatment was a low of 31 minutes in France to a high of 60 minutes in Italy.

The efficiency of rituximab administration and the cost associated with administration can be improved by switching from IV to subcutaneous administration.

“As a last step, we calculated cost savings, and they are in a similar range. A couple hundred of Euros saved for a typical course of therapy, based on assistant technical staff and nurse salary, among others,” he said.

The estimated HCP cost saving per patient in the first year of treatment ranged from 25% in Spain to 52% in Russia. HCP opportunity cost savings were driven mainly by a reduction in pharmacy staff time in Spain and the UK, and by a reduction in physician/ nurse time in other countries.

The time savings could allow more time to be used for other patient care activities or increasing the number of patients who could be treated and thus increasing the overall efficiency of treatment centers, said Wiesner. u

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2014 GENITOURINARY CANCERS SYMPOSIUM

Angiotensin System Inhibitors Extend Survival in Patients With Metastatic Renal Cell Carcinoma

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se of angiotensin system inhibitors (ASIs) improved survival in patients with renal cell carcinoma (RCC) by 9 months compared with patients not taking any of these agents, according to a retrospective pooled analysis of a number of clinical trials presented at the symposium and discussed at a premeeting press cast. Survival was further improved if patients were also taking vascular endothelial growth factor (VEGF) receptor–targeted agents. These data are intriguing and need confirmation in a larger prospective study, stated the authors.

“Results suggest that for patients with metastatic RCC who are hypertensive at baseline, ASIs may be the best choice of antihypertensive therapy.”

– Rana McKay, MD

“Based on results of this study, an ASI should be considered for patients with metastatic RCC who require antihypertensive therapy and have no contraindications that preclude their use, especially patients receiving VEGF-targeted treatments. However, it is too early to determine if ASIs should be used for patients with metastatic RCC who do not have coexisting hypertension or another medical condition to warrant ASI treatment,” stated lead author Rana McKay, MD, clinical oncology fellow at Dana-Farber Cancer Institute, Boston, MA. VEGF is an established target in metastatic RCC, she continued. ASIs include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These 2 classes of drugs act on the renin-angiotensin system and are used singly and in combination to treat hypertension

as well as other medical conditions. Recent research suggests that the peptide hormone angiotensin II modulates VEGF-depending angiogenesis.

The study – the largest retrospective study to date evaluating the role of ASIs on outcomes in cancer patients – was based on a database of 4736 patients with metastatic RCC participating in phase 2 and phase 3 Pfizer-sponsored clinical trials conducted between 2003 and 2013. ASI use was defined as taking an ASI at baseline or within 30 days of cancer treatment initiation.

Baseline hypertension was present in 48% of all patients; 1487 patients were taking an ASI, and 783 were taking other antihypertensive agents.

RCC treatments included VEGF-targeted agents such as sunitinib, sorafenib, axitinib, and bevacizumab, an mTOR inhibitor (temsirolimus), and interferon.

Overall survival (OS) for patients on ASI treatment was 26.68 months versus 17 months for non-ASI users (hazard ratio [HR] 1.213; P<.0009). In patients taking VEGF agents for metastatic RCC, ASI use significantly prolonged OS: 31 months for ASI users versus 21.94 months for nonusers (HR 1.38; P=.0003).

Moreover, tumor shrinkage was more likely in patients on ASIs. Median progression-free survival was 8.3 months for ASI users versus 6.5 months for nonusers (P=.0042).

A subgroup analysis of type of anticancer therapy showed that only concomitant VEGF and ASI use was associated with a significant survival benefit that persisted in a multivariate analysis adjusted for a number of cofactors, including age, gender, type of metastatic RCC therapy, presence of bone metastases, and risk groups.

This association was not seen with mTOR inhibitors or interferon.

“The effect of ASIs on RCC needs to be studied further. For now, results suggest that for patients with metastatic RCC who are hypertensive at baseline, ASIs may be the best choice of antihypertensive therapy,” McKay said. u

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Enzalutamide Extends Survival in Previously Untreated Metastatic Prostate Cancer

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nzalutamide prolonged survival and delayed radiographic progression of disease in men who had not received chemotherapy for metastatic castration-resistant prostate cancer (mCRPC), according to complete results from the phase 3 PREVAIL trial.

An interim analysis in 2013 was so favorable that the trial was halted prematurely, and all placebo patients were offered enzalutamide.

“Enzalutamide provides clinically meaningful benefit for men with mCRPC. It is approved by the FDA in men previously treated with docetaxel but not yet approved for use prior to docetaxel. If it does get expanded approval for this indication, it is likely to become an important standard option for use in patients with asymp­ tomatic or minimally symptomatic advanced prostate cancer,” said lead author Tomasz Beer, MD, deputy director of the Knight Cancer Institute at Oregon Health & Science University, Portland, OR. Between September 2010 and September 2012, PREVAIL included 1717 patients with asymptomatic or mildly symptomatic mCRPC who had not received previous chemotherapy. They were randomized to enzalutamide or placebo plus standard hormone therapy.

For the coprimary end points of the trial, enzalutamide reduced the risk of death by 29% (hazard ratio [HR] 0.70; P<.0001), and reduced the risk of radiographic progression by 81% (HR 0.19; P<.0001).

Overall response rate according to imaging of soft tissue disease was 59% with enzalutamide (20% complete responses and 39% partial responses) versus 5% with placebo (P<.0001).

Importantly, enzalutamide delayed the need for chemotherapy by a median of 28 months versus 10.8 months for placebo.

“This is important from a pragmatic perspective.

Many men don’t want to take chemotherapy, especially if they are asymptomatic or mildly symptomatic,” Beer commented.

Safety observation was 3 times longer with enzalutamide, reflecting the longer duration of treatment in this arm, he continued. Enzalutamide was well tolerated after 17 months of treatment; the most common side effects (in 20% or more of patients) were fatigue (36% of enzalutamide patients, 26% of placebo patients),

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constipation (22% and 27%, respectively), back pain (27% and 22%, respectively), and joint pain (20% and 16%, respectively).

Any adverse event was reported by 97% of the enzalutamide group and 93% of the placebo group. Grade 3 or higher adverse events were reported in 43% of the enzalutamide group versus 37% of the placebo group.

Six percent of patients in both arms discontinued treatment due to adverse events.

“Enzalutamide is approved by the FDA in men previously treated with docetaxel but not yet approved for use prior to docetaxel. If it does get expanded approval for this indication, it is likely to become an important standard option for use in patients with asymptomatic or minimally symptomatic advanced prostate cancer.”

– Tomasz Beer, MD Charles Ryan, MD, moderator of the press cast where these data were discussed, emphasized that this study breaks new ground for enzalutamide in chemotherapy-naive patients with mCRPC. “The interim analysis showed benefit in this patient group, and this is an important study in our field, to be sure,” Ryan noted.

Beer said that both abiraterone and enzalutamide have shown benefit in docetaxel-naive patients with metastatic disease, but at present there are no head-tohead comparisons to guide treatment selection. Decisions should be made on an individual patient basis, he stated.

Further studies comparing these treatments and sequencing them are needed, as well as studies earlier in the disease process, Beer noted. u

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The Cancer Genome Atlas Project Explores Bladder Cancer

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esearchers have successfully completed a comprehensive molecular characterization of muscle-invasive urothelial bladder carcinoma as part of The Cancer Genome Atlas (TCGA) project. Results of the analysis were presented at the Genitourinary Cancers Symposium and published simultaneously online in Nature. Excitement about the discoveries was palpable, and the authors hope that this effort to characterize the bladder cancer genome will identify new therapies targeted to actionable mutations for clinical use in appropriately selected patients.

“Results bring to light promising actionable targets that may lead to more personalized therapeutic options beyond cisplatin-based chemotherapy.”

– Jonathan E. Rosenberg, MD

“We are not in our infancy, but you could say we are on the verge of adolescence [in this effort],” said lead investigator Jonathan E. Rosenberg, MD, section chief of the Non-Prostate Program in the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City.

Bladder cancer has been the “stepchild” regarding new drugs. There has been an explosion of new therapies for both prostate and renal cancer, while no new drugs for bladder cancer have been discovered since the 1970s. The hope is that the TCGA research will lead to filling this unmet need.

The TCGA Bladder Cancer Working Group successfully analyzed samples from 131 high-grade muscle-invasive urothelial carcinomas not previously treated with cytotoxic chemotherapy.

“Results paint an intricate picture of the multiple molecular players altered in this potentially lethal type of the disease, but they also bring to light promising actionable targets that may lead to more personalized therapeutic options beyond cisplatin-based chemotherapy,” Rosenberg stated.

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Analysis of the tumor tissue revealed multiple abnormalities with a high mutation rate. The research team found that each tumor, on average, featured 302 exon mutations, 204 alterations in DNA copy number, and 22 large-scale genomic arrangements. This represented 7.7 somatic mutations per megabase, he explained, which is second only to lung cancer and melanoma. Cigarette smoking did not correlate with the mutations identified.

Sifting through the wealth of data, 32 genes were identified that showed significant levels of recurrent somatic mutation. Some of the genes have been implicated in other cancers (eg, p53, PI3CA, ATM, and HER2), while several genes have not been identified previously in any cancer; these include CDKN1A, ERCC2, RXRA, ELF3, KLF5, and others.

Potential targets were identified in 69% of the tumors, including 42% with targets in the PIK3/AKT/ mTOR pathway and 45% with targets in the RTK/ MAPK pathway (including ERBB2).

Three clusters of abnormalities were identified based on an integrated analysis of both mutations and copy number: a genomic amplification cluster, a P16-deleted cluster, and a P53-mutated cluster. Rosenberg said that the clusters suggest that discrete oncogenic mechanisms may be implicated in the development of muscle-invasive bladder cancer, but it is not clear if this finding has clinical applicability.

The key messages from this massive undertaking are as follows: 1. The majority of patients with muscle-invasive urothelial bladder carcinoma have actionable mutations that can be targeted with either FDA-approved drugs or investigational agents in appropriately selected populations.

2. Epigenetic regulatory genes are frequently altered in this type of bladder cancer, suggesting another therapeutic approach with drugs that target these alterations. Seventy-six percent of tumors had 1 inactivating epigenetic mutation, and 41% had 2.

This research opens the door for opportunities to study both FDA-approved and experimental therapies that can target some of the abnormalities that have been identified. The trials must be carefully designed, Rosenberg said. u

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Immunotherapy Holds Promise to Extend Survival in GI Cancers

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ecent advances in molecular technologies have enabled the dissection of inhibitory pathways within tumors and identification of inflammatory signals within the tumor microenvironment that regulate host immune responses. These responses can be altered to effectively treat cancers, including gastrointestinal (GI) malignancies, said Elizabeth M. Jaffee, MD, in her keynote address at the 2014 Gastrointestinal Cancers Symposium.

She provided an overview of immunotherapy for the treatment of GI cancers and described the signaling networks that regulate immune responses to different cancers.

“The main goal of immunotherapy is to raise an army of T cells to attack the tumor. These T cells need to get into the tumor, but they also have to be activated,” said Jaffee, professor of oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD. “To do this...we have to understand the many signals within the tumor microenvironment that inhibit effective T-cell trafficking and function into tumors.”

A T cell has inhibitory and activating signals. Whether it receives a downregulatory or an activating signal is determined by the summation of signals that are ongoing in the tumor microenvironment, she said.

New immune checkpoint agents act on T cells. “This is important because if you don’t have a T cell in a cancer, the agent won’t work,” said Jaffee. Only 20% to 30% of renal cell carcinomas and 10% to 20% of colorectal tumors have T cells. For most cancers, therefore, immune modulation alone is insufficient for treatment; a T-cell–generating agent is also needed.

“Combinations are needed to achieve the full potential of the immune system to recognize and kill all cancers,” she said. “Understanding all of the signaling networks that regulate responses to the different cancers is necessary to figure out the right combinations.”

Many signals can inhibit an immune response in the tumor, and there are also many ways to activate T cells.

The goal is to achieve an anticancer response when the tumor microenvironment naturally wants a procarcinogenic response, she explained. It may require not only targeting a specific antigen but also costimulation to present antigens in the right form so that an activated T cell can be generated. Activated T cells in combination with 1 or more immune checkpoint blockers will be necessary.

Vaccines are especially needed for cancers that do not

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naturally induce intratumoral immune responses. Radiation and chemotherapies can act like adjuvants and potentiate the T-cell response obtained with vaccines.

Effector T-cell infiltration is not a natural response to pancreatic cancer, but there is evidence that the immune system can be provoked in pancreatic cancer, she said.

The combination of gemcitabine and an agonist signal (CD40 agonist) was able to induce tumor regression, which means that “T cells are likely getting in and are associated with the clinical response,” she said.

A pancreatic tumor vaccine study at Johns Hopkins provides new evidence for antitumor immunity. The vaccine is administered 2 weeks before surgical resection of the tumor. A single dose of IV cyclophosphamide is given with the vaccine in an effort to enhance immune response. Cyclophosphamide allows trafficking of antigen-specific T cells to the tumor. “In 85% of the patients studied, we found lymphoid aggregates coming into the tumors,” said Jaffee. “They’re located throughout the tumor, and they’re located around the tumor. When examined closely, they look like germinal center–like structures; they stain for T cells on the outside, B cells on the inside.”

What is known so far is that vaccines can induce tumor-infiltrating lymphocytes in traditionally “nonimmunogenic” tumors. “But vaccine-induced infiltrating T cells likely get downregulated by suppressive mechanisms within the tumor,” she said. “Vaccines must be given with agents that modulate these suppressive mechanisms to activate the T-cell response.”

In the mouse model, anti–PD-1 therapy enhances infiltration of vaccine-induced tumor-specific infiltrating lymphocytes. In pancreatic cancer, regulatory pathways can be modulated to enhance vaccine efficacy. Ipilimumab plus a vaccine extended median overall survival compared with ipilimumab alone in a small pilot study of patients with metastatic pancreatic cancer in whom 2 or more chemotherapies had failed.

Two vaccines may be better than 1, she said. A vaccine platform based on live attenuated, double-deleted Listeria monocytogenes targeting mesothelin (GVAX/ CRS-207 combination) improved median overall survival in patients with metastatic pancreatic cancer in whom chemotherapy was refused or had failed. Listeria is an intracellular bacterium that induces a T-cell response against antigen targeting the tumor, but it also induces T-cell responses against helper T cells that propagate that T-cell response. u

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Promising Vaccine Combination Identified for Patients With Metastatic Pancreatic Cancer

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dual vaccine strategy improved survival more than a single vaccine in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

Data from a randomized phase 2 trial were reported by Dung T. Le, MD. It is the first randomized study to show improved overall survival for patients with metastatic pancreas cancer treated with immunotherapy.

“The advantage of this platform is that using whole cells allows presentation of a wide variety of tumorassociated antigens to the immune system.”

– Dung T. Le, MD

“This study is just a first step, and we believe we’ll be able to take this approach further,” said Le, assistant professor of medicine, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD. The approach used in the study involves 2 distinct immunotherapy platforms. GVAX is an allogeneic whole cell vaccine created from 2 pancreatic cancer cell lines.

These cells have been genetically modified to express granulocyte-macrophage colony-stimulating factor (GM-CSF).

“The advantage of this platform is that using whole cells allows presentation of a wide variety of tumor-associated antigens to the immune system,” said Le. “The GM-CSF serves to attract dendritic cells to the vaccine site that will then pick up the antigens and present them to the immune system, resulting in an activation of tumor-specific T cells.” Low-dose IV cyclophosphamide is administered the day before GVAX to inhibit regulatory (suppressive) T cells.

The second immunotherapy platform, CRS-207, is

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attenuated Listeria monocytogenes engineered to elicit an immune response against mesothelin. Mesothelin is a tumor-associated antigen expressed in a majority of pancreatic cancers. Prior studies have shown that induction of mesothelin-specific T-cell responses is associated with improved survival.

The modified strain of Listeria decreases pathogenicity but retains immunogenicity. “Listeria is unique in that it is able to stimulate both innate and adaptive immunity,” she said. “Because it is an intracellular organism, it has access to both class I and class II antigen processing pathways and can deliver the encoded antigen directly to the encoded antigen-presenting cell.”

The study investigators randomized 90 patients with previously treated, metastatic PDAC in a 2:1 ratio to 2 doses of GVAX and low-dose cyclophosphamide followed by 4 doses of CRS-207 every 3 weeks, or to 6 doses of cyclophosphamide and GVAX every 3 weeks.

At a planned interim analysis, the median overall survival on an intent-to-treat basis was 6.1 months with the 2-vaccine therapy compared with 3.9 months with GVAX alone (P=.0343). One-year survival was doubled by giving dual immunotherapy compared with single GVAX (24% vs 12%). The study met the early stopping rule for efficacy at this interim analysis, said Le. Among the patients who received at least 3 doses (per protocol analysis), the median survival was 9.7 months in the group randomized to dual vaccine and 4.6 months in those randomized to a single vaccine (P=.03).

The side effects of the vaccine were relatively mild and resolved quickly, she said. Toxicities included local reactions after GVAX, and transient fevers, rigors, and lymphopenia after CRS-207.

“These are exciting results in a poor-prognosis cancer.

This is a phase 2 study, but it is the first randomized study of immunotherapy in metastatic pancreatic cancer demonstrating an improvement in survival,” said Smitha Krishnamurthi, MD, associate professor of medicine, University Hospitals Case Medical Center, Cleveland, OH. “This is accomplished without the side effects of chemotherapy.” u

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Molecular Therapy Beyond Sorafenib in HCC: New Pathways, Targets Being Explored

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any molecularly targeted agents that inhibit different pathways of hepatocarcinogenesis are under clinical development, and novel targets are being assessed in hepatocellular carcinoma (HCC). These efforts were described by Andrew X. Zhu, MD, PhD. Sorafenib remains the only systemic agent to improve survival in advanced HCC. It improves median overall survival (OS), but median survival is still only about 10 months. Unfortunately, multiple more potent or selective antiangiogenic agents have failed to improve on this outcome.

“While we develop new therapies, a concerted and parallel effort must be made to identify and validate biomarkers of response, resistance, and toxicity to better match patients with safe, effective therapies,” said Zhu, director of liver cancer research at Massachusetts General Hospital, Boston, MA. Surpassing sorafenib may require a combination of antiangiogenic agents with cytotoxic chemotherapy or with other molecularly targeted therapies to allow for synergy or additive effects. “Alternatively, it might require moving beyond the antiangiogenesis approach and targeting cell-autonomous pathways involved in hepatocarcinogenesis, such as the HGF/c-MET, PI3K/ AKT/mTOR, or FGF/FGFR pathways,” he said.

Antiangiogenic Strategies Antiangiogenic agents including pazopanib, lenvatinib, axitinib, and ramucirumab are in clinical development for treating HCC. Based on phase 2 data, lenvatinib and ramucirumab have advanced to phase 3 evaluation.

Although HCCs are highly vascular tumors with increased levels of vascular endothelial growth factor (VEGF), multiple VEGF receptor (VEGFR) inhibitors have failed to improve OS in HCC. This failure has prompted reconsideration of targeting VEGFR in HCC, said Zhu. Future efforts should focus on developing surrogate and predictive markers to identify patients likely to benefit from antiangiogenic treatment.

Antiangiogenics are being combined with chemotherapy (sorafenib plus doxorubicin) in late-stage clinical trials, and with targeted therapies (ie, bevacizu­ mab) in early-phase trials. mTOR Inhibitors mTOR regulates protein translation, angiogenesis, and cell cycle progression in HCC. mTOR inhibitors

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have been shown to inhibit cell growth and tumor vascularity in HCC cell lines and HCC tumor models. The mTOR inhibitor everolimus failed to extend OS compared with best supportive care in the multicenter EVOLVE-1 trial of 546 patients with advanced HCC. Nevertheless, the preclinical promise of inhibiting the mTOR pathway has led to the development of other mTOR inhibitors, such as temsir­ olimus and sirolimus, and CC-223, which is a dual inhibitor of TORC1/TORC2.

“While we develop new therapies, a concerted and parallel effort must be made to identify and validate biomarkers of response, resistance, and toxicity to better match patients with safe, effective therapies.”

– Andrew X. Zhu, MD, PhD Immune-Based Therapy In the realm of immune-based therapy for HCC, “perhaps the most excitement comes from the inhibitors targeting the checkpoint pathway,” said Zhu. A phase 1 trial has been conducted with tremelimumab, a fully human IgG2 monoclonal antibody that blocks cytotoxic CTLA-4 in hepatitis C virus–related HCC. It generated a modest response rate of 17% and a progression-free survival of approximately 6 months in 17 evaluable patients. It also modulated hepatitis C viral load. The PD-1 inhibitor nivolumab is also entering clinical trials.

HGF/c-MET Inhibitors The HGF/c-MET pathway has a significant role in promoting angiogenesis, proliferation, and metastasis in HCC. c-MET inhibitors have shown early evidence of modest efficacy. Tivantinib, a selective, non-ATP– competitive inhibitor of c-MET, improved time to

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progression, particularly in patients with tumors with a high MET signature, compared with placebo in a phase 2 study. The median OS in patients with MET-high

Tivantinib improved time to progression, particularly in patients with tumors with a high MET signature, compared with placebo. tumors was 7.2 months with tivantitib versus 3.8 months with placebo. “If you enrich the right population, you may achieve the clinical benefit,” he said.

Cabozantinib, a receptor tyrosine kinase inhibitor

of c-MET/VEGFR2, is also in phase 3 evaluation in patients in whom sorafenib has failed or could not be tolerated. It demonstrated antitumor activity in a randomized discontinuation phase 2 study, with a median progression-free survival of 4.2 months.

Cancer Stem Cells Novel approaches to targeting cancer stem cells (CSCs) are being explored in multiple cancers, including advanced HCC. Hepatocarcinogenesis and the regulation of CSCs have both been shown to involve the Wnt pathways. OMP-54F28, a fusion protein, targets CSCs, bulk tumor cells, and tumor stromal cells. A phase 1/2 study combining OMP-54F28 and sorafenib for the first-line treatment of advanced HCC is under way. u

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THE LAST WORD

The Affordable Care Act and Cancer Patients – Winners and Losers in an Unsteady Paradigm Shift Kip Piper

Kip Piper

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he implementation of the Affordable Care Act (ACA) brings with it new rules of engagement for patients and their oncologists. Challenges posed to oncologists by the ACA will be addressed in next month’s The Last Word column. Herein, I will address the “good news” surrounding the ACA. To start, there are coverage expansions under the ACA, beginning with the positive effects for patients. Coverage expansion is taking 2 forms. The first is expanded Medicaid coverage in about half the states in the country for low-income adults who were previously ineligible for Medicaid. The second is the health insurance exchanges: the federal healthcare insurance exchanges at healthcare.gov and the state-run insurance exchanges. There, if their income was below 400% of the poverty level, they were able to apply for substantial federal subsidies in the form of subsidized premiums. On a sliding scale, patients between 100% and 200% of the poverty level are receiving the most federal subsidies. In addition, individuals and families with incomes between 100% and 250% would also receive subsidized cost sharing: ie, lower deductibles, copayments, and coinsurance as a result of additional federal subsidies. Medicaid for the most part has no premium, no deductible, no coinsurance, and only nominal copayments for prescription drugs.

Consequently, the goal here is that many individuals with a history of cancer who were uninsured or underinsured would be able to be insured and receive coverage. The big question is, how many people ultimately will enroll? And of those who do enroll in either the Medicaid or the federal exchange market, how many were actually formerly uninsured, versus those who were previously insured but were moving from various forms of private insurance: individual coverage or employer-sponsored coverage? At this point, there is no way of knowing how many of those signing up for the new insurance plans are making a lateral move and how many are newly insured as a result of the ACA. Put another, and important, way, how many people are moving from the private insurance market to the government-insured market? What is important to note is that even with the most optimistic projections about the ACA, at the end of this decade we will still have more than half the number of uninsured that we cur-

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rently have – leaving us with approximately 30 million uninsured people.

Another positive side of the ACA with respect to oncology is what is termed adjusted community rating. This is the idea that requires health insurers to price, to set their premiums, in a certain way and limits how a health insurer can calculate its premiums, starting in 2014 and beyond. Specifically, health insurers are no longer able to vary premiums based on the health status of the individual or group of individuals being insured. In the past, health insurers could charge individuals who were sick, or a group of sicker-than-average employees, higher premi-

Coverage expansion is taking 2 forms. The first is expanded Medicaid coverage in about half the states for low-income adults. The second is the health insurance exchanges. ums. Conversely, they would charge lower premiums for healthy people. In short, insurers could vary premiums based on the health status of the individuals being insured. Starting in 2014, they are no longer able to do that: insurance premiums are now an entirely egalitarian matter – a radical shift from the basic premise of insurance, which is to base a premium on risk.

Secondly, historically, in many states, insurers were able to charge women more than men and older adults more than younger adults. State regulations on insurance rates vary, but in most cases an insurer could charge an employer with a disproportionately female population more than a disproportionately male population. The reason is simple: during their working years, women tend to use more healthcare services than men, and insurers would charge women higher premiums to reflect that reality. Premiums also varied by the age of the individual or group of individuals being insured.

Kip Piper, MA, FACHE, is a health policy and business advisor and former federal and state health official. He is president of Health Results Group and CEO of Medonomics.

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THE LAST WORD

Consequently, someone in their early 60s, pre-Medicare, would see their premiums escalate to 5 or 6 times that of a 20-year-old. But the overriding factor determining one’s premium was health status.

Everything changes under the ACA, with the rare exceptions of some grandfathered plans. In most cases, insurers may no longer vary premiums based on health status, age, or sex. This has the effect of causing healthy young men to subsidize those who account for greater healthcare utilization than they do, ie, the older people, the infirm, and women. This is in addition to the subsidies built into the ACA, wherein the taxpayers and employers are subsidizing the uninsured. In addition to the effects of this adjusted community rating mecha-

The ACA has also prohibited any annual or lifetime caps on how much insurers will pay for a patient’s treatment... nism, childless adults will be cross-subsidizing healthcare for children, particularly their vision and dental services, while men will be cross-subsidizing the cost of maternity and prenatal care. This is part of a massive redistribution of hundreds of billions of dollars over the coming years from some groups of people to other groups of people.

What this means for people with or at risk for cancer is that they will not have to pay more. Prior to these provisions of the ACA going into effect starting in 2014, if a member of a group developed cancer, the premium for the group would increase. This can no longer happen, and in many cases those who had been paying very high premiums due to current or past illnesses could even see their premiums go down.

Preventive Services Another advantage of the ACA affecting access is the coverage of preventive services. Most health plans are now required to cover a range of federally endorsed preventive services – specifically, services that have been endorsed by the United States Preventive Services Task Force. Anything that the task force recommends, such as cancer screenings, health plans must cover automatically and do so without applying any deductible and without imposing any cost sharing – no copayment. So the hope is that this will improve access to critically important cancer screenings and catch cancer early on, when treatment can be optimized.

Another advantage of the ACA is guaranteed issue and the prohibition of excluding coverage on the basis of preexisting conditions. If the individual has the money to sign up, the health plan must cover them,

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and related to that, once someone is insured, the insurer cannot exclude any other preexisting conditions.

That again is a boon for access to cancer care. The ACA has also prohibited any annual or lifetime caps on how much insurers will pay for a patient’s treatment – historically a major fear of cancer patients receiving biologics that succeeded so well that once-terminal, acute conditions had been transformed into long-term conditions. Now patients will no longer have the fear of running out the clock with an end to coverage of life-preserving treatment.

But Will It Fly? The foregoing description of the ACA and its desired impact on cancer patients and the oncologists who treat them took considerable space even to summarize. But this is only the first half of the story. In the next issue, I will provide a feasibility analysis of the ACA, providing special focus on its feasibility in oncology. For while the ACA was written with the intent of reforming all fields of medicine, oncologists know the special nature of cancer care, and so an in-depth reality check is in order. Certainly the complex infrastructure of personalized medicine in the treatment of cancer, requiring a unique provider team and reimbursement process, is not handily dispensed with as if it were a matter of no depth. The concluding portion of this story will examine the factors involved in delivering on the promises made in the ACA. We will examine the basic problems to medicine posed by this insurance paradigm, and those especially challenging to cancer care and research supporting the massive, growing infrastructure required to “make it fly.” Can it? Is the ACA the visionary step forward it claims to be or just a politician’s dream with no medical or economic substance? Is the answer to this question “Yes,” “No,” or “Only if you fix this”? The needs of cancer patients are so extraordinarily profound, the research discoveries concerning personalized cancer care so complex, that it would do the question a disservice to attempt answering it in a few sentences here, where space does not permit even a brief feasibility assessment/gap analysis.

Consequently, I will attempt to provide useful perspective in part 2 of this article, laying out the specific challenges to carrying out the mission of the ACA as described above and seeking an answer to the question, “But will it fly?” This astonishing legislative foray into the demanding field of personalized medicine in oncology requires its own space, and it will receive it in the next issue. Until then, I hope that the foregoing description of the provisions of the ACA has provided clarity not only on the viability of the act in cancer care but simply on the intent of those who drafted it. u

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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

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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

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ONCOLYTIC IMMUNOTHERAPY is an innovative area of research that uses a modified virus designed to help T cells find and fight cancer cells as part of a hypothesized systemic, tumor-specific immune response.1

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Reference: 1. Melcher A, Parato K, Rooney CM, Bell JC. Thunder and lightning: immunotherapy and oncolytic viruses collide.

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Amgen. Leading the way in the study of Oncolytic Immunotherapy.