PMO December 2013 by The Oncology Nurse

A Peer-Reviewed Journal

December 2013 • Volume 2 • Number 8

BIOMARKERS • IMMUNOTHERAPY • TARGETED THERAPIES • DIAGNOSTICS

P M O

The official publication of

Global biomarkers Consortium Clinical Approaches

to Targeted Technologies

Personalized Medicine in Oncology TM

COLORECTAL CANCER Predicting Response to EGFR-Targeting mAbs in Colorectal Cancer – Is the KRAS Mutation Test Sufficient?…..................................................Page 430

WORLD CUTANEOUS MALIGNANCIES CONGRESS Personalized Strategies for the Management of Cutaneous Malignancies: Highlights From the 2013 World Cutaneous Malignancies Congress.......Page 438

INTERVIEW WITH THE INNOVATORS Personalized Medicine and the Biopharmaceutical Industry: The Marrying of Science, Research, and Policy. An Interview With Dr William Chin of the Pharmaceutical Research and Manufacturers of America.....................................................Page 448

BREAST CANCER TAILORx: A Trial Design Toward Our Goal of Personalized Medicine..................................Page 452

CASE STUDY Lower-Risk Myelodysplastic Syndromes…...Page 458

THE LAST WORD Preserving Personalized Medicine – Holding Fast to Healthcare’s Governing Dynamics...............Page 466

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%).

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.

DECEMBER 2013

VOLUME 2, NUMBER 8

TABLE OF CONTENTS COLORECTAL CANCER

430

Predicting Response to EGFR-Targeting mAbs in Colorectal Cancer – Is the KRAS Mutation Test Sufficient?

Niklas K. Finnberg, PhD; Bora Lim, MD The authors discuss the limitations associated with the use of KRAS as a single “negative” biomarker for response to EGFR-targeting mAbs.

WORLD CUTANEOUS MALIGNANCIES CONGRESS

438

Personalized Strategies for the Management of Cutaneous Malignancies: Highlights From the 2013 World Cutaneous Malignancies Congress An in-depth review of emerging treatment options for personalized therapy in cutaneous malignancies discussed at the recent WCMC annual conference.

INTERVIEW WITH THE INNOVATORS

448

Personalized Medicine and the Biopharmaceutical Industry: The Marrying of Science, Research, and Policy. An Interview With Dr William Chin of the Pharmaceutical and Research Manufacturers of America

BREAST CANCER

452

TAILORx: A Trial Design Toward Our Goal of Personalized Medicine M. Janakiram, MD; A. Assal, MD; J. Sparano, MDBU

The authors discuss the need to develop assays predictive of chemotherapy benefit and to evaluate and refine their clinical utility in prospective clinical trials.

CASE STUDY

458

Lower-Risk Myelodysplastic Syndromes A case presented by Rami Komrokji, MD, from the H. Lee Moffitt Cancer Center and Research Institute at the recent BGC annual conference.

EDITORIAL

459 You Also Can’t Keep Your Doctor Edie Littlefield Sundby

460

ObamaCare 2016: Happy Yet?

Bradley Allen OUR MISSION The mission of Personalized Medicine in Oncology is to deliver practice-changing information to clinicians about customizing healthcare based on molecular profiling technologies, each patient’s unique genetic blueprint, and their specific, individual psychosocial profile, preferences, and circumstances relevant to the process of care. 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.

422

Personalized Medicine in Oncology

www.PersonalizedMedOnc.com

PUBLISHING STAFF Senior Vice President/Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Group Director, Sales & Marketing John W. Hennessy jhennessy2@the-lynx-group.com Publisher Russell Hennessy rhennessy@the-lynx-group.com Editorial Director Kristin Siyahian ksiyahian@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 Director, Human Resources Blanche Marchitto 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

December 2013

Vol 2, No 8

Think outside the box to see inside the cell.

Are your breast cancer assays missing the real story? The conventional thinking in breast cancer diagnosis relies on the identification of ER, PR and HER2 receptors. To us, that misses the biggest part of the picture. That’s why our scientists created a new approach to let you see inside the cell and learn if the molecular pathway is functional or not. By understanding which compromised pathway is fueling the tumor growth, you can target therapies specifically to your patient’s molecular profile to improve outcomes. The SYMPHONY™ Personalized Breast Cancer Genomic Profile is the only test platform that can give you this comprehensive insight. Now you can safely eliminate indeterminate results and have confidence that your treatment decisions are targeting the correct molecular pathway. Breast Cancer Recurrence Signature Molecular Subtyping Signature

ER/PR/HER2 Expression Assay

Therapy Gene Assay

Call us at 888.321.2732 customercare@agendia.com | www.agendia.com ©Copyright 2013 Agendia. All rights reserved. Agendia, MammaPrint, BluePrint, TargetPrint and TheraPrint are registered trademarks of Agendia. SYMPHONY is a trademark of Agendia.

DECEMBER 2013

VOLUME 2, NUMBER 8

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

NEWS

462 MPDL3280A in Advanced NSCLC 462 Second-Generation ALK Inhibitor Regresses CNS Metastasis in NSCLC 463 T-DM1 Prolongs Survival in Advanced HER2-Positive Breast Cancer 464 Genomics of Acute Myeloid Leukemia Explored 465 Idelalisib and Ibrutinib Are Promising B-Cell Receptor Signaling Inhibitors in B-Cell Malignancies THE LAST WORD

466

Preserving Personalized Medicine – Holding Fast to Healthcare’s Governing Dynamics Robert E. Henry

ERRATUM

The September 2013 issue of Conquering the Cancer Care Continuum, funded by Teva Pharmaceuticals, contained errors. In the article by Beth Faiman, PhD(c), MSN, APRN-BC, AOCN, titled “The Role of Biosimilars in Oncology: A Nurse’s Perspective,” the FDA approval language and indication for GRANIX™ (tbo-filgrastim) was incorrect, as was the package insert information cited in reference 7. Also, in the article by Steve Stricker, PharmD, MS, BCOP, titled “The Role of Biosimilars in Oncology: A Pharmacist’s Perspective,” Dr Stricker mistakenly refers to tbo-filgrastim as a biosimilar. The correct approval language, indication, and reference are provided below. GRANIX (tbo-filgrastim) was approved by the FDA on August 29, 2012, through a Biologics License Application and is therefore not a biosimilar as stated in the article. GRANIX (tbo-filgrastim) is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Reference 7 should be listed as follows: Granix [package insert]. North Wales, PA: Teva Pharmaceuticals USA, Inc; 2013. Teva Pharmaceuticals did not have any control or involvement in the content development of this newsletter.

to Targeted Technologies

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

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 6 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 ©2013 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 December 2013

Vol 2, No 8

GE Healthcare Clarient Diagnostic Services

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JB15955US

EDITORIAL BOARD

EDITORS IN CHIEF Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania Al B. Benson III, MD Northwestern University Chicago, Illinois SECTION EDITORS 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

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

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

Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona

Steven O’Day, MD John Wayne Cancer Institute Santa Monica, California

Kenneth Bloom, MD Clarient Inc. Aliso Viejo, California

David A. Proia, PhD Synta Pharmaceuticals Lexington, Massachusetts

Mark S. Boguski, MD, PhD Harvard Medical School Boston, Massachusetts

Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain

Gilberto Castro, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil

Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois

Madeleine Duvic, MD The University of Texas MD Anderson Cancer Center Houston, Texas

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

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio Stephen Gately, MD TGen Drug Development (TD2) Scottsdale, Arizona Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland K. Peter Hirth, PhD Plexxikon, Inc. Berkeley, California 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

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

Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington

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

Gene Morse, PharmD University at Buffalo Buffalo, New York

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Afsaneh Motamed-Khorasani, PhD Radient Pharmaceuticals Tustin, California

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Danielle Scelfo, MHSA Genomic Health Redwood City, 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 Darren Sigal, MD Scripps Clinic Medical Group San Diego, California 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

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SCIENTIFIC CONFERENCES 2013-2014:

AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Co-Chairpersons: Jeffrey A. Engelman, Lee J. Helman, and Sabine Tejpar October 19-23, 2013 • Boston, MA Twelfth Annual International Conference on Frontiers in Cancer Prevention Research Chairperson: Paul J. Limburg October 27-30, 2013 • National Harbor, MD Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes Co-Chairpersons: John M. Maris, Stella M. Davies, James R. Downing, Lee J. Helman, and Michael B. Kastan November 3-6, 2013 • San Diego, CA The Translational Impact of Model Organisms in Cancer Co-Chairpersons: Cory Abate-Shen, A. Thomas Look, and Terry A. Van Dyke November 5-8, 2013 • San Diego, CA Ninth Annual Personalized Medicine Conference Chairperson: Raju Kucherlapati November 6-7, 2013 • Boston, MA Advance registration deadline: Friday, October 11 Sixth AACR Conference on The Science of Cancer Health Disparitites in Racial/Ethnic Minorities and the Medically Underserved Co-Chairpersons: John D. Carpten, Christopher I. Li, and Olufunmilayo I. Olopade December 6-9, 2013 • Atlanta, GA Advance registration deadline: Thursday, October 24 CTRC-AACR San Antonio Breast Cancer Symposium Co-Directors: Carlos L. Arteaga, C. Kent Osborne, and Peter M. Ravdin December 10-14, 2013 • San Antonio, TX Early registration deadline: Thursday, October 31

AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer Co-Chairpersons: Roy Herbst, Elisabeth Brambilla, Pasi Jänne, and William Pao January 6-9, 2014 • San Diego, CA Abstract submission and award application deadline: Monday, October 14 Advance registration deadline: Tuesday, November 26 AACR-Prostate Cancer Foundation Conference on Advances in Prostate Cancer Research Co-Chairpersons: Arul M. Chinnaiyan, William G. Nelson, June M. Chan, and Jonathan W. Simons January 18-21, 2014 • San Diego, CA Cancer Susceptibility and Cancer Susceptibility Syndromes Co-Chairpersons: Alan D. D’Andrea, Phillip A. Dennis, and Pier Paolo Pandolfi January 29-February 1, 2014 • San Diego, CA Abstract submission deadline: Wednesday, November 13 Advance registration deadline: Monday, December 9 RAS Oncogenes: From Biology to Therapy Co-Chairpersons: Frank McCormick, Dafna Bar-Sagi, and Channing J. Der February 24-27, 2014 • Lake Buena Vista, FL Abstract submission and award application deadline: Friday, December 6 Advance registration deadline: Monday, January 13 Cellular Heterogeneity in the Tumor Microenvironment Co-Chairpersons: Mary Helen Barcellos-Hoff, Michele De Palma, and M. Celeste Simon February 26-March 1, 2014 • San Diego, CA Abstract submission and award application deadline: Monday, December 16 Advance registration deadline: Monday, January 13 AACR Annual Meeting 2014 Chairperson: Scott W. Lowe April 5-9, 2014 • San Diego, CA

LETTER TO OUR READERS

Happy Holidays From the PMO Editorial Board Dear Colleague,

A Al B. Benson III, MD

Sanjiv S. Agarwala, MD

s we close out another year, we would like to thank you, our Personalized Medicine in Oncology reading community, for your support, encouragement, and loyal readership. We have relied on your guidance throughout our 2-year tenure to put forth the best possible journal addressing personalized medicine in all its forms. The successes that personalized medicine has effected are not just in changing prognoses but also in changing the culture of medicine regarding prevention, diagnosis, and treatment. The possibilities in personalizing treatment are immensely greater than anything we have seen in the past. To this end, we strive to bring you the ways in which personalizing treatments impact your practice. In our pages you will find topics related to the following: • Biomarkers and Diagnostics PMO provides in-depth articles on genetic mutations, protein expressions, and other indicators and their implications for treatment in different subsets of patients with cancer • Case Studies To enhance reader learning, PMO offers case studies from presentations by key opinion leaders at the Global Biomarkers Consortium conference and the World Cutaneous Malignancies Congress • Immunotherapy Harnessing the power of the immune system to combat cancer is not a new idea; however, the new generation of immunotherapeutic agents has captured the imagination of the oncology community and sparked a renewed interest in the potential capabilities of an empowered immune system. PMO explores the new generation of immunotherapies as monotherapy as well as in combination with molecularly targeted therapies • Interview With the Innovators In an effort to take readers behind the scenes, PMO conducts interviews with leaders in all sectors of the personalized medicine continuum and brings you their game-changing strategies, missions, and impact on personalizing oncology care • Policy An important variable in practicing personalized medicine is the vehicle by which it is covered. PMO covers the payers’ perspective on effectively implementing personalized care in the oncology community It is our pleasure to serve you as Editors in Chief of PMO. If ever you have a request for a topic, or feedback on our journal, please contact our Editorial Director, Kristin Siyahian, at ksiyahian@the-lynxgroup.com. Our very best to you this holiday season and in the New Year. Sincerely,

Al B. Benson III, MD

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SAVE THE DATE

WORLD CUTANEOUS MALIGNANCIES S CONGRESS

& ™

GLOBAL BIOMARKERS CONSORTIUM

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Clinical Approaches to Targeted Technologi Technologies

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CONFERENCE

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

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

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

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

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

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

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Predicting Response to EGFR-Targeting mAbs in Colorectal Cancer – Is the KRAS Mutation Test Sufficient? Niklas K. Finnberg, PhD; Bora Lim, MD Penn State Hershey Cancer Institute, Hershey, Pennsylvania

lthough metastatic colorectal cancer (mCRC) has a poor overall prognosis, the introduction of monoclonal antibodies (mAbs) that antagonize signaling from the epidermal growth factor receptor (EGFR) has led to improvements in response rate and survival.1,2 There are currently 2 FDA-approved antagonist mAbs (cetuximab [Erbitux] Niklas K. Finnberg, PhD and panitumumab [Vectibix]) targeting EGFR for the treatment of mCRC. EGFR is a protein tyrosine kinase aberrantly expressed in many cancers.3,4 The EGFR ligand EGF activates 2 well-characterized signal transduction pathways of RAS-RAF-MEK-ERK and PI3K-AKTmTOR signaling5 (Figure 1). KRAS functions as an essential molecular switch for both normal cell and tissue homeostasis. Once turned Bora Lim, MD on, KRAS promotes the propagation of signals from, for example, growth factors such as RAF and PI3K (Figure 1). KRAS activity is tightly regulated in a rheostat-like manner in normal cells. A single nucleotide substitution is responsible for oncogenic KRAS Dr Finnberg is an Assistant Professor at Penn State Hershey Cancer Institute. He received his PhD degree from Karolinska Institutet in Stockholm, Sweden, and has worked extensively to characterize the role of apoptosis in tissue toxicity to conventional and targeted cancer therapeutics. Dr Finnberg’s current research focuses on understanding tissue responses to DNA damage inflicted by cancer therapy, addressing molecular pathways activated following radio/chemotherapy to modulate toxicity of treatment, and developing biomarkers that can predict toxicity to therapy. Dr Lim is a clinical fellow in the Division of Hematology/Oncology, Penn State Hershey Cancer Institute. She received her MD from the Ewha Womans University, Seoul, South Korea, and later joined the laboratory of Dr Marcia S. Brose at the Hospital of the University of Pennsylvania where she studied Rap1 and Rap1GAP as clinical outcome markers in breast cancer. Dr Lim has a special interest in the molecular biology of triple-negative breast cancer (TNBC) and identifying new biomarkers and strategies employing targeted therapeutics to treat TNBC and other cancers. Dr Lim is an active preclinical scientist and a coinvestigator on clinical trials conducted at Penn State Hershey Cancer Institute.

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mutations that are frequent in cancers such as leukemia, colon cancer, pancreatic cancer, and lung cancer. Mutation of the KRAS gene results in a constitutively active GTP-bound form and produces a constitutive “switchon” state. This triggers aberrant activity of the downstream signaling cascade, thus allowing cell growth independent of extracellular stimuli.6 Aberrant constitutive activation of these pathways leads to cellular proliferation and invasive behavior of cancer cells. It is estimated that EGFR is overexpressed in 65% to 70% of CRCs, and EGFR overexpression tends to be associated with advanced disease stage.7 However, only subsets of patients show clinical benefit to treatment using cetuximab and panitumumab, and expression of EGFR alone is not predictive for response to EGFR-targeting mAbs. This is in part explained by the fact that 40% to 50% of mCRC patients have the gainof-function KRAS mutation in codons 12 or 13, a genetic lesion that bypasses the requirement of upstream EGFR stimuli8 (Figure 1). The American Society of Clinical Oncology provisional opinion and the National Comprehensive Cancer Network recommend testing patients with mCRC for KRAS mutations. The KRAS mutation in codons 12 and 13 exclude EGFR-targeting mAbs as a treatment option.9,10 Thus, patients with mCRC and these specific KRAS gene mutations are not treated with cetuximab or panitumumab. KRAS mutation analysis is carried out in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. DNA is isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue and sequenced to identify KRAS mutations in codons 12 and 13. The use of the KRAS mutation as a negatively predictive biomarker for response to EGFR-targeting mAbs is associated with several technical obstacles, as well as hurdles related to tumor biology and histology. A recent case report may have exemplarily illustrated the symptoms of said hurdles. Lamparella et al11 reported that KRAS mutation analysis by 2 independent CLIA-certified laboratories resulted in conflicting information regarding 1 patient’s CRC mutation status. The discordant reports complicated the decision with respect to the inclusion of EGFR-targeting mAbs as part of personalized therapy. The patient was

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subjected to FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan) and cetuximab as the second test indicated that the original tumor was KRAS wildtype. This treatment seemed to yield a short-lived response to the treatment (commonly seen in “responders” to EGFR targeting) as evidenced by a reduction of the serum tumor markers CA19-9 and CEA, suggesting that the tumor indeed might have been KRAS wild-type. Herein we discuss the limitations associated with the use of KRAS as a single “negative” biomarker for response to EGFR-targeting mAbs and emerging methodology that is likely to improve the prediction of response to EGFR targeting.

Simplified Illustration of the Epidermal Growth Factor Receptor (EGFR) Figure 1 Pathways With the RAS/MAPK and PIK3CA/PTEN Cascades That May Inhibit the Response to EGFR Targeting in Wild-Type KRAS CRC

Determinants of Response to EGFR Targeting Despite the value of the KRAS mutations as an exclusionary biomarker for response to EGFR targeting, the presence of wild-type KRAS does not guarantee a favorable response to EGFR-targeting mAbs. In fact, KRAS mutations may only account for 30% to 40% of patients who do not respond to cetuximab.12 Thus, it is clear that Specific components of the pathways are correlated with resistance to anti-EGFR monoclonal antibodies (mAbs). As shown, KRAS and RAF mutations (percentage) are correlated there are additional molecular mechawith resistance to anti-EGFR mAbs, while further evaluation is required for PI-3K and PTEN nisms that dictate the response to mutations. Proteins are subjected to oncogenic activating mutations (red rhombs) and inactiEGFR-targeting mAbs. Preclinical vating mutations (green rhomb). data have indicated that mutations of the RAF oncogene might confer resistance to EGFR targeting (Figure 1). It is estimated that 5% to 10% of CRCs carry a mutation have been proposed to predict for patients who are in the BRAF V600E allele. However, the CRYSTAL less likely to respond to the mAbs against EGFR.18 and OPUS trials suggest that BRAF mutations are poor PI3K signaling is inhibited by the phosphate and prognostic markers regardless of treatment types, and tensin homologue deleted on chromosome ten (PTEN) they lack the predictive value for cetuximab treatment.13 (Figure 1). Preclinical data indicate that cell lines lackPI3K belongs to a family of intracellular lipid kinases ing PTEN are more resistant to cetuximab.19 PTEN that phosphorylate the 3′-hydroxyl group of phosphatimutations occur in approximately 30% of sporadic dylinositol and phosphoinositides (Figure 1). PI3K is CRCs, and inactivating mutations of PTEN may be activated by EGFR and RAS signaling and is responsible associated with an impaired response to cetuximab.20-22 for the activation of AKT (protein kinase B) through an Taken together, additional mutations downstream of intermediate step. PI3K-AKT signaling regulates prolifEGFR could influence the response to mAbs targeting eration of intestinal epithelia, malignant transformation, the receptor, and subsequently such alterations might and propagation of CRC cells.14-17 The PI3K gene (PIKneed to be considered to better predict responses to 3CA) is mutated in approximately 15% of all CRCs.18 cetuximab and panitumumab. Patients who seem to PI3K mutations result in the upregulation of AKT in the benefit the most from EGFR targeting are those who absence of upstream signals via gain of enzymatic funchave the combination of wild-type BRAF, KRAS, tion in the p110α subunit of PI3K, and those mutations PI3K-intact PTEN expression (Figure 1). However, an

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KEY POINTS Efficient targeted therapy is contingent on successful determination of the “correct” tumor genotype/biomarker ➤ Determining KRAS mutation status based on single mutation testing may be challenging due to tumor heterogeneity, surrounding tissue contamination, and limited sensitivity of standardized sequence applications ➤ Next genome sequence (NGS) approaches may offer increased sensitivity and accuracy in determining tumor genotype since future therapy will likely have multiple molecular targets ➤ Novel use of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) may serve as more easily accessible predictive biomarkers for response that allow for better application of personalized medicine since an actionable genetic profile of the tumor cell population may be established ➤

assessment of all of these factors is not routinely included in predicting response to cetuximab or panitumu mab and may explain why some patients with wild-type KRAS do not respond to treatment with EGFR-targeting mAbs. Moreover, recent clinical data also indicate that mutations in the NRAS gene have to be considered in addition to mutations in the KRAS gene to predict response to panitumumab and FOLFOX4 (leucovorin, 5-fluorouracil, and oxaliplatin).23

ADCC results from the effector cells of the immune system targeting the cells that have antibodies bound to membrane surface antigens. Antibody-Dependent Cell-Mediated Cytotoxicity The value of mutated KRAS as a biomarker has come into question since occasionally patients with mutation of the KRAS gene respond to treatment that includes cetuximab. Cetuximab and panitumumab are considered antagonist mAbs that inhibit the interaction between EGFR and its ligand through targeting of the extracellular domain. Rare responses to cetuximab in KRAS-mutant CRC may be explained by antibody-dependent cell-mediated cytotoxicity (ADCC) (Figure 2). ADCC results from the effector cells of the immune system targeting the cells that have antibodies bound to membrane

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surface antigens.24 The primary purpose of ADCC in the human body is to limit the spread of infected cells. Typically this mechanism involves the activity of natural killer (NK) cells, macrophages, neutrophils, and eosinophils. ADCC can be modulated by specific sequences of the Fc domain of mAbs. NK cells express CD16/FcγRIII, which functions as a receptor for the Fc domain. Interaction between CD16 and the Fc domain triggers the release of cytokines such as interferon-gamma. ADCC is one of the important mechanisms of response to mAbs. Thus, ADCC could potentially enable patients with mutated KRAS to respond to EGFR-targeting mAbs. Polymorphisms in the FcγRIII gene can negatively impact ADCC following treatment with mAbs that target cell surface receptors. The high-affinity FcγRIIIa-158valine (V) polymorphism is associated with more potent ADCC response compared with the low-affinity FcγRIIIa-158-phenylalanine (F) polymorphism. Approximately 45% of all patients are homozygous for FcγRIIIa-158-phenylalanine (F/F) and subsequently impaired in their ability to generate an ADCC. In order to increase the likelihood of an ADCC response, novel EGFR-targeting mAbs have been developed that interacts with the FcγR with higher affinity.25 Preclinical data suggest that KRAS mutation status does not affect ADCC, but KRAS status and FcγRIII polymorphisms as covariants have not been studied. In conclusion, it is likely that ADCC will be an important cofactor of the EGFR-targeted therapy response (Figure 2).

New Diagnostic Methodology Will Pave the Way for Personalized Medicine in the Treatment of CRC Typically, analyses of KRAS mutations are based on polymerase chain reaction (PCR)-based genotyping in which DNA is isolated from FFPE tumor tissue. Blocks are identified by an expert pathologist for the content of tumor tissues. Unfortunately, despite appearing trivial, sequencing tumor tissue can present technical challenges, including the analysis of a heterogeneous tumor cell population and contamination by normal tissue. Also, part of the challenge consists of the isolation of macromolecules from FFPE material, a procedure that involves cutting sufficiently large tissue slides from the FFPE blocks followed by a dewaxing procedure. The captured tissues are then subjected to proteinase K digestion in order to extract a sufficient amount of DNA that can be used for PCR amplification of exon 1 and 2 of the KRAS gene and subsequent sequencing. Findings should be repeated in at least 2 experiments. DNA that is isolated by such procedures is often degraded, and the remnants from the fixation can interfere with the analysis. Successful analysis of DNA from an FFPE block ranges from 70% to 88% when dewaxing is used in combination with

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proteinase K digestion.26,27 More reAntibody-Dependent Cell-Mediated Cytotoxicity That Can Trigger an cently, novel methodologies that omit Figure 2 Antitumor Response in KRAS-Mutant CRCs the use of xylene for dewaxing and proteinase K for digestion of the tissues have been developed that are automated in function and remove some of the variables from the procedures. Nevertheless, despite being routinely used for diagnostic purposes, isolation of DNA from FFPE tissue remains suboptimal compared with the use of fresh tumor tissue. Routine Sanger sequencing currently used for diagnostic purposes is unlikely to detect mutations that are present in less than 10% of the CRC cell population. Therefore, rare tumor populations are unlikely to be detected by current diagnostic tools. Next genome sequencing (NGS) broadly describes those technologies that share the ability to massively parallel sequence millions of DNA templates.28 NGS may address some of the issues with Sanger sequencing since such approaches provide higher sensitivity and the ability to sample rare mutant alAntibodies bound to epidermal growth factor receptor (EGFR) are recognized by natural killer leles present in a background that are (NK) cells through their Fc domain and FcγRIII. This interaction causes the NK cells to enter an active state in which they release complements such as perforin and granzyme B. predominant wild-type ones.29 Furthermore, NGS may offer increased speed, enhanced sensitivity in mutation detection, and lower cost compared with Sanger sequencmay be the only method to improve the sensitivity of ing.30 Recent data suggest that NGS is equal or superior Sanger sequencing. Despite the development of different when sequencing DNA from FFPE CRC specimens with techniques to genotype CRCs, a thorough clinical valirespect to sensitivity and specificity.31,32 One additional dation of NGS methodologies has yet to be completed. advantage of massive parallel sequencing is the lack of The advent of NGS will result in an increased dedependency on an a priori selection of mutation “hot mand to assess tumor purity in the samples analyzed in spots” compared with Sanger sequencing. Enhanced anorder to accurately estimate the tumor heterogeneity. alytical sensitivity may be required to accurately identify Tumor purity has traditionally been assessed by a patholpatients who are most likely to benefit from the inclusion of targeted therapeutics. A comparison between Sanger Despite the development of different sequencing and massively parallel sequencing on EGFR-mutant non–small cell lung cancer (NSCLC) techniques to genotype CRCs, a thorough specimens revealed that only massively parallel sequencclinical validation of NGS methodologies ing was able to detect all the relevant EGFR mutations 33 present in responders to EGFR inhibition. In contrast, has yet to be completed. Sanger sequencing misdiagnosed 25% (6/24) of the tumor samples. Furthermore, the authors found a low correlation between tumor cell content and the frequenogist or by image analysis. However, tumor heterogeneity cy of mutant alleles, indicating that routine survey of is not being addressed by such methods. The clonal thehistopathological sections cannot be relied on to accuory of cancer progression states that cancerous cells in a rately estimate the degree of bystander cells that carry tumor are descendents of a single founder cell.34 Descenwild-type alleles in NSCLC. Therefore, microdissection dents have acquired mutations that promote tumorigen-

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eses that are distinct from each other. Thus subpopulations of tumor cells may harbor distinct somatic mutations. Tumor heterogeneity has a role in resistance to EGFR-targeting therapy. Patients with wild-type KRAS mCRC who are subjected to treatment with EGFR-targeting mAbs typically show short-lived responses. Recent data indicate that the mechanism of acquired resistance frequently involves the expansion of CRC clones with KRAS mutations that reside within the primary tumor (de novo).35,36 Subsequently, treatment

Efforts have been made to develop a highthroughput assay for detection of KRAS mutations in the blood for patients treated with FOLFOX and FOLFIRI. with EGFR-targeting mAbs may shift the population dynamics of wild-type KRAS and mutant KRAS CRC cell clones within the primary tumor by selective pressure. Recent data underline tumor heterogeneity as one of the important mechanisms to acquired resistance to EGFR targeting. Thus, it will be important to develop diagnostic techniques that are sufficiently sensitive to detect a rare population of “resistance DNA” in the analyzed tissue. NGS offers the opportunity to assess tumor heterogeneity through the analysis of copy number and mutational heterogeneity.37 Recent methodologies couple high-throughput DNA sequencing with computational methods to make an assessment of the presence of distinct tumor clones within a tumor. Such methods may help the oncologist design a proper therapeutic targeting strategy to avoid recurrence or secondary resistance development. Unfortunately, this knowledge comes at an increased cost due to the requirement of increased sequencing “depth.” Part of the challenge will be to make such methodology affordable.

Circulating Tumor DNA and Cells The development of novel diagnostic methods that are inexpensive, allowing for early detection and/or continuous assessment of the molecular profile of the (relapsed) tumor is highly desirable. Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are good examples of novel biomarkers that can be identified in the blood of CRC patients and allow for the assessment of tumor burden and molecular profiling. These biomarkers are present in the majority of patients with metastatic disease.38-41 CTCs have been validated as an independent prognostic factor in cancer patients and a predictive biomarker for treatment efficacy, whereas ctDNA is just

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beginning to be recognized as a putative biomarker.42 CTC and ctDNA analysis are considered as real-time “liquid biopsy” due to easy sampling by obtaining blood rather than invasive tissue biopsy in cancer patients.43 The presence of CTCs in the blood of patients with mCRC has been known for some time. An overall reduced survival was seen in patients with advanced CRC and high levels of CTCs who were treated with cetuximab.44 The concentration of ctDNA is high in cancer patients since apoptotic and necrotic cells of the primary tumor release DNA into the bloodstream, where it tends to exist in the form of nucleosomes. CTCs and ctDNA can be studied as a surrogate to primary tumor tissue that allow for an assessment of genetic/epigenetic alterations present in the primary tumor.45 CTCs and ctDNA may complement each other in that they tend to predict the presence of one another in the blood. In order to analyze CTCs they need to be enriched and detected through different strategies since they occur at a very low frequency of 1 CTC per million blood cells. A number of innovative technologies have been developed recently, including CRC microchips, filtration devices, quantitative reverse transcriptase-PCR assays, and automated microscopic systems that facilitate detection and analysis.43 Negative selection strategies based on the depletion of the leukocytes surrounding CTCs or high-speed scanning of all nucleated blood cells might be feasible approaches for an unbiased selection strategy of tumor cells, including those subsets of disseminating cells that may lack epithelial markers and cannot be selectively enriched for. However, the current gold standard for the detection of CTCs is the FDA-approved CellSearch system (Veridex), which provides prognostic value in metastatic breast cancer, prostate cancer, and CRC.41 Changes in the CTC count after therapy was correlated with response in CRC and in the neoadjuvant setting of breast cancer.44,46 Profiling of CTCs also provided a “drug resistance profile” of the primary tumor in a recent study.47 This suggests that responses of CTCs may provide additional prognostic/predictive information following cancer therapy. The analysis of ctDNA is one step closer as a tool with which to study the molecular profile of tumors. Efforts have been made to develop a high-throughput assay for detection of KRAS mutations in the blood for patients treated with FOLFOX and FOLFIRI.48,49 A strong correlation was observed between the lack of response to cetuximab and the detection of mutated KRAS DNA in the blood. Thus, the presence of disseminated tumor cells and DNA in the cancer patient’s blood may serve as an important predictive biomarker for targeted therapy. Another methodology to assess the presence of oncogene mutations in plasma involves

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the use of picodroplet multiplex digital PCR (dPCR) that can facilitate simultaneous detection of multiple mutations in circulating DNA obtained from blood.50 Of 19 patients with known KRAS mutations, 14 were detected to have KRAS mutations in blood plasma by screening for the 7 most common mutations of codons 12 and 13 of the KRAS gene, using the multiplex dPCR technique. KRAS mutations were also identified in blood plasma from patients with primary tumors that had been genotyped as wild-type KRAS. Furthermore, exciting new technology has been developed that allows for NGS to be performed on a single CTC.51

Summary The Future of EGFR Targeting in CRC It is likely that EGFR will continue to be an impor tant target for the treatment of CRC. Several novel EGFR-targeting mAbs are being evaluated for the treatment of CRC. Preclinical data suggest that targeting EGFR with a mixture of mAbs is superior at inhibiting the growth of cancer cells compared with cetuximab and panitumumab as single agents.52,53 One such mixture of 2 mAbs to EGFR, Sym004, is being subjected to a clinical trial in mCRC with wild-type KRAS. Improved methodology that allows for sensitive detection of KRAS-mutant CRC and the development of novel biomarkers that predict response to EGFR-targeting therapeutics are in great need. As such, NGS is a promising candidate methodology that can improve sensitivity with reduced cost compared with the currently used sequencing methodology. Furthermore, mutations of target genes outside of conventional “hot spots” may be detected with better sensitivity by NGS. The clinical relevance of such genetic aberrations has yet to be established, but such knowledge can help refine current inclusion criteria for EGFR targeting. It is clear that bioinformatics/computational software have to be codeveloped to help in identifying the presence of DNA in surrounding tissue and establish tumor heterogeneity. However, one potential problem is that the NGS concept encompasses numerous sequencing methodologies, while a single platform is preferable in clinical use. Thus, an appropriate methodology from the NGS cluster remains to be identified and thoroughly evaluated for clinical application. Targeted therapy of today tends to focus on a single molecule. It is likely that future targeted therapies will become increasingly complex to improve treatment efficacy. Primary tumor heterogeneity, clonal selection, and acquired mutations are likely the causes of tumor resistance to such therapeutics. Subsequently, it is likely that continuous monitoring of disease response to therapy on the molecular level will be required. Methodology that allows for the detection of de novo or secondary mutations

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will be a prerequisite for successful therapy. As such, ctDNA and CTCs may offer additional (noninvasive) means to assess CRC and help prognosticate the response to EGFR-targeting and future targeted therapeutics.

Targeted therapy of today tends to focus on a single molecule. It is likely that future targeted therapies will become increasingly complex to improve treatment efficacy. Conclusion The development of novel diagnostic tools that allow for the molecular profiling of CRC will help eliminate the chance of receiving contradictory diagnostic test results. Blood-based biomarkers can help in providing a direct real-time correlative between molecular events and response parameters. Further development of biomarkers that would predict a favorable response to EGFR targeting would benefit patients with CRC. u References

1. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040-2048. 2. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658-1664. 3. Mammano E, Belluco C, Sciro M. Epidermal growth factor receptor (EGFR): mutational and protein expression analysis in gastric cancer. Anticancer Res. 2006;26:3547-3550. 4. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer. 2001;37(suppl 4):9S-15S. 5. Merla A, Goel S. Novel drugs targeting the epidermal growth factor receptor and its downstream pathways in the treatment of colorectal cancer: a systematic review. Chemother Res Pract. 2012;2012:387172. 6. Velho S, Moutinho C, Cirnes L, et al. BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: primary or secondary genetic events in colorectal carcinogenesis? BMC Cancer. 2008;8:255. 7. Beaven AW, Goldberg RM. Adjuvant therapy for colorectal cancer: yesterday, today, and tomorrow. Oncology (Williston Park). 2006;20:461-469. 8. Lievre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374-379. 9. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009;27:2091-2096. 10. Engstrom PF, Arnoletti JP, Benson AB III, et al. NCCN Clinical Practice Guidelines in Oncology: colon cancer. J Natl Compr Canc Netw. 2009;7:778-831. 11. Lamparella NE, Saroya BS, Yang Z, et al. Contradictory KRAS mutation test results in a patient with metastatic colon cancer: a clinical dilemma in the era of personalized medicine. Cancer Biol Ther. 2013;14:699-702. 12. Qiu LX, Mao C, Zhang J, et al. Predictive and prognostic value of KRAS mutations in metastatic colorectal cancer patients treated with cetuximab: a meta-analysis of 22 studies. Eur J Cancer. 2010;46:2781-2787. 13. Bokemeyer C, Van Cutsem E, Rougier P, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012;48:1466-1475. 14. Sheng H, Shao J, Townsend CM Jr, et al. Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut. 2003;52:1472-1478. 15. Philp AJ, Campbell IG, Leet C, et al. The phosphatidylinositol 3’-kinase p85 alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res. 2001;61:7426-7429. 16. Khaleghpour K, Li Y, Banville D, et al. Involvement of the PI 3-kinase signaling pathway in progression of colon adenocarcinoma. Carcinogenesis. 2004;25:241-248. 17. Leystra AA, Deming DA, Zahm CD, et al. Mice expressing activated PI3K

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rapidly develop advanced colon cancer. Cancer Res. 2012;72:2931-2936. 18. Zhang J, Roberts TM, Shivdasani RA. Targeting PI3K signaling as a therapeutic approach for colorectal cancer. Gastroenterology. 2011;141:50-61. 19. Jhawer M, Goel S, Wilson AJ, et al. PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 2008;68:1953-1961. 20. Frattini M, Saletti P, Romagnani E, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007;97:11391145. 21. Shen Y, Yang J, Xu Z, et al. Phosphatase and tensin homolog expression related to cetuximab effects in colorectal cancer patients: a meta-analysis. World J Gastroenterol. 2012;18:2712-2718. 22. Tural D, Batur S, Erdamar S, et al. Analysis of PTEN, BRAF and PI3K status for determination of benefit from cetuximab therapy in metastatic colorectal cancer patients refractory to chemotherapy with wild-type KRAS [published online September 1, 2013]. Tumour Biol. 23. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023-1034. 24. Adams GP, Weiner LM. Monoclonal antibody therapy of cancer. Nat Biotechnol. 2005;23:1147-1157. 25. Jain A, Poonia B, So EC, et al. Tumour antigen targeted monoclonal antibodies incorporating a novel multimerisation domain significantly enhance antibody dependent cellular cytotoxicity against colon cancer. Eur J Cancer. 2013;49:3344-3352. 26. Ritter JH, Wick MR, Adesokan PN, et al. Assessment of clonality in cutaneous lymphoid infiltrates by polymerase chain reaction analysis of immunoglobulin heavy chain gene rearrangement. Am J Clin Pathol. 1997;108:60-68. 27. Inghirami G, Szabolcs MJ, Yee HT, et al. Detection of immunoglobulin gene rearrangement of B cell non-Hodgkin’s lymphomas and leukemias in fresh, unfixed and formalin-fixed, paraffin-embedded tissue by polymerase chain reaction. Lab Invest. 1993;68:746-757. 28. Meldrum C, Doyle MA, Tothill RW. Next-generation sequencing for cancer diagnostics: a practical perspective. Clin Biochem Rev. 2011;32:177-195. 29. Do H, Krypuy M, Mitchell PL, et al. High resolution melting analysis for rapid and sensitive EGFR and KRAS mutation detection in formalin fixed paraffin embedded biopsies. BMC Cancer. 2008;8:142. 30. Martinez DA, Nelson MA. The next generation becomes the now generation. PLoS Genet. 2010;6:e1000906. 31. Altimari A, de Biase D, De Maglio G, et al. 454 next generation-sequencing outperforms allele-specific PCR, Sanger sequencing, and pyrosequencing for routine KRAS mutation analysis of formalin-fixed, paraffin-embedded samples. Onco Targets Ther. 2013;6:1057-1064. 32. McCourt CM, McArt DG, Mills K, et al. Validation of next generation sequencing technologies in comparison to current diagnostic gold standards for BRAF, EGFR and KRAS mutational analysis. PloS One. 2013;8:e69604. 33. Querings S, Altmüller J, Ansén S, et al. Benchmarking of mutation diagnostics in clinical lung cancer specimens. PloS One. 2011;6:e19601. 34. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194:23-28.

35. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486:532-536. 36. Diaz LA Jr, Williams RT, Wu J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486:537-540. 37. Ding L, Raphael BJ, Chen F, et al. Advances for studying clonal evolution in cancer. Cancer Lett. 2013;340:212-219. 38. Diehl F, Schmidt K, Durkee KH, et al. Analysis of mutations in DNA isolated from plasma and stool of colorectal cancer patients. Gastroenterology. 2008;135:489498. 39. Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14:985-990. 40. Holdhoff M, Schmidt K, Donehower R, et al. Analysis of circulating tumor DNA to confirm somatic KRAS mutations. J Natl Cancer Inst. 2009;101:1284-1285. 41. Allen JE, El-Deiry WS. Circulating tumor cells and colorectal cancer. Curr Colorectal Cancer Rep. 2010;6:212-220. 42. Dawson SJ, Tsui DW, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:1199-1209. 43. Alix-Panabieres C, Schwarzenbach H, Pantel K. Circulating tumor cells and circulating tumor DNA. Annu Rev Med. 2012;63:199-215. 44. Kuboki Y, Matsusaka S, Minowa S, et al. Circulating tumor cell (CTC) count and epithelial growth factor receptor expression on CTCs as biomarkers for cetuximab efficacy in advanced colorectal cancer. Anticancer Res. 2013;33:3905-3910. 45. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11:426-437. 46. Hou JM, Krebs MG, Lancashire L, et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol. 2012;30:525-532. 47. Gazzaniga P, Naso G, Gradilone A, et al. Chemosensitivity profile assay of circulating cancer cells: prognostic and predictive value in epithelial tumors. Int J Cancer. 2010;126:2437-2447. 48. Chen YF, Wang JY, Wu CH, et al. Detection of circulating cancer cells with K-ras oncogene using membrane array. Cancer Lett. 2005;229:115-122. 49. Yen LC, Yeh YS, Chen CW, et al. Detection of KRAS oncogene in peripheral blood as a predictor of the response to cetuximab plus chemotherapy in patients with metastatic colorectal cancer. Clin Cancer Res. 2009;15:4508-4513. 50. Taly V, Pekin D, Benhaim L, et al. Multiplex picodroplet digital PCR to detect KRAS mutations in circulating DNA from the plasma of colorectal cancer patients. Clin Chem. 2013;59:1722-1731. 51. Zhao L, Lu YT, Li F, et al. High-purity prostate circulating tumor cell isolation by a polymer nanofiber-embedded microchip for whole exome sequencing [published online March 26, 2013]. Adv Mater. 52. Pedersen MW, Jacobsen HJ, Koefoed K, et al. Sym004: a novel synergistic anti-epidermal growth factor receptor antibody mixture with superior anticancer efficacy. Cancer Res. 2010;70:588-597. 53. Koefoed K, Steinaa L, Søderberg JN, et al. Rational identification of an optimal antibody mixture for targeting the epidermal growth factor receptor. mAbs. 2011;3:584-595.

SAVE THE DATE FIFTH ANNUAL

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

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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

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PMO Interviewees include:

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

Edith Perez, MD Mayo Clinic

Kimberly Popovits Genomic Health

Edward Abrahams, PhD Personalized Medicine Coalition

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To receive credit, complete the posttest at www.mlicme.org/P13003E.html.

Personalized Strategies for the Management of Cutaneous Malignancies: Highlights from the 2013 World Cutaneous Malignancies Congress

Sanjiv S. Agarwala, MD

Steven J. O’Day, MD

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

Beverly Hills Cancer Center Department of Medical Oncology Director, Clinical Research Director, Los Angeles Skin Cancer Institute Adjunct Member, John Wayne Cancer Institute Santa Monica, California

Axel Hauschild, MD

Professor of Dermatology Department of Dermatology Skin Cancer Center University Hospital Schleswig-Holstein Campus Kiel Kiel, Germany

CME Information Sponsors This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Genentech, Inc. and Prometheus Laboratories Inc. Target Audience This activity was developed for medical and surgical oncologists, dermatologists, radiation oncologists, and pathologists actively involved in the treatment of cutaneous malignancies. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

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Learning Objectives Upon completion of this activity, the participant will be able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as they relate to the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, Merkel cell tumors, and malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

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t the Second Annual World Cutaneous Malignancies Congress, which took place in July 2013 in San Diego, California, experts from around the world came together to discuss personalized strategies for the management of cutaneous malignancies. Presentations included updates on epidemiology, molecular biology, pathogenesis, novel agents, and ongoing clinical trials. This monograph summarizes some key highlights of the meeting.

Melanoma Melanoma, the leading cause of death from skin disease, will be diagnosed in an estimated 76,690 individuals in 2013, and 9480 deaths attributable to melanoma will occur this year.1 Melanoma is highly curable if detected in its earliest stages and treated properly; however, it is more likely than other skin tumors to metastasize. The 5- and 10-year relative survival rates for patients with melanoma are 91% and 89%, respectively. For localized melanoma (84% of cases), the 5-year survival rate is 98%; however, survival declines to 62% and 15% for regional and distant stage disease, respectively.1

The major risk factors for melanoma include a personal or family history of the disease and the presence of atypical or numerous (>50) moles. Other risk factors include sun sensitivity (ie, sun burning easily, difficulty tanning, and/or natural blond or red hair color), a history of excessive sun exposure (ie, sunburns and/or use of tanning booths), diseases that suppress the immune system, and a history of skin cancer.1 While exposure to ultraviolet light is a major causative factor in melanoma, the relationship between risk and exposure is complex.2 Melanoma arises due to the accumulation of mutations in critical genes, including BRAF, NRAS, and KIT.2,3 In 2002, Davies and colleagues reported that BRAF somatic missense mutations occur in 66% of metastatic melanomas.4,5 In melanomas with a BRAF mutation, ≥95% of the reported point mutations are substitutions at the valine at position 600 (V600, most commonly V600E).6 In 2005, Curtin and colleagues hypothesized that genetically distinct types of melanoma have different susceptibilities to ultraviolet light.2 They divided 126 melanoma samples into 4 groups: (1) melanomas on skin with chronic sun-induced

CME Information (continued) The associates of Medical Learning Institute Inc, the accredited provider for this activity, Center of Excellence Media, LLC, and Core Principle Solutions, LLC do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME activity for any amount during the past 12 months. Planners’ and Managers’ Disclosures William J. Wong, MD, MLI Reviewer, has nothing to disclose. Karen Cooksey, Medical Writer, has nothing to disclose. She does intend to discuss non–FDA-approved or investigational use for the following products/devices: arsenic trioxide, brentuximab, carfilzomib, erismodegib, everolimus, IL-12, improved purity denileukin diftitox, ipilimumab, itraconazole, lambrolizumab, lenalidomide, LEQ506, lorvotuzumab, LY2835219, MCPyV-specific T-cells + IL-2, MEK162, mogamulizumab, nivolumab, nonmyeloablative allo-SCT using total lymphoid irradiation and antithymocyte globulin, octreotide, pasireotide, pazopanib, pralatrexate, romidepsin, TAK-441, and vorinostat (with and without TSEBT). Faculty Disclosures Sanjiv S. Agarwala, MD, is a consultant for and receives honoraria from Bristol-Myers Squibb, Genentech, and Prometheus. He does not intend to discuss any non−FDA-approved or investigational use of any product/device. Steven J. O’Day, MD, has conducted research and is a consultant for Bristol-Myers Squibb, Genentech, and Roche. He does intend to discuss either non−FDA-approved or investigational use for the following products/ devices: PD-1 and PDL-1. Axel Hauschild, MD, is a consultant, on the speaker’s bureau, has been an advisory board member for, and has received honorarium from Amgen, Bristol-Myers Squibb, Celgene, Eisai, GlaxoSmithKline, MedImmune, ME-

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LA-Sciences, Merck Serono, MSD/Merck, Novartis, Oncosec, and Roche Pharma. He does intend to discuss either non-FDA-approved or investigational use for the following products/devices: all new agents currently on clinical trial in CTCL, BCC, Merkel cell tumors, and malignant melanoma. Disclaimer The information provided in this CME activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for any agent discussed in this program should be inferred. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www. mlicme.org/P13003E.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org. Estimated time to complete activity: 1 hour Date of initial release: December 18, 2013 Valid for CME credit through: December 18, 2014

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Table 1 Melanoma: Multiple Molecular Subsets Defined by “Driver” Mutations2,3,7,8 Melanoma Subtype

“Driver” Mutations

Arising from skin without chronic sun damage

• 50% BRAF • 20% NRAS • 0% KIT

Arising from skin with chronic sun damage

• 10% BRAF • 10% NRAS • 5%-10% KIT

Arising from mucosal surfaces

• 5% BRAF • 15% NRAS • 20% KIT

Arising from acral surfaces

• 15% BRAF • 15% NRAS • 15% KIT

Uveal

• 50% GNAQ • 35% GNA11

damage; (2) melanomas on skin without chronic sun-induced damage; (3) acral melanomas (eg, from palms, soles, and subungual sites); and (4) mucosal melanomas. They found that melanomas at different sites and with different levels of sun exposure had different genetic alterations, indicating that there are distinct genetic pathways in the development of the disease.2 For example, 81% of melanomas on skin without chronic sun-induced damage had mutations in BRAF or NRAS; the majority of melanomas in the other groups had mutations in neither gene. Melanomas with wild-type BRAF or NRAS frequently had increases in the number of copies of the genes for cyclin-dependent kinase 4 and cyclin D1, downstream components of the RAS-BRAF pathway.2 In another report, Curtin and colleagues analyzed 102 melanoma samples for DNA copy number aberrations specific to melanoma subtypes in which mutations in BRAF and NRAS are infrequent. Mutations and/or copy number increases of KIT were found in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any melanomas on skin without chronic sun damage.3 Van Raamsdonk and colleagues found that uveal melanomas have frequent mutations in GNAQ and GNA11, whereas these same mutations are essentially absent in cutaneous and mucosal melanomas.7,8 Thus, different types of melanomas were found to be driven by different types of mutations (Table 1).2,3,7,8 FDA-Approved Systemic Therapies for Advanced Melanoma Recombinant interferon alfa-2b (IFN α-2b) is approved by the US Food and Drug Administration (FDA) as adjuvant therapy to surgical treatment within 56 days of surgery in patients 18 years of age or older with malignant melano-

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ma who are free of disease but at high risk for systemic recurrence.9 High-dose IFN α-2b has been the only adjuvant agent to show relapse-free survival (RFS) consistently in randomized trials.10 Pegylated IFN α-2b is also approved as adjuvant therapy for stage III melanoma, based on improved RFS in the EORTC 18991 trial.11 Until recently, the only approved systemic treatments for metastatic melanoma were dacarbazine or aldesleukin (interleukin-2 [IL-2]). Dacarbazine has been shown to produce an objective response rate (ORR) of approximately 10% (all partial responses [PRs]) with a median response duration of 4 to 8 months.12 IL-2 has produced a similar ORR, at 16%, but 6% of patients receiving this agent were able to achieve durable complete responses (CRs).13 In addition to IL-2, 4 agents have recently been approved by the FDA for the treatment of unresectable or metastatic melanoma.14-17 Ipilimumab, approved in 2011, works by blocking the activity of cytotoxic T-lymphocyte antigen 4.14 Vemurafenib and dabrafenib, approved in 2011 and 2013, respectively, are BRAF inhibitors indicated for the treatment of patients with melanoma whose tumors express the BRAF V600E gene mutation. Trametinib, approved in 2013, has a related but slightly different mechanism of action; it is a MEK inhibitor and is the first drug in its class to be approved for use in patients whose tumors express BRAF V600E or V600K gene mutations (Table 2).14-17 Unfortunately, a large percentage of patients, including those who experience initial, profound tumor regression have evidence of disease progression within 6 to 8 months after commencing therapy with one of these agents, since melanomas with the BRAF V600E mutation may undergo further mutation, leading to secondary resistance.18,19 Future research will focus on identifying the mechanisms of resistance to such treatments and how these may best be overcome, including the rational use of combinations of targeted inhibitors for the initial treatment of patients with BRAF-mutant cancers.11,19 Investigational Therapies for Melanoma Currently, no targeted treatments are available for patients with wild-type BRAF tumors, including those with NRAS mutations. Ascierto and colleagues conducted an open-label, nonrandomized phase 2 study of MEK162, a small-molecule MEK 1/2 inhibitor, in patients with NRAS-mutated (n=30) or BRAF V600–mutated (n=41) advanced melanoma.20 In this study, previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor therapy was not allowed. Preliminary results after a median follow-up of 3.3 months showed 20% of patients with NRAS-mutated melanoma and 20% of patients with BRAF-mutated melanoma had achieved PR. The most frequent adverse events (AEs) in patients with NRAS-mutated and BRAF-mutated melanoma, respectively, were

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Table 2 Recently Approved Agents for Unresectable or Metastatic Melanoma14-17 Year of Approval

Agent

2011

Ipilimumab

Indication

Clinical Trial Results

Pts with unresectable or metastatic melanoma

Pts who had received â&#x2030;Ľ1 prior systemic treatment (N=676) were randomized to ipilimumab alone, ipilimumab plus gp100, or gp100 alone 34% reduced risk of death with ipilimumab alone vs gp100 alone 32% reduced risk of death with ipilimumab plus gp100 vs gp100 alone Median OS: 10 months for both ipilimumab groups vs 6 months for gp100 alone

Vemurafenib15 2011

Pts with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test (Not indicated for wildtype BRAF melanoma)

2013

Dabrafenib16

Pts with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test

Phase 3 study (N=675) of vemurafenib vs dacarbazine in previously untreated pts 56% reduced risk of death and 74% reduced risk of progression with vemurafenib vs dacarbazine Median PFS: 5.3 months with vemurafenib vs 1.6 months with dacarbazine ORR: 48.4% with vemurafenib (1% CR, 47.4% PR) vs 5.5% (all PRs) with dacarbazine Previously untreated pts with BRAF V600E mutationpositive, unresectable, or metastatic melanoma (N=250) were randomized to receive either dabrafenib or dacarbazine 2.4-month delay in tumor growth with dabrafenib vs dacarbazine

(Not indicated for wildtype BRAF melanoma) 2013

Trametinib17

Pts with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDAapproved test (Not indicated for pts who have received prior BRAF inhibitor therapy)

Pts with BRAF V600E or V600K mutation-positive metastatic melanoma (N=322) were randomized to receive either trametinib or dacarbazine 3.3-month delay in tumor growth with trametinib vs dacarbazine Patients who previously used dabrafenib or other BRAF inhibitors did not appear to benefit from trametinib

CR indicates complete response; FDA, US Food and Drug Administration; gp100, glycoprotein 100; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response, pts; patients.

acneiform dermatitis (60% vs 37%), rash (20% vs 39%), peripheral edema (33% vs 34%), facial edema (30% vs 17%), diarrhea (27% vs 37%), and creatine phosphokinase increases (37% vs 22%), the last of which was also the most common grade 3/4 AE (23% vs 17%). Four patients experienced serious AEs, which included diarrhea, dehydration, acneiform dermatitis, general physical deterioration, irregular heart rate, malaise, and small intestinal perforation. No deaths occurred from treatment-related causes. Combining BRAF and MEK inhibitors is also being inVol 2, No 8

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vestigated. In a phase 1/2 open label study of patients with metastatic melanoma and BRAF V600 mutations, a regimen of dabrafenib and trametinib was shown to prolong progression-free survival (PFS), compared with dabrafenib monotherapy (9.4 months vs 5.8 months).21 The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer.11 Two antibodies against the PD-1 receptor, MK-3475 (formerly known as lambrolizumab) and nivolumab, continue to be evaluated in patients

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Table 3 AEIOU: A Mnemonic Summarizing Typical Clinical Characteristics of Merkel Cell Carcinoma34 A = Asymptomatic or not tender E = Expanding rapidly I = Immune suppressed O = Older than 50 years of age U = Ultraviolet-exposed fair skin

with advanced melanoma. In a trial by Hamid and colleagues, MK-3475 was given to patients with advanced melanoma (some patients had received prior treatment with ipilimumab while others had not). Response rates did not differ significantly between the 2 cohorts of patients (38% vs 37%, respectively). Common toxicities included fatigue, rash, pruritus, and diarrhea; most of these were grade 1/2 in severity.22 Wolchok and colleagues investigated the feasibility of combining ipilimumab and nivolumab in patients with advanced melanoma who had received up to 3 prior therapies. They reported a 53% ORR, with tumor regression of at least 80% in every patient who had a response.23 The only grade 3/4 AEs occurring in more than 10% of patients receiving concurrent therapy were asymptomatic laboratory abnormalities, including elevations of aspartate transaminase (13%), alanine transaminase (11%), and lipase (13%), which usually resolved spontaneously. Based on these results, a phase 3 trial is now open to accrual, investigating the efficacy of concurrent nivolumab and ipilimumab versus nivolumab or ipilimumab alone in patients with advanced melanoma.24

Merkel Cell Carcinoma Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin associated with ultraviolet light exposure.25 MCC is one of the most lethal skin cancers, with a 46% disease-associated mortality rate (higher than that of melanoma).26 Although uncommon, its incidence in the United States is increasing and has quadrupled in the past 2 decades to approximately 1600 cases per year.27-32 Reasons for this increased incidence include new pathologic techniques that diminish missed diagnoses and an increased population at risk due to ultraviolet exposure, advanced age, and immune suppression.26 Although the skin lesion is most commonly found on sun-exposed areas of the head and neck or extremities, it also can occur on the trunk, genitalia, and perianal region.33 A mnemonic summarizing typical clinical characteristics of MCC has been proposed (Table 3), since 89% of patients presenting with a primary cutaneous MCC had 3 or more of these 5

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characteristics.34 Currently, standard of care includes surgical intervention (wide surgical excision or Mohs surgery) to the primary and locoregional site with adjuvant radiotherapy for high-risk disease. Merkel cell polyomavirus, a DNA virus that expresses T-antigen oncoproteins, has been detected in 8 of 10 MCC tumors (80%) and has been found to be clonally integrated into the genome of the majority of MCC tumors.35,36 Tumor progression is believed to be associated with the development of immune evasion mechanisms, and multiple lines of evidence (eg, higher incidence in immunocompromised populations, reports of spontaneous regression, responses to immune modulators, and improved prognosis associated with CD8+ intratumoral lymphocytes) suggest that immunotherapy may improve outcomes in patients with advanced MCC.30,33,34,37-40 A number of ongoing clinical studies are investigating various immunotherapeutic strategies in the treatment of MCC. Experimental Therapies for Merkel Cell Carcinoma Systemic administration of recombinant IL-12 has been limited by toxicity and temporary immune suppression, promoting investigation into local administration routes. In a mouse melanoma model, intratumoral injection of a plasmid encoding IL-12 followed by electroporation resulted in IL-12 and IFN-Îł induction, enhanced lymphocyte migration, reduced tumor vascularity, and tumor elimination in 47% of treated mice. Intratumoral IL-12 is currently being investigated for use in MCC in a phase 2 study.41 Adoptive T-cell therapy using MCPyV-specific T-cells plus IL-2 is a process that involves the enrichment and reinfusion of autologous antitumor T-cells into patients with cancer. The persistent expression of non-self (Merkel polyomavirus) antigens in most MCC tumors makes adoptive T-cell therapy for this cancer particularly attractive. Adoptive T-cell therapy for MCC is currently under investigation in a phase 1/2 study.42 Lorvotuzumab mertansine (IMGN901; BB-10901) is an antibody-drug conjugate consisting of a maytansinoid microtubule assembly inhibitor coupled with a humanized monoclonal antibody to CD56, which is expressed on nearly all MCCs. This therapy is being investigated in a phase 1 study.43 Octreotide is a potent, biologically stable octapeptide analog of the naturally occurring hormone somatostatin. Somatostatin has an antiproliferative effect on neuroendocrine tumor cells and may inhibit tumor angiogenesis. The somatostatin receptor 2 is expressed on 90% of MCCs, providing the rationale for treatment of the disease with this class of drugs. Octreotide is being investigated in a phase 2 study.44 Pasireotide is a novel multireceptor-targeted somatostatin analog being investigated in a phase 2 study in patients

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with advanced neuroendocrine tumors whose symptoms were no longer responsive to octreotide therapy.45 Pazopanib, a receptor tyrosine kinase inhibitor that targets VEGFR-1, -2, -3, PDGFR-α, -β, and c-kit is hypothesized to inhibit both tumor growth and angiogenesis and is currently FDA approved for the treatment of patients with renal cell carcinoma and soft tissue sarcoma. Immunohistochemistry has detected VEGF-A, VEGF-C, VEGF-R2, and PDGF-α expression in 72% to 91% of MCCs. Pazopanib is therefore being investigated for use in this disease in a phase 2 study.46 Ipilimumab, which has been shown to improve survival of metastatic melanoma patients, is also being investigated for use in MCC in a phase 2 study.47

Basal Cell Carcinoma Basal cell carcinoma (BCC) is the most frequently occurring type of cancer; however, data on the epidemiology of BCC are limited in the United States, since most national registries do not collect information on this type of cancer.48 Conservative estimates suggest that approximately 1 million BCC cases occur each year in the United States, although the actual incidence may be much higher.49 BCC occurs more often in men than in women, and risk is strongly associated with several phenotypic and exposure factors, as well as with certain hereditary skin disorders such as Gorlin syndrome or xeroderma pigmentosum (Table 4).48,50-55 BCC can be highly disfiguring if allowed to grow, but only in exceedingly rare cases (.003%-.5%) does it metastasize and become life-threatening.51 BCC is usually cured by surgery or radiation; however, in some cases the patient is not amenable to local therapy, the tumor occurs in a location where treatment may cause a severe change in appearance or loss of function, or the disease progresses to advanced or metastatic BCC.52 FDA-Approved Therapy for Advanced or Metastatic Basal Cell Carcinoma The discovery that mutations in hedgehog pathway genes, primarily genes encoding patched homologue 1 and smoothened homologue (SMO), occur in BCC led to the development of a systemic therapy for advanced or metastatic BCC.56 In January 2012, the FDA approved vismodegib, a first-in-class oral hedgehog pathway inhibitor (ie, an inhibitor of SMO), for the treatment of adults with metastatic BCC, or for those with locally advanced disease that has recurred following surgery or who are not candidates for surgery or radiation.57 The FDA approval of vismodegib was based on results of a multicenter phase 2 study of patients with either metastatic (n=33) or locally advanced (n=71) BCC.57,58 Of the 104 patients enrolled, 96 were evaluable for ORR. Twenty-one percent of patients were diagnosed with Gorlin syndrome. In the 33 patients with metastatic Vol 2, No 8

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Table 4 Risk Factors for the Development of Basal Cell Carcinoma48,50-55 Type of Risk Factor

Risk Factor

Phenotypic factors

• • • •

Blond or red hair color Blue or green eye color Light skin color Higher number of extremity moles

History

• Family history of melanoma • History of sunburn as a child/ adolescent • History of high number of severe/blistering sunburns • Organ transplant recipient • Other settings of immunosuppression (lymphoma, drug-induced, HIV, etc)

Genodermatoses (hereditary skin disorders)

• • • • •

Gorlin syndrome Albinism Xeroderma pigmentosum Rombo syndrome Bazex syndrome

BCC, the independently assessed ORR was 30% (Figure).57,58 In the 63 evaluable patients with locally advanced BCC, the independently assessed ORR was 43%, with CR in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Toxicities occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue; 25% of patients experienced serious AEs; and 7 patients died due to toxicities.58 Patients treated with vismodegib should be warned that the drug can cause embryo-fetal death or severe birth defects, necessitating effective contraceptive methods. In addition, patients should be advised not to donate blood or blood products while receiving vismodegib and for at least 7 months after taking the last dose of the drug.57,58 For many patients, the toxicities associated with daily vismodegib are difficult to tolerate. Therefore, a phase 2 study is under way to assess the efficacy and safety of intermittent dosing regimens.59 Investigational Therapies for Advanced or Metastatic Basal Cell Carcinoma Unfortunately, most patients treated with vismodegib eventually experience disease progression.60,61 While other SMO inhibitors are in development, additional research is under way to design agents that bind to both wild-type and mutant SMO as a means of overcoming vismodegib resistance. Such agents, which are currently being evaluated in phase 1 or 2 clinical trials, include erismodegib (LDE225),62

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Figure

50 Percentage of Patients Achieving Response

LEQ506,63 arsenic trioxide,64 itraconazole,65 and TAK-441.66 Additionally, agents that target downstream molecules in the hedgehog pathway, such as Gli, or other pathways that contribute to hedgehog pathway inhibitor resistance, such as the phosphoinositide 3-kinase pathway, are also candidates for overcoming resistance.60,67-69

Evaluable Responses with Vismodegib in Patients With Metastatic BCC vs Locally Advanced BCC57,58

ORR CR

30 21

0 Metastatic BCC (n=33)

Locally Advanced BCC* (n=63)

*For locally advanced BCC, CR was defined as an ORR with no residual BCC on sampling tumor biopsy. BCC indicates basal cell carcinoma, CR, complete response; ORR, objective response rate; PR, partial response.

Cutaneous T-Cell Lymphomas Cutaneous T-cell lymphomas (CTCLs) are types of non-Hodgkin lymphomas that develop in the T lymphocytes in the skin.70 CTCLs are relatively rare, with approximately 3000 new cases diagnosed in the United States each year.71 More common among men than women, CTCLs also occur more often in individuals older than 50 years than in younger individuals. The most common subtype of CTCL is mycosis fungoides (MF), with approximately 16,000 to 20,000 current cases across the United States, accounting for approximately 50% of all CTCLs. MF is typically slow growing, and most often remains localized to the skin.70,71 The second most common type of CTCL, which accounts for approximately 15% of all cases, is Sézary syndrome (SS), a chronic and systemic disease that affects the skin, blood, and lymph nodes. Patients with SS often have extensive erythroderma covering more than 80% of their body surface area.70 The prognosis for patients with MF or SS is based on the

Table 5 FDA-Approved Agents for CTCLs76-80 Agent

Year of Approval

Indication

Comments • In the pivotal study of 71 pts with stage IIBIVA CTCL, 30% achieved an ORR and DOR was 4 months

Denileukin diftitox76

1999

• Pts with persistent or recurrent CTCL whose malignant cells express the CD25 component of the IL-2 receptor

Bexarotene77

1999

• Pts with cutaneous manifestations • In the pivotal study of 62 pts with stage of CTCL who are refractory to ≥1 IIB-IVB CTCL, 32% achieved an ORR and prior systemic therapy DOR was 5+ months

Vorinostat78

2006

• Pts with cutaneous manifestations • In the pivotal study of 74 pts with stage of CTCL who have progressive, IA-IVB CTCL, 30% achieved an ORR and persistent, or recurrent disease on DOR was 6+ months or following 2 systemic therapies

Romidepsin79

2009

• Pts with CTCL who have • In the pivotal study of 96 pts with stage received ≥1 prior systemic therapy IB-IVA CTCL, 34% achieved an ORR and DOR was 15 months

Mechlorethamine 2013 (nitrogen mustard) gel80

• Pts with stage IA and IB MF who have received prior skin-directed therapy

• This represents the first and only FDAapproved topical formulation of mechlorethamine. Nitrogen mustard was previously approved in 1949 as an IV treatment for the same disease

CTCL indicates cutaneous T-cell lymphoma; DOR, duration of response; FDA, US Food and Drug Administration; IL-2, interleukin-2; IV, intravenous MF, mycosis fungoides; ORR, objective response rate; pts, patients.

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Table 6 Investigational Agents for CTCLs81-93 Agent

Type

Stage of Development

Improved purity denileukin diftitox (E7777)81

CD25-directed cytotoxin (fusion protein) indicated for pts with persistent or recurrent CTCL whose malignant cells express the CD25 component of the IL-2 receptor

Phase 3 (in persistent and recurrent CTCL)

Mogamulizumab (KW-0761)82

Anti-CCR4 monoclonal antibody

Phase 3 (vs vorinostat in pts with relapsed or refractory CTCL)

Brentuximab vedotin (SGN35)83,84

CD30-directed antibody-drug conjugate

Phase 2 (in CD30-positive lymphoproliferative disorders: ALL, MF, and extensive LyP Phase 3 (vs physician’s choice [methotrexate or bexarotene] in pts with CD30-positive CTCL)

Romidepsin (as monotherapy)85

HDAC inhibitor

Phase 2

Nonmyeloablative allo-SCT using total lymphoid irradiation and antithymocyte globulin conditioning86

A unique nonmyeloablative preparative regimen

Phase 2

Intratumoral electroporation of IL-12 plasmid87

DNA plasmid expressing IL-12 plasmid

Phase 2 (in pts with MF/SS)

Vorinostat88

HDAC inhibitor

Phase 2 (in pts with primary CTCL)

Immunomodulatory

Phase 2 (open-label as adjuvant treatment for refractory CTCL)

mTOR inhibitor

Phase 2

Low-dose TSEBT + vorinostat

HDAC inhibitor

Phase 1/2 (vs TSEBT monotherapy in pts with MF)

Pralatrexate92

Folate analog metabolic inhibitor

Phase 1 (+ bexarotene in patients with relapsed or refractory CTCL)

Carfilzomib93

Proteasome inhibitor

Phase 1 (± romidepsin)

Lenalidomide

Everolimus90 91

ALL indicates acute lymphocytic leukemia; allo-SCT, allogeneic stem cell transplantation; CTCL, cutaneous T-cell lymphoma; HDAC, histone deacetylase; IL-12, interleukin-12; LyP; lymphomatoid papulosis; MF, mycosis fungoides; mTOR; mammalian target of rapamycin; SS, Sézary syndrome; TSEBT, total skin electron beam therapy.

stage of disease at presentation.72 Factors indicative of poor prognosis include presence of lymphadenopathy, involvement of peripheral blood and viscera, and worsening cutaneous involvement. The median survival following diagnosis also varies according to stage. Patients with stage IA disease have a median survival of 20 years or more, and the cause of death in these patients is generally unrelated to CTCL. However, more than 50% of patients with stage III through stage IV CTCL die of the disease, with a median survival of less than 5 years.72 FDA-Approved Therapies for Cutaneous T-Cell Lymphomas Other than allogeneic stem cell transplantation, there Vol 2, No 8

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are no curative therapies for MF or SS.73 In the 1940s, mechlorethamine, an alkylating agent commonly known as nitrogen mustard, was the first systemic chemotherapeutic agent to be approved in the United States for the intravenous treatment of patients with MF.74 However, an accepted treatment approach has been to delay traditional chemotherapy, which can cause excessive toxicity without durable benefit.73,74 Therefore, management of these conditions uses a “stage-based” approach: treatment of early-stage disease (stage IA-IIA) typically involves skin-directed therapies that include topical corticosteroids, phototherapy (psoralen plus ultraviolet A or B radiation), topical chemotherapy, and radiotherapy.74,75

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Systemic approaches are used for recalcitrant early-stage disease and advanced-stage disease (stage IIB-IV). These include the fusion toxin denileukin diftitox, which targets the IL-2 receptor expressed on malignant T-cells; the retinoid bexarotene; and the histone deacetylase inhibitors vorinostat and romidepsin, which may reverse the epigenetic states associated with cancer (Table 5).76-80 Investigational Therapies for Cutaneous T-Cell Lymphomas Examples of drugs under active investigation for CTCLs include an improved purity formulation of the fusion protein denileukin diftitox, monoclonal antibodies, an antibody-drug conjugate, new histone deacetylase inhibitors, a proteasome inhibitor, and the immunomodulatory agent lenalidomide (Table 6).81-93

Conclusions and Future Directions Advances in the understanding of the molecular biology, cytogenetics, immunology, and pathogenesis of cutaneous malignancies (including malignant melanoma, MCC, BCC, and CTCLs), as well as a greater appreciation for the epidemiology and genetic/environmental factors contributing to these diseases, are beginning to impact standards of care for the optimal treatment of patients with cutaneous malignancies in oncologistsâ&#x20AC;&#x2122; practices. Personalized treatment strategies, based on stage, risk, and molecular criteria, are already being implemented using targeted FDA-approved agents, although acquired resistance to these agents is an emerging problem that limits their clinical benefit. In addition, numerous investigational therapies targeting different oncogenic pathways or immune checkpoints are making their way through clinical trials. Other research is focusing on identifying mechanisms of resistance to treatments and how these might best be overcome, including the rational use of drug combinations and the identification of biomarkers predictive of treatment response. Ultimately, it is hoped that the ability to select patients for treatment based on molecular targets, in both the advanced and adjuvant disease settings, might lead to long-term disease control or even cure of cutaneous malignancies in a significant proportion of patients. u References

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69. Kim J, Aftab BT, Tang JY, et al. Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell. 2013;23:23-34. 70. Cutaneous Lymphoma Foundation. About cutaneous lymphoma. http://www.clfoun dation.org/about-cutaneous-lymphoma. Accessed October 6, 2013. 71. Porcu P, Tawa M, eds. A Patient’s Guide to Understanding Cutaneous Lymphoma. Birmingham, MI: Cutaneous Lymphoma Foundation; 2012. http://www.clfoundation.org/ sites/default/files/publications/Guide%20Final.pdf. Accessed October 6, 2013. 72. National Cancer Institute. PDQ® Mycosis Fungoides and the Sézary Syndrome Treatment. Bethesda, MD: National Cancer Institute. Date last modified August 12, 2013. http://www.cancer.gov/cancertopics/pdq/treatment/mycosisfungoides/HealthProfessional. Accessed October 7, 2013. 73. Lansigan F, Foss FM. Current and emerging treatment strategies for cutaneous T-cell lymphoma. Drugs. 2010;70:273-286. 74. Weberschock T, Strametz R, Lorenz M, et al. Interventions for mycosis fungoides. Cochrane Database Syst Rev. 2012;9:CD008946. 75. Prince HM, Whittaker S, Hoppe RT. How I treat mycosis fungoides and Sézary syndrome. Blood. 2009;114:4337-4353. 76. Ontak [package insert]. Woodcliff Lake, NJ: Eisai Inc; August 2011. 77. Targretin [package insert]. Woodcliff Lake, NJ: Eisai Inc; October 2011. 78. Zolinza [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; April 2013. 79. Istodax [package insert]. Summit, NJ: Celgene Corp; June 2013. 80. Valchlor [package insert]. Malvern, PA: Ceptaris Therapeutics, Inc; August 2013. 81. A trial of E7777 in persistent and recurrent cutaneous T-cell lymphoma (NCT01871727). http://clinicaltrials.gov/ct2/show/NCT01871727?term=nct01871727& rank=1. Accessed November 18, 2013. 82. Study of KW-0761 versus vorinostat in relapsed/refractory CTCL (NCT01728805). http://clinicaltrials.gov/ct2/show/NCT01728805?term=nct01728805&rank=1. Accessed November 18, 2013. 83. A phase 3 trial of brentuximab vedotin (SGN-35) versus physician’s choice (methotrexate or bexarotene) in patients with CD30-positive cutaneous T-cell lymphoma (NCT01578499). http://clinicaltrials.gov/ct2/show/NCT01578499?term=nct01578499 &rank=1. Accessed November 18, 2013. 84. SGN-35 in CD30-positive lymphoproliferative disorders (ALCL), mycosis fungoides (MF), and extensive lymphomatoid papulosis (LyP) (NCT01352520). http://clinicaltrials. gov/ct2/show/NCT01352520?term=nct01352520&rank=1. Accessed November 18, 2013. 85. A single agent phase II study of romidepsin (depsipeptide, FK228) in the treatment of cutaneous T-cell lymphoma (CTCL) (NCT00106431). http://clinicaltrials.gov/ct2/show/ NCT00106431?term=nct00106431&rank=1. Accessed November 18, 2013. 86. Ph II of non-myeloablative allogeneic transplantation using TLI & ATG in patients w/ cutaneous T cell lymphoma (NCT00896493). http://clinicaltrials.gov/ct2/show/ NCT00896493?term=nct00896493&rank=1. Accessed November 18, 2013. 87. Phase II intratumoral pIL-12 electroporation in cutaneous lymphoma (NCT01579318). http://clinicaltrials.gov/ct2/show/NCT01579318?term=nct01579318&rank=1. Accessed November 18, 2013. 88. Vorinostat in patients with primary cutaneous T-cell lymphoma (NCT00958074). http://clinicaltrials.gov/ct2/show/NCT00958074?term=nct00958074&rank=1. Accessed November 18, 2013. 89. Open-label pilot study of lenalidomide (Revlimid) as adjuvant treatment for refractory cutaneous T cell lymphoma (RevMM2009) (NCT01132989). http://clinicaltrials.gov/ ct2/show/NCT01132989?term=nct01132989&rank=1. Accessed November 18, 2013. 90. Everolimus in treating cutaneous T-cell lymphoma (CTCL) (NCT01637090). http:// clinicaltrials.gov/ct2/show/NCT01637090?term=nct01637090&rank=1. Accessed November 18, 2013. 91. Low-dose (12 Gy) TSEBT+vorinostat versus low-dose TSEBT monotherapy in mycosis fungoides (NCT01187446). http://clinicaltrials.gov/ct2/show/NCT01187446?term= nct01187446&rank=1. Accessed November 18, 2013. 92. Pralatrexate and bexarotene in patients with relapsed or refractory cutaneous T-cell lymphoma (NCT01134341). http://clinicaltrials.gov/ct2/show/NCT01134341?term= nct01134341&rank=1. Accessed November 18, 2013. 93. Dose-escalation trial of carfilzomib with and without romidepsin in cutaneous T-cell lymphoma (NCT01738594). http://clinicaltrials.gov/ct2/show/NCT01738594?term= nct01738594&rank=1. Accessed November 18, 2013.

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Personalized Medicine and the Biopharmaceutical Industry: The Marrying of Science, Research, and Policy

An Interview With Dr William Chin of the Pharmaceutical Research and Manufacturers of America

he Pharmaceutical Research and Manufacturers of America (PhRMA) was formed in 1958 to represent America’s biopharmaceutical research companies and to seek essential alignment between public policy and medical research to address patient needs. Its members are committed to finding treatDr William Chin ments and cures for some of the most serious diseases such as cancer, Alzheimer’s disease, cystic fibrosis, and Parkinson’s disease. PhRMA’s mission is to conduct effective advocacy for public policies that encourage discovery of important new medicines for patients by pharmaceutical and biotechnology research companies. PhRMA maintains that a vibrant biopharmaceutical research industry is critical to patients and global health. Continued US leadership in biopharmaceutical research and development is foundational to American economic growth and competitiveness. This requires a business environment that inspires and rewards investment in research and development, while recognizing the unique risks and costs of the industry’s marketplace; a thriving and collaborative scientific ecosystem that advances

knowledge and innovation; a modern, transparent regulatory system that evolves with the science to bring safe and effective medicines to patients quickly; and a proper valuation for innovative medicines. PhRMA companies spent an estimated $48.5 billion in 2012 to discover and develop new medicines. More than 300 new medicines were approved by the FDA in the last decade, and roughly 2900 compounds are currently being studied in the United States alone – more than in any other region. Headquartered in Washington, DC, with offices in leading biopharmaceutical research communities, PhRMA advocates in the United States and around the world on public policy issues critical to the discovery and development of innovative medicines. The publisher of Personalized Medicine in Oncology (PMO) had the pleasure of interviewing Dr William Chin, Executive Vice President for Science and Regulatory Affairs for PhRMA, at the recent meeting of the Personalized Medicine Coalition where Dr Chin was a presenter. The two discussed the role of PhRMA in the healthcare system, the definition of “discovery ecosystem,” and the value of personalized medicine.

Dr Chin is an internist and endocrinologist who spent much of his early career studying the molecular mechanisms of hormonal control of gene expression. After 25 years in academia, including positions as investigator at Howard Hughes Medical Institute, Professor of Medicine at Harvard Medical School, and Chief, Division of Genetics at the Brigham & Women’s Hospital, he joined Eli Lilly and Company in 1999 as Vice President of Discovery Research and Clinical Investigation. In 2010, Dr Chin returned to Harvard Medical School as the Executive Dean for Research, Bertarelli Professor of Translational Medical Science, and Professor of Medicine. Currently, Dr Chin is Executive Vice President for Science and Regulatory Affairs for the trade group Pharmaceutical Research and Manufacturers of America. Dr Chin received his AB in chemistry from Columbia College and his medical degree from Harvard Medical School.

PMO Thank you for meeting with us today, Dr Chin. To begin our discussion, how do you define personalized medicine? Dr Chin This is actually a difficult question because personalized medicine means something different to everyone. I think the best description of personalized medicine is getting the right drug to the right patient at the right dose at the right time. A key idea in personalized medicine is that in a real sense everybody is different. People with what we consider the same disease will have the disease appear differently, respond to therapy differently, and will have different complications. Personalized medicine is a field that is based on the hope that we can utilize specific individual information to help our patients so they can truly have the best med-

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icine for a specific disease or condition, with the appropriate efficacy and safety. PMO Can you please describe the role of PhRMA in the healthcare system? Dr Chin PhRMA is a major trade organization that represents the majority of large- and medium-sized pharmaceutical companies in the United States, which ultimately means many companies throughout the world because many of our companies are multinational. A key goal of PhRMA is to advocate for policies that favor the maintenance of innovation in the system. It seeks to assure that the science voice is heard, and that science advocacy will allow personalized medicine to continue to grow and flourish. In my talk [at the Personalized Medicine Coalition, November 2013], I referred to the number of barriers that I think we continue to face. If we don’t deal with these barriers effectively, I think it will greatly slow the growth of personalized medicine and the future of medicine. PMO Can you talk about some of those barriers you foresee? Dr Chin I’m happy to highlight a few of these for you. One obstacle is how our regulatory system looks at diagnostics. The FDA is making great progress here, but I think there’s still more to be done. I think the agency needs to clarify the necessary qualities of a diagnostic in order for it to be approved. The FDA talks about how biomarkers and diagnostics could be qualified relative to context of use. I think the FDA can make it even more clear in terms of how that’s done so that those who want to develop them have a better understanding of the goal line. I think regulatory systems also need to appreciate how a potential therapeutic can be developed along with a companion diagnostic, and not allow one to slow the progress of the other. Right now they’re approved by different parts of the FDA, and while there is ample interaction, sometimes there can be better communication. Another hurdle is the issue of how payers rely on mandated clinical effectiveness research to make decisions. If we’re not careful about how we utilize that information, payers might decide not to fund therapies for personalized medicine by saying, “You might have been convincing in a relatively small randomized controlled trial, but you need more data to prove outcomes in much larger cohorts.” Thus, an obstacle is decision making – on what data do you base your decisions? Do they require a randomized controlled trial? What about the role of observational studies? Can studies using nontrial data such as medical records or claim reports demonstrate whether a drug works and is safe, even though they are not a gold standard approach?

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PMO The term “discovery ecosystem” is used quite frequently when we talk about drug development. Can you please define this term and describe the impact of PhRMA on its maintenance? Dr Chin The term “ecosystem” is thrown around a lot, and the “drug discovery ecosystem” is also used quite frequently. What do these terms mean? First, we understand that making medicines is a very difficult process. It is challenging for a lot of reasons, but I believe the main one is that diseases are generally complex in origin. Diversity can also affect disease expression in what we call heterogeneity of disease. Different patients with the same disease can manifest their illness in variable ways. Hence, our knowledge is incomplete, and yet we are asked to make medicines that are efficacious and safe in these uncertain settings.

One obstacle is how our regulatory system looks at diagnostics. The FDA is making great progress here, but I think there’s still more to be done. The “ecosystem” refers to the many groups and institutions that are necessary in order to make a medicine. These include not only companies in the pharmaceutical industry, but very importantly, academic institutions and investigators, patient advocacy groups, and governmental agencies such as the FDA and the National Institutes of Health. All these entities can come together to identify the important problems we need to face and to define the key unmet medical needs. They can also put their heads together to begin solving these very important problems. Cancer is one; another is Alzheimer’s disease. These vexing conditions will continue to affect our country and the world in terms of burden on health, burden on patients’ families, and governments. It will take the “ecosystem” to provide impor tant solutions. PMO In the advent of personalized medicine and companion diagnostics, biopharmaceutical companies face exciting and evolving scientific opportunities. Please comment on the ways in which PhRMA is working to advance the scientific processes to meet patient needs. Dr Chin PhRMA is partnering with many groups – I’ve emphasized that we’re not alone in this – to attack the problem of defining and diagnosing disease more precisely. One way seeks to develop better biomarkers and how to qualify them. In other words, how do we make them sufficiently standardized and rigorous so they

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can be used in drug development for both preclinical and clinical trials by the FDA and others? Also, PhRMA can help improve the understanding of how clinical trials can be conducted more effectively and efficiently. When you think about this in terms of personalized medicine, it’s kind of a “which came first, the chicken or the egg” situation. If you suspect a subpopulation will benefit from a certain kind of medicine, then you’d want to test it in that population. The problem is you still have to conduct a very large trial to find that subpopulation first. So until we can proactively identify subpopulations, we’re not going to be able to conduct trials as efficiently as we wish.

Companion diagnostics and biomarkers will be critical if we’re going to make progress in finding new medicines for personalized medicine. PhRMA is also working with the ecosystem to divine pathways for better implementation of clinical trials, improved trial design, and increased patient enrollment in studies. One of the major challenges is engaging patients from underrepresented minorities in clinical trials. There are a number of diseases such as prostate cancer that unfortunately is very prevalent in African Americans, and yet it has been difficult to have sufficient African American patients in those studies. We are also thinking about how we can better engage children in studies, but with obvious and appropriate safety considerations. PMO As you mention, we still have to conduct the large-scale trials to identify subpopulations of patients that could benefit from a particular therapy. Can you expand on your comments about the discovery of biomarkers in oncology and the impact of the companion diagnostic? Dr Chin Companion diagnostics and biomarkers will be critical if we’re going to make progress in finding new medicines for personalized medicine; new medicines and new diagnostics come hand in hand. A classic biomarker is a subject’s blood pressure, weight, or height. Imaging such as x-rays is also an example. We need to figure out how to bring all these signals together in order to help identify subpopulations. Now, at first, they might just represent a hypothesis, but if we think that there is a subpopulation that will respond to a certain medicine, then we could perform the experiment to determine whether that hypothesis is true. PMO Is the Affordable Care Act (ACA) financially compatible with the growth of personalized medicine

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overall and specifically in oncology, or will its additional costs reduce the spread of personalized medicine? Dr Chin I believe that the ACA will not limit the advancement of personalized medicine. It certainly doesn’t limit the hope for progress in this area. However, there are some features of the ACA to which we might pay particular attention. For instance, for our cancer patients, what effect will the role of comparative effectiveness research and health technology assessment have on determining whether a medicine will be reimbursed and hence accessible? If you try to use the studies across the whole population, you might conclude that it really is not all that effective. On the other hand, if you focus on a subpopulation, you might conclude that it is. Comparative effectiveness research will need to work closely with the healthcare system. If not, this can limit the impact of the ACA on the future of medicine. PMO Value is more than cost; it is the balance of quality, cost, and access. Considering the value proposition of personalizing medicine, how long will it take for personalized medicine to begin paying dividends economically and become attractive to payers by showing value? Further, how would you articulate the value proposition justifying the cost of personalized medicine in cancer and overall to the clinical business and government sectors and to patients? Dr Chin This is a very important question because there is a current feeling that personalized medicine will end up being so costly that we won’t be able to afford it, and hence there will be limited access. My view is that personalized medicine has already proven its value. In support of this notion, I would give you the example of Gleevec, or imatinib, for the treatment of chronic myelogenous leukemia. These patients with the Philadelphia chromosome often fare well on this medicine. In the first couple years, we did not appreciate the full value of this cancer medicine because we didn’t know how many people would survive after treatment. A 6-year review is showing remarkable gains in patient survivor rates. And this is just 1 example. So the point is that success with proof of value may take time to reveal itself. If you think about value in terms of paying for the medicine this year and an outcome the next year, then that’s 1 determination. But if you are able to follow the patient for a longer period of time, that positive value might reveal itself. The other question is, what is the appropriate end point? Survival is one; there is no question of this. But how about quality of life; how about whether the individual goes back to work or lives long enough to be able to witness a granddaughter’s wedding? Sometimes we

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don’t account for these factors in our assessment of value, and we need to do that. I would argue that if you can decrease the progression of diseases meaningfully or have significant prolonged survival, then you have achieved value for the individual patient and for the whole system. Ultimately, society will need to answer the question of what benefits need to be balanced by costs. PMO Moving away from policy, I’m curious to know your opinion on immunotherapy’s place in personalized medicine. Do you view immunotherapy as a personalized approach to treating patients with cancer? Dr Chin I don’t think we know enough about it yet. Some immunotherapies are highly personalized. So if

you used a dendritic cell approach to vaccine therapy where you take the cells from the patient for his own use, I don’t see how we can get more personalized. Not everybody gets a response from a vaccine in the same way. It will vary between individuals, but also from vaccine to vaccine. What determines that? It’s likely the variation of the immune system from individual to individual. So while I don’t have an example yet on this, I would predict that there will be many in the future where specific individual variation in immune response will require a personalized medicine approach to cancer immunotherapy. PMO Thank you so much for your time and insights. Dr Chin Thank you. u

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TAILORx: A Trial Design Toward Our Goal of Personalized Medicine M. Janakiram, MD

M. Janakiram, MD; A. Assal, MD; J. Sparano, MD Department of Oncology, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, New York

reast cancer is a significant public health problem; in 2009 (the most recent year for which numbers are available), 211,731 women were diagnosed with breast cancer and 40,676 died of breast cancer in the United States.1 Breast cancer mortality rates have decreased by 2.2% per year from 1990 to A. Assal, MD 2007, and the decline has been more prominent (3.2% per year) in women older than 50 years.2 Statistical modeling indicates that this decline is due to screening mammography and improved adjuvant therapy.3 The absolute benefit of adjuvant chemotherapy for earlystage disease varies depending on recurrence risk. The Early Breast Cancer Trialists’ CollabJ. Sparano, MD orative Group showed that the mortality benefit derived from adjuvant chemotherapy was little affected by age, nodal status, tumor differentiation, estrogen receptor (ER) expression, or tamoxifen use.4 On the other hand, a large proportion of patients with operable breast cancer, especially if associated with ER-positive, lymph node–negative disease, may be cured with Dr Janakiram is a postdoctoral fellow in immunology and breast cancer at the Albert Einstein College of Medicine. He completed his oncology fellowship at the Albert Einstein College of Medicine/Montefiore Medical Center and his internal medicine residency at Case Western Reserve University. His research interests include investigating and role of coinhibitory B7 molecules in human malignancies. Dr Assal received his medical degree at New York University School of Medicine. He completed an internal medicine residency at New York University, Langone Medical Center. He is currently a fellow in hematology and medical oncology at Albert Einstein College of Medicine and is active in clinical research. His research interests include tumor immunology and immunotherapies. Dr Sparano is Professor of Medicine and Professor of Obstetrics, Gynecology, and Women’s Health at the Albert Einstein College of Medicine and Associate Chairman of the Department of Oncology at Montefiore Medical Center. He also serves as Associate Director for Clinical Research at the Einstein Cancer Center and leads the Einstein Breast Cancer Working Group, a multidisciplinary group of physicians and scientists focused on translational breast cancer research. He currently serves as the study chair of TAILORx.

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primary local therapy and endocrine therapy, resulting in overtreatment with chemotherapy in many patients who may otherwise have been cured without it.5 Hence there is a compelling need to develop assays predictive of chemotherapy benefit and to evaluate and refine their clinical utility in prospective clinical trials.

Risk Assessment in ER-Positive Disease Classic Clinicopathologic Prognostic Factors The traditional method for assessing prognosis has been the TNM staging,6 which is based upon the premise that prognosis is determined by the anatomic extent of disease (ie, tumor size, nodal status). The disadvantage of TNM staging is that even within the same stage, tumors can have variable prognosis, and it provides no predictive information about benefit from systemic therapy. The Nottingham grading system7 classifies breast tumors into 3 grades based on degree of tubule formation, nuclear pleomorphism, and mitotic counts and is independently correlated with prognosis in ER-positive breast cancer.8 A limitation of grading is that this suffers from interobserver variability,9 and the prognosis is variable for grade 2 tumors, which account for most tumors. Online decision-making tools – Adjuvant! Online10 and PREDICT11 – were later developed, and Adjuvant! Online is popular in the United States. This web-based decision aid estimates the risk of recurrence with and without adjuvant systemic therapy based on Surveillance, Epidemiology, and End Results estimates on disease-free and overall survival, and hence provides information regarding the absolute benefit likely to be achieved with systemic endocrine therapy, chemotherapy, or both. The estimates from Adjuvant! have been validated in a population-based study, although estimates may be less reliable in certain patient subsets.12 While Adjuvant! accurately predicts recurrence risk in patient populations, it does not accurately identify a benefit from adjuvant systemic therapy in individual patients. Hence, other tools are required to assist in making more informed decisions for individual patients. Gene Expression Profiling Gene expression profiling quantitates the transcrip-

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Table Comparison of the TAILORx, MINDACT, and RxPONDER trials Trial/Characteristic

TAILORx

MINDACT

RxPONDER

Coordinating group

ECOG

EORTC

SWOG

Design

Prospective, randomized, open-label trial

No. of patients registered/ randomized

10,263/6908

6000/1920

8800/4400

Biomarker

Oncotype DX

MammaPrint

Oncotype DX

Key eligibility criteria

ER+, HER2–, LN–

LN– or 1-3 LN+

ER+, HER2–, 1-3 LN+

Randomized group

RS 11-25

Discrepant risk between MammaPrint and Adjuvant! Online

RS <25

Randomized treatment

Endocrine vs endocrine + chemotherapy

Treatment by clinical crite- Endocrine vs endocrine + ria (Adjuvant! Online) or chemotherapy gene expression (MammaPrint)

Primary end point

Disease-free survival

Distant metastasis-free survival

Disease-free survival

Status

Completed accrual

Accruing

Tissue banking is a common feature for all 3 trials. ECOG indicates Eastern Cooperative Oncology Group; EORTC, European Organization of Research and Treatment of Cancer; ER, estrogen receptor; LN, lymph node; RS, recurrence score; SWOG, Southwest Oncology Group.

tional expression of genes in a tumor and provides information about tumor biology that is not otherwise captured by classic clinicopathologic features.13,14 The most widely available gene expression assays are the Oncotype DX and MammaPrint for invasive cancer, and the Oncotype DX DCIS Score for ductal carcinoma in situ.15 Other validated available assays have been described elsewhere.16

Oncotype DX and Rationale for TAILORx Oncotype DX was developed and validated as a reverse transcriptase-polymerase chain reaction assay by Paik et al17 in 2004 in collaboration with Genomic Health, Inc. Prognostic genes were identified by evaluating a panel of 250 rationally selected candidate genes, and the expression was correlated with distant recurrence in a cohort of ap-

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Figure 1 List of Genes in Oncotype DX and Calculation of Recurrence Score

Oncotype DX 21-Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 Studies Reference Genes

Cancer Genes

Proliferation Ki-67 STK15 Survivin Cyclin B1 MYBL2

Estrogen ER PR Bcl2 SCUBE2

Invasion Stromelysin 3 Cathepsin L2 Her 2 GRB 7 HER2

RS = +0.47 x HER2 Group Score - 0.34 x ER Group Score +1.04 x Proliferation Group Score +0.10 x Invasion Group Score +0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1

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GSTM 1 BAG1 CD68

Beta-actin GAPDH RPLPO GUS TFRC

Category

RS (0-100)

Low Risk

RS <18

Int Risk

RS 18-30

High Risk

RS >30

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KEY POINTS There is a need to develop assays predictive of chemotherapy benefit and to evaluate and refine their clinical utility in prospective clinical trials ➤ The TAILORx is a prospective, randomized, open-label trial designed to evaluate the effect of adjuvant chemotherapy in ER-positive, HER2negative, node-negative patients who met established NCCN guidelines for recommending adjuvant chemotherapy in addition to endocrine therapy ➤ Additional ongoing trials integrating gene expression profiles include the RxPONDER and MINDACT trials ➤ By integrating biomarker-based information reflecting individual tumor biology, trials like TAILORx, RxPONDER, and MINDACT will refine the clinical utility of these assays that are already widely used in clinical practice ➤

proximately 450 patients with localized breast cancer. The top-performing 16 genes with 5 reference genes for normalization were selected for a 21-gene assay (Figure 1), and an algorithm was developed that translated the gene expression profile into a quantitative “Recurrence Score” (RS). A prospective validation in 668 tamoxifen-treated patients with ER-positive, node-negative early breast cancer enrolled in National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B14 indicated that the RS provides prognostic information about the risk of distant recurrence independent of other clin-

The rationale for amending the RS cut points for defining low, intermediate, and high risk was to minimize the potential for undertreatment of high-risk patients. ical features, whether evaluated as a continuous variable or as a categorical variable of low (0-17), intermediate (18-30) or high (>30) RS. Additional validation was confirmed in a population-based study from Kaiser Permanente that included patients with early breast cancer treated with tamoxifen in which RS was significantly correlated with breast cancer mortality.18 In another prospective validation study that included a clinical trial population of patients with ER-positive, node-negative breast cancer randomized to receive tamoxifen alone or in combination with cyclophosphamide, methotrexate,

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and 5-fluorouracil chemotherapy,19 it was demonstrated that only the high RS group derived a large benefit from chemotherapy (hazard ratio [HR] 0.26; 95% CI, 0.130.53), whereas the benefit from chemotherapy was unlikely in the low-risk group and uncertain in the intermediate RS group (HR 0.61; 95% CI, 0.24-1.59). Similar results were found when the RS was evaluated in a cohort of 367 postmenopausal patients with ER-positive, node-positive disease enrolled in trial S8814 who were randomized to receive either tamoxifen or tamoxifen plus adjuvant chemotherapy consisting of cyclophosphamide, doxorubicin, and 5-fluorouracil.20 Similar to the NSABP B20 trial, there was no benefit from chemotherapy in the low and intermediate RS groups, whereas chemotherapy resulted in improvement in disease-free survival (HR 0.59; 95% CI, 0.35-1.01; log-rank P=.03) and overall survival (HR 0.56; 95% CI, 0.31-1.02; P=.057) in those with a high RS. Upon application of the assay in clinical practice in patients selected to have the test done because of therapeutic equipoise (eg, intermediate-grade tumors), it was found that a larger proportion of patents had an intermediate RS than originally observed in the validation studies.21 Based on these considerations, the North American Breast Cancer Intergroup designed the TAILORx (Trial Assigning Individualized Options for Treatment) to evaluate the effect of treatment in this intermediate RS group.

TAILORx: Design and Objectives Trial Design The TAILORx is a prospective, randomized, openlabel trial designed to evaluate the effect of adjuvant chemotherapy in ER-positive, HER2-negative, nodenegative patients who met established National Comprehensive Cancer Network guidelines for recommending adjuvant chemotherapy in addition to endocrine therapy. Patients were risk-stratified based on their RS according to the following 3 categories: Low risk with an RS of 0 to 10, intermediate risk with an RS of 11 to 25, and high risk with an RS above 25. The rationale for amending the RS cut points for defining low, intermediate, and high risk was to minimize the potential for undertreatment of high-risk patients. When these ranges were used to analyze the data in the NSABP B20 trial, the treatment effect for adjuvant chemotherapy was found to be similar for the high RS group, and the risk of recurrence was found to be 5% or less for the low and intermediate RS groups when treated with tamoxifen alone.19 In addition, when the risk of relapse is analyzed as a continuous variable, a trend favoring the addition of chemotherapy becomes evident when the RS is approximately 11 or higher, and the 95% confidence intervals overlap in the 11 to 25 RS

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range; hence this recurrence Figure 2 TAILORx Study Design score range was selected. Patients in the intermediate-risk group (RS 11-25), TAILORx Study Design the primary study group (Figure 2), were randomized to receive chemotherapy Key Eligibility with hormonal therapy (the Preregister Node-Negative standard treatment arm) HR-Positive versus hormonal therapy Her2-Negative Oncotype DX alone (the experimental Age â&#x2030;¤75 years treatment arm). RandomizaMeets Standard Criteria for Chemotherapy tion was stratified according Register to tumor size, menopausal Specimen Banking status, planned chemotherapy (taxane-containing or Primary Study Group Secondary Study Group 1 Secondary Study Group 2 not) or radiation therapy RS 11-25 RS <11 RS >25 (whole breast irradiation with or without boost, partial breast irradiation, or no ARM D ARM A RANDOMIZE radiation therapy), and RS Chemotherapy Plus Hormonal Therapy Stratification Factors: Hormonal Therapy Only group (RS 11-15 vs 16-20 vs Tumor Size, Menopausal 21-25). The choice of horStatus, Planned Chemo, mone therapy and chemoPlanned Radiation therapy was at the discretion of the treating physician as long as it was consistent ARM B ARM C with one of the several stanHormonal Therapy Chemotherapy Plus dard treatment options deOnly Hormonal Therapy scribed in the protocol. The final 1000 patients enrolled underwent quality-of-life assessments. The low-risk group (RS <11) was assigned to receive hormone therpatients provided consent for future studies. A biospecapy only, whereas the high-risk group (RS >25) was imen repository was also established to study determiassigned to receive chemotherapy in addition to hornants of late relapse; blood samples are being collected mone therapy. from patients who are recurrence free at 4.5 to 7.5 years After registration and informed consent, a tumor after registration. The samples will serve as a resource specimen was submitted to Genomic Health for deterto define and/or validate biomarkers predictive of late mination of the RS by the Oncotype DX. Patients were relapse, including tumor-associated factors (eg, plasma asked to provide blood samples for the banking of plastumor DNA) and host factors (eg, estrogen, insulin ma and peripheral mononuclear cells at the time of and/or IGF levels, and inflammatory cytokines). registration. The Eastern Cooperative Oncology Group Pathology Coordinating Office collected tissue speciObjectives and Outcome Measures mens to allow for central testing and confirmation of The primary objective of TAILORx was to deterER and progesterone receptor expression, creation of mine whether adjuvant hormone therapy is noninferior tissue microarrays, and RNA extraction for future studto adjuvant chemotherapy plus hormone therapy in ies. By banking tumor RNA, formalin-fixed paraffinwomen in the primary study group (RS 11-25) whose embedded tissue microarrays, plasma, and germline tumors meet established clinical guidelines for adjuvant DNA, future clinical cancer tests, such as genomic and chemotherapy. The primary study end point was disepigenomic tests, tumor and serum proteomic patterns, ease-free survival; other coprimary end points include and single nucleotide polymorphisms in drug and/or distant recurrence-free interval, recurrence-free interestrogen metabolizing enzymes, can be performed if the val, and overall survival. Another objective of this trial

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was to establish a tissue and specimen bank for patients enrolled in this trial for use in future tests as they emerge. Secondary objectives of the trial were to determine whether hormone therapy is indeed sufficient to achieve a distant disease-free survival of 95% at 10 years for patients in the first secondary study group (RS ≤10). The prognostic significance of the Oncotype DX RS as well as individual RS gene groups will be determined (proliferation group, HER2 gene group, ER gene group, invasion gene group, and other genes), and outcomes projected at 10 years by Adjuvant! (using classic pathologic parameters such as tumor size, hormone receptor status, and histologic grade) will be compared with those made by the Oncotype DX test. Failure rates as a function of the Oncotype DX RS are estimated separately in the chemotherapy and nonchemotherapy arms. The purpose is to develop more precise estimates of the relationship between RS and chemotherapy treatment effect at the upper range of the primary study group (RS 11-25). Statistical Considerations The trial, designed as a noninferiority trial, is powered to detect a 3% or greater difference between the randomized arms. The accrual goal of the primary study group (RS 11-25) was raised to 6860 patients from 4390 due to higher than expected rates of nonadherence to the treatment assignment (based on data as of October 30, 2008, 17% of patients in the hormone plus chemotherapy arm were not receiving chemotherapy, and 7% of the hormone therapy only arm were receiving chemotherapy). Disease-free survival will be compared using a stratified log-rank test, with the test stratified on the same factors used during randomization. It is estimated the primary trial results will be available in 2015 or later.

Current and Future Directions Two other ongoing trials integrating gene expression profiles include the RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial and the MINDACT (Microarray in Node-Negative Disease May Avoid Chemotherapy) trial; a comparison of the trials is presented in the Table. The RxPONDER trial integrates the Oncotype DX assay as a biomarker in ER-positive, HER2-negative breast cancer patients who have 1 to 3 positive axillary nodes. Patients with an RS >25 are assigned to chemotherapy plus endocrine therapy, whereas patients with an RS <25 are randomized to receive chemotherapy plus endocrine therapy or endocrine therapy alone.22 This study is currently open to accrual. The MINDACT trial integrates the MammaPrint assay as a

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biomarker to evaluate the benefit of chemotherapy in patients whose risk classification is discrepant between Adjuvant! and MammaPrint, with these patients being randomized to treatment by clinical criteria (Adjuvant!) versus genomic criteria (MammaPrint).23 By integrating biomarker-based information reflecting individual tumor biology, trials like TAILORx, RxPONDER, and MIND ACT will refine the clinical utility of these assays that are already widely used in clinical practice. u

References

1. Centers for Disease Control and Prevention. Breast cancer statistics. www.cdc.gov/ cancer/breast/statistics/. Accessed September 12, 2013. 2. DeSantis C, Siegel R, Bandi P, et al. Breast cancer statistics, 2011. CA Cancer J Clin. 2011;61:409-418. 3. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353:1784-1792. 4. Early Breast Cancer Trialists’ Collaborative Group; Peto R, Davies C, Godwin J, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432-444. 5. Hayes DF. Targeting adjuvant chemotherapy: a good idea that needs to be proven! J Clin Oncol. 2012;30:1264-1267. 6. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471-1474. 7. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19:403-410. 8. Rakha EA, El-Sayed ME, Lee AH, et al. Prognostic significance of Nottingham histologic grade in invasive breast carcinoma. J Clin Oncol. 2008;26:3153-3158. 9. Rakha EA, Reis-Filho JS, Baehner F, et al. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 2010;12:207. 10. Ravdin PM, Siminoff LA, Davis GJ, et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol. 2001;19:980-991. 11. Wishart GC, Azzato EM, Greenberg DC, et al. PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer. Breast Cancer Res. 2010;12:R1. 12. Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol. 2005;23:27162725. 13. Kim C, Paik S. Gene-expression-based prognostic assays for breast cancer. Nat Rev Clin Oncol. 2010;7:340-347. 14. Sparano JA, Fazzari M, Kenny PA. Clinical application of gene expression profiling in breast cancer. Surg Oncol Clin N Am. 2010;19:581-606. 15. Solin LJ, Gray R, Baehner FL, et al. A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2013;105:701-710. 16. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009;360:790-800. 17. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817-2826. 18. Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 2006;8:R25. 19. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726-3734. 20. Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11:55-65. 21. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26:721-728. 22. Ramsey SD, Barlow WE, Gonzalez-Angulo AM, et al. Integrating comparative effectiveness design elements and endpoints into a phase III, randomized clinical trial (SWOG S1007) evaluating oncotypeDX-guided management for women with breast cancer involving lymph nodes. Contemp Clin Trials. 2013;34:1-9. 23. Cardoso F, Van’t Veer L, Rutgers E, et al. Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 2008;26:729-735.

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PMPM O

The official publication of

ersonalized edicine in Oncology

BIOMARKERS • IMMUNOTHERAPY • TARGETED THERAPIES • DIAGNOSTICS

MDS CASE STUDY

Case Study: Lower-Risk Myelodysplastic Syndromes At the 2013 conference of the Global Biomarkers Consortium, which took place October 4-6, 2013, in Boston, Massachusetts, Rami Komrokji, MD, from the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, discussed the use of personalizing therapy in the management of myelodysplastic syndromes.

yelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders that have as their hallmark dysplastic cytologic morphology. MDS occur predominantly in older patients. Various risk stratification schemes have been used in MDS to define MDS subtypes; one such classification system is the International Prognostic Scoring System (IPSS). Lower-risk MDS is characterized mostly by anemia. Survival in lower-risk MDS is measured in years. MDS is mainly a disease of splicing and genetic abnormalities, said Rami Komrokji, MD, who presented this case at the second annual Global Biomarkers Consortium conference. More than 40 recurrently mutated genes have been identifıed in patients with MDS (Figure). Epigenetic dysregulation and mutations of the tyrosine kinase pathway and transcription factors are possible. Most likely, every patient with MDS carries 1 or more somatic mutations responsible for disease development and progression. The diverse manner in which these

Figure

Genes Recurrently Mutated in MDS

Tyrosine Kinase Pathway JAK2

Transcription Factors

KRAS BRAF NRAS

PTPN11

RUNX1

WT1

CBL

DNMT3A

TET2

TP53

GATA2

NPM1 NOTCH? MAML? ZSWIM4? UMODL1?

RTKs

Epigenetic Dysregulation IDH 1&2

ETV6

Others

UTX ATRX

PHF6

BCOR

Splicing Factors EZH2

ZRSF2

U2AF1 SF3B1 SETBP1

U2AF2 SRSF2

ASXL1 SF1

PRPF8 SF3A1

Courtesy)of)R.)Bejar.)

PRPF40B

driver mutations coexist can help explain the clinical variability associated with MDS. Single gene mutations likely provide prognostic significance that is independent of the IPSS and other scoring systems. Mutations in genes can often coexist, and weighing each abnormality to accurately predict prognosis is difficult.

Case: Female With Macrocytic Anemia A 58-year-old female with a history of hypothyroidism was found to have macrocytic anemia and mild thrombocytosis. Bone marrow aspirate and biopsy confirmed MDS without an increase in myeloblasts. Would you perform cytogenetic analysis on this patient? Common to the importance of risk scoring systems in MDS is the importance of cytogenetics. MDS subtypes are defıned by the number of dysplastic cell lines, the proportion of myeloblasts, and in the case of patients with a sole deletion of chromosome 5q [del(5q)], by the presence of a cytogenetic abnormality; del(5q) is the most common cytogenetic abnormality in MDS, accounting for 10% to 15% of cases. “Deletion 5q is probably one of the best understood subtypes of MDS in terms of biology,” said Komrokji, clinical director, department of malignant hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. “There is a common deleted region usually around 5q33.” The haploinsufficiency for RPS14 contributes to the phenotype of the disease, as it is a key determinant of ineffective erythropoiesis. The haploinsufficiency recapitulates the defect in erythroid differentiation in 5q– syndrome and activates the tumor suppressor p53 preferentially in the erythroid progenitors, leading to erythroid hypoplasia and macrocytic anemia in the del(5q) subtype of MDS. Cytogenetics revealed a del(5q) in 20/20 cells. How would you treat this patient? The category of MDS delineated by isolated deletion of the long arm of chromosome 5 carries a favorable prognosis, even if it coexists with another abnormality (except for a deletion of chromosome 7). In lower-risk disease, the treatment goal is to correct or improve the cytopenia, minimize complications related to cytopenia, and prevent anemia recurrence, said Komrokji. For this purpose, erythropoietin-stimulating agents are often used to treat the anemia of lower-risk MDS, which may minimize the consequences of anemia and delay the need for red blood cell transfusions. Continued on page 461

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EDITORIAL

You Also Can’t Keep Your Doctor

I had great cancer doctors and health insurance. My plan was cancelled. Now I worry how long I’ll live. Edie Littlefield Sundby

veryone now is clamoring about Affordable Care Act winners and losers. I am one of the losers. My grievance is not political; all my energies are directed to enjoying life and staying alive, and I have no time for politics. For almost seven years I have fought and survived stage-4 gallbladder cancer, with a five-year survival rate of less than 2% after diagnosis. I am a determined fighter and extremely lucky. But this luck may have just run out: My affordable, lifesaving medical insurance policy has been canceled effective Dec. 31. My choice is to get coverage through the government health exchange and lose access to my cancer doctors, or pay much more for insurance outside the exchange (the quotes average 40% to 50% more) for the privilege of starting over with an unfamiliar insurance company and impaired benefits. Countless hours searching for non-exchange plans have uncovered nothing that compares well with my existing coverage. But the greatest source of frustration is Covered California, the state’s Affordable Care Act health-insurance exchange and, by some reports, one of the best such exchanges in the country. After four weeks of researching plans on the website, talking directly to government exchange counselors, insurance companies and medical providers, my insurance broker and I are as confused as ever. Time is running out and we still don’t have a clue how to best proceed. Two things have been essential in my fight to survive stage-4 cancer. The first are doctors and health teams in California and Texas: at the medical center of the University of California, San Diego, and its Moores Cancer Center; Stanford University’s Cancer Institute; and the M.D. Anderson Cancer Center in Houston. The second element essential to my fight is a United Healthcare PPO (preferred provider organization) health-insurance policy. Since March 2007 United Healthcare has paid $1.2 million to help keep me alive, and it has never once Reprinted by permission of The Wall Street Journal, Copyright © 2013 Dow Jones & Company, Inc. All Rights Reserved Worldwide. License number 3274360628788.

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questioned any treatment or procedure recommended by my medical team. The company pays a fair price to the doctors and hospitals, on time, and is responsive to the emergency treatment requirements of late-stage cancer. Its caring people in the claims office have been readily available to talk to me and my providers. But in January, United Healthcare sent me a letter announcing that they were pulling out of the individual California market. The company suggested I look to Covered California starting in October. You would think it would be simple to find a health-exchange plan that allows me, living in San Diego, to continue to see my primary oncologist at Stanford University and my primary care doctors at the University of California, San Diego. Not so. UCSD has agreed to accept only one Covered California plan – a very restrictive Anthem EPO Plan. EPO stands for exclusive provider organization, which means the plan has a small network of doctors and facilities and no out-of-network coverage (as in a preferred-provider organization plan) except for emergencies. Stanford accepts an Anthem PPO plan but it is not available for purchase in San Diego (only Anthem HMO and EPO plans are available in San Diego). So if I go with a health-exchange plan, I must choose between Stanford and UCSD. Stanford has kept me alive – but UCSD has provided emergency and local treatment support during wretched periods of this disease, and it is where my primary-care doctors are. Before the Affordable Care Act, health-insurance policies could not be sold across state lines; now policies sold on the Affordable Care Act exchanges may not be offered across county lines. What happened to the president’s promise, “You can keep your health plan”? Or to the promise that “You can keep your doctor”? Thanks to the law, I have been forced to give up a world-class health plan. The exchange would force me to give up a world-class physician. For a cancer patient, medical coverage is a matter of life and death. Take away people’s ability to control their medical-coverage choices and they may die. I guess that’s a highly effective way to control medical costs. Perhaps that’s the point. u

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EDITORIAL

ObamaCare 2016: Happy Yet?

The website problems were finally solved. But the doctor shortage is a nightmare Bradley Allen

hree years after the disastrous launch of the Affordable Care Act, most of the website troubles finally have been ironed out. People are now able to log on to the government’s ACA website and to most of the state health-insurance exchanges. The public has grudgingly come to accept higher insurance premiums, new taxes and increases in part-time workers who were formerly full-time. But Americans are irate anyway – because now they’re seeing the health-care law’s destructive effect on the fundamental nature of the way their care is delivered.

Three years ago members of Congress got themselves exempted from the Affordable Care Act. They may have passed the law, but they’re not stupid. Even before the ACA’s launch in 2013, many physicians – seeing the changes in their profession that lay ahead – had begun talking their children out of going to medical school. After the launch, compensation fell, Reprinted by permission of The Wall Street Journal, Copyright © 2013 Dow Jones & Company, Inc. All Rights Reserved Worldwide. License number 3274360495873.

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while nothing in the ACA stopped lawsuits and malpractice premiums from rising. Doctors must now see many more patients each day to meet expenses, all while dealing with the mountains of paperwork mandated by the health-care law. The forecast shortage of doctors has become a real problem. It started in 2014 when the ACA cut $716 billion from Medicare to accommodate 30 million newly “insured” people through an expansion of Medicaid. More important, the predicted shortage of 42,000 primary-care physicians and that of specialists (such as heart surgeons) was vastly underestimated. It didn’t take into account the ACA’s effect on doctors retiring early, refusing new patients or going into concierge medicine. These estimates also ignored the millions of immigrants who would be seeking a physician after having been granted legal status. It is surprising that the doctor shortage was not better anticipated: After all, when Massachusetts mandated health insurance in 2006, the wait to see a physician in some specialties increased considerably, the shortage of primary-care physicians escalated and more doctors stopped accepting new patients. In 2013, the Massachusetts Medical Society noted waiting times from 50 days to 128 days in some areas for new patients to see an internist, for instance. But doctor shortages are only the beginning. Even before the ACA cut $716 billion from its budget, Medicare only reimbursed hospitals and doctors for 70%-85% of their costs. Once this cut further reduced reimbursements, and the ACA added stacks of paperwork, more doctors refused to accept Medicare: It just didn’t cover expenses. Then there is the ACA’s Medicare (government) board that dictates and rations care, and the board has begun to cut reimbursements. Some physicians now refuse even to take patients over 50 years old, not wanting to be burdened with them when they reach Medicare age. Seniors aren’t happy. Medicaid in 2016 has similar problems. A third of physicians refused to accept new Medicaid patients in 2013, and with Medicaid’s expansion and government cuts, the numbers of doctors who don’t take Medicaid skyrocketed. The uninsured poor now have insurance, but they can’t find a doctor, so essentially the ACA was of no help.

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The loss of private practice is another big problem. Because of regulations and other government disincentives to self employment, doctors began working for hospitals in the early 2000s, leaving less than half in private practice by 2013. The ACA rapidly accelerated this trend, so that now very few private practices remain. When doctors are employed like factory workers by hospitals, data from the Medical Group Management Association and others indicate, their productivity falls – sometimes by more than 25%. They see fewer patients and perform fewer timely procedures, exacerbating the troubles caused by physician shortages. Continuity of care also declines, since now a physician’s responsibilities end when his shift is over. Of those doctors still in private practice, many have taken refuge from the health-care law by going into concierge medicine, where the patient pays an annual fee (typically $500-$3,000 a year per individual) to a primary-care physician. This doctor provides enhanced care, grants quicker appointments and spends more time with each patient, working with a base of 300-600 patients instead of the 3,000-5,000 typical in the ACA era. Doctors and patients who can afford it love concierge medicine: It allows treatment to be administered as the doctor sees fit, instead of as if the patient is on an assembly line with care directed on orders from Washington. Patients who can’t afford concierge medicine but have seen their doctor take that route are out of luck: They have been added to the swelling rolls of patients taken care of by the shrinking pool of physicians. So even people with “private” insurance have found that

the quality of their health care declined. Nowadays, many are forced instead to see a nurse or other healthcare provider. The traditional doctor-patient relationship is now reserved primarily for those who can pay extra. Concierge-type care was easily expanded to specialists. The top surgeons now simply opt out of Medicare or become “out of network” providers, allowing them to bill patients directly. Many have joined the plastic surgeons and ophthalmologists who work on a straight fee-for-service basis. Equally important: With the best and most successful doctors disappearing into concierge medicine or refusing new Medicare and Medicaid patients, replacing these experienced physicians with bright young doctors to work with the “general public” has become difficult. Why? Because such doctors are hard to find – going into medicine doesn’t have the professional allure it once did. With an average of $300,000 in student loans, eight years of college and medical school, and three to seven years as underpaid, overworked residents, a prospective physician in the ACA era would be starting a career at age 30 in a job that requires working 70-80 hours a week in an assembly-line fashion to earn perhaps $100,000 a year. No wonder so many qualified individuals these days are choosing careers on Wall Street or in Silicon Valley instead of medicine. It is also no wonder that three years ago members of Congress got themselves exempted from the Affordable Care Act. They may have passed the law, but they’re not stupid. u

MDS CASE STUDY

Case Study: Lower-Risk Myelodysplastic…

Continued from page 458

The patient was started on erythropoietin for 10 weeks with no response. How should treatment proceed? The anemia of lower-risk MDS responds to lenalidomide, an immunomodulatory drug that is approved for the treatment of transfusion-dependent lower-risk patients with del(5q). Pellagatti and colleagues demonstrated that lenalidomide selectively inhibits growth of del(5q) erythroid progenitors in vitro.1 Lenalidomide treatment reduced the need for transfusion in 76% of patients with

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MDS associated with del(5q), and cytogenetic improvement was observed in 73%.2 The median hemoglobin increase was 5.4 g/dL, the time to response was 4.6 weeks, and the duration of response exceeded 2 years. u

References

1. Pellagatti A, Jäderstern M, Forsblom AM, et al. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q-syndrome patients. Proc Natl Acad Sci U S A. 2007;104:11406-11411. 2. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456-1465.

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MPDL3280A in Advanced NSCLC

or the first time, a therapy – the antibody MPDL 3280A (Genentech) – for non–small cell lung cancer (NSCLC) has achieved responses in both smokers and nonsmokers, including responses in tumors with squamous and adenocarcinoma histology. These results of a phase 1 study in patients with metastatic NSCLC were so encouraging that experts suggested bypassing phase 2 studies and going on to phase 3 directly. Genentech’s development program for the monoclonal antibody includes ongoing recruitment for phase 2 and 3 trials in NSCLC. “We are at the beginning of a new era. After 30 years of research in immunotherapy for lung cancer, we have one that works, and it works in smokers,” said lead author Jean-Charles Soria, MD, PhD, Institut Gustave Roussy, Paris, France. “In this study, smokers responded much better than nonsmokers. This is great news for lung cancer patients, the majority of whom are current or former smokers. The data are preliminary, but the trends are extremely promising,” Soria added. The study results were based on a cohort of 85 patients (53 evaluable for efficacy). Patients were treated with an IV infusion of MPDL3280A every 3 weeks for a median duration of 106 days (range, 1-450 days). Of the 85 NSCLC patients, 55% were heavily pre-

treated with at least 3 prior therapies, and the majority were smokers or ex-smokers (81%); 19% were never smokers. MPDL3280A was considered safe. The majority of adverse events were mild. No dose-limiting toxicities were identified in this trial, nor were any grades 3 to 5 adverse events reported. Objective response rate (ORR) was 21% in the overall population (all tumor types, N=175) and 23% in NSCLC patients; 17% of responders were stable over 24 weeks. The 24-week progression-free survival rate was 44% in squamous cell NSCLC and 46% in nonsquamous cell NSCLC. PD-L1 expression (the target of MPDL3280A) was directly correlated with response, with the best response seen in those with the highest expression of PD-L1 on immunohistochemistry (IHC) 3. Those with IHC 3 also had less progressive disease. Although based on a very small number of patients, ORR was 46% in patients with PD-L1 IHC 2 and IHC 3, and 83% in those with IHC 3. Responses were sustained over time in all patients except 1, Soria said. Smoking status was a predictor of response; former/ current smokers had an ORR of 26% (n=43) compared with 10% in never smokers (n=10). u

Second-Generation ALK Inhibitor Regresses CNS Metastasis in NSCLC

novel ALK/EGFR inhibitor – AP26113 (ARIAD Pharmaceuticals) – achieved good responses in crizotinib-resistant and crizotinib-naive patients with non–small cell lung cancer (NSCLC) and achieved radiographic regression of central nervous system (CNS) metastases in these patients. These results from the firstin-human phase 1/2 dose-finding study of AP26113 were presented by D. Ross Camidge, MD, PhD, University of Colorado, Denver. Half of all ALK-positive NSCLC patients who develop crizotinib resistance become resistant in the brain, suggesting that crizotinib has inadequate CNS exposure. Systemic

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progression typically occurs later in the course of disease. Phase 1 was a 3×3 dose-escalation study in 30 to 60 patients with various advanced malignancies. Phase 2 had 5 cohorts – 4 with NSCLC (n=85 total) and 1 with other ALK-positive cancers (n=20). The identified dose of 180 mg/day was used in phase 2 initially, but some patients developed pulmonary symptoms at that level; symptoms resolved with steroids tapered over 1 week. Because of the pulmonary symptoms on the higher dose, a step-up approach will be used in future studies, starting with 90 mg/day for the first week on drug, and then moving to 180 mg/day, Camidge said.

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EUROPEAN CANCER CONGRESS 2013

Other adverse events included mostly mild gastrointestinal disturbances. Elevated liver enzymes were noted in 12% of patients. Treatment-emergent grade 3 or higher adverse events were reported in 2% to 4% of patients across all dose levels. The objective response rate (ORR) was 65%. The ORR rate was 61% in patients previously treated with crizotinib and 100% in all 4 crizotinib-naive patients (1 had a complete response). Eight of 10 patients with CNS metastasis had radiographic evidence of regression lasting from 8 to 40 weeks.

Responses were seen in some patients whose tumors expressed the T790M mutation. Among 12 patients with the T790M mutation, 5 had stable disease, 4 had progressive disease, and 3 discontinued the study before going on treatment. These data are preliminary, Camidge emphasized. More experience is needed to determine if the new ALK inhibitor will be an improvement on crizotinib. At least 2 other second-generation ALK inhibitors are in development, and these drugs also appear to achieve radiographic regression in CNS metastases. u

T-DM1 Prolongs Survival in Advanced HER2Positive Breast Cancer

he antibody-conjugate T-DM1 (Kadcyla, Genentech) prolonged progression-free survival (PFS) in advanced HER2-positive breast cancer in a heavily pretreated population, according to final results from the phase 3 TH3RESA trial. The study included cancer that progressed on 2 or more previous HER2-directed therapies (trastuzumab and lapatinib). TH3RESA extended the results of the EMILIA trial, in which T-DM1 extended PFS versus capecitabine/lapatinib in HER2-positive advanced breast cancer in women previously treated with trastuzumab and a taxane. T-DM1 was granted FDA approval for previously treated progressive metastatic HER2-positive breast cancer based on EMILIA results. “In TH3RESA, T-DM1 achieved a significant improvement in PFS, and the effect was clear and consistent across subgroups. These data affirm the results from EMILIA, demonstrating a consistent PFS benefit of T-DM1 in patients with previously treated HER2-positive advanced breast cancer,” said Hans Wildiers, MD, University Hospitals Leuven, Belgium. He presented these results at the 2013 European Cancer Congress. “T-DM1 should become the new standard of care for second-line treatment,” Wildiers stated. TH3RESA enrolled 602 patients with advanced breast cancer previously treated with at least 2 HER2-directed therapies and randomized them in a 2:1 ratio to T-DM1 or physician’s choice of chemotherapy (83% received trastuzumab-based regimens and 17% received chemotherapy). Treatment was continued until disease progression. Patients were allowed to cross over to T-DM1 at progression. Median PFS was 6.2 months for T-DM1 versus 3.3

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months in the control arm, representing an almost doubling of PFS in the experimental arm. The PFS difference between groups was highly significant (P<.001). A prespecified subgroup analysis showed similar PFS results favoring T-DM1 across all subgroups, including age, geographic area, race, performance status, tumor characteristics, and visceral disease.

No new safety signals for T-DM1 were reported in TH3RESA. Adverse events grade 3 or higher were more frequent in the control arm. Wildiers also presented the first interim analysis of overall survival (OS) from TH3RESA: median OS 14.9 months in the control arm and “not yet reached” for T-DM1. Longer-term follow-up will determine if there is a survival advantage. No new safety signals for T-DM1 were reported in TH3RESA. Adverse events grade 3 or higher were more frequent in the control arm: 43.5% versus 32.3% in the T-DM1 arm. Adverse events leading to discontinuation of therapy occurred in 10.9% of controls versus 6.7% in the T-DM1 group. The rate of cardiac events was low in both arms: left ventricular ejection fraction <50 was reported in 1.1% and 1.5%, respectively. First-line therapy with T-DM1 is being evaluated in an ongoing phase 3 trial in advanced HER2-positive breast cancer. u

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Genomics of Acute Myeloid Leukemia Explored

o paraphrase Winston Churchill, “We are at the end of the beginning” of the era of clinical genomics in acute myeloid leukemia (AML), said Richard M. Stone, MD, Dana-Farber Cancer Institute/ Brigham and Women’s Hospital, Boston, MA. Stone updated listeners on this topic at the National Comprehensive Cancer Network (NCCN) 8th Annual Congress: Hematologic Malignancies. Faced with a wealth of information from the recently published genome atlas for AML (The Cancer Genome Atlas Research Network. N Engl J Med. 2013;368:20592074), oncologists must choose wisely on what studies to order for risk assessment of AML. Stone said that 2 studies should definitely be done: FLT3-ITD and CEBP alpha. It is still not clear whether to assess for the KIT mutation, he noted. “The publication of the genome atlas for AML is very exciting and an important milestone. We understand the molecular biology to a certain degree. AML has fewer mutations than some other cancers,” Stone said. Twenty-three mutated genes that fall into 9 categories have been identified in AML. Founder mutations could provide the best target for treatment because they are present throughout the disease, he explained. Mutations that confer unfavorable prognosis include the FLT3-ITD and KIT mutations; the NPM1 and CEBP alpha mutations confer a favorable prognosis. “Right now, I would not recommend deep genomic sequencing for every patient, but the list will change, and then knowing mutations might influence protocols and trial eligibility for patients,” he told listeners. Established prognostic factors for AML include patient age, cytogenetics, type of AML, tumor burden at diagnosis, and other molecular markers. Adverse molecular markers include FLT3-ITD, and good prognosis markers include CEPB alpha. At diagnosis, key assessments in the workup include bone marrow aspiration, CBCD, cytogenetics, and mutational analysis for FLT3-ITD, NPM1, CEBP alpha, and c-KIT (but KIT only because it is cheaper to include it in the mutational analysis), he said. Relapse-free survival depends on 2 genes: combined NPM1 and FLT3-ITD. Patients with the best prognosis are those with NPM1-positive and FLT3-ITD–negative disease. NPM1-positive patients with FLT3-ITD mutations do not have good outcomes. Older patients with AML have worse outcomes, and it is important to be able to distinguish between those with a bad and very bad prognosis, Stone said. Perhaps

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older patients with AML have an intrinsically more difficult biological disease, he suggested. The balance of cytogenetics is tilted toward unfavorable ones, he added. They may have comorbidities and may also be more resistant to treatment. There are not many good options for patients younger than 60 years, Stone said. In younger patients (but not older ones), those treated with daunorubicin 90 mg do better than those receiving 45 mg if they have non-FLT3 mutations and have lower white blood cell counts at presentation. Younger patients who are chemosensitive can probably benefit from intensified therapy, he noted. The role of allogeneic stem cell transplantation is evolving. It appears to be as good as chemotherapy alone in patients in first remission (CR1). “In general we restrict allogeneic stem cell transplant to patients who cannot do well on high-dose chemotherapy. A good matched unrelated transplant is as good as a sibling match, and a young unrelated donor is better than an older sibling,” he told the audience. There is no benefit from allogeneic stem cell transplantation in patients with mutated NPM1 and wildtype FLT3-ITD, but in all other cases allogeneic stem cell transplantation may be superior to high-dose chemotherapy. Chromosomal findings and genetic findings in AML can be integrated. AML can be separated into 9 subgroups based on clinical genomics. The favorable group does not need stem cell transplantation in CR1. NCCN guidelines for younger patients are as follows. In younger patients, a clinical trial is preferred. Standard induction is with 3×3 therapy (idarubicin, daunorubicin, or doxorubicin). Postremission therapy depends on whether a matched unrelated donor or a sibling donor is available; stem cell transplantation should be considered for those with poor cytogenetics. In intermediate-risk cytogenetics, allogeneic stem cell transplantation is probably preferred, but autologous stem cell transplantation or high-dose chemotherapy can be considered. In patients with a true adverse prognosis who lack a sibling or matched unrelated donor, consider an alternative donor. For older patients, the guidelines also state that a clinical trial is preferred. “3×7” induction therapy remains the standard (daunorubicin and ara-C). Less intensive therapy can be considered, especially if the response is likely to be poor (older patients, nonfavorable karyotype, and performance status 2). In all patients who

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achieve a complete remission (CR), consider reducedintensity allogeneic stem cell transplantation. In cases of relapse, the following targetable mutations may be implicated: FLT3-ITD, FLT3-TKD, RAS, KIT, and IDH1/2. “In summary, genetic analysis is important at diagnosis for de novo AML, at least for prognosis and choice of

post-CR therapy. Mutations may point toward certain clinical trials, and the landscape of important mutations is likely to change with more data,” Stone said. Investigational therapies for AML include quizartinib, a potent and selective FLT3 inhibitor, and trametinib, a MEK inhibitor, which may be useful in patients with a RAS mutation. u

Idelalisib and Ibrutinib Are Promising B-Cell Receptor Signaling Inhibitors in B-Cell Malignancies

argeted therapy to the B-cell receptor (BCR) signaling is paying off in chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Two novel agents – the PI3K inhibitor idelalisib and the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib – show great promise for these malignancies. These drugs have been studied in phase 3 trials, and current studies are focusing on combination strategies and new schedules to improve outcomes. “These drugs are breakthrough drugs in [B-cell malignancies],” said Jeffrey Jones, MD, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Solove Research Institute, speaking at the NCCN 8th Annual Congress: Hematologic Malignancies. The BCR is present on the surface of healthy cells and cancer cells. Abnormal BCR signaling is implicated in B-cell malignancies, promoting leukemia cell survival and proliferation. Thus, BCR signaling is a therapeutic target. Idelalisib achieves rapid regression in lymph node volume accompanied by a concomitant rise in absolute lymphocyte count (ALC). Many patients treated with the drug do not achieve a complete response because of the rise in ALC and lymphocytosis. The toxicity profile is good, with relatively little grade 3 and 4 toxicity, with the exception of pneumonitis (~24%) and neutropenia (~18%) reported in clinical trials. Hematologic toxicity is easily managed. Combination strategies are being studied to improve response rates in relapsed/refractory CLL, relapsed non-Hodgkin lymphoma (NHL), and mantle cell lym-

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phoma (MCL). Also, idelalisib plus rituximab is under study for frontline CLL therapy. Another PI3K inhibitor – IPI-145 – is less well studied. The drug has achieved excellent responses in indolent lymphomas and NHL. A major concern is risk of pneumocystis pneumonia, suggesting that patients should receive prophylaxis. Approval of idelalisib is expected soon, and IPI-145 is about to enter phase 3 testing. Most of the clinical data on BTK inhibitors – which also affect BCR signaling – are on ibrutinib. In CLL, response rates were 68% in treatment-naive patients and 71% in relapsed/refractory and high-risk patients (Byrd et al. N Engl J Med. 2013;369:32-42). Ibrutinib achieves excellent responses even in patients with poor-risk cytogenetics, such as deletions of 17p13.1 and 11q22.3. Stable remission has been achieved in this group. Ibrutinib causes mostly mild adverse events such as diarrhea, nausea, and fatigue. Ibrutinib combined with rituximab achieves marked reduction in lymphocytosis in previously untreated highrisk CLL/small cell leukemia. However, longer-term follow-up is needed to determine the value of this strategy. Higher doses of ibrutinib achieve overall response rates above 70% in patients with MCL, and response continues to improve on treatment. Ibrutinib is also being studied in combination with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) in large cell lymphoma. Studies of CC-292, an oral BTK inhibitor, have not been as promising as those of ibrutinib. u

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THE LAST WORD

Preserving Personalized Medicine – Holding Fast to Healthcare’s Governing Dynamics

hat do we say at the end of this contentious year in healthcare, when government, the least of healthcare’s 3 siblings – clinical, business, and government – pushed its brethren aside and demanded to lead the parade? To be certain, the “dynamic tension” between our healthcare’s sectors hisRobert E. Henry torically has been more tense than dynamic and certainly not noted for seeking ways to pool resources. One sometimes has the impression that some regard this essential triad as a zero-sum game where one winner can take all, ignoring the collegiality inherent to its nature and essential for its success. Certain patients need the collaboration of all sectors and all the stakeholders who reside in them if they are to receive the care that only an unshakably humane, intelligent, financially solvent, and well-synchronized system can provide. But the sheer number of stakeholders that has emerged as specialization and subspecialization of tasks has its own tendency to breed isolationism, call it unilateralism, which breeds fear of other stakeholders whose methods and agendas are only weakly understood by them. Occasional examples arise of just such abuses of the system, and the stakeholders tend to react by pulling the wagons together in a circle to keep the “other guys” out of their group.

The “dynamic tension” between our healthcare’s sectors historically has been more tense than dynamic and certainly not noted for seeking ways to pool resources. Fortunately, healthcare is blessed with visionaries and more humanists than manipulators: over my nearly 40 years in healthcare, I have seen some of the most ardent dedication to patients from within the walls of Pharma, which is supposed to be just an abuser rather than an innovator, and likewise some of the most appalling examples of self-interest on the part of those whose profession is presumed to be above suspicion. The visionaries at various organizations recognize this, and so we have witnessed self-governing of this top-heavy multidisciplinary industry that reaches out to all stakeholders and integrates what they have to offer patient care into a largely laudable process of care.

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If there is one caveat worth mentioning, and without trying to unfairly single out government as overreaching its grasp in attempting to establish order consistent with progress and value in care, it comes from a line uttered by Thomas More in A Man for All Seasons: “Some men think the world is round, others think it flat. It is a matter for discussion. But if it is flat, will the King’s command make it round, and if it is round, will the King’s command flatten it? No, I will not sign.” And he did not sign an edict he found to set, in that case, religion on its ear. Kings should not rule religion, for that would bastardize it into just an extension of politics, not spirituality. He died rather than participate in a farce. The art of healing is almost as holy an undertaking; let those who lead it do so with intellectual humility and collegiality toward their fellows. Kingship went out several centuries ago, and with good cause. We can and must apply More’s marvelously civil understatement to our current desire to the harmonious interaction of all the players involved in the innovations of personalized medicine in the treatment of cancer patients – indeed throughout every disease state in healthcare. A core reason involves the irrefutable connection between personalized medicine and the costs needed to continue the development and implementation of the massive technology driving it. Personalized medicine is joined at the hip with biomarkers to certify patient eligibility to be administered the multitude of costly biologics that cannot be administered to the wrong patients. Personalized medicine is likewise joined at the hip with genomics, proteomics, and metabolomics – and a host of other high-level partners, like healthcare technology assessment, the topic of the recent International Society for Pharmacoeconomics and Outcomes Research European Conference. And the host of personalized medicine drivers continues to grow, for we have opened up the door to the cosmos, nothing less, in our insistence on targeted care that is personalized medicine. This technology will not fall off a tree while we wait, Newton-like, for the apple to fall onto our heads. It is being ground out in centers of research and in think tanks looking down the road to anticipate how to connect the dots. Healthcare’s “iron triangle” of value, demanding a balance of cost, quality, and access, is constantly demanding a balanced pursuit of all this, and we must demand that all parties to healthcare understand the difference between leading healthcare and commandeering it. The rules of engage-

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THE LAST WORD

ment are inherent, not subject to being ignored: they must be satisfied or this house of cards will come tumbling down around us...and no one, but no one, will stand for that. Personalized medicine has come and is as likely to be overlooked as the invention of the wheel. Should any 1 of the 3 healthcare sectors make the foolhardy attempt to establish unshakable hegemony over its fellows, it will only invite a market correction – it couldn’t work if it tried. Thomas More knew that there are certain very special endeavors – be it religion or the science of medicine – that have governing dynamics inherent to them that no edict can ignore. Neither the king nor the physician nor the businessman (be it payer or pharma or financier) can demand obeisance to its particular agenda if it runs counter to the laws of engagement necessary for healthcare to operate, be innovative, and remain humane! But that has never stopped zealots from trying. Churchill put it well: “A fanatic is someone who can’t change his mind and won’t change the subject.” The time for tunnel vision zealots in all sectors of healthcare was never...and particularly now. For the well-being of cancer patients, let it remain so in the new year. When the cancer patient comes through your door, you must be operating in an environment that enriches the patient’s individualized needs. You must have the up-front knowledge of patient proclivity to respond to a given product, rather than pretending that biomarker diagnostic tests do not exist when they do. You must have access to this and other tools of personalized medicine, just as the patient needs financial access to them,

just as the shareholders of the companies that invented them must be incented to financing this disruptive innovation. It is a matter of balance, not bludgeoning edicts that momentarily place power in the hands of any 1 of the 3 sectors. The innovations of personalized medicine in cancer care are producing stunning life-extending results. One other incontrovertible fact of healthcare is that once

When the cancer patient comes through your door, you must be operating in an environment that enriches the patient’s individualized needs. proof of healing is found, society will insist on finding a way to obtain it – political or business conveniences matter not at that point. The sectors must hammer out a mutually satisfactory “pact” that ensures continuation of the marvels of personalized medicine. As we enter the new year, let that be the governing condition of healthcare. u

Robert E. Henry

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ANNUAL INDEX 2013

Biomarkers Physician-Reported Clinical Utility of the 92-Gene Molecular Classifier in Tumors With Uncertain Diagnosis Following Standard Clinicopathologic Evaluation. Kim B, Schroeder BE, Schnabel CA, Erlander MG, Malin JL........................................... 2:68 Breast Cancer TAILORx: A Trial Design Toward Our Goal of Personalized Medicine. Janakiram M, Assal A, Sparano J................................................................ 8:452 Colorectal Cancer Crizotinib and Colorectal Cancer – A Couple to Be Tested? Stintzing S, Lenz HJ................................ 3:123 Gene Profiling in Colon Cancer: How to Integrate Profiling Into Practice. Van Loon K, Atreya CE, Kelley RK, Venook AP......................................... 4:204 Predicting Response to EGFR-Targeting mAbs in Colorectal Cancer – Is the KRAS Mutation Test Sufficient? Finnberg NK, Lim B........................... 8:430

Editorial The Supportive Face of the FDA in the Advancement of Personalized Medicine. Henry RE...................... 1:46 The Affordable Care Act and Oncology Personalized Medicine: Compatibility and the Governing Dynamics of Healthcare. Henry RE....................... 2:98 The MHealth Factor: A Bioinformatics Platform for Arming the Oncology Personalized Medicine Revolution. Henry RE.......................................... 3:161 Trouble at the Beginning: Diagnostic Acumen and the Relentless Search for Red Flags. Henry RE.........4:224 Immunotherapy in Cancer Care: Personalized or Population-Based Medicine...and the Janusian Factor. Henry RE................................................... 5:289 To PARP or Not to PARP – What Is the Question? Henry RE............................................................... 6:349 To PARP or Not to PARP – What Is the Question? Part 2. Henry RE................................................... 7:413 Preserving Personalized Medicine – Holding Fast to Healthcare’s Governing Dynamics. Henry RE....8:466

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Hematology Current Treatment of Myelofibrosis: How Far We Have Come and How Far We Have Yet to Go. Schiffer C............................................................... 3:153 Faculty Perspectives. Advances in the Treatment of Hematologic Malignancies: Updates From ASCO, EHA, and ICML 2013. Brown J, Gregory SA, Mesa RA, Richardson P, Steensma DP......................... 6:318 Faculty Perspectives. Advances in the Treatment of Chronic Myeloid Leukemia. Highlights From EAH 2013. Radich JP, Richardson P, Steensma DP.... 7:388

Immunotherapy Immune-Related Endocrinopathies Associated With Ipilimumab Therapy. Min L, Ibrahim N.............. 5:270 How Do Melanoma Experts Use the New Agents? Helwick C............................................................. 6:306

Interview With the Innovators Next-Generation Sequencing: An Interview With Michael J. Pellini, MD, of Foundation Medicine.................................................................. 1:34 Promoting the Adoption of Personalized Medicine Concepts: An Interview With Edward Abrahams, PhD, of the Personalized Medicine Coalition....... 2:79 Personalizing Cancer Care, Policy, and the Payer Perspective: An Interview With Peter F. Hayes of Healthcare Solutions........................................ 3:134 Personalized Medicine and Value: The Intersection of Science and Financial Viability. An Interview With Experts in Healthcare Strategy.............................4:192 Providing Molecular Profiling for Patients With Ovarian Cancer: An Interview With Laura Shawver, PhD, of Clearity Foundation.......................................... 5:254 Utilizing a Personalized Diagnostic in a Class of Hodgkin Lymphoma Patients: An Interview With Lawrence M. Weiss, MD, of Clarient Diagnostic Services, Inc........................................................... 6:308 Multiple Myeloma and the MMRF CoMMpass Study: Revolutionizing Clinical Trial Data Dissemination: A Panel Discussion With the Researchers...............7:380

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Personalized Medicine and the Biopharmaceutical Industry: The Marrying of Science, Research, and Policy. An Interview With Dr William Chin of the Pharmaceutical Research and Manufacturers of America................................................................. 8:448

Lung Cancer Resistance to Targeted Molecular Therapies in NSCLC. Johnson ML, Gentzler RD, Yu HA, Riely GJ................................................................... 1:24 Personalizing Therapy in the Management of Recurrent Nonâ&#x20AC;&#x201C;Small Cell Lung Cancer: Case Study of a Patient With an EGFR Mutation........................ 7:410

Multiple Myeloma Considerations in Multiple Myeloma. Ask the Experts: Frontline and Retreatment Settings. Siegel D, Bilotti E, Eskinazi G................................ 2:82 Considerations in Multiple Myeloma. Ask the Experts: Maintenance Settings. Lonial S, Anderson KC, Flaherty T, Leblebjian H............. 3:138 Faculty Perspectives: Recent Advancements in the Treatment of Multiple Myeloma. Proceedings From a Post-IMW Roundtable. Richardson P, Dimopoulos M, Giralt SA, San Miguel JF........... 4:196 Considerations in Multiple Myeloma. Ask the Experts: Combination Versus Sequential Therapy. Nooka AK, Gleason C, Sanvidge Shah K............................... 5:262 Considerations in Multiple Myeloma. Ask the Experts: The Role of Transplantation. Lonial S, Stadtmauer EA, Mangan PA, Ganetsky A.............................. 7:396

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Myelodysplastic Syndrome Case Study: Lower-Risk Myelodysplastic Syndromes.............................................................. 8:458 Pancreatic Cancer A Path Toward Pancreatic Cancer Predictive Biomarkers. Rosenberg JD, Sigal D.................................... 4:182 Pharmacoeconomics Budget Impact Model: Epigenetic Assay Can Help Avoid Unnecessary Repeated Prostate Biopsies and Reduce Healthcare Spending. Aubry W, Lieberthal R, Willis A, Bagley G, Willis SM III, Layton A................................................................ 4:212 Renal Cell Carcinoma Sequential Therapy for Renal Cell Carcinoma. Cho DC................................................................. 3:146 Antiangiogenic Tyrosine Kinase Inhibitors and Their Diverse Spectra of Inhibitory Activity: Implications for Personalized Therapy in Renal Cell Carcinoma. Agarwala SS, Wong MKK.................................... 5:243 Genetic Susceptibility to Renal Cell Carcinoma. Radford C.............................................................. 6:338

Special Reports Global Biomarkers Consortium Conference Coverage................................................................ 7:378 Value-Based Cancer Care Introducing the Third Annual Conference of the Association for Value-Based Cancer Care. Zweigenhaft B.......................................................... 2:90

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AUTHOR INDEX 2013

Agarwala SS.............................................................5:243 Anderson KC...........................................................3:138 Assal A.....................................................................8:452 Atreya CE.................................................................4:204 Aubry W...................................................................4:212 Bagley G...................................................................4:212 Bilotti E.......................................................................2:82 Brown J.....................................................................6:318 Cho DC....................................................................3:146 Dimopoulos M..........................................................4:196 Erlander MG...............................................................2:68 Eskinazi G...................................................................2:82 Finnberg NK.............................................................8:430 Flaherty T.................................................................3:138 Ganetsky A...............................................................7:396 Gentzler RD...............................................................1:24 Giralt SA..................................................................4:196 Gleason C.................................................................5:262 Gregory SA...............................................................6:318 Helwick C ...............................................................6:306 Henry RE...................................1:46, 2:98, 3:161, 4:224, 5:289, 6:349, 7:413, 8:466 Ibrahim N.................................................................5:270 Janakiram M.............................................................8:452 Johnson ML................................................................1:24 Kelley RK..................................................................4:204 Kim B .........................................................................2:68 Layton A...................................................................4:212 Leblebjian H.............................................................3:138 Lenz HJ.....................................................................3:123 Lieberthal R..............................................................4:212

Lim B........................................................................8:430 Lonial S........................................................ 3:138, 7:396 Malin JL......................................................................2:68 Mangan PA..............................................................7:396 Mesa RA...................................................................6:318 Min L........................................................................5:270 Nooka AK................................................................5:262 Radford C.................................................................6:338 Radich JP..................................................................7:388 Richardson P..................................... 4:196, 6:318, 7:388 Riely GJ......................................................................1:24 Rosenberg JD............................................................4:182 San Miguel JF...........................................................4:196 Sanvidge Shah K......................................................5:262 Schiffer C..................................................................3:153 Schnabel CA..............................................................2:68 Schroeder BE..............................................................2:68 Siegel D......................................................................2:82 Sigal D......................................................................4:182 Sparano J..................................................................8:452 Stadtmauer EA.........................................................7:396 Steensma DP................................................ 6:318, 7:388 Stintzing S................................................................3:123 Van Loon K..............................................................4:204 Venook AP...............................................................4:204 Willis A....................................................................4:212 Willis SM III............................................................4:212 Wong MKK..............................................................5:243 Yu HA........................................................................1:24 Zweigenhaft B.............................................................2:90

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LETTER

FROM THE

EDITOR-IN-CHIEF

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

to learn more!

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

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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

Steve M. Horwitz, MD

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

2013 CONFERENCE GUIDE

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Fourth Annual Navigation and Survivorship Conference November 15-17, 2013 The Peabody Memphis • Memphis, Tennessee CONFERENCE CO-CHAIRS Program Director: Lillie D. Shockney, RN, BS, MAS University Distinguished Service Associate Professor of Breast Cancer Departments of Surgery and Oncology Administrative Director, The Johns Hopkins Breast Center Administrative Director, Johns Hopkins Cancer Survivorship Programs Associate Professor, JHU School of Medicine Departments of Surgery, Oncology & Gynecology and Obstetrics Associate Professor, JHU School of Nursing Baltimore, Maryland

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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.

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