PMO November 2013

A Peer-Reviewed Journal

November 2013 • Volume 2 • Number 7

BIOMARKERS • IMMUNOTHERAPY • TARGETED THERAPIES • DIAGNOSTICS

PM O

The official publication of

Global biomarkers Consortium Clinical Approaches

TM

to Targeted Technologies

TM

Personalized Medicine in Oncology TM

SPECIAL REPORT Second Annual Global Biomarkers Consortium Conference Highlights…...............................Page 366

INTERVIEW WITH THE INNOVATORS Multiple Myeloma and the MMRF CoMMpass Study: Revolutionizing Clinical Trial Data Dissemination: A Panel Discussion With the Researchers..................................................Page 380

HIGHLIGHTS FROM EHA 2013 CME Faculty Perspectives. Advances in the Treatment of Chronic Myeloid Leukemia.......................Page 388

MULTIPLE MYELOMA CME Considerations in Multiple Myeloma. Ask the Experts: The Role of Transplantation ...........Page 396

NSCLC CASE STUDY Personalizing Therapy in the Management of Recurrent Non–Small Cell Lung Cancer: Case Study of a Patient With an EGFR Mutation….....................................................Page 410

THE LAST WORD To PARP or Not to PARP – What Is the Question?

Part 2.............................................................Page 413

www.PersonalizedMedOnc.com © 2013 Green Hill Healthcare Communications, LLC

In partnership with

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

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

RECHARGE THE POSSIBILITIES

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

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

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

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

www.istodax.com

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

15% ~60% 25%

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

9.2 months

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

1.8 months a

(~2 cycles) median time to Objective Response

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

NOVEMBER 2013

VOLUME 2, NUMBER 7 PUBLISHING STAFF Senior Vice President/Sales & Marketing Philip Pawelko phil@greenhillhc.com Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Publisher Russell Hennessy russell@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Strategic Editor Robert E. Henry

TABLE OF CONTENTS

Senior Copy Editor BJ Hansen

SPECIAL REPORT

366

Second Annual Global Biomarkers Consortium Conference Highlights

The Global Biomarkers Consortium (GBC) is a community of world-renowned healthcare professionals that convene to discuss the clinical application of predictive molecular biomarkers and personalized care for patients. Coverage from the second annual GBC conference is presented to educate physicians specializing in hematology/oncology, pathology, and genetics on the state-of-the-art advances in our understanding of tumor biomarkers and their use in the clinical management of a variety of solid tumors and hematologic malignancies.

INTERVIEW WITH THE INNOVATORS

380

Multiple Myeloma and the MMRF CoMMpass Study: Revolutionizing Clinical Trial Data Dissemination: A Panel Discussion With the Researchers The COO of the Multiple Myeloma Research Foundation leads a panel discussion with CoMMpass study investigators Drs Jagganath, Lonial, and Orloff about their ground- breaking trial.

HIGHLIGHTS FROM EHA 2013 CME

388 Faculty Perspectives. Advances in the Treatment of Chronic Myeloid Leukemia

Jerald P. Radich, MD; Paul Richardson, MD; David P. Steensma, MD, FACPB MULTIPLE MYELOMA CME

396

Considerations in Multiple Myeloma. Ask the Experts: The Role of Transplantation Sagar Lonial, MD; Edward A. Stadtmauer, MD; Patricia A. Mangan, MSN, CRNP; Alex Ganetsky, PharmD, BCOPBU

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 Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salemo 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 Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma

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.

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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

November 2013

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Vol 2, No 7

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

NOVEMBER 2013

VOLUME 2, NUMBER 7

T

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.

TABLE OF CONTENTS

Global biomarkers Consortium Clinical Approaches

(Continued)

TM

NEWS

404

Multiplex Genetic Assays Identify Mutations Beyond BRCA1/2 in 10% of Patients at Risk for Breast Cancer

406

Molecular Profiling in Breast Cancer: Still Not Ready for the Clinic

407

Role of Radiation and Imaging in DCIS Explained

NSCLC CASE STUDY

310 Personalizing Therapy in the Management of Recurrent Non–Small Cell Lung Cancer: Case Study of a Patient With an EGFR Mutation A case presented at the second annual Global Biomarkers Consortium conference by Roy S. Herbst, MD, PhD, of the Yale Comprehensive Cancer Center.

THE LAST WORD

413 To PARP or Not to PARP – What Is the Question? Part 2

Robert E. Henry

Mr Henry discusses the emerging role of PARP inhibitors in fighting cancer.

Personalized Medicine in Oncology is included in the following indexing and data-

to Targeted Technologies

TM

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%

base 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 November 2013

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Vol 2, No 7

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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

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

Afsaneh Motamed-Khorasani, PhD Radient Pharmaceuticals Tustin, California

Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona

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

Kenneth Bloom, MD Clarient Inc. Aliso Viejo, California

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

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

David A. Proia, PhD Synta Pharmaceuticals Lexington, Massachusetts

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

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

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

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

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio Stephen Gately, MD TGen Drug Development (TD2) Scottsdale, Arizona

Lung Cancer Vincent A. Miller, MD Foundation Medicine Cambridge, Massachusetts

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

Predictive Modeling Michael Kattan, PhD Case Western Reserve University Cleveland, Ohio

K. Peter Hirth, PhD Plexxikon, Inc. Berkeley, California

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 Prostate Cancer Oliver Sartor, MD Tulane University New Orleans, Louisiana EDITORIAL BOARD Gregory D. Ayers, MS Vanderbilt University School of Medicine Nashville, Tennessee

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

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Hope S. Rugo, MD University of California, San Francisco San Francisco, California 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 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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LETTER TO OUR READERS

PMO Proudly Announces Dr Sanjiv S. Agarwala to Join Dr Al Benson as Co-Editor in Chief Dear Colleague,

I Al B. Benson III, MD

t is with great pleasure that I announce our newly appointed Co-Editor in Chief, Sanjiv S. Agarwala. Dr Agarwala joins me in this position to bring the oncology community the latest advances in our ability to personalize care for patients.

Dr Agarwala is Professor of Medicine at Temple University School of Medicine in Philadelphia and Chief of Oncology & Hematology at St. Lukeâ&#x20AC;&#x2122;s Cancer Center in Bethlehem, Pennsylvania.

Dr Agarwala is an internationally recognized investigator in the field of melanoma and immunotherapy. He has published on a variety of therapeutic approaches to melanoma and has led promising clinical trials of immunotherapy and targeted therapy of melanoma. He received his degree and completed an internship and residency at the Seth G.S. Medical College and King Edward Memorial Hospital in Bombay, India. He also completed residency training in internal medicine and a fellowship in hematology-oncology at the University of Pittsburgh School of Medicine.

We are delighted to work with him at PMO, and it is my pleasure to welcome him in this capacity.

Sincerely,

Al B. Benson III, MD

Dear Colleague,

I Sanjiv S. Agarwala, MD

t is my pleasure to write to you as Co-Editor in Chief of PMO alongside Dr Benson. The world of oncology has seen more promise, change, and improvements in the past decade than ever before.

The Editors and Staff of PMO are proud to be part of that change by meaningfully disseminating potentially life-changing information to our readership. In my new capacity, I hope to continue this tradition by featuring articles within our pages that provide in-depth information about emerging therapies, various genetic mutations, protein expressions, and other indicators and their implications for treatment in different subsets of patients with cancer.

It is our hope that these pages assist you in providing optimal care for your patients. I look forward to serving you.

Sincerely,

Sanjiv S. Agarwala, MD

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2013 GBC CONFERENCE Global biomarkers Consortium Clinical Approaches

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The Global Biomarkers Consortium (GBC) is a community of world-renowned healthcare professionals that convene to discuss the clinical application of predictive molecular biomarkers and personalized care for patients. Coverage from the second annual GBC conference is presented to educate physicians specializing in hematology/oncology, pathology, and genetics on the state-of-the-art advances in our understanding of tumor biomarkers and their use in the clinical management of a variety of solid tumors and hematologic malignancies.

Redesigning Clinical Trials Necessary to Improve Odds of Finding Effective Targeted Agents in the Genomic Era

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efining optimal therapeutic efficacy in the genomic era will require that clinical trial design in oncology move from a drug-centric to a patient-centric approach. Retrofitting current knowledge into old paradigms will slow the progress in discovering effective targeted agents, said Razelle Kurzrock, MD, at Razelle Kurzrock, the second annual Global Biomarkers ConsorMD tium conference.

Common cancers are comprised of multiple subgroups in which different pathways may be activated.

Patients with cancer may have hundreds of different genetic mutations, especially in the metastatic setting. “The individual landscape of a patient is unique,” said Kurzrock, director, Center for Personalized Therapy and Clinical Trials, University of California, San Diego, Moores Cancer Center.

This uniqueness means that each patient requires a specially tailored treatment regimen. In a randomized trial of unselected patients, however, a drug that hits the more common pathway will be declared the superior drug to one that hits a less common pathway. This unselected approach runs the risk of abandoning an effective therapy that works on the less common pathway, she said.

Tailored treatment regimens may include drug combinations to hit the multiple targets involved in a patient’s cancer. Conducting clinical trials the traditional way, it would take a millennium to decipher the optimal drug combination for a cancer, as the number of 2-drug combinations would approach 45,000 assuming 300 effective oncology drugs, and would exceed 4 million 3-drug combinations.

Genomic Profiling: Impact on Outcomes Enriching clinical trial populations for molecular targets is more efficient at finding successful treatments. Genomic profiling has resulted in superior response rates compared with the traditional clinical

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trial paradigm in unselected patients.

Prior to the genomic era, complete response rates obtained with therapies approved for solid tumors based on clinical trial results in unselected patients were typically near 0%, and the survival gains were in the range of 1 to 3 months. In contrast, when phase 2 clinical trials of single agents in the treatment of lung cancer were enriched for patients with putative molecular drug targets, the median response rate improved to 49% versus 9.7% in clinical trials of unselected patients, and overall survival reached 11.3 months versus 7.5 months in trials of unselected patients.

The PI3K/AKT/mTOR pathway is activated in a subset of a large number of cancers. In some patients, other pathways, such as MAP kinase, may also be activated at the same time, and may form a resistance pathway. Many drugs target the PI3K/AKT/mTOR pathway, and others target the resistance pathway. “There are trials in which both pathways are targeted simultaneously by 2 drugs that are matched to target part of each pathway,” Kurzrock said. “Pathways are a different way of looking at cancer rather than organ of origin. We are looking at it by the molecular driver.”

A PIK3CA mutation is evident in 10% of advanced cancers originating in various organs. About 30% of heavily pretreated patients with PIK3CA-mutant gynecologic and breast metastatic malignancies exhibit a partial response when treated with inhibitors of P13K/ AKT/mTOR. Patients with the PIK3CA H1047R mutation are more amenable to treatment than other mutations, with a 38% response rate. “We can’t be simplistic enough to just say there’s a mutation in a gene,” she said.

“We have to know precisely where that mutation occurs.

It may make a big difference in how the disease behaves and what therapies it will respond to.”

PTEN mutations can also activate the PIK3CA pathway. Patients having either of these mutations are much more likely to also have the resistance path-

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way (ie, KRAS, BRAF) activated, adding another layer of complexity to treatment. “If we target the PIK3CA pathway…we have to look for mutations in the resistance pathways and give combination therapy to those patients,” she said.

The complexity of cancer means that clinical trials of new targeted agents will also have to be smaller to improve the chance of finding effective agents in patients with particular subsets of cancer. Phase 1 cancer trials should be redesigned to include patients with the relevant mutations or genetic defects, Kurzrock believes.

Example in Colorectal Cancer FOCUS4 is an integrated clinical trial program of parallel, molecularly stratified, randomized comparisons for patients with advanced or metastatic colorectal cancer who are fit for first-line chemotherapy. The trial design exploits a “window of opportunity” to test the clinical efficacy of targeted agents after first-line chemo-

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therapy but before resistance to standard agents occurs in prespecified biomarker-defined subgroups, explained Rob Coleman, MD, MBBS, director, Sheffield Cancer Research Centre, United Kingdom.

The program is designed to be “adaptable to new biomarker and clinical data as they proceed,” he said. “We want to evaluate multiple treatments and biomarkers in the same protocol. We don’t want to have to write a new protocol every time there’s a new drug or biomarker because of the delays that brings in.” Each biomarker and treatment has its own control group.

The goal is to look for early signals of efficacy and also early stopping rules for lack of efficacy. “We’re not looking for small differences with targeted therapy…we’re looking for a hazard ratio of 0.4 to 0.6,” said Coleman.

The adaptive design allows for interim analyses to test new hypotheses, biomarker cohorts, and agents after patients are randomized. Select arms of the study can be closed when a conclusion is reached. u

Biomarker Development and Validation Crucial to Use of Emerging Treatments in Solid Tumors and Hematologic Malignancies

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iomarker development and validation are essential for the rational use of emerging cancer treatments, said presenters at the second annual Global Biomarkers Consortium conference.

“If we don’t identify biomarkers, we’re likely to miss a therapeutic effect,” said Rob Coleman, MD, MBBS. “We want to separate our patients into those that express the biomarker and those that do not, with the expectation that those that do will be enriched and it will be easier to show benefit.”

The 3 phases in the development of a clinically useful biomarker are discovery, validation, and application.

Clinical and biological validity of a potential biomarker is common, analytic validity is less common, while proving clinical utility, whether prognostic or predictive, is rare, said Coleman, director, Sheffield Cancer Research Centre, United Kingdom.

“To be accepted as clinically useful, a biomarker needs to have gone through prospective clinical trial testing or at least have been subjected to a meta-analysis,” he said.

“Relatively few achieve that.”

Showing value to a new biomarker requires complete publication of the methodology used in its evaluation,

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according to the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) criteria. These include patient characteristics; the type of biologic material used and its collection, preservation, and storage; study design and case selection; a list of candidate variables examined or considered; and the handling of marker values and cut point deter- Rob Coleman, MD, mination. REMARK is one of several guideMBBS lines established for reporting and evaluating biomarker studies.

Biomarker trial design relies on the availability of adequate archived specimens for analysis to have adequate statistical power, said Coleman. The marker-based test should be analytically and preanalytically validated for use with the archived specimens. Results from Jorge Cortes, MD archived specimens should be validated using specimens from 1 or more similar but separate studies.

Searching for Bone Metastasis Markers in Breast Cancer The use of adjuvant bisphosphonates in early breast cancer is being studied in over 3000 patients in the

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AZURE study, with the rationale that such treatment may enhance endocrine therapy and prevent metastasis.

Although invasive disease-free survival was similar between the groups randomized to zoledronic acid and controls, there was a 23% reduction (P<.05) in such events in postmenopausal women treated with the bisphosphonate. The agent may be working to prevent bone metastases, but to use the agent in the most appropriate and cost-effective manner “you need to pull out a group of patients who are more likely to develop bone metastases,” Coleman said, “and there’s no tool for doing that. We don’t have any biomarkers that do this.”

Not every BCR-ABL rearrangement is the same, and the response to therapy is different between those with a typical and an atypical rearrangement.

As an example of biomarker discovery and validation, his group has used a proteomic discovery platform to identify 2 candidate proteins for prediction of bone metastases that are being evaluated using tissue microarray samples from the AZURE study population. When both proteins are expressed (15% of the study cases), the risk for bone metastases plus metastases at other sites was increased more than 3-fold in the control group, and the risk of bone metastases only was increased more than 4-fold in controls. No such increase was found in the groups randomized to the bisphosphonate.

Markers in Hematologic Malignancies In the case of biomarkers for hematologic malignancies, chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome, creating the fusion gene BCR-ABL. The Ph chromosome is not only pathogenic for CML but is also a tumor marker. A tyrosine kinase inhibitor (TKI) is a specific therapy to block excess tyrosine kinase activity caused by BCR-ABL, changing the natural history of the disease.

“As good as the treatment is, the testing for the presence of molecular abnormalities at the BCR level is poorly homogenized,” said Jorge Cortes, MD, chair, CML and AML sections, MD Anderson Cancer Center, Houston, Texas. Standardization of the test is lacking, resulting in large differences between laboratories in the measurement of the number of leukemic cells.

An undetectable molecular abnormality achieved with therapy has been associated with excellent long-

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term survival. Not every BCR-ABL rearrangement is the same, and the response to therapy is different between those with a typical and an atypical rearrangement, said Cortes. The e1a2 transcript is rare in CML, and patients with this transcript have inferior outcomes compared with those with more common transcripts.

Another marker of response in CML is the human organic cation transporter (hOCT1). Patients with an active hOCT1 experience cytogenetic and molecular responses to a standard dose of a TKI, whereas those with a less active transporter require higher doses.

In CML, BCR-ABL can mutate to confer resistance to a TKI. “There are more than 100 mutations that can occur, and they create different levels of resistance to imatinib,” he said. Second- and third-generation TKIs have been developed to overcome resistance caused by specific mutations, “and they overcome some mutations better than others,” Cortes said. “Knowing which mutation is more likely to respond to which drug helps you individualize treatment for that patient.”

CML patients with the T315I mutation currently have no treatment options. Ponatinib is a potent pan– BCR-ABL inhibitor that is active against all tested resistant mutants, including the T315I mutation. In a phase 1 study of 403 patients resistant to or intolerant of dasatinib or nilotinib or who had the T315I mutation, early complete cytogenetic responses were achieved in 58% of patients treated with ponatinib, Cortes said.

In acute myelogenous leukemia (AML), a mutation in FLT3 is associated with frequent and rapid relapse and worse overall survival. In a retrospective study of patients with myelodysplastic syndrome or AML, 23 were treated with an FLT3 inhibitor as part of their induction, and 9 achieved either a complete remission or a complete remission with incomplete platelet recovery. A secondary tyrosine kinase domain mutation can arise after the use of FLT3 inhibitors in patients with single FLT3 internal tandem duplication mutated AML, conferring resistance and a poor prognosis.

A molecular mechanism of AML is the process of farnesylation, which is required for the activation of renin-angiotensin system proteins. The farnesyltransferase inhibitor tipifarnib has been evaluated in untreated elderly patients with AML, producing a complete remission in 18% to 20%. A genetic predictor of response to tipifarnib is the ratio of RASGRP1/APTX gene expression. The utility of this classifier for predicting response to tipifarnib was validated in a set of 58 samples from relapsed or refractory AML and was found to predict for improved survival in newly diagnosed and refractory/ relapsed AML. u

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Next-Generation Sequencing Identifies Actionable Genomic Alterations in Solid Tumors

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ext-generation sequencing (NGS) is a valuable tool to identify actionable genomic alterations that may be present in a tumor sample, said Gary A. Palmer, MD, JD, MPH, senior vice president of medical affairs at Foundation Medicine Inc, Cambridge, Massachusetts, at the second annual, Global Biomarkers Consortium conference.

NGS techniques can overcome many of the shortcomings associated with conventional sequencing of clinical cancer samples, and routine use of NGS in the clinic could potentially aid clinical trial enrollment and off-label drug treatment.

Matching the correct targeted therapy to the patient is diagnostically challenging as the number of clinically relevant genomic alterations (ie, base substitutions, mutations, short insertions/deletions, focal amplification, homozygous deletion, and gene fusion) increases. Performing multiple tests may exhaust the biopsy material.

“NGS can find all of these different types of alterations,” Palmer said.

There are many potentially targetable alterations in any particular tumor type, “so I think that the days of panel testing, where you only test for 3 or 4 alterations in lung cancer and a different 3 or 4 in colon cancer, are probably rapidly coming to a close because alterations tend to be shared across different solid tumors,” he said.

Many of the alterations are found in a small percentage of cancer cells, so a high degree of sensitivity is needed to find actionable alterations in a tumor sample.

Sanger sequencing has a level of sensitivity of only about 20%, “so if you have a mutant allele that’s less than 20% of the tumor DNA, you’re not likely to find it with Sanger sequencing,” Palmer said. In the first 107 cases of non–small cell lung cancer for which NGS was used at Foundation Medicine, 55% of biologic driver alterations were present in <20% of tumor DNA. With NGS, alterations can be found using small amounts of tissue (50 ng of DNA, the equivalent of 8-10 microscope slides of tissue) in a clinically relevant time frame (approximately 2 weeks).

The sample gene list that Foundation is looking at numbers 236 genes. “You want a comprehensive list of genes you’ll be able to pick up in any particular solid tumor, those genes that have alterations that are clinically significant,” he said. “These alterations are not restricted to 1 tumor type.” HER2 alterations have been

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found in over 15 solid tumors, for example.

Keys to making NGS work routinely are the availability of tissue that has viable DNA and issuing relevant results to oncologists – “the biologic drivers of the particular tumor.” Not all will be targetable at present but may become targetable with the discovery of new agents. A high degree of specificity is also desirable.

Gary A. Palmer, Foundation Medicine’s report to the cliniMD, JD, MPH cian includes the biologic drivers that are found and a table of actionable alterations. It also lists any FDA-approved drugs for the alteration found as well as FDA-approved drugs for a different tumor type, potentially supporting off-label use of a drug, and relevant clinical trials based on genomic alterations identified.

Many of the alterations are found in a small percentage of cancer cells, so a high degree of sensitivity is needed to find actionable alterations in a tumor sample.

The initial experience with NGS at Foundation Medicine consists of 2200 solid tumor cases in which gene alterations have been found. More than 80% had actionable findings, many with off-label drugs or drugs being tested in clinical trials. The mean number of reportable alterations was 3 to 4, with 1.6 actionable alterations per sample.

The most frequently altered gene in cases in which alterations have been found is p53, present in about 50% of cases with alterations. About three-fourths of specimens harbored ≥1 actionable gene. No 2 patients had the same findings, although many had similar alterations, he said. “That gives credence to this whole idea of personalized medicine,” said Palmer.

Of the 2200 cases, 116 had ERBB2 alterations. “We’re up to 18 solid tumors in which we found what we feel are biologically important ERBB2 alterations,” he said. The majority has been found in breast cancer, but a sizable number of ERBB2 alterations have been found in lung cancer as well. In the lung cancers, 17 have been activating point mutations, “the great majority post amplification,” he said. Whether anti-HER2 agents will work in solid tumors other than breast cancer will need to be determined, he added. u

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VA Takes Lead Role in Using Informatics to Validate and Translate Biomarkers

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linical informatics – the use of data from the electronic medical record (EMR) to inform the development and improvement of evidence-based medicine, the dissemination and implementation of health outcomes research, and translational research initiatives – can facilitate the validation and translation of biomarkers, said Julie Lynch, PhD, RN, MBA, at the second annual Global Biomarkers Consortium conference.

She spoke of the Veterans Administration (VA) experience in using clinical informatics and how it is uniquely positioned to evaluate the real-time translation of biomarkers to the bedside.

Clinical informatics is different from bioinformatics in that clinical informatics contains data within the EMR. Translational information bridges bioinformatics with clinical information, explained Lynch, nurse scientist at the VA, and a research associate at Dana-Farber Cancer Institute, Boston, Massachusetts. Although structured data sets of sequenced genes do not yet exist in the EMR, “with the $29 billion investment in the HITECH act with a move toward enabling electronic medical records throughout the whole US healthcare system in community hospitals, the possibility of doing that is real,” she said.

Data from reference laboratories illustrated a 10-fold greater utilization of biomarker tests than what was identified in the VA administrative data.

Translational informatics requires increased use of standardized data in the EMR, such as tumor SNOMED codes, so that clinical data can inform research.

Delays in the translation of cancer genomics and underrepresentation of minorities in National Cancer Institute (NCI) clinical trials have significant negative consequences for patients and the entire healthcare industry. Lynch used the example of the epidermal growth factor receptor (EGFR) assay, which was commercialized in 2005. In 2010, only 7800 lung cancer patients were being tested for EGFR, and there was a strong indication that black patients were not being tested. “The perception at NCI cancer centers was that

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everybody was doing EGFR testing in 2010,” she said.

Current diagnostics and drugs are being developed based on analysis of tumor tissue from patients enrolled in clinical trials at NCI hospitals or academic medical centers, but minorities are not well represented at these hospitals. “We have to move the clinical trials to the community, even if it’s a registration trial,” said Lynch. Because the incidence of mutations is very small, “to get the data we need we have to get out into the community, but it’s most likely to take place post approval.”

The VA is uniquely positioned to make significant contributions to translational informatics because each of the 158 VA medical centers and 958 outpatient clinics uses a nationally integrated EMR. The amount of data available from the VA is massive, with 83.6 million outpatient visits and 703,500 inpatient admissions. Each year, 52,000 veterans are diagnosed with cancer, of whom 18.5% are minority cancer patients. The VA has also maintained a cancer registry since 1995. In 2011, this registry began incorporating molecular data, including ALK tyrosine kinase receptor and EGFR mutation status for patients with lung cancer and KRAS for patients with colon cancer.

“The rapid and explosive growth of biomarkers has created challenges for large healthcare systems to consistently and accurately integrate test orders and results into the EMR,” she said. “With genomics becoming an increasingly important component of high-quality cancer care, and with the increasing price of targeted oncology drugs, evaluating appropriate biomarkers and targeted treatments is a priority in the VA.” A single integrated computerized patient record system is used throughout the VA in all healthcare settings.

It delivers an integrated record that covers all aspects of patient care and treatment. “The system allows us to do a key word search of the veteran’s entire medical record.

The research that can be conducted using key word search, and natural language processing is substantially better than structured data sets,” said Lynch.

A 2012 analysis of the VA’s structured data sets revealed that there were substantial inconsistencies in the ordering, use, and reporting of biomarker tests within the data sets. Yet key word searches of the clinical notes discovered that the tests were being done but not captured in the structured data sets.

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Data from reference laboratories illustrated a 10-fold greater utilization of biomarker tests than what was identified in the VA administrative data.

Factors that impeded accurate reporting of genomics are: 1) tests are entering clinical practice faster than updates can be made to the EMR, 2) most genetic diagnostic tests have been billed using a stack of Current Procedural Terminology (CPT) codes, and 3) in some cases veterans undergo testing outside the VA. VA national clinical leadership and VA Health Informatics supported the development of a translational informatics application to address this problem.

“We established collaborations with reference labora-

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tories to develop ongoing electronic data interfaces that would capture biomarker test orders and results from all VA medical centers,” she said. A data set that identifies clinical genetic diagnostic test orders and results is being stored in the Veterans Informatics, Information, and Computing Infrastructure.

As well, structured data sets are being adapted to include the 101 newly published CPT codes for clinical genetic diagnostic tests.

Using natural language processing tools, the VA is developing algorithms that will automatically scan the EMR to identify the use of genomic applications not captured by structured data sets. u

Understanding Molecular Subtypes Is Basis for Genomic Medicine in Prostate Cancer

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ncorporating genomics into the practice of medicine requires demonstration of the ability of biomarkers to impact clinical decision making and ensuring that patients receive the best therapy based on genomic findings. Scott Tomlins, MD, PhD, reviewed efforts to realize genomic medicine into prostate cancer diagnosis and management at the second annual Global Biomarkers Consortium conference.

Genomic medicine starts with understanding basic molecular subtypes. Numerous microarray studies, array CGH studies, and characterization of the prostate cancer transcriptome and genome have identified common alterations. “As in lung cancer, we can define prostate cancer molecular subtypes,” said Tomlins, assistant professor, pathology and urology, University of Michigan Medical School, Ann Arbor. “The easiest way to do this is to look for the presence of ETS gene fusions. Like an ALK rearrangement, these are chromosomal rearrangements that occur in prostate cancer, but they occur in about 50% of prostate cancers.”

More than 50% of prostate-specific antigen (PSA)screened prostate cancers harbor fusions between the TMPRSS2 and ERG genes.

No clear individual driver has been identified in prostate cancer patients without an ETS fusion.

Exome sequencing of prostate tumor and normal pairs has discovered focal loss in common tumor suppressor genes such as PTEN, TP53, and RB1. Point mutations have been found in several genes including TP53, SPOP, PTEN, FOXA1, and MED12, each with a prevalence of <10%.

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“We have things in prostate cancer that we know are potentially targetable, but there hasn’t been the momentum to do what’s been done in lung cancer, where we looked for these patients to find them,” he said.

“Interestingly, there are almost no high-level focal amplifications in prostate cancer until the posttreatment setting. There is a high level of genomic aberrations, and we’re seeing these as you start to do whole genome studies.”

Scott Tomlins, MD, PhD

Point mutations have been found in several genes including TP53, SPOP, PTEN, FOXA1, and MED12, each with a prevalence of <10%.

A TMPRSS2:ERG fusion serves as a urine biomarker for prostate cancer. It has been shown to improve on serum PSA for predicting cancer in men undergoing diagnostic biopsy. “It is as specific for prostate cancer as we can get,” he said.

A urine-based test developed at the University of Michigan uses quantification of TMPRSS2:ERG and PCA3 along with PSA to calculate the prostate cancer risk on needle biopsy. Rather than provide a positive or negative value, the test will provide the risk of having cancer and high-grade cancer, with estimates of what constitutes low, intermediate, and high risk, said Tomlins.

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Mutational Landscape Integrative profiling of lethal castration-resistant prostate cancer (CRPC) has been conducted at the University of Michigan in an effort to characterize mutations present. The exomes of 50 lethal, heavily pretreated metastatic CRPCs obtained at rapid autopsy were sequenced.

The exome data revealed 9 genes that were significantly mutated, 6 of which are recurrently mutated in prostate cancer: TP53, AR, ZFHX3 , RB1, PTEN, and APC. “Prostate cancer has a low mutational burden, but you do see patients with high numbers of mutations,” he said.

The exome data revealed 9 genes that were significantly mutated, 6 of which are recurrently mutated in prostate cancer: TP53, AR, ZFHX3, RB1, PTEN, and APC. Three of the mutated genes did not have roles in prostate cancer: MLL2, OR5L1, and CDK12.

Clinical Sequencing Program: Finding What’s Actionable To translate these findings into potentially target­ able actions for individual patients, a clinical sequencing program for advanced cancers was started at the University of Michigan: the Michigan Oncology Sequencing Center. “We do profiling of the normal germline as well. We do full exome and transcriptome studies, and we do the exome of the normal sample, run it through pipelines, and we present the results to a sequencing tumor board [now called a precision medicine tumor board],” said Tomlins. The board discusses actionable results and sends a report to the genetic counselor and the referring physician. A multidisciplinary tumor board determines which biomarker candidates are actionable.

The University of Michigan has recently initiated one of the first genetically stratified clinical trials (a multiinstitution randomized phase 2 trial) in which ETS gene fusions are assessed (ERG by immunohistochemistry and ETV1 by fluorescence in situ hybridization), and patients are stratified to treatment with either an antiandrogen alone or a PARP inhibitor plus an antiandrogen. u

Practical Problems Must Be Overcome to Move Personalized Medicine Forward in Oncology

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ncorporating personalized medicine into everyday oncology clinical practice will require new paradigms in an effort to match cancer patients with the best therapies and attempts to treat solid tumors at an earlier stage with targeted agents, said Razelle Kurzrock, MD, at the second annual Global BioRazelle Kurzrock, markers Consortium conference.

MD “In a very real way, it’s very hard to institute personalized medicine both in clinical trials and in the community,” she said.

A practical problem to implementing personalized medicine is that common cancers are difficult to treat because each may be >100 different diseases, especially in the metastatic setting, as multiple subtypes of each exist. “Even if some of these tumors have things in common, the individual landscape of each patient may be very distinct,” said Kurzrock, director, Center for Personalized Therapy and Clinical Trials, University of

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California San Diego (UCSD), Moores Cancer Center.

Molecular testing of tumors can make a difference in early clinical trials. “The old way of thinking was that we needed new drugs to treat patients,” she said. “We do need new drugs; no question about it, but very fundamentally, it doesn’t matter how good your drug is; if you don’t give it to the right set of patients, it’s not going to work. Matching the drugs with the right patient is crucial to the future of oncology and maybe to all of medicine.”

The tools to match patients with target-based agents are becoming available, “but in a practical way, this is hard to do.”

The PREDICT study used a histology-independent targeted approach in which multiple molecular aberrations were assessed and used to match patients with targeted agents. When the study started in 2008, molecular profiling was primitive compared with today, said Kurzrock. Single gene assays were used to identify

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12 genetic mutations. Conventional therapy had failed in all 1144 patients enrolled in PREDICT. Many of the molecular aberrations did not segregate by tumor histology. Molecular aberrations were found in up to 73% of patients depending on organ of tumor origin. Most of the molecular aberrations identified were actionable.

Patients for whom a matched therapy was available in a phase 1 setting had a complete/partial response rate of 27%, whereas those who did not have a matching therapeutic had a response rate of only 5% (P<.0001).

Progression-free survival improved with phase 1 matched therapy but not unmatched therapy compared with prior conventional therapy. Overall survival improved with matched treatment (RAF/MEK inhibitor) compared with unmatched (P<.01). PREDICT was not a randomized trial, said Kurzrock, “but our clinical impressions were very positive.”

Another practical problem with personalized medicine in oncology is that patients with metastatic disease usually relapse. Chronic myelogenous leukemia (CML) is a fatal disease that has been transformed with imatinib therapy, with median survival extended to 20 to 25 years, but such success is rare with solid tumors. The conventional wisdom is that solid tumors are more complex than CML, and elucidating combinations of therapies to treat solid tumors is a Herculean task because of this complexity, she said.

However, the conventional wisdom does not account for the precipitous decline in response rates with advancing disease in CML. In the blast crisis, median survival is only about 12 months, and patients develop resistance. “That sounds a little bit like solid tumors to me,” said Kurzrock. She compared blast crisis in CML to metastases in solid tumors.

The transformation in CML outcomes was made possible by treating newly diagnosed disease. “We have

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not done that in solid tumors,” she said. “Comparing metastatic solid tumors to newly diagnosed CML is not an apt comparison.” A practical solution to enhancing outcomes with personalized medicine in solid tumors, therefore, is to treat newly diagnosed patients.

The future of personalized medicine in oncology is actionable cancer gene sequencing, but a practical problem is individual host differences. “The host reaction may be critical to how the tumor responds and also critical to toxicity,” she said.

The future of personalized medicine in oncology is actionable cancer gene sequencing, but a practical problem is individual host differences.

Tumor microheterogeneity is another practical problem. The molecular profile can differ even within a single lesion. A potential solution is liquid biopsy to obtain cell-free or circulating DNA from patients with tumors and performing gene sequencing on this DNA. The technology is moving rapidly.

Lack of training in genomics is a barrier to personalized cancer therapy trials and treatment. At UCSD, a molecular tumor board was started in 2012. It involves a multidisciplinary discussion of patients who have had molecular profiling performed, after which targeted tailored treatment recommendations are issued. “In the future, we’ll have to train oncologists in genomics,” she said.

Another challenge is proving the concept of personalized medicine. To this end, the Worldwide Innovative Network in personalized cancer medicine has been initiated as a signature global trial with genomics and transcriptomics used to navigate end-stage cancer patients to clinical trials. u

Personalized Medicine in Oncology™ offers reprints of individual articles in printed or electronic form to increase awareness of your product or company.

ORDER TODAY! Russell Hennessy • 732.992.1888 • russell@greenhillhc.com

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Personalized Cancer Treatment: Combination Therapies May Be Key to Hitting Tumor Heterogeneity

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ombinations of targeted therapies will be key to overcome resistance that occurs in tumor cells that leads to eventual failure of a single targeted agent, said Alex Adjei, MD, PhD, at the second annual Global Biomarkers Consortium conference.

“Tumor heterogeneity is the predominant Alex Adjei, MD, reason for therapeutic failure in cancer,” he said.

The 2 types of resistance that occur in PhD tumor cells are 1) initial resistance to treatment, and 2) an initial response to treatment followed by resistance (secondary resistance). Secondary resistance may occur as the result of the formation of a resistance mechanism or a secondary mutation.

Inhibiting ALK signaling with agents such as crizotinib has proven to be effective therapy against diseases with ALK-driven pathways.

Personalized medicine has 3 principles: treat those who will benefit, avoid treatment of those who will not benefit, and avoid unnecessary toxicity. Even targeted agents produce toxicities. Identifying those patients who have the highest likelihood of benefit and the lowest likelihood of toxicity will require the use of genomics-driven therapies made possible by detecting genome alterations through techniques such as next-generation sequencing, said Adjei, professor and chair, department of medicine, Katherine Anne Gioia Chair in Cancer Medicine, senior vice president of clinical research, Roswell Park Cancer Institute, Buffalo, New York.

Actionable Targets in NSCLC “The good news is that we are finding actionable targets, and there are drugs in the clinic to target them,” he said. He discussed some of the targets in non–small cell lung cancer (NSCLC).

A translocation of EML4 and ALK is a potent oncogenic driver, responsible for both initiation and maintenance of certain cancers. It has been identified in a small subset of patients with NSCLC who respond to ALK inhibitors.

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Inhibiting ALK signaling with agents such as crizotinib has proven to be effective therapy against diseases with ALK-driven pathways. In a phase 1 study of patients with ALK-positive refractory NSCLC, median progression-free survival with crizotinib was 10 months.

ROS1 rearrangements occur in about 1% of patients with NSCLC. The ROS1 and the ALK tyrosine kinase domains are similar; “they share about 77% of sequence homology,” said Adjei. As such, crizotinib has also been shown to have antitumor activity in advanced ROS1-positive NSCLC, with overall response rates approaching 60%.

RET kinase has also recently been identified as a potential new oncogenic driver in a subset of patients with NSCLC. Cabozantinib has activity in NSCLC with rearrangements in RET, with clinical studies in patients with RET-translocated tumors starting soon, he said.

In NSCLC, activating BRAF V600E mutations occur in 2% or less of tumors, primarily adenocarcinoma, and is a therapeutic target. Dabrafenib is a reversible, small-molecule inhibitor of BRAF V600E kinase. It has been studied in a single-arm open-label study of patients with NSCLC and the BRAF V600E mutation whose disease had progressed on prior chemotherapy. In the first 20 patients treated, the overall response rate was 40%, and the disease control rate was 60%. There was no difference in outcome by smoking status.

Targeting Resistance With Combinations The not-so-good news with the targeted drugs, Adjei said, “is that we don’t cure anybody.” Forty percent or more of patients do not experience tumor regression with the targeted drugs. In NSCLC, most patients will develop resistance to crizotinib within 2 years. These mechanisms of resistance are diverse, from development of ALK resistance mutations to alternative signaling pathways.

“When it comes to ALK, we have second-generation compounds that appear to be very active,” he said. For example, alectinib has shown activity in patients in whom crizotinib has stopped working. LDK378 is an investigational selective inhibitor of ALK that appears to have activity both in crizotinib-naive patients and those with molecularly defined crizotinib-resistant tumors.

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In solid tumors, the critical question in personalizing therapy is whether primary resistance mechanisms (tumor heterogeneity) or acquired resistance is at play.

The first convincing evidence of tumor heterogeneity came from Gerlinger et al in 2012 (N Engl J Med. 2012;366:883-892). In presurgical and postsurgical biopsies of renal cell tumors, they found that 66% of mutations detected in single biopsies were not uniformly present in multiple tumor biopsies. A “favorable prognosis” and “unfavorable prognosis” gene profile were present in different regions of the same tumor, and different inactivating PTEN mutations were present in different portions of the tumor.

With the discovery of different molecular profiles within tumors, “combination therapy will be key,” said Adjei. Combination therapies have been difficult to execute because of overlapping toxicities, such as erythematous rash and stomatitis with MEK and AKT inhibitors.

Drug combinations should employ agents that have nonoverlapping dose-limiting toxicities and the ability to be administered at the full dose of each agent. True cytotoxic synergy is important in the combination, as is dose schedule and sequence.

An example is the response obtained with the addition

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of a MEK inhibitor to continued treatment with the BRAF inhibitor vemurafenib in patients whose cancers progress on single-agent vemurafenib. Inhibiting MEK downstream from BRAF is an indirect attack on RAS proteins that activate the MEK and other signaling pathways that lead to cell proliferation and survival, he explained.

In solid tumors, the critical question in personalizing therapy is whether primary resistance mechanisms or acquired resistance is at play.

Vemurafenib blocks the mutated BRAF protein in melanoma cells but also activates the MEK pathways driven by the formation of RAF dimers that lead to signaling through CRAF. MEK pathway hyperactivation induces secondary cutaneous squamous cell cancers. Blocking this pathway activation with a MEK inhibitor is a strategy that can induce improvement of hyperproliferative skin lesions in patients treated with a BRAF inhibitor. u

Gene Expression Tests Using Bronchial, Nasal Epithelium Under Development for Early Detection of Lung Cancer

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iagnosing lung cancer by swabbing a patient’s nose may be possible in the not too distant future. Changes in nasal gene expression in patients with lung cancer have been found to correlate with changes in gene expression in the bronchus, opening the door to the possibility of nasal gene expression as an early diagnostic biomarker of lung cancer, said Avrum Spira, MD, MSc, chief, Division of Computational Biomedicine, and director of Translational Bioinformatics, Boston University School of Medicine.

“What’s in the nose may be a very good surrogate for what’s going on deeper within your lung, “ he said.

He delivered his remarks at the second annual Global Biomarkers Consortium conference.

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Using Biomarkers for Early Detection Because the discovery of molecular biomarkers has not yet resulted in cures with the use of targeted therapies, efforts should be directed toward early detection and screening.

Currently, fewer than 1 in 5 patients with lung cancer is diagnosed at stage 1, a potentially Avrum Spira, curable stage, and a similarly small proportion MD, MSc is alive 5 years after their diagnosis, he said.

The vast majority of lung cancers occur in persons with a history of tobacco smoke exposure, but only 10% to 15% of smokers will develop lung cancer during their lifetime. The challenge, said Spira, is how to identify the high-risk subset.

The National Lung Screening Trial (NLST) was a

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landmark study that found that annual lung CT scans in asymptomatic smokers reduced lung cancer mortality by 20%. By the criteria used in NLST (age >50 years, >30 pack-years of smoking), about 9 million individuals in the United States would be eligible for screening. But only half of lung cancers occur in this group, he said, creating a need for molecular biomarkers to personalize screening decisions.

“I would argue that the second and more urgent need right now is developing biomarkers that can distinguish a benign lesion from a malignancy that’s found on routine CT screening,” said Spira. “CT screening is incredibly sensitive but has a very high false-positive rate… leading to a lot of unnecessary invasive procedures.”

Numerous molecular biomarkers are in development.

“In the next 3 to 5 years, a number of them are going to be emerging in the clinic to guide both screening and diagnostic decisions in this setting,” he said.

A bronchial airway gene expression biomarker will be available as a CLIA (Clinical Laboratory Improvement Amendments) test in early 2014. “We’re in the process of extending that same type of biomarker into the nasal epithelium so that we have less invasive sampling and the ability to go into the screening setting,” he said.

Field of Injury Paradigm The bronchial biomarkers are based on the “field of injury” paradigm that smoking alters epithelial gene expression through the respiratory tract and that variability in airway epithelial cell genomic response to and damage from smoking are linked to lung cancer.

The sensitivity of bronchoscopy for diagnosing lung cancer is only 50% to 60%, and even lower in the early stages of lung cancer. Many bronchoscopies are therefore nondiagnostic, in which case gene expression information can be used to select patients for biopsy and those that can be noninvasively monitored with repeat imaging studies.

In Spira’s work as founder of Allegro Diagnostics, bronchial epithelial cells were collected at the time of bronchoscopy, allowing for a relatively pure population of epithelial cells that line that airway. RNA was extracted from the epithelial cells and processed on a microarray platform that allows for interrogation of the gene expression of all genes in the genome. An 80-gene biomarker profile was identified that could distinguish between smokers who do and do not have lung cancer.

The 80-gene expression biomarker has been validated on 2 independent cohorts. It has an 80% sensitivity and specificity for lung cancer. “More importantly, if we combine our gene expression biomarker with the routine cytology collected at bronchoscopy, you get 95% sensitivity and 95% negative predictive value,” he said. “So we

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can almost, not quite but almost, rule out lung cancer.”

Based on successful validation, the BronchoGen genomic test will be launched as a CLIA assay in 2014. A clinical validation study of smokers undergoing bronchoscopy for suspected lung cancer is ongoing. Data from the first 350 patients show an area under the curve (AUC) of 0.77 in distinguishing cancer from noncancerous nodules, and a negative predictive value of about 90%. The sensitivity of BronchoGen for nodules <3 cm and for stage I was 88%, compared with 66% for bronchoscopy, and the sensitivity for stage I and II disease was 86% compared with only 40% for bronchoscopy. When the biomarker test was combined with bronchoscopy, the sensitivities increased to 96% and 93%, respectively.

Early data suggest that airway gene expression alterations precede the development of lung cancer in highrisk smokers with dysplasia, making intervention in the preventive setting a possibility.

Further research has extended the field of injury to the upper airway. RNA obtained from nasal mucosal brushings has been used to demonstrate that the gene expression changes in the nasal epithelium reflect the changes observed in the bronchial epithelium in smokers. In a diagnostic trial, cells are being collected from the bronchus and nasal epithelium; microarray analysis is being performed to identify biomarkers in the nose in an attempt to diagnose lung cancer. From the first 100 patients, 60 genes were found to be altered in patients with lung cancer compared with those without lung cancer.

“Those genes that change in your nose when you have lung cancer change in almost the identical matter in your bronchus,” said Spira.

A nasal gene expression biomarker has since been developed. From a training set of 100 patients, a 5-gene nasal biomarker yielded the maximum AUC (0.74). The biomarker was tested on 84 independent samples, achieving an AUC of 0.71. “It’s not quite as good as what we’ve seen in the bronchial airways, but there’s still a relatively good signal-to-noise ratio for lung cancer diagnosis,” he said.

In the clinical workflow, he envisions the nasal test being used in patients who have a very small lung lesion on CT who would not undergo bronchoscopy. “A more important place for the nasal testing is as a screening tool, upstream of CT,” he said. “It might be used to decide who should get annual CTs of their chest. The most exciting potential unmet need is to stratify high-risk smokers, not simply to a CT screening protocol, but also into chemoprevention trials.”

His group is in the process of looking at micro-RNA– based biomarkers in airway epithelial cells as potentially more robust biomarkers. u

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Bench to Bedside, Gene to Drug Discovery Defines New Era of Precision Medicine

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he next decade in anticancer drug discovery promises to be a complicated era of attempts to further define and overcome tumor heterogeneity, cancer evolution, and drug resistance, said Paul Workman, PhD, DSc, at the second annual Global Biomarkers Consortium conference. Killing off multiple cancer cell populations early in the disease through combinations of drugs may represent the future of personalized cancer treatment.

Anticancer drug discovery starts at the molecular level, where the abnormalities in genes and biochemical pathways that cause cancer are identified, allowing for the discovery of gene products that become potential drug targets.

Building on the prior decade of characterization of large-scale genomics, “we now have an incredible amount of information to exploit,” said Workman, head, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.

“Although the amount of genetic complexity in tumors has proven to be huge, we can reduce it down to maybe a dozen or so survival pathways,” he said, which means that the challenge, although daunting, is not insurmountable.

The goal in discovery is to exploit oncogene, nononcogene, and metabolic addictions; microenvironment dependencies; and vulnerabilities of cancer cells to discover innovative small-molecule drugs and essential biomarkers that will constitute the personalized cancer medicine of the future.

Discovery of genes, drugs, and biomarkers is an integrated process in the quest for precision diagnosis and treatment of cancer. Requirements for a drug discovery project start with evidence of a cancer gene followed by development of an instructive gene algorithm that will serve as a target for the drug. In selecting the target, the clinical path and predictive biomarkers must be known.

Patient selection markers must also be actionable. Ultimately, “we’re finding a weak spot in the otherwise strong phenotype of a cancer,” said Workman.

“The discovery of [tumor] heterogeneity means that we are going to have to revisit combinations, either longitudinally by switching the coded genome sequence, or vertically by combining multiple approaches, as the way forward,” he said. To use combinations optimally, drugs must be available for identified molecular pathways and

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cancer hallmark traits (ie, self-sufficiency in growth signals, their resistance to inhibitory signals and their own programmed cell death, their ability to multiply, a limitless reproductive potential, and sustained angiogenesis).

He and colleagues conducted a primary computation analysis of biological and chemical space to prioritize targets for therapeutic Paul Workman, exploration and to identify potentially drugPhD, DSc gable cancer-associated proteins that had been poorly explored. They discovered that of the 500 cancer genes known, 95% did not have a drug developed to act on it. “That’s a devastatingly low basis from which to build armamentariums of combinations,” said Workman.

Killing off multiple cancer cell populations early in the disease through combinations of drugs may represent the future of personalized cancer treatment.

They recommended prioritizing targets based on biology, 3-dimensional structure, and druggability. Forty-six genes have no associated chemical matter (ie, inhibitor) despite being predicted as druggable. “A massive amount of the cancer genome is waiting for drug discoveries,” he said.

Histone H3.3 Mutation as a Driver of Pediatric Glioblastoma One example of a discovery project is the attempt to find a drug that targets a histone 3.3 mutation in pediatric glioblastoma. The breakthrough came when novel, specific mutations in the histone H3.3 gene in pediatric glioblastoma were discovered. Key residues in these genes are associated with posttranslational modification of the histone tail. K27M was predicted to be repressive, while G34 was activating for gene expression. These predictions proved correct. Gene set enrichment analysis confirmed that G34 mutations define distinct expression subgroups of pediatric glioblastoma.

Chromatin immunoprecipitation sequencing for gene localization of H3Kme3 marks and RNA polymerase II identified MYCN – a neuroblastoma-derived proto-

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oncogene – as the top hit. These results were confirmed by quantitative polymerase chain reaction. Knockdown of MYCN was found to reduce cell viability in G34-mutant pediatric glioblastoma, but MYCN is not druggable directly, said Workman.

A robotic siRNA kinome screen revealed that the kinases CHK1 and AURKA stabilize MYCN and thus may be candidate targets in the treatment of G34-mutant pediatric glioblastoma.

HSP90 inhibitors are now in phase 2/3 clinical trials, showing particular promise in HER2+ breast cancer and EGFR-mutant, ALK-rearranged NSCLC...

Heat Shock Protein 90 as Cancer Chaperone Heat shock protein 90 (HSP90) represents a cancerselective network target to overcome tumor resistance.

HSP90 is especially important for folding and activation of oncogenic client proteins, including mutant/amplified oncoproteins and drug-resistant forms. Inhibitors of HSP90 hit multiple cancer targets, pathways, and hallmark traits;

hence they can act as network drugs, said Workman.

HSP90 inhibitors are now in phase 2/3 clinical trials, showing particular promise in HER2+ breast cancer and EGFR-mutant, ALK-rearranged non–small cell lung cancer (NSCLC), consistent with activity where the key oncogenic driver is an HSP90 client.

The HSP90 inhibitor AUY922 exploits heightened dependence of oncogenic client proteins on HSP90. The ERBB2 client protein is highly dependent on HSP90.

This protein is rapidly and extensively depleted by AUY922 in ERBB2+ breast cancer cells. In phase 1 studies, ERBB2+ breast tumor xenograft was highly responsive to AUY922. Activity has been confirmed in trastuzu­ mab-refractory ERBB2+ breast cancer as well as in EGFR-mutant and ALK-translocated NSCLC. This agent has a broader potential to treat prostate cancer, he said.

HSP90 may represent part of a 2-drug combination used early in the treatment of cancer to kill multiple cancer cell populations at once and prevent resistant tumor cells from arising, said Workman.

“As a drug developer, identifying network combination targets is the key to overcome heterogeneity,” he said. “I think resistance will be overcome by adaptive combination treatments in the future, and biomarkers are going to be essential to guide therapy.” u

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INTERVIEW WITH THE INNOVATORS

Walter M. Capone

Multiple Myeloma and the MMRF CoMMpass Study: Revolutionizing Clinical Trial Data Dissemination A Panel Discussion With the Researchers

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he Multiple Myeloma Research Foundation (MMRF) launched the CoMMpass study in 2011 to uncover the molecular segments and variations in multiple myeloma.

This study, the cornerstone of the larger MMRF Sundar Jagannath, MD Personalized Medicine Initiative, is designed to profile multiple myeloma in a way that no other myeloma trial has attempted, by comprehensively characterizing the disease in over 1000 newly diagnosed patients and obtaining their clinical and genomic information at an unprecedented level of detail from initial diagnosis through the course of at least 15 years.

With this effort, the hope is to find the AchilSagar Lonial, MD les’ heel of multiple myeloma in order to accelerate both the science and the testing of new therapeutic approaches to achieve a cure for this disease. The goals of the study include: • Targeting of existing therapies. Patients with different genetic markers are known to react more positively to some therapies than others. The aim is to create a guide to which treatments work best for specific patients, alGregory Orloff, MD lowing doctors to select the most effective treatment for each patient • Personalized treatments. Genetically targeted treatments may offer the best hope for treating and curing multiple myeloma. The MMRF CoMMpass study will

give researchers access to data and insights that will help them design the next generation of multiple myeloma treatments targeted toward patients with specific genetic markers A notable detail of this trial is that the data collected will be made available via the world’s first and only open access data platform in myeloma. The MMRF launched 2 of these first-of-their-kind open access gateways – one for researchers and one for patients – that will facilitate data sharing and accelerate drug development and cancer research. The MMRF Researcher Gateway will upload comprehensive genomic data and clinical data from the CoMMpass study and other global data sets and make them accessible to all scientists, with the goal of speeding up the development of precision therapies and ultimately advancing cures. The MMRF CoMMunity Gateway will aggregate subtypes of myeloma patients and steer them to treatments and trials that are specific to their profile.

The staff of Personalized Medicine in Oncology had the pleasure of working with Walter M. Capone, Chief Operating Officer of the MMRF, to conduct a panel discussion with the researchers and clinicians who have helped to initiate the CoMMpass study; Dr Sundar Jagannath of the Mount Sinai School of Medicine; Dr Sagar Lonial (principal investigator of the CoMMpass study) of Winship Cancer Institute of Emory University; and Dr Gregory Orloff of Virginia Cancer Specialists. To view the interview in its entirety, please go to www.PersonalizedMedOnc.com/videolibrary.

Walter M. Capone is Chief Operating Officer of the MMRF. Sundar Jagannath, MD, is Director of the Multiple Myeloma Program and Professor of Medicine at The Tisch Cancer Institute, Mount Sinai School of Medicine. He is an Investigator for the MMRF CoMMpass study.

Sagar Lonial, MD, is an Associate Professor at the Winship Cancer Institute of Emory University, Director of Translational Research, B-Cell Malignancy Program as well as Associate Director of Hematology Oncology Fellowship Program. He is Principal Investigator of the MMRF CoMMpass study.

Gregory Orloff, MD, is a Medical Oncologist at Virginia Cancer Specialists. He is an Investigator for the MMRF CoMMpass study.

Mr Capone I would like to begin our discussion by asking each of you to define precision medicine in your own words, particularly as it relates to the treatment of patients with multiple myeloma. Dr Orloff, would you mind offering the first perspective?

Dr Orloff I would define personalized medicine in a number of different ways. It is the molecular profiling of individuals to better stratify their risk, to study the molecular story of multiple myeloma, and to find new drug targets.

At the same time, as a clinician, personalized medicine is the individual’s assessment of a patient. Some-

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times the patient may have comorbidities that would lead us to choose a drug therapy that would be different than for another individual.

Dr Jagannath I agree with your statement, Dr Orloff. We always try to take each patient as they come with their clinical presentation as well as their disease characteristics.

We are trying to understand the disease biology in greater depth. Personalizing medicine is important because multiple myeloma is not a single genetic disorder, and so there are multiple abnormalities happening. Even in a single patient there are a number of clones of myeloma, and at any particular time there is a driver mutation that causes clinical manifestation of the disease. Then we treat the disease and it goes into remission, but not all the clones are being eradicated. Once we understand in greater depth through the CoMMpass trial what the driver mutation is, we can decide how to approach it.

Mr Capone Thank you very much, Dr Jagannath. Dr Lonial, your perspective?

Dr Lonial In many other cancers when we think about driver mutations, we think about a single abnormality.

When you block that abnormality, the disease responds tremendously. And in many of those diseases – such as lung cancer or breast cancer – they don’t have great therapies outside of those single driver mutation tumors.

In myeloma we’re fortunate. If you take a proteasome inhibitor and an IMiD and a steroid, almost everybody will respond, but the durability of that response is what’s so different, and that’s where the individual mutation states and the differences in genetic heterogeneity really present themselves. So in my mind, using CoMMpass will help us to build on what we already have as a good platform – proteasome inhibitors, IMiDs, corticosteroids – and put in that fourth drug potentially, whether in sequence or in combination, that helps get to that Achilles’ heel.

Defining Goals of the CoMMpass Trial Mr Capone Dr Lonial, could you give your perspectives as the principal investigator for the CoMMpass trial and what you see as perhaps the most important goal in the trial?

Dr Lonial I think there are lots of large trials being done around the world in which patients all get uniform therapy throughout the entire course of a given protocol.

What CoMMpass allows us to do is get real-world experience with patients who are treated in everybody’s clinic, not just patients who fit these very selective clinical trial enrollment criteria. Basically to enroll, you have to have myeloma. It’s really pretty simple.

Then it allows us to get that nice diversity of treatment approaches with the genetics and long-term fol-

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low-up so that we can really sit down with patients and say, “there are 40 or so patients who had exactly what you have and were treated just like you were in this clinical experience, and this is what happened to them.” So I find the heterogeneity of the treatments to be helpful in trying to tailor treatments to patients.

Dr Orloff I have a comment that’s a bit sobering. The great advances we’ve made in the last 10 years for the majority of patients – nearly doubling survival – unfortunately haven’t had significant impact in that subset of patients we define as high-risk based on our current methodology for stratifying patients at the time of their diagnosis, even at the molecular level. And I think perhaps a significant goal of the CoMMpass trial will be to identify new targets and therapies for that subset of patients we have unfortunately been unable to affect.

Before CoMMpass, we’ve never had a prospective way to say this particular subset of patients do poorly or do well with these treatment approaches.

Dr Jagannath I completely agree with both of you.

We need new targets, especially for high-risk myeloma patients. But in general practice it’s good to know that patients are treated in different places in different ways, but their outcomes are more or less similar, because we have information from individual clinical trials on patients who are treated uniformly, and their outcomes.

Before CoMMpass, we’ve never had a prospective way to say this particular subset of patients do poorly or do well with these treatment approaches.

Mr Capone That’s very helpful to understand just what differentiates CoMMpass from efforts that have gone on before. The heterogeneity of multiple myeloma makes it very complex in terms of defining and pursuing

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treatment approaches. Could you please give us your perspectives about how the MMRF CoMMpass study will help to more accurately link outcomes to genetic profiles.

Dr Jagannath The main purpose of the CoMMpass trial is not only do the deep sequencing and know the biology of the disease; it is also tied to the clinical outcome of the patient, so you’re going to be able to put both of them together – how the patient fared on the treatment and how the disease presented in that particular patient.

Dr Orloff I think the CoMMpass trial has already in its interim analyses uncovered the extraordinary heterogeneity of this disease. For many years we thought that all cancers were due to just 1 cell transforming, growing, and proliferating abnormally. We’ve come to understand through much of the cancer research that that is not the case.

To be able to include our European and Canadian colleagues in this kind of a trial is important because it does build that larger team.

And as has been uncovered in the first of the interim analyses, there are subclones of this disease that remain permanently in patients, unfortunately leading to the incurability of the disease. It is the study of those subclones that will be paramount.

Dr Lonial Heterogeneity is clinically challenging as well as biologically challenging. I think we’ve all had patients who were sitting next to other patients in the waiting room and said, “You know, I was on drug X and it worked for me for 5 years. Why didn’t it work for the person who was sitting next to me?”

With the longitudinal follow-up of patients in the CoMMpass study, we’re able to look at genetics. We’ll be able to not just analyze how patients did in a clinical trial based on whether they received regimen A versus B, we’ll be able to individualize the treatment, recognize the genetic differences, and observe the outcomes, which no trial to date has really been able to do.

Dr Orloff Dr Lonial, I think your analogy of the waiting room is correct. We all see patients whose workup and stratification based on our current methodology would be considered equivalent, but their outcomes are clearly distinctly different.

Implications of International Involvement in the CoMMpass Trial Mr Capone Dr Lonial, the MMRF CoMMpass study

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is on the verge of becoming international. We’ve just started enrolling new sites and new centers in Canada, and soon we will be opening sites in Europe as well. Can you provide your perspective on how international sites and patients in the study will have an impact on the data?

Dr Lonial I think it’s a real opportunity for us. Myeloma investigators and clinicians have really enjoyed the global approach to myeloma drug development.

We may have done some of the early trials in the United States, but the large phase 3 trials are usually done around the world with our European and Asian partners.

To be able to include our European and Canadian colleagues in this kind of a trial is important because it does build that larger team. I think it also adds some level of genetic diversity, to be honest with you, and knowing that it’s a heterogeneous disease, genetic diversity helps us to better understand the drivers and how to treat myeloma overall.

Dr Jagannath I think that one of the strengths of the CoMMpass trial is that it is not a defined treatment protocol. You are able to incorporate not only multiple sites in the United States but in Canada and Europe as well and still fulfill the objective of the CoMMpass trial; that is, no matter how you are treated and where you are treated, we would like to know what the outcomes and challenges are. It also gives us a better perspective about certain subtypes.

The Europeans and the Canadians don’t treat exactly like the Americans. That by itself will be fundamentally important. I think that’s the beauty and the strength of the CoMMpass trial compared with an individualized, single-institution trial or a single cooperative group trial.

Dr Orloff I think even beyond the science component of the heterogeneity of our populations is what we’re launching today – the new platform through the Web in order that researchers everywhere will be able to use this information. And even if the CoMMpass trial remained as an undertaking just in North America, that endeavor would still be fulfilled, but I think this will allow scientists and researchers around the world to embrace it to a much greater extent and in fact utilize intellectual property to the betterment of all.

Dr Lonial And from the patient perspective, if you’ve got people from both sides of the ocean banding together to say, “We all have the same abnormalities, where are the trials,” I think it does bring the community, both the treating side and the patient side, closer.

Dr Orloff In that respect, build the critical mass, so we need to truly accelerate the scientific and therapeutic advances we’re all striving for.

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Advancing Therapeutic Approaches to Cancer Mr Capone Dr Orloff, I’d like to ask you how you believe the CoMMpass trial might help impact and perhaps enhance the development of new therapeutic approaches for different tumor types.

Dr Orloff I would want to begin by saying the launch today of the research gateway is probably the greatest component that will lead to the molecular understanding of this disease and allow for this information to be parlayed into the research undertaken all over the world studying other malignancies. And I have no doubt that by the careful profiling of more than 1000 patients worldwide and the ability of researchers everywhere to utilize this information, this information will spill over to better the outcomes for patients with other malignancies.

Dr Jagannath This is a wonderful opportunity, as we saw when the MMRF published an original study in Nature in which BRAF mutations were identified in 5% of multiple myeloma patients. We already knew BRAF was a very important mutation in melanoma, and there is a drug being used there. My feeling is there will be common pathways and driver mutations that are shared across cancers, so the drug that is being developed in one disease could be repositioned in other diseases. And likewise, as you understand the pathway of the driver mutation in one disease, it will immediately facilitate the understanding of the other diseases. There will be a lot of give and take because of the heterogeneity of myeloma. This is why patients have to be sequenced in deep sequencing and followed.

Dr Lonial I think a great example of that is the MMGI [Multiple Myeloma Genomics Initiative] in which KRAS and NRAS were identified as very common abnormalities and mutations seen in a small subset of patients.

The lung cancer and the colon cancer researchers were all over NRAS and KRAS because it’s pretty significant for their outcomes as well. We’re all playing on the same team. We all want to target KRAS and NRAS, and in fact, KRAS and NRAS may have an impact on our own existing therapies. There may be certain subsets that are more or less likely to respond based on KRAS or NRAS. NF-κB is another one. There are mutations, and then you have NF-κB pathways that are really relevant for lymphomas.

I think if we can identify those common mutations, it’s not just our team working against them, it’s a larger group of people that helps us to attack cancer globally.

Mr Capone It really does reemphasize the underlying biological basis and the shared connection that we have with many other types of cancer.

Dr Lonial, how do you believe the CoMMpass trial

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www.themmrf.org. data will help to inform and standardize, perhaps improve, laboratory testing for molecular biomarkers and the development of companion diagnostics for myeloma therapies?

Dr Lonial I think one of the things that we have done in myeloma therapy is to treat patients with myeloma in somewhat of a homogenous way.

What I think CoMMpass will allow us to do is to look at the patient’s treatment regimen and their genetic profile to see if their mutations have predicted for responses. If they did, those become biomarkers. Biomarkers may not be as important in the induction therapy setting, but they may be really important in the maintenance setting.

Biomarkers may not be as important in the induction therapy setting, but they may be really important in the maintenance setting.

If you know that people with certain mutations are more likely to respond to an IMiD in the maintenance setting, you’re almost always going to treat them with an IMiD as maintenance therapy.

I think as these get more and more defined, we will start to identify the predictors of response or lack of response.

Dr Orloff I might extend upon your comment that biomarkers may be very helpful in determining a more ideal second-line therapy, Dr Lonial, to push it a little earlier in the course of therapies. While we don’t have an enormous portfolio of choices at this time, I think we are all quite confident there will be new drugs and new families of drugs available within a short period, and we’ll be better able to understand what would be the better strategy for second- and third-line therapy.

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Dr Jagannath Dr Orloff, you spoke earlier about the high-risk patients in whom we really need to make progress. Now we may actually find out that there are not just low-risk and high-risk patients, there are multiple subsets of patients, and as new drugs come out for different driver mutations, even how we may treat these patients may change over a period of time. They may not all be starting with the proteasome inhibitor, and IMiD modular molecular, etc. We started out with the term “personalized medicine.” It may come to fruition that we may understand that these patients could be handled differently at the different phases of the disease. I think this is an important discovery.

By providing this information to the entire world – to all researchers – we’re in fact breaking down the barriers regarding intellectual property.

Mr Capone Longitudinal follow-up really is key to be able to do that, because what you’re going to see are patients who present with a certain profile at diagnosis.

They receive a certain treatment, and when they relapse, if unfortunately they do relapse, we’ll see what that profile has changed to as a consequence of original mutations and treatment, and that will help us to select a second, third, and fourth line to try and avoid those kinds of problems.

Dr Orloff I think what we just said is so important.

This is a discovery. We’re looking for new answers.

Open Access Through the MMRF Researcher Gateway Mr Capone Being able to map and anticipate and create as long as possible pathways for patients to achieve durable remissions clearly will be aided by this type of approach.

Certainly, obtaining all the comprehensive information over an extended period as we’ve talked about – clinical, genomic, and the full profile of disease – will be critically important and an elemental step of the MMRF CoMMpass study.

Could you describe what the significance of providing that kind of information openly to researchers around the world would be? What goal would you like to see coming from that type of approach? Also, what is the significance of the MMRF Researcher Gateway, the approach by which many researchers will be able to access this information? Dr Orloff, would you start with the idea of making this kind of data open and available to researchers worldwide?

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Dr Orloff Intellectual property is certainly an issue in the development of all strategies to care for patients throughout medicine. By providing this information to the entire world – to all researchers – we’re in fact breaking down the barriers regarding intellectual property.

Dr Jagannath It’s a change in paradigm approach.

Dr Orloff Exactly.

Dr Jagannath That’s important. Researchers have different interests and certain patterns of thinking about their particular research. By making our database universally available, researchers who are working on something completely different can access the myeloma database and make observations that sometimes even the people working in the field may not have picked up. This is a quantum leap. To me this is really a major advance in the way we want to move the field.

Dr Lonial I think that’s absolutely right. I think there are data that ultimately do get put on portals for availability, but that’s often years after the data have been acquired and somebody else has had a chance to get the first evaluation and publication on those data. Once that occurs, then the data are put up on a public site. This is going out from the get-go. Giving everybody access to the information and knowledge is incredibly powerful and creates a bigger team. People all over the world are going to have access to the genetics and genomics with longitudinal follow-up. Patients are going to be able to partner better with institutions to say, “This is what I have, how can you help me?”

Dr Jagannath I think the strength of allowing Canadians and Europeans to participate, in addition to rapid accrual, is that you are actually bringing international investigators to the table so to speak. That in itself is important.

Mr Capone That supports the effort to really unite and create that critical mass and also create the methods by which we can actively share the information and the insights, as you described, which might have no direct connection or application to myeloma. And, Dr Jagannath, I also recall that you viewed the MMRF Researcher Gateway in a certain context as leveling the playing field among different types of institutions and the investigators and researchers regardless of their vantage point of the disease. So thank you very much for that perspective.

Thank you, because really what you have just described was one of the fundamental premises of establishing the MMRF Researcher Gateway, which was really an effort to unite many different types of researchers and research centers and the ability to not only analyze but share the data that they’re deriving and, as Dr Jagannath has said in a previous context, level the playing field among centers so that everyone can benefit and acceler-

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ate their own individual discoveries and benefit from the work that other centers are doing at the same time.

Dr Lonial, I’d like to ask you, from the data that have been released on the CoMMpass study so far, what conclusions or observations would you offer?

Dr Lonial I think what we’ve seen already in the first patients who have been enrolled is that there is a tremendous variation among what different patients are receiving, and that diversity of treatment will be tracked over time so we can look at outcomes based on the individualized treatment approaches.

From the genomics perspective, which is the other real gold mine in the trial, what we’ve already seen in the first patients who have been sequenced is validation of some of the discoveries that were presented in the original MMGI that was published in Nature. What we don’t have from the MMGI is tracking as to what that meant and identifying what therapy patients received that led to that clinical outcome.

So those 2 pieces of information really are why this trial is going to be even more important than what we learned from the early studies of sequencing.

Dr Orloff When we were first putting together the trial, we wrestled with what would be first-line therapies for patients. While initially there was some debate and thought that it should be just 1 single course of treatment, in fact a 3-drug regimen was what many favored, as there was agreement within the MMRC [Multiple Myeloma Research Consortium] that it was necessary to offer the opportunity for physicians to personalize the approach to the care of their patients based on their needs. And for that very reason, the data now are probably a bit confusing but are going to be very helpful in long-term follow-up.

Dr Jagannath The strength of this whole CoMMpass trial is allowing the physicians to treat in the community the way they would like to treat the patients. We don’t dictate how they should be treated, but we will collect all the information, and thereby the data become robust so we can actually answer all these important questions for the future.

Mr Capone Dr Jagannath, I’d like to ask how you would expect to utilize the data from the MMRF CoMM­pass trial to help guide treatment decisions in your patients.

Dr Jagannath The CoMMpass trial is really a paradigm shift. Here, as the patients are accrued, the data are made available in real time through the portal for investigators. They are not sequestered. They won’t be analyzed at the end of 2 years and somebody’s going to present them. You can actually know what is happening.

In the meantime, there are other investigators, other clinical trials that are releasing information. There are

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KRAS and NRAS mutations as Dr Lonial alluded to, and there are drugs in clinical trials. I hear that one of the patients whose disease was progressing was given this inhibitor for the RAS mutation, and the patient went into remission. We’ve also heard about a BRAF mutation in Germany. One of the patients received a medication for the BRAF mutation, and his myeloma went into remission.

I would be getting all this information in real time, so when my patient’s disease comes back, I can go back into the database and find out about other patients with this particular genetic feature. So this really is a remarkable opportunity.

I think what we’ve seen already in the first patients who have been enrolled is that there is a tremendous variation among what different patients are receiving...

Dr Orloff I do want to make one cautionary statement. In the field of clinical medicine and oncology we do believe in evidence-based approaches, and those are the approaches to deciding what would be the best therapy for the individual and the aggregate. And a little caution to say that a single individual’s outcome utilizing an agent because they had a specific molecular profile could benefit the larger population, it still remains a question.

Dr Lonial Regarding the BRAF mutation, I think we’re all excited that we have drugs on the shelf that we can use, but we don’t know the natural history of BRAF from diagnosis. So to be able to get a collection of 50 patients who had BRAF mutations at the time of diagnosis and see what happened with treatment X is very exciting. We’ve heard the great stories from Germany and from the UK in the refractory/relapsed setting where there was nothing else left to do, and that drug really made a big difference, but it may do just as well from the beginning for people who are BRAF negative. That to me is an incredibly exciting opportunity to learn about the natural history of these mutations from diagnosis.

Dr Jagannath I completely agree. I also understand evidence-based medicine is important. What I want to convey is the palpable excitement that I feel in having something like CoMMpass rolled out to a large number of patients and in what it could do by making the information available in real time. It also excites the pharmaceutical industry. They may have a drug with 1 indication. But where else can they move with this molecule?

So that makes them excited because this information is made available to them too.

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I think it is multiple combinations. But I completely agree, we are to be cautious, and evidence-based medicine is very important.

Mr Capone I’d say the one aspect that perhaps really distinguishes or differentiates the initiatives that we’re all embarking on with the MMRF CoMMpass trial is that the strength of having so many centers – over 50 in the United States, over a dozen across Canada, and about an equal number eventually in Europe – is the ability to move from one approach or interpretation, like you just mentioned, Dr Orloff, to one in which we’re actually rapidly bringing together numbers of patients with a similar profile to assess and determine: is this real? is this signal actually happening? and is that outcome replicable or not? That is really helping to advance the science at a much more rapid pace.

I think this opens up many opportunities.

We cannot necessarily predict the future, but this is a good beginning, and it’s very important for the field.

And the infrastructure that you’ve all helped to create and the vision that you had from the very outset has enabled that platform to go forward. So in this way hopefully we’ll move forward that much faster.

Dr Orloff I heard the CEO of the MMRF used the phrase “big science,” and that’s really what the goal is here too. Larger numbers will reveal answers more quickly.

Shaping the Future of Clinical Trials Mr Capone Dr Lonial, I’d like to ask if a chromosomal abnormality or biomarker is detected in the MMRF CoMMpass trial, how do you think this would be tested in future clinical trials through the CoMMpass network and perhaps involving patients from the trial?

Dr Lonial I think a lot of what we’re going to be seeing in terms of the small data sets that come out of that giant, 1000-patient database are hypothesis-generating ideas. So we see somebody that has, let’s just take something simple, p53 deletion, 17p. We see that occurring.

We see the outcomes, we see the other genetic abnormalities that are associated with patients with p53. Not all p53 deletions are the same. There are patients who do better, there are patients who do worse, and we can look at those individual components and enroll them on a trial within the MMRC or other large trial sets, and patients will know, “I have this mutation. Is there a trial somewhere that focuses just on this mutation?”

And that concept is exciting because it really does take it out of just the individual investigator’s hands. We

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all like to enroll patients, suitable patients for suitable trials, but it also gives the patients who may not live in that city the opportunity to say, “This is what I have, and if I go to this place 2½ hours away I can get this drug that may target specifically what I have.” And those kinds of small hypotheses that we generate from the CoMMpass trial will, I think, be useful in helping to fuel faster enrollment to those targeted trials.

Dr Jagannath Regarding the findings in the CoMMpass trial, we are making them available globally, and others are also doing clinical trials, and they would have access to them. So the hypothesis-generation testing becomes universally available, and people can decide which needs to be tested right away for which new drugs that are available. So that will also help shape how progress is made.

I think this opens up many opportunities. We cannot necessarily predict the future, but this is a good beginning, and it’s very important for the field.

Mr Capone To make these kinds of trials happen for targeted therapeutics, a large network that connects patients and researchers working together more actively will help enable this progression much more quickly.

As we bring this discussion about the MMRF CoMM­ pass clinical trial to a close, I’d like to ask you for your perspectives on the future prospects for this kind of groundbreaking initiative and in one sense how we can ensure, whether through education or other initiatives, that the broader oncology community is able to benefit from the findings and the science that is being generated.

Dr Orloff I’ll begin by saying I think this is an enormous task of the MMRF and the MMRC. This is an unprecedented study. There is no doubt that in the years to follow we’re going to find new drug targets, develop new agents, and improve survival of individuals with this disease. It’s incumbent upon the MMRF to find ways to bring this information to the larger community, a very difficult task.

Dr Jagannath I agree with that. This is really a groundbreaking advance and a way to bring all the physicians and patients together. What I mean by that is you’re going to collect all these deep secrets, information on all these patients, and the clinical information is tied to the data, so the data are extremely valuable, and you are making these data available in real time to the physicians and the patients who are participating in the clinical trial, for their benefit, but also to the wider community of investigators, and to the pharmaceutical industry. So I’m pretty sure everybody will be watching for the success of this particular program, and if it is successful, and it makes rapid transformation in the treatment and finding a cure for myeloma, I’m pretty sure this paradigm will be readily adopted by others.

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So I think this has great potential in many ways. It is groundbreaking. It levels the playing field because the information is made available to everyone at the same time, in real time. That has never been done so far.

Dr Lonial I think one of the things we struggle with as a myeloma community is that if you ask 5 different myeloma doctors how to treat a given patient, you’ll get 7 different answers because there’s no clear-cut standard way to approach patients. We debate regimen A versus regimen B, and there’s a lot of confusion in the world about what the best regimen or treatment is because we’re trying to look at a small subset of patients here or there and are not able to answer the question.

What I think CoMMpass will allow us to do is to get a large enough data set with clinical heterogeneity, lots of patients, genetic heterogeneity, lots of different types of patients, and treatment heterogeneity so that you could then go back and say well, if you have a 414 with this mutation, and you got a 3-drug regimen, your outcome was actually really very good. That could be incredibly valuable for the oncologists to help decide how to navigate through this menu of 8 different regimens to choose the one that he or she thinks is going to be the best for the patient. Disseminating that information is really important.

Dr Orloff And I think there are guidelines and there are pathways for the treatment of patients with the different malignancies. Myeloma has a pathway, but it’s really a bit complicated at this point, and what we’re really going to be able to do is build a more careful pathway for people, both physicians in academic centers and within the community, to follow along in the treatment of their patients.

Mr Capone I’d like to thank each of you for your time this afternoon and for your very helpful and insightful perspectives about the MMRF CoMMpass trial, the MMRF Researcher Gateway, and the MMRF CoMMunity Gateway, and how this entire effort is intended to help accelerate the advancement of our understanding of this disease and accelerate the assessment and rapid progression of new therapeutic approaches to help extend and improve the lives of myeloma patients.

We’re just a

I’d just like to close by recognizing your individual contributions to help making this program a success so far and to creating such great promise and vision for it.

Dr Orloff, you actually enrolled the first CoMMpass patient back in July 2011. Getting the trial up and running was really through Virginia Cancer Specialists, so we can’t thank you enough for that effort.

Dr Jagannath, yours was the first academic institution along with Washington University Medical Center to sign on to the CoMMpass trial, to understand what we were trying to do, to convey information to the public rapidly to advance the science dramatically, and you’re also the leading enrolling center in CoMMpass right now.

It is groundbreaking. It levels the playing field because the information is made available to everyone at the same time, in real time. That has never been done so far.

Dr Lonial, you have stood with us along with Drs Orloff and Jagannath to help design the studies from the outset, and you are the pioneer who agreed to sign on for this mission for the duration of time that we have, up to 10 years, so with your vision and your inspiration collectively this will be an unprecedented success.

My thanks to you all. u For more information about the MMRF Personalized Medicine Initiative and the CoMMpass trial, please contact MMRF, 383 Main Avenue, 5th Floor, Norwalk, CT 06851. Phone: (203) 229-0464. E-mail: info@themmrf. org. www.them mrf.org

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CONTINUING EDUCATION

Faculty Perspectives

NOVEMBER 2013 • VOLUME 4 • NUMBER 3

™

ADVANCES IN THE TREATMENT OF CHRONIC MYELOID LEUKEMIA

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

LETTER

FROM THE

EDITOR

Progress in the treatment of hematologic malignancies has been remarkable over the past decade, primarily due to the introduction of targeted agents, a better understanding of prognostic indicators, and new data on biomarker analysis. There is no doubt that these advances have great potential for improving outcomes; however, hematologists and oncologists who seek to provide state-of-the-art therapy for their patients may be challenged by the rapidly shifting paradigm of care. In 2013, a wealth of new data regarding the treatment of chronic lymphocytic leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndromes, myelofibrosis, and multiple myeloma has been presented at major scientific meetings throughout the world. In this “Faculty Perspectives” newsletter series, we will continue to feature highlights from these meetings, along with perspectives from highly respected thought leaders in the field, which will provide valuable practice implications for the management of your patients with hematologic malignancies.

Sincerely,

Vice President of Finance Andrea Kelly

Paul Richardson, MD RJ Corman Professor of Medicine Harvard Medical School Clinical Director Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute Boston, Massachusetts

Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede

FACULTY

Director, Creative & Design Robyn Jacobs

Jerald P. Radich, MD Member and Professor Clinical Research Division Fred Hutchinson Cancer Research Center Seattle, Washington

Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean

David P. Steensma, MD, FACP Leukemia Program, Dana-Farber Cancer Institute Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

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

Supported by educational grants from Millennium: The Takeda Oncology Company, Celgene Corporation, and Incyte Corporation.

Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

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

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

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FACULTY PERSPECTIVES Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Millennium: The Takeda Oncology Company, Celgene Corporation, and Incyte Corporation.

Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with chronic myeloid leukemia (CML).

Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of CML. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.25 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.

Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.25 contact hours.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this applicationbased activity provides for 1.25 contact hours (0.125 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-025-H01-P.

Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss emerging data and recent advances in the personalized treatment of patients with CML, and integrate key findings into clinical practice • Outline contemporary prognostic and predictive biomarkers and patient characteristics for CML and apply the results to create an individualized approach to managing each patient

Paul Richardson, MD, is on the Advisory Board for Bristol-Myers Squibb, Celgene Corporation, Genmab, Johnson & Johnson, Millennium: the Takeda Oncology Company, Novartis, and Onyx.

He does not intend to discuss any non-FDA-approved or investigational use of any products/devices.

David P. Steensma, MD, FACP, is a stockholder for Ariad. He does not intend to discuss any non-FDA-approved or investigational use of any products/devices.

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.

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Estimated time to complete activity: 1.25 hours Date of initial release: November 14, 2013 Valid for CME/CPE/CE credit through: November 14, 2014

Faculty Disclosures Jerald P. Radich, MD, is on the Speaker’s Bureau and is a Consultant for Amgen, Ariad, Bristol-Myers Squibb, Incyte, Novartis, and Pfizer, and has a research contract for laboratory supplies with Novartis. He does not intend to discuss any non-FDA-approved or investigational use of any products/devices.

Highlights from EHA 2013 Introduction Chronic myeloid leukemia (CML) accounts for 15% of all adult leukemias. The median age of disease onset is 67 years; however, CML occurs in all age groups.1 In 2013, an estimated 5920 cases (3420 men and 2500 women) will be diagnosed in the United States, and 610 patients will die from the disease.2 CML is characterized by a consistent chromosomal abnormality (the Philadelphia [Ph] chromosome), which carries a unique fusion gene, termed BCR-ABL1.3 Three tyrosine kinase inhibitors (TKIs) are currently approved by the US Food and Drug Administration (FDA) as frontline therapy for chronic-phase (CP) CML: imatinib, dasatinib, and nilotinib.4-6 Dasatinib and nilotinib are also approved for the treatment of patients resistant or intolerant to imatinib.5,6 Two other TKIs, bosutinib and ponatinib, were also recently approved for the treatment of patients with resistance or intolerance to prior TKI therapy.7,8 Several presentations at the 18th Congress of the European Hematology Association (EHA), held in Stockholm, Sweden, on June 13-16, 2013, discussed novel treatments and strategies for CML. In this supplement, Jerald P. Radich, MD, from the Fred Hutchinson Cancer Research Center, and David P. Steensma, MD, FACP, from the Dana-Farber Cancer Institute, offer their perspectives on key data from these presentations.

A NOVEL METHOD FOR DETECTING RESIDUAL DISEASE IN PATIENTS WITH DURABLE REMISSION

Imatinib, an adenosine triphosphate analog, selectively inhibits the enhanced tyrosine kinase activity of the BCR-ABL1 oncoprotein and induces a complete cytogenetic response (CCyR; defined as a state in which the Ph chromosome is no longer detectable) in the majority of patients.3,9,10 However, patients who achieve CCyR can still carry as many as 109 leukemic cells.11 Therefore, in patients who achieve CCyR, BCR-ABL1 transcript levels are monitored using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) to assess the amount of residual leukemia.12,13 A consensus standardized measurement scale, known as the BCR-ABL International Scale (BCR-ABL[IS]) is used to allow direct comparison of BCR-ABL RNA levels (measured by qRT-PCR) from one laboratory to another.14 Using this scale, a major molecular response (MMR) is defined as a BCR-ABL(IS) transcript level of ≤0.1%.15

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An MMR is defined as a ≥3-log reduction in BCR-ABL1 mRNA.15 However, laboratories that are running at the IS sensitivity use equipment that is capable of higher sensitivities—up to 4.0-log and 4.5-log reductions—and thus can assess deeper, more durable molecular responses. With the increased sensitivity of PCR testing equipment, molecular responses are "graded" as MR3.5, MR4.0, and MR4.5: An MR4.0 is defined as BCR-ABL(IS) transcripts of ≤0.01%, and an MR4.5 is defined as BCR-ABL(IS) transcripts of ≤0.0032%.15 A complete molecular response (CMR) occurs when there is no detectable BCR-ABL mRNA as assessed

by PCR using IS with a sensitivity of ≥4.5-log reduction or more from the standardized baseline.1 Studies indicate that approximately 40% of patients with CML who achieve a stable CMR on imatinib for at least 2 years are able to stop imatinib treatment and remain in molecular remission after drug discontinuation for at least 2 years, suggesting the possibility of an “operational cure.”16 However,

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Figure 1. Percentage of Patients Newly Diagnosed With Philadelphia Chromosome–Positive CML Reaching MMR With Nilotinib vs Imatinib: 24 Months and 4 Years.18,19 100

71%

Nilotinib 300 mg BID

Imatinib 400 mg QD

Nilotinib 400 mg BID Imatinib 400 mg QD

80

73%

67% 60

56%

44% 40

Percentage of patients with MR

Percentage of patients with MMR

76%

Nilotinib 400 mg BID

20

60

56% 50% 40%

40

37%

32% 23% 20

0 24 Months

4 Years

BID indicates twice daily; CML, chronic myeloid leukemia; MMR, major molecular response; QD, once daily.

the safe introduction of a TKI withdrawal policy would require a reliable and cost-effective method of identifying patients with the lowest likelihood of relapse, which is likely to be related to presence of residual disease. At EHA 2013, Alikian and colleagues described a novel method for detection of residual disease.17 This method, based on targeted next-generation sequencing (NGS), allows identification of BCR-ABL1 breakpoints from enriched genomic BCR and ABL1 DNA, followed by rapid generation of DNA-based qPCR assays. In clinical samples from 9 patients in CMR, the new method detected residual disease in 3 of 9 patients, demonstrating that DNA-based qPCR assays can detect residual disease in patient samples in which CML cells persist below the detection threshold of qRT-PCR. The authors noted that their results also demonstrated the variation in residual disease levels that can be found among patients who have achieved a CMR: While 3 of 9 patients had detectable residual disease, disease levels in the remaining 6 were presumed to be exceedingly low or completely absent. The authors concluded that NGS-facilitated DNA-qPCR may prove valuable for the stratification of patients with low levels of residual disease and, therefore, in the identification of patients for whom TKI therapy could be safely reduced or discontinued.

Perspectives Since approximately half of all patients with CML relapse shortly after discontinuation of therapy, investigators are striving to develop more sensitive tests to detect residual disease. A common hypothesis for why certain patients relapse is that they have a slightly higher level of disease than those who stay in remission. One approach to identifying patients who are likely to relapse is to look at genomic DNA via next-generation sequencing. This method basically uses multiple probes to go over hundreds of thousands of kilobases and target the BCR-ABL at the DNA level.

Although this type of sequencing is becoming faster and less expensive, it still requires an enormous amount of work and commitment. Therefore, I would say that while this is an interesting approach, it is certainly not ready for “prime time.”

-Jerald P. Radich, MD

l

100

Nilotinib 300 mg BID

80

390

Figure 2. Percentage of Patients Newly Diagnosed With Philadelphia Chromosome–Positive CML Reaching MR4.0 and MR4.5 With Nilotinib vs Imatinib.19

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MR4.0

MR4.5

An MR4.0 is defined as BCR-ABL(IS) transcripts of ≤0.01%, and an MR4.5 is defined as BCR-ABL(IS) transcripts of ≤0.0032%.

BID indicates twice daily; CML, chronic myeloid leukemia; MR, molecular response; QD, once daily.

This study looked at a new genomic DNA sequencing method for identifying whether patients who appear to be in molecular remission using current RT-PCR assays are truly free of BCR-ABL1. The context of this investigation is that some patients who are in a CMR for an extended period on TKI therapy will remain in CMR following discontinuation of therapy, whereas others experience a recurrence of their disease, and we currently don’t know how to predict which patients will relapse if we stop treatment.

Although this is a very early study, it is still exciting and has the potential to be instrumental for determining which patients can avoid unnecessary treatment and the related toxicities that extended treatment incurs.

-David P. Steensma, MD, FACP

4-YEAR FOLLOW-UP FROM THE ENESTnd STUDY

Nilotinib is a second-generation oral TKI that has been shown to be significantly more potent than imatinib.1 In the phase 3, multicenter, open-label, randomized Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) trial (N=846), nilotinib demonstrated greater efficacy than imatinib in patients with newly diagnosed Philadelphia chromosome–positive (Ph+) CML in CP after a minimum follow-up of 24 months.18 Nilotinib showed superior MMR rates, defined as BCR-ABL transcript levels on the BCR-ABL(IS) of ≤0.1%; deeper molecular responses (MR4.0, BCR-ABL[IS] ≤0.01%; MR4.5, BCR-ABL[IS] ≥0.0032%); and reduced rates of progression to accelerated phase (AP) or blast phase (BP), compared with imatinib.

At EHA 2013, Hochhaus and colleagues presented follow-up data from the ENESTnd study.19 With 4 years of follow-up, nilotinib continued to demonstrate significantly higher rates of MMR (Figure 1). Molecular responses obtained using increased sensitivity PCR testing equipment, showing 4.0-log (MR4.0) and 4.5-log (MR4.5) reductions, were consistently higher with nilotinib versus imatinib (Figure 2).

Patients in both nilotinib cohorts had significantly lower rates of progression to AP or BP on study (including follow-up after discontinuation of treatment) compared with patients in the imatinib cohort (3.2%, 2.1%,

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FACULTY PERSPECTIVES and 6.7% in the nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib groups, respectively). Of the patients who progressed on core study treatment (0.7%, 1.1%, and 4.2% in the nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib groups, respectively), the majority never achieved CCyR. No patient who had achieved MR4.5 had progressed. The 4-year overall survival (OS) rates were 94.3%, 96.7%, and 93.3% for nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib, respectively. Treatment-emergent BCR-ABL mutations were less common in patients on nilotinib versus imatinib; only 2 patients had newly emergent mutations in year 4.

The long-term safety profiles of both drugs were consistent with those previously reported. By 4 years, peripheral arterial occlusive disease (PAOD) was reported in 4, 5, and 0 patients, and ischemic heart disease was reported in 11, 14, and 3 patients in the nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib arms, respectively. The annual frequency of these events has not increased with longer follow-up. Seven of the 9 patients with a PAOD event on nilotinib were at high risk for this toxicity at baseline, based on a combination of baseline risk factors.

The authors concluded that with 4 years of follow-up, nilotinib continued to demonstrate significantly higher rates of molecular response, lower rates of progression to AP/BP, and fewer treatment-emergent BCR-ABL mutations versus imatinib.

Perspectives This study shows that the results reported at 12 months in the ENESTnd trial hold true even after 4 years. Specifically, we are seeing more and deeper molecular responses with nilotinib compared with imatinib. However, this update still shows no difference in OS between the nilotinib and imatinib arms. One issue that I find slightly concerning is that at 4 years, the investigators reported more cases of PAOD with nilotinib than with imatinib.

Although the incidence of this toxicity hasn’t increased significantly over time, it should still be noted in light of recent reports of arterial disease associated with the use of ponatinib.

-Jerald P. Radich, MD

Although nilotinib was shown in the ENESTnd study to produce more rapid and deeper molecular remissions in newly diagnosed patients, the question that has been asked is whether imatinib will eventually catch up with time. The bottom line from this study was that even after 4 years of follow-up, nilotinib was still better than imatinib in terms of inducing both higher rates of molecular remission and also a lower incidence of progression to AP or BP. Although there was not a large difference such that imatinib is still reasonable initial therapy for some patients (eg, older patients with lower Sokal scores), these results suggest that the benefit of nilotinib is sustained.

-David P. Steensma, MD, FACP

5-YEAR FOLLOW-UP RESULTS OF THE PHASE 2 GIMEMA CTs CML0307 STUDY

Gugliotta and colleagues from the GIMEMA CML Working Party presented updated results of a multicenter, investigator-initiated, phase 2 study (GIMEMA CML0307) designed to evaluate the long-term (5-year minimum follow-up) efficacy of frontline treatment with nilotinib, with particular focus on the stability of the deep molecular response (MR4.0).20 Seventy-three patients (median age, 51 years; 45% low, 41% intermediate, and 14% high Sokal risk) enrolled in the study; median follow-up presented at EHA 2013 was 55 months (range, 50-62 months). Two patients never achieved an MR3.0; 1 of these patients progressed to AP/BP, and the other was in stable and confirmed CCyR at 48 months. Only 3 patients had a confirmed loss of MR3.0 due to poor adherence (all 3 remained on nilotinib).

The overall estimated probability of MR4.0 was 82%, with a median time to MR4.0 of 18 months. Overall, 19/73 patients (26%) showed a stable MR4.0 during the third and fourth year of therapy.

Only 1 patient progressed at 6 months to AP/BP and subsequently died (high Sokal risk, T315I mutation). The estimated probability of OS, progression-free survival, and failure-free survival was 97% at 5 years; the estimated probability of event-free survival (EFS) was 83% at 5 years. The authors

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concluded that after 5 years of follow-up, the great majority of patients are still on nilotinib, and a significant proportion have a stable deep molecular response (MR4.0) and may potentially enter into TKI-free remission trials.

Perspective This Italian study evaluated deep molecular responses in patients who were given 400 mg of nilotinib twice daily. The updated results showed that 82% of patients reached an MR4.0 from baseline; 26% had stable MR4.0, which means that they stayed at that level or better for at least a few years, which is very good. Amazingly, only 1 patient progressed to AP/BP. Even more impressive is the fact that only 15% of patients discontinued treatment due to toxicity or lack of efficacy; this rate is lower than in most studies, including those conducted in the United States. The OS and EFS rates of 97% and 83% confirm that second-generation TKIs are very effective in CML. -Jerald P. Radich, MD

24-MONTH RESULTS FROM THE PHASE 3 ENESTcmr STUDY

At EHA 2013, Cervantes and colleagues presented the 24-month follow-up results from the ENESTcmr study, an open-label, randomized, prospective, multicenter, phase 3 study that is evaluating the potential benefit of switching patients with persistent residual disease on long-term imatinib therapy to nilotinib.21 ENESTcmr includes patients with Ph+ CML-CP who achieved a CCyR but had detectable BCR-ABL transcripts after ≥2 years of imatinib therapy. Patients were randomized to continue their imatinib dose (400 or 600 mg once daily [QD; n=103]) or switch to nilotinib 400 mg twice daily (BID; n=104). Molecular response (including MMR, BCR-ABL[IS] ≤0.1% and MR4.5, BCR-ABL[IS] ≤0.0032%) was determined by qRT-PCR. Confirmed undetectable BCR-ABL was achieved if 2 consecutive samples (with sensitivity of ≥4.5 logs) had negative qRT-PCR results.

Treatment-emergent BCR-ABL mutations were less common in patients on nilotinib versus imatinib; only 2 patients had newly emergent mutations in year 4.

With 24 months of follow-up, confirmed undetectable BCR-ABL was achieved by significantly more patients who switched to nilotinib versus patients continuing imatinib (22.1% vs 8.7%, respectively; P=.0087). Twice as many patients achieved and maintained undetectable BCR-ABL on 3 consecutive assessments on nilotinib versus imatinib (n=10 vs 5, respectively). In patients without MR4.5 at study start, significantly more patients in the nilotinib arm than in the imatinib arm achieved MR4.5 by 24 months than in the imatinib arm (42.9% vs 20.8%, respectively; P=.0006). Rates of MR4.5 were superior on nilotinib regardless of response at study start, but the difference between the treatment arms was particularly pronounced in patients without MMR at study start (MR4.5 achieved in 29.2% vs 3.6% of patients on nilotinib vs imatinib; P=.016). No patient without MMR at study start who continued on imatinib achieved confirmed MR4.5 or undetectable BCR-ABL (on 2 consecutive assessments). No patient progressed to AP/BP since the 12-month follow-up.

Events were experienced by 3 patients on nilotinib (confirmed loss of MMR, n=2; death, n=1) and 7 on imatinib (confirmed loss of MMR, n=4; confirmed loss of CCyR, n=3). Prior interferon therapy (with vs without) and length of prior imatinib therapy (≤36 vs >36 months) did not significantly affect the rate of MR4.5 in either treatment arm. The safety profiles of nilotinib and imatinib were consistent with previous studies. The authors concluded that in patients with detectable residual disease on long-term imatinib therapy, nilotinib induced deeper molecular responses than continued imatinib, and these responses were more frequently maintained in consecutive assessments. The difference between arms in rates of MR4.5 and undetectable BCR-ABL increased between 12 and 24 months. These deeper molecular responses achieved after the switch to nilotinib may increase eligibility for TKI-free remission studies.

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Figure 3. Probability of Cumulative Progression/Death at 24 Months: MCyR vs No MCyR.22

Figure 4. Probability of OS at 24 Months: MCyR vs No MCyR.22 MCyR

No MCyR P=.049

P=.018

100

P=.026

42% 39%

40 P=.002

P<.001

28%

27%

25%

36%

P<.001

21%

20 14%

12%

19% 15%

13%

0 3 Months

6 Months

9 Months

Bosutinib as second-line therapy

3 Months

6 Months

9 Months

Probability of OS at 24 months

Probability of cumulative progression/death at 24 months

No MCyR

MCyR

60

P=.005 98%

P=.011 97%

88%

88%

3 Months

6 Months

P=.009

P=.232

P=.027

96% 89%

88%

92% 86%

P=.022 95% 88%

84%

80

60

40

20

Bosutinib as third-/ fourth-line therapy 0

Major cytogenic response (MCyR) is defined as having the Ph chromosome detectable in ≤35% of cells.

Perspective

One of the questions that investigators have tried to answer is whether adding a next-generation TKI can benefit patients on imatinib who have achieved a response but who still have detectable disease. The results of this study show that, in fact, such patients can be pushed into a lower molecular burden by adding a more potent drug, namely, nilotinib. This approach may be especially beneficial for certain populations, such as younger patients and those who are looking to get pregnant, as it may allow them to get to a CR status where they would be eligible for a discontinuation trial.

-Jerald P. Radich, MD

EARLY RESPONSE TO BOSUTINIB AS A PREDICTOR OF LONG-TERM OUTCOMES

Bosutinib is a third-generation, oral, dual Src/Abl TKI that was approved by the FDA in 2012 for the treatment of adult patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.7 At EHA 2013, Cortes and colleagues presented results of a phase 1/2, open-label study investigating early response to bosutinib as a predictor of long-term outcomes in patients with CML-CP who were receiving bosutinib as second-line therapy (after imatinib only) or third-/fourth-line therapy (after imatinib plus dasatinib and/or nilotinib).22

The authors concluded that early attainment or maintenance of an MCyR by second-line therapy patients was associated with a decreased likelihood of on-treatment progression/death and better OS. A total of 288 patients were receiving bosutinib as second-line therapy and 119 patients were receiving bosutinib as third-/fourth-line therapy.

Among 266 evaluable second-line therapy patients, a major cytogenic response (MCyR; defined as having the Ph chromosome detectable in ≤35% of cells) was newly attained or maintained from baseline by 157 (59%) patients, including 128 (48%) patients with a CCyR (ie, Ph chromosome undetectable). An MCyR was attained/maintained by 45/110 evaluable third-/fourth-line therapy patients, including 35 (32%) patients with a CCyR. The Kaplan-Meier probability of maintaining a MCyR at 2 years

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Bosutinib as second-line therapy

3 Months

6 Months

9 Months

Bosutinib as third-/ fourth-line therapy

Major cytogenic response (MCyR) is defined as having the Ph chromosome detectable in ≤35% of cells.

OS indicates overall survival.

was 77% (95% CI, 69-83) for second-line therapy patients and 71% (95% CI, 54-83) for third/fourth-line therapy patients. An MMR was achieved by 69/200 (35%) evaluable second-line therapy patients and 17/106 (16%) evaluable third/fourth-line therapy patients.

In second-line therapy patients, attaining/maintaining an MCyR by Months 3, 6, 9, and 12 on bosutinib versus no MCyR was significantly associated with a lower cumulative incidence of on-treatment progression/death (Figure 3) and longer OS (Figure 4). Similar results were observed when the analysis separately evaluated patients attaining/maintaining a CCyR versus partial cytogenetic response versus no MCyR. In third-/fourth-line therapy patients, a borderline significant association between attaining/maintaining an MCyR versus no MCyR by Month 3 was found for on-treatment progression/death, but not OS; however, both analyses achieved significance at later response time points. Achievement of an MMR by Month 3 versus no MMR was not predictive of on-treatment progression/death in second- and third-/fourth-line therapy patients, although a numerically lower cumulative incidence was observed (second-line therapy, 5% [95% CI, 1-34] versus 20% [95% CI, 15-28]; third-/fourth-line therapy, 11% [95% CI, 2-71] vs 35% [95% CI, 26-48]). There was also no significant association between response by Month 3 and OS in the second-line therapy group (100% [not estimable to 100] vs 90% [95% CI, 84-93]) and third-/ fourth-line therapy cohorts (75% [95% CI, 32-93] vs 88% [95% CI, 79-93]).

The authors concluded that early attainment or maintenance of an MCyR by second-line therapy patients was associated with a decreased likelihood of on-treatment progression/death and better OS. Among third-/ fourth-line therapy patients, association with long-term outcomes was borderline for MCyR by Month 3, but significant for MCyR by Months 6, 9, and 12. Achievement of MMR by Month 3 was not predictive of long-term outcomes in either cohort, perhaps due to the fewer number of patients with MMR, thus increasing variability in the long-term estimates.

Perspectives In this study, patients who had disease progression after 1 or more lines of prior TKI therapy were given bosutinib as salvage. The investigators found

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FACULTY PERSPECTIVES that at the 3-month mark, patients who had a major cytogenetic response to this drug also experienced longer OS. The same was true at the 6- and 9-month marks. However, in patients who were the most heavily pretreated (those who had received 3 TKIs prior to bosutinib), early responses were not as predictive of overall outcomes. It is not surprising that at 3 months, there were no fast responders in this trial. However, by the time you get out to 9 months, it becomes easier to separate those who have had a better response from those who haven’t. The real money is on this longer term data.

-Jerald P. Radich, MD

Table 1. Common AEs Associated With Imatinib Intolerance23 Grade 3/4 AEs Associated With Imatinib Intolerance

Percentage of Patients Who Experienced the Same Grade 3/4 AE on Bosutinib

Thrombocytopenia (n=29)

66% (19/29)

Neutropenia (n=19)

32% (6/19)

Rash (n=18)

11% (2/18)

Anemia (n=14)

21% (3/14)

Edema (n=12)

We know that with up-front therapy with nilotinib and imatinib, early robust response (ie, less than 10% BCR-ABL RT-PCR level by 3 months) predicts better long-term clinical outcomes. In this study, the investigators looked at whether early attainment of molecular remission was associated with better outcomes in patients receiving bosutinib in the second- or third-line settings. In the second-line setting, the answer was a clear “yes,” although in the third-line setting, the benefit was a little less clear. I think these results are potentially helpful for telling us how to look at landmarks of response with bosutinib, although we don’t know yet what to do if the patient doesn’t achieve a rapid remission (should we switch the drug?) if the landmarks are not achieved.

-David P. Steensma, MD, FACP

EVALUATION OF CROSS-INTOLERANCE BETWEEN BOSUTINIB AND PRIOR TKI THERAPY

As mentioned above, bosutinib is indicated for the treatment of patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior TKI therapy. The bosutinib toxicity profile is characterized primarily by hematologic adverse events (AEs), gastrointestinal toxicities, and rash.7

The authors concluded that hematologic cross-intolerance between bosutinib and recent imatinib or dasatinib therapy was relatively low, although many patients experienced the same grade 3/4 cytopenia on bosutinib.

At EHA 2013, Cortes and colleagues presented the results of a phase 1/2 study evaluating the potential for cross-intolerance between bosutinib and prior TKI therapy.23 Patients were evaluated for cross-intolerance (ie, AEs leading to permanent treatment discontinuation of both bosutinib and prior TKI therapy), and subsequent occurrence of these AEs on bosutinib therapy. Intolerance to prior imatinib therapy was reported for 122 CP-CML patients. The most common AEs associated with imatinib intolerance were cytopenias (Table 1). Fifty-one percent (29/57) of CP-CML patients with imatinib intolerance due to cytopenias experienced the same grade 3/4 AE on bosutinib, while cross-intolerance (ie, discontinuation of bosutinib due to the same AE) due to cytopenias occurred in 12/57 (21%) of CP-CML patients. Although diarrhea is the most frequently reported AE on bosutinib, only 4/10 (40%) CP-CML patients with imatinib intolerance due to diarrhea subsequently experienced grade 3/4 diarrhea on bosutinib, and 2/10 (20%) CP-CML patients experienced true cross-intolerance (ie, discontinued bosutinib due to diarrhea).

Intolerance to prior dasatinib (after imatinib) was reported for 21 CP-CML patients. The most common AEs associated with dasatinib intolerance were pleural effusion (n=19) and thrombocytopenia (n=8).

In patients with dasatinib intolerance due to thrombocytopenia, grade 3/4 thrombocytopenia was experienced by all patients on bosutinib; however, cross-intolerance was observed in 4/8 (50%) patients. Pleural effusion occurred in (3/19) 16% of patients on bosutinib; however, there was no cross-intolerance. Neither of the 2 patients with dasatinib intolerance due to diarrhea experienced cross-intolerance.

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Diarrhea (n=10)

40% (4/10)

Bone marrow failure (n=7)

71% (5/7)

Fatigue (n=7)

0

AE indicates adverse event.

An additional 2 CP-CML patients had intolerance to prior nilotinib (after imatinib), including intolerance due to rash (n=3), thrombocytopenia (n=2), neutropenia (n=1), and headache and pleural effusion (n=1); however, none of these patients experienced cross-intolerance and discontinued bosutinib due to the same AE. No deaths due to the AEs leading to prior TKI discontinuation were reported on bosutinib in patients with cross-intolerance.

The authors concluded that hematologic cross-intolerance between bosutinib and recent imatinib or dasatinib therapy was relatively low, although many patients experienced the same grade 3/4 cytopenia on bosutinib.

Cross-intolerance due to nonhematologic AEs, including diarrhea, was rare.

These results suggest that most patients intolerant to prior TKI therapy will tolerate long-term therapy with bosutinib.

Perspective There is not much cross-intolerance between TKIs. In other words, if patients develop an AE with a specific TKI and they are switched to a different TKI, they will often not have that same AE. In this study, the investigators wanted to see whether patients who had intolerance to other TKIs would have the same problems if they were switched to bosutinib. Interestingly, results varied depending on their original intolerance. For most AEs related to other TKIs, patients could be given bosutinib and tolerated it very well.

The exception was hematologic toxicities, especially thrombocytopenia.

For example, if patients developed thrombocytopenia while on dasatinib, they had the same problem on bosutinib.

-Jerald P. Radich, MD

RESISTANCE TO TKI THERAPY

Point mutations in the BCR-ABL kinase domain (including T315I, V299L, T315A, F317L/V/I/C, Y253H, E255K/V, and F359V/C/I) are emerging as the most frequent mechanism of resistance to TKI therapy.1,24 The emergence of resistance to imatinib25 prompted the development of next-generation agents, including dasatinib, nilotinib, and bosutinib, which are active against several imatinib-insensitive mutant forms of BCR-ABL.1 However, the presence of the T315I mutation, which results in an amino acid substitution at position 315 in BCR-ABL1 (from a threonine to an isoleucine), confers resistance to these agents as well.26-29 Ponatinib is a multikinase inhibitor approved in 2012 by the FDA for the treatment of adult patients with chronic, accelerated, or blast phase CML that is resistant or intolerant to prior TKI therapy.8 Evidence suggests that ponatinib is active against many of the BCR-ABL kinase domain mutations, including T315I.30,31 At the 2011 annual meeting of the American Society of Hematology, Cortes and colleagues presented initial findings from an international, single-arm, open-label, phase 2 study (PACE; Ponatinib Ph+ ALL and CML Evaluation) of ponatinib in patients with CML or Ph+ acute lymphoblastic leukemia who are resistant to or intolerant of dasatinib or nilotinib, or who harbor the T315I mutation.32 Results showed that among the 23 CML patients with T315I, 13/23 (57%) had an MCyR and 11/23 achieved a CCyR.

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Table 2. MCyR Rates Against Mutations Other Than T315I33 Mutation

MCyR Rate

E459K

3/3 (100%)

G250E

7/8 (88%)

E255K

6/8 (75%)

F359I

3/4 (75%)

T315I

45/64 (70%)

M244V

3/5 (60%)

V299L

3/5 (60%)

F317L

11/22 (50%)

E355A

1/2 (50%)

L248V

1/2 (50%)

Y253H

1/2 (50%)

E255V

1/2 (50%)

F359V

6/13 (46%)

F359C

1/4 (25%)

H396R

1/5 (20%)

Major cytogenic response (MCyR) is defined as having the Ph chromosome detectable in ≤35% of cells.

At EHA 2013, Hughes and colleagues presented results of an analysis of the impact of baseline mutations on response to ponatinib treatment in the PACE study, as well as an analysis of the mutations present at the end of treatment in the study.33 At baseline, no mutations were detected in 136 (51%) patients, 1 mutation was detected in 105 (39%) patients, ≥2 mutations were detected in 26 (10%) patients; 27 unique mutations were observed. Responses were observed regardless of baseline mutation status.

MCyR rates were as follows: 56% overall, 49% in patients with no mutations, 64% in patients with 1 mutation, 62% in patients with ≥2 mutations, 57% in patients with mutation(s) other than T315I (n=67), 74% in patients with T315I only (n=50), and 57% in patients with T315I + other mutation(s) (n=14). Although higher response rates were observed in patients with T315I, multivariate analyses showed that T315I is not an independent predictor of response. Responses (MCyR) were seen against each of the 15 mutations present in >1 patient at baseline (Table 2) Ninety-nine patients discontinued treatment, including 35 due to AEs, 20 due to progressive disease, and 11 due to lack of efficacy; 56 of these patients had end-of-treatment mutations assessed. Results showed that 5 patients had lost a mutation, 46 had no change, and 5 had gained mutations. Overall, 11 patients lost MCyR (none with T315I at baseline); 6 of the 11 discontinued, and 4 had end-of-treatment mutations assessed and no changes from baseline that were observed. The authors concluded that responses to ponatinib were observed regardless of baseline mutation status. No single mutation conferring resistance to ponatinib in CP-CML was observed.

Perspectives This study asks the question: What is the efficacy of ponatinib across the different mutation spectrums in heavily pretreated patients? The investigators reported that this drug was effective regardless of a patient’s mutation status. The fact that a high percentage of patients with the T315I mutation had a MCyR response to ponatinib is very impressive. However, the FDA currently has temporarily halted ongoing trials, as well as the sale and marketing of this drug, due to an increasing amount of treatment-related arterial events. Therapy may be continued for appropriate patients under an Emergency-Use Investigational New Drug application.

-Jerald P. Radich, MD

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One of the important aspects of this study is that the investigators really didn’t find any specific mutation that conferred resistance to ponatinib.

This included T315I, which confers resistance to all of the other tyrosine kinase inhibitors that are FDA approved for CML, and which is very problematic when it develops. We have a number of patients with T315I who are back in a deep remission on ponatinib. Therefore, this drug appears to be very effective across various mutations in CML. The problem, of course, is that the drug was recently taken off the market based on data regarding a high incidence of cardiovascular and thromboembolic events, and that is an important safety signal, so we will have to wait and see how that plays out in the future.

-David P. Steensma, MD, FACP

CONCLUSION

The approval of imatinib in 2001 changed the way CML is treated and induced CCyRs in the majority of patients, although many of these patients became resistant to or intolerant of imatinib. Second- and third-generation TKIs are now available for the treatment of patients refractory to prior TKI therapy, and some second-generation TKIs are also approved for first-line therapy—and are demonstrating improved efficacy over imatinib. Point mutations in the BCR-ABL kinase domain (eg, T315I) are emerging as the most frequent mechanism of resistance to TKI therapy, and ponatinib—the most recently approved TKI—is active against many of the BCR-ABL kinase domain mutations, including T315I. Some patients who achieve a stable CMR on TKI therapy may be able to discontinue therapy, and research is under way to identify patients in whom TKI treatment could be safely reduced or discontinued.

References

1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines).® Chronic Myelogenous Leukemia. Version 1.2014. http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed November 2, 2013.

2. American Cancer Society. Cancer Facts & Figures. 2013. http://www.cancer.org/acs/ groups/content/@epidemiologysurveilance/documents/document/acspc-o36845.pdf.

Accessed November 2, 2013.

3. Goldman JM, Melo JV. Chronic myeloid leukemia: advances in biology and new approaches to treatment. N Engl J Med. 2003;349:1451-1464.

4. Gleevec® (imatinib mesylate) tablets. Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; October 2013.

5. Sprycel® (dasatinib) tablets. Prescribing Information. Princeton, NJ: Bristol-Myers Squibb Company; June 2013.

6. Tasigna® (nilotinib) capsules. Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; September 2013.

7. Bosulif (bosutinib). Prescribing Information. New York, NY: Pfizer, Inc; September 2013.

8. Iclusig® (ponatinib). Prescribing Information. Cambridge, MA. ARIAD Pharmaceuticals USA Inc. December 2012.

9. Druker B, Guilhot F, O’Brien SG, et al; IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.

10. de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol. 2008;26:3358-3363.

11. Vigil CE, Griffiths EA, Wang ES, Wetzler M. Interpretation of cytogenetic and molecular results in patients treated for CML. Blood Rev. 2011;25:139-146.

12. Lin F, Chase A, Bungey J, et al. Correlation between the proportion of Philadelphia chromosome-positive metaphase cells and levels of BCR-ABL mRNA in chronic myeloid leukaemia. Genes Chromosomes Cancer. 1995;13:110-114.

13. Löwenberg B. Minimal residual disease in chronic myeloid leukemia. N Engl J Med. 2003; 349:1399-1401.

14. Müller MC, Cross NC, Erben P, et al. Harmonization of molecular monitoring of CML therapy in Europe. Leukemia. 2009;23:1957-1963.

15. Cross NC, White HE, Müller MC, Saglio G, Hochhaus A. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia. 2012;26:2172-2175.

16. Melo JV, Ross DM. Minimal residual disease and discontinuation of therapy in chronic myeloid leukemia: can we aim at a cure? Hematology Am Soc Hematol Educ Program. 2011; 2011:136-142.

17. Alikian M, Ellery P, Gerrard G, et al. Targeted Next-Generation Sequencing for the Identification of Genomic BCR-ABL1 Fusion Junctions to Quantify Residual Disease in CML Patients in CMR. Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P138.

18. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12:841-851.

19. Hochhaus A, Saglio G, Larson R, et al. Nilotinib shows sustained benefit compared with imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic

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phase (CML-CP): ENESTnd 4-year follow-up (F/U). Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P712.

20. Gugliotta G, Castagnetti F, Breccia M, et al. High rate of deep molecular response after 5 years of nilotinib 400 mg BID in early chronic phase chronic myeloid leukemia – update of the GIMEMA CML WP Trial CML0307. Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P141.

21. Cervantes F, Hughes T, Etienne G, et al. Continued deeper molecular response with nilotinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) with detectable disease on long-term imatinib: ENESTcmr 24-month results. Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P133.

22. Cortes J, Gambacorti-Passerini C, Kantarjian H, et al. Assessment of early cytogenetic response as a predictor of long-term clinical outcomes in a phase 1/2 study of bosutinib in chronic phase (CP) chronic myeloid leukemia (CML). Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P148.

23. Cortes J, Lipton J, Kantarjian H, et al. Evaluation of cross-intolerance between bosutinib and prior tyrosine kinase inhibitor therapy in patients with Philadelphia chromosome-positive (Ph+) leukemia. Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P151.

24. Soverini S, Hochhaus A, Nicolini FE, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118:1208-1215.

25. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876-880.

26. Soverini S, Colarossi S, Gnani A, et el. Resistance to dasatinib in Philadelphia-positive

leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica. 2007;92:401-404.

27. Lange T, Ernst T, Gruber FX, et al. The quantitative level of T315I mutated BCR-ABL predicts for major molecular response to second-line nilotinib or dasatinib treatment in patients with chronic myeloid leukemia. Haematologica. 2013;98:714-717.

28. Cortes JE, Kantarjian HM, Brümmendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118:4567-4576.

29. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood.

2012;119:3403-3412.

30. O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401-412.

31. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075-2088.

32. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. Initial findings from the PACE trial: a pivotal phase 2 study of ponatinib in patients with CML and Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. Blood (ASH Annual Meeting Abstracts) 2011;118:Abstract 109.

33. Hughes T, Cortes J, Kim D, et al. Impact of baseline mutations on response to ponatinib and end of treatment mutation analysis in patients with Philadelphia chromosome-positive (Ph+) leukemias. Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P134.

COE104-3

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CONTINUING EDUCATION 6th Annual

OCTOBER 2013 • VOLUME 6 • NUMBER 4

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: The Role of Transplantation PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen Grants/Project Associate Susan Yeager The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris

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 6th 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 fourth issue, experts from Abramson Cancer Center answer questions related to the use of transplantation in patients with MM. 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

Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno

FACULTY

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

Edward A. Stadtmauer, MD Professor of Medicine Chief, Hematologic Malignancies Abramson Cancer Center University of Pennsylvania Philadelphia, PA

Patricia A. Mangan, MSN, CRNP Coordinator Bone Marrow and Stem Cell Transplant Program Abramson Cancer Center University of Pennsylvania Philadelphia, PA

Alex Ganetsky, PharmD, BCOP Hematology/Oncology Clinical Pharmacy Specialist Abramson Cancer Center University of Pennsylvania Philadelphia, PA

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

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

Executive Administrator Rachael Baranoski

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

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

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CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company.

Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM).

Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. 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 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.

Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-022-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss existing and emerging therapeutic options for patients with newly diagnosed or relapsed/refractory MM and how to tailor therapy for individual patients • Describe the pharmacokinetics and pharmacodynamics of novel

ceuticals. She does not intend to discuss any non-FDA-approved or investigational use for any products/devices.

Alex Ganetsky, PharmD, BCOP, is on the advisory board for Cephalon. He does intend to discuss either non-FDA-approved or investigational use for the following product/device: cyclophosphamide.

agents when integrating these agents into treatment regimens for MM • Evaluate adverse event management strategies for patients with MM receiving novel therapies and multidrug regimens 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.

Disclaimer The information provided in this CME/CPE/CE 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/CPE/CE 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/P13008D.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.

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months.

Planners’ and Managers’ Disclosures Dana Delibovi, Medical Writer, has nothing to disclose. She does not intend to discuss non-FDA-approved or investigational use for any products/devices.

William J. Wong, MD, MLI Reviewer, has nothing to disclose.

Shannon Woerner, RN, MSN, MLI Reviewer, has nothing to disclose.

Shelly Chun, PharmD, MLI Reviewer, has nothing to disclose.

For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org.

For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net.

Faculty Disclosures Sagar Lonial, MD, is on the advisory board for and is a Consultant to Bristol-Myers Squibb, Celgene Corporation, Millennium: the Takeda Oncology Company, Novartis, Onyx Pharmaceuticals, and sanofi-aventis. He does not intend to discuss any non–FDA-approved or investigational use for any products/devices.

Edward A. Stadtmauer, MD, is a consultant to Celgene Corporation, Millennium: the Takeda Oncology Company, and Onyx Pharmaceuticals. He does not intend to discuss non-FDA-approved or investigational use for any products/devices.

Patricia A. Mangan, MSN, CRNP, is on the advisory board for sanofi-aventis and the speaker’s bureau for Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharma-

Estimated time to complete activity: 1.0 hour Date of initial release: October 15, 2013 Valid for CME/CPE/CE credit through: October 15, 2014 SCAN HERE to Download the PDF or Apply for Credit.

To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone

The Role of Transplantation in Improving Patient Outcomes in Multiple Myeloma Edward A. Stadtmauer, MD

Professor of Medicine, Chief, Hematologic Malignancies Abramson Cancer Center, University of Pennsylvania Philadelphia, PA

Introduction With the advent of upfront transplantation, survival rates among patients with multiple myeloma (MM) have improved dramatically. Ongoing debate continues, however, on the utility of early transplantation, given the increasing efficacy of multidrug induction regimens that include such novel, molecularly targeted agents as bortezomib and lenalidomide. In this article, Edward A. Stadtmauer, MD, shares his insights and experience regarding the clinical pathway from induction, to high-dose melphalan therapy and transplantation, to posttransplant maintenance in transplant-eligible patients with MM.

Should all transplant-eligible patients receive early high-dose therapy and autologous stem cell transplantation (HDT/ASCT), or can transplantation be delayed in some cases?

This is a very interesting and important question—particularly here in the United States. Most centers in the rest of the world that have the capability

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for transplantation have concluded that induction therapy to achieve remission, followed by consolidation with 1 or 2 cycles of high-dose melphalan and ASCT, followed by some form of maintenance therapy, are the steps that lead to the best outcomes among transplant-eligible patients.1 In the United States, however, some debate exists regarding the timing of HDT/ASCT. According to some experts, in the era of very effective initial treatment with novel agents, it may be possible to delay transplantation until first relapse with no untoward effect on patient survival.2,3 Recent data showing high response rates and similar survival for early versus delayed transplant provide support for this view (Figure).3 In clinical practice, prudent individualization of care dictates that not all transplant-eligible patients with MM should receive upfront HDT/ASCT as part of initial treatment. Nevertheless, all potentially transplant-eligible individuals should be evaluated for the procedure. Although not every patient needs to consult with a transplant specialist, the oncology team should inform every patient that HDT/ASCT is one of many options that may fit into his or her treatment plan.

Let’s not be too quick to minimize the positive impact of the new chemotherapies for myeloma on patient outcomes. A major miracle has occurred over the last decade with the increased likelihood of deep durable remissions for patients with MM.4 A decade ago, we were pleased if half of our patients responded to initial therapy and, with good supportive care, survived for an additional 2 or 3 years. We now expect that more than 90% of our patients will respond to therapy and will survive for many years or even for decades.

Contributing to this improvement is the use of such agents as thalidomide,

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Patients (%)

Figure. Comparable OS with early vs delayed transplantation in patients treated with novel agent-based initial therapy.3 100 90 80 70 60 50 40 30 20 10 0

Study 82.0% 72.7% 73.4%

67.8%

86.0%

Delayed ASCT

Parameter

Median duration (months) Lenalidomide

Placebo

P value

McCarthy et al17

460

TTP

46

27

<.001

Attal et al18

614

PFS

41

23

<.001

HDT/ASCT indicates high-dose therapy/autologous stem cell transplantation; PFS, progression-free survival; TTP, time to progression.

4-year OS

OS from diagnosis, TD initial treatment

OS from diagnosis, RD initial treatment

lenalidomide, and bortezomib, and, more recently, pomalidomide and carfilzomib. We cannot ignore, however, the fact that widespread use of HDT/ASCT even before these agents were widely available had generated improved survival across the MM population. Well-designed clinical trials have demonstrated that compared with nontransplant approaches, the incorporation of 1 or 2 cycles of high-dose melphalan and ASCT into first-line therapy is associated with both prolonged remission and improved overall survival (OS).5-7 Thus, although the results are very promising for initial multidrug therapy that includes novel agents,8,9 evidence continues to support the use of early transplantation. For example, an Italian study randomized patients to 1 of 2 treatment arms: (1) induction followed by either 1 or 2 doses of high-dose melphalan and ASCT or (2) induction followed by treatment with lenalidomide, melphalan, and a corticosteroid with no ASCT. Then, patients were once again randomly assigned to maintenance therapy with lenalidomide or observation. A substantial prolongation of time to relapse was reported among patients who received HDT/ASCT, despite the use of lenalidomide both in induction and maintenance.10,11 More clinical evidence is warranted to determine the conditions under which HDT/ASCT might be delayed. Currently, clinical trials in France and the United States are comparing early versus late transplantation; within the next 5 years, we hope to have data available that can help with this decision-making.12 Currently, however, upfront transplantation remains the standard of care for eligible patients with MM,13 which generally means an individual who is 70 years of age or younger has adequate organ function and good performance status, and is responding well to initial therapy.

Are the high initial response rates seen with novel agents translating into improved outcomes following transplantation?

Definitely. Data show that a complete response (CR) or very good partial response (VGPR) following induction with novel agents trends toward prolonged survival following HDT/ASCT.14 With some of the current induction regimens, at least two-thirds of patients achieve VGPR and one-third to onehalf of patients achieve CR,8,9,15 which is predictive of a favorable outcome following HDT/ASCT. VGPR has been defined by the Intergroupe Francophone du Myélome (IFM) and the International Myeloma Working Group as a 90% decrease in serum monoclonal component level or, in the subset of patients with BenceJones MM, a urine monoclonal component lower than 100 mg/24 hours.16 In clinical practice, however, our definition of response is multifactorial, including the serum monoclonal component level but also taking into account symptomatic response. When treatment is initiated in a patient, we want to rapidly reduce or reverse the symptoms that led to a diagnosis of active MM— that is, painful bone lesions, renal dysfunction, low blood counts, fatigue, and infections. Our goal is to protect patients from permanent organ dysfunction, prevent fractures, and offer a substantial improvement in quality of life.

Fortunately, current initial treatments allow us to achieve these goals in the

l

Number of patients

Early ASCT

63.6%

All between-group (early vs delayed ASCT) differences nonsignificant; P≥.3.

ASCT indicates autologous stem cell transplantation, OS, overall survival; RD, lenalidomide plus dexamethasone; TD, thalidomide plus dexamethasone.

398

Table. Significant Improvement in PFS/TTP with Lenalidomide Maintenance vs Placebo Following HDT/ASCT17,18

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great majority of patients. An ancillary benefit is that patients feel well and are fit to proceed to stem cell harvest and transplantation.

Data show that effective induction resulting in deep remission prior to HDT/ASCT is clearly a good strategy. This does not translate, however, into an obligation to do everything possible to pound the patient into remission prior to harvesting his or her stem cells. Philosophically, we need moderation, and we need to know our patients. If a patient shows a modest response to therapy but is experiencing organ dysfunction or serious treatment-related adverse events, we cannot be overzealous about moving on to transplantation.

If patients are feeling well and their symptoms have improved to a certain degree, but they have only a 50% reduction in measurable disease, we do not have to keep driving them into a deeper remission before we proceed to transplantation. Such patients may have disease that is somewhat resistant to the proteasome inhibitors, immunomodulators, and/or corticosteroids used for induction. It is likely that the best treatment for these individuals will be highdose melphalan, an alkylating agent, and ASCT. We do not delay treatment in such patients. In fact, a useful approach is to intensify the stem cell mobilization technique with chemotherapy using cyclophosphamide alone or multichemotherapy regimens (such as combinations of doxorubicin, etoposide, and cisplatin) in order to attempt to get these patients into a deeper remission while collecting their stem cells, in preparation for HDT/ASCT. What is the role played by the use of novel agents as consolidation and maintenance therapy following HDT/ASCT? Even though we now have excellent regimens for induction therapy and evidence-based protocols for HDT/ASCT, the vast majority of patients with MM will nonetheless eventually experience disease progression. This suggests that despite all that we do up front, residual disease still remains a key issue. A major recent finding is that we can improve duration of remission and survival by providing continuous therapy (also called posttransplant maintenance therapy) with regimens that are based on molecularly targeted agents.

Data from clinical trials reveal that following HDT/ASCT, a maintenance course of lenalidomide, at a dose range of 5 to 15 mg daily for 1 year or more improves patient outcomes compared with placebo.17,18 The use of lenalidomide maintenance in the posttransplant population was associated with significant improvement in the primary end points of progression-free survival (PFS) or time to progression (TTP) (Table).17,18 OS was also significantly improved in one trial among patients who received lenalidomide maintenance.17 In this study, at a median follow-up of 34 months, 35 patients (15%) who received lenalidomide maintenance had died, compared with 53 patients (23%) in the placebo group (P=.03).17 These studies were designed to continue lenalidomide treatment to either intolerable toxicity or disease progression, and thus provide robust evidence that lenalidomide is generally well tolerated and effective as maintenance therapy. In one of the trials,17 TTP was improved to the extent that the study was unblinded at a median follow-up of 18 months, and patients receiving placebo who did not experience progressive disease were allowed to cross over to lenalidomide. Despite the crossover, however, patients who initially received lenalidomide maintenance benefited more in terms of PFS and OS than did those who received placebo.17 Continuous treatment with lenalidomide is associated with certain toxicities—in particular, cytopenias, gastrointestinal effects, and fatigue.17,18 More worrisome is the finding of an increased incidence of second primary malignancies (SPMs)—predominantly hematologic—among patients who receive lenalidomide maintenance. In the Cancer and Leukemia Group B 100104 and IFM Continued on Continued onpage page403 395

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Patient-Centered Nursing Care in the Transplant Setting Patricia A. Mangan, MSN, CRNP

Coordinator, Bone Marrow and Stem Cell Transplant Program Abramson Cancer Center, University of Pennsylvania Philadelphia, PA

Introduction In the setting of high-dose therapy/autologous stem cell transplantation (HDT/ASCT) for multiple myeloma (MM), nurses encourage patients through the process while providing supportive care for myelotoxicity and other adverse events associated with treatment. In this article, Patricia Mangan, MSN, CRNP, describes the advantages and disadvantages of early versus delayed HDT/ASCT. Ms. Mangan also advocates for multidisciplinary psychosocial support for the patient undergoing ASCT, utilizing a team that encompasses clinicians—social workers, nurses, and nurse navigators—as well as patient support groups. Finally, she offers her perspectives on older transplant recipients—a special population that must be selected judiciously and treated with extreme caution.

What are some of the advantages and disadvantages of early versus delayed transplantation in patients with MM? The main advantage of early transplantation is a robust evidence base.

When we incorporate transplantation into initial therapy when myeloma disease is active, it offers patients very good outcomes and improves the likelihood of survival.1-3 Another advantage of early transplantation is that it facilitates easier collection of stem cells. With a delayed transplant, we are prolonging the time that patients receive drugs that can hinder the harvest of peripheral stem cells. One of these drugs is lenalidomide, which in some studies has been associated with a decline in peripheral stem cell collection when used for an extended period of time.4-7 Delaying transplant also increases the likelihood that a patient may be treated with melphalan, an alkylating agent that is generally contraindicated pre-ASCT because it interferes with stem cell harvest. Granted, we can sometimes solve this problem by collectTable 1. Evidence-Based Transplant Recommendations9 • Patients: Active, symptomatic myeloma eligible for transplantation - Sufficient liver, renal, pulmonary, cardiac function to tolerate high-dose therapy (melphalan)

ing stem cells early and cryopreserving them for transplantation later on.

This is an option that appeals to many patients, because it provides them with a kind of “transplant insurance.” Moreover, even if the stored cells are not used for ASCT, they can be administered later in the course of therapy to manage cytopenias associated with the use of myelosuppressive agents.

Conversely, if we do not perform early stem cell collection in a patient or if too many cells are lost during a very long period of preservation, we may face the difficult task of late stem cell harvest.

Early rather than late transplantation also makes sense for patients who are on the older end of the eligibility range. Someone who is 68 years of age at the time of MM diagnosis may have organ function and performance status sufficient to allow HDT/ASCT. Two years later, however, at the time of relapse, this same patient may no longer be eligible for transplantation.

Thus, delaying transplant deprives such patients of a treatment that may improve survival.

Early rather than late transplantation also makes sense for patients who are on the older end of the eligibility range.

Of course, some disadvantages to early transplantation exist as well. The HDT/ASCT process requires hospitalization and exposes patients to significant treatment-related toxicities—especially risk for infection and organ dysfunction from HDT.2 The patient’s family, employment, and quality of life (QoL) all can be adversely affected, too. It takes approximately 3 months for individuals to recover from a transplant. Patients undergoing transplantation are not usually acutely ill for 3 months, but they can experience a considerable amount of fatigue. At 1 year posttransplant, patients are generally functioning well again,8 but recovery during that year is a gradual process.

When we weigh the advantages and disadvantages, the balance favors early transplantation in those individuals with good organ function up to the age of 70 years; this has become the standard of care. At our center, we follow current evidence-based recommendations (Table 1)9 and offer early transplantation to eligible patients; we believe this provides the best outcome in terms of QoL and prolonged disease remission.

What strategies do you use to guide your transplant-eligible patients through the process? Do you utilize a multidisciplinary approach to patient education and counseling?

The overarching goal of patient education in the MM population must be

• Induction: Antimyeloma therapy that does not contain melphalan • Collection: Stem cell harvest sufficient for 2 transplants • HDT/ASCT - Patients who have ≥ partial response to induction—HDT/ASCT upfront (Category 1* evidence) or perform allogeneic transplant in clinical trial or continue antimyeloma therapy until best response - Patients who do not respond to induction—HDT/ASCT upfront (Category 1 evidence) • Posttransplant - Response or stable disease—Maintenance therapy or second tandem transplant or observation - Progression—Salvage, including additional transplantation if patient remains a candidate *Category 1 = the most robust clinical evidence from randomized trials.

HDT/ASCT indicates high-dose therapy/autologous stem cell transplantation.

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Table 2. Patient Concerns in Anticipation of HDT/ASCT10-12 • Fear of being overwhelmed physically, emotionally, psychologically10 • Concern over missing work, losing productivity, job security10 • Inability to cover out-of-pocket costs of HDT/ASCT; concerns exacerbated by lack of open discussion of cost10 • Expectation of unmanageable, dangerous symptoms or adverse events during the process10* • Worries about family relationships and support11 • Sense of isolation11 *May be a mythical belief or exaggerated fear, since nursing practice for infection control is very consistent, and 72% of nurses surveyed report having institution-wide policies for transplantation nursing care.12 HDT/ASCT indicates high-dose therapy/autologous stem cell transplantation.

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Figure. Stem cell reinfusion with reduced-intensity melphalan (MEL100) conditioning vs standard therapy with melphalan plus prednisone (MP) in older patients (55 to 74 years; n=142).14

48

Median overall survival (months)

56 MP (standard Tx) MEL100 17.7

Median event-free survival (months)

34

0

10

20

30

40

50

60

Treatment groups: MEL100 = 2 to 3 courses of vincristine, doxorubicin, and dexamethasone, followed by stem cell harvest, melphalan dosed at 100 mg/m2, stem cell reinfusion, and 2 additional cycles of melphalan 100 mg/m2 at 2-month intervals post–stem cell reinfusion; MP = melphalan (6 mg/m2) and prednisone (60 mg/m2) administered for six 7-day courses at 4-week intervals.

to alleviate fears about transplantation. Many patients, regardless of their willingness to undergo HDT/ASCT, have a preconceived, negative notion of transplantation. They are burdened by worries, concerns, and sometimes myths about the experience (Table 2).10-12 For a few individuals, anxiety may be so great that they elect to postpone or avoid transplantation despite their oncologist’s recommendation.

If we determine that early transplant is appropriate, we invite the patient to our center to meet with the transplant team, which includes a physician, a nurse, and a social worker or nurse navigator. If possible, we have patients and families speak with other patients who have undergone transplant. We utilize our waiting room as one of the best opportunities for patients to talk very casually. Myeloma support groups have sprung up across the country, and they provide new patients with a valuable opportunity to meet others who have undergone HDT/ASCT. Creating patient-to-patient rapport need not always be formal.

HDT/ASCT is often successful in this older population, but careful selection of patients and diligent monitoring throughout the process is critical for success.

The International Myeloma Foundation and the Multiple Myeloma Research Foundation provide excellent online and printed materials. That being said, we tend to caution patients that online information may not always be accurate and can lead them astray. The multidisciplinary team, including the support group, is a much better source of information.

In our role as nurse educators, we need to remember that the patient is not the only person who needs support. Caregivers benefit from help as well.

Getting to know the family and friends involved in a patient’s care enables nurses to ascertain the needs of each individual. Many patients rely on loved ones to help them navigate through the HDT/ASCT process—from traveling to the transplant center to sharing ideas and feelings.

Finally, nurses can encourage patients a great deal by always keeping the focus on the overarching goal of extending survival while maintaining QoL. Focusing on this goal helps to alleviate a lot of the stress involved in trans-

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plant decision-making, because you retain the perspective that the purpose of transplantation is a longer, more productive life.

What are some of the special considerations in older patients undergoing transplantation?

Today, patients with MM who are between 60 and 70 years of age and in otherwise good health are usually candidates for transplantation. HDT/ ASCT is often successful in this older population, but careful selection of patients and diligent monitoring throughout the process is critical for success.

In selecting patients, a person’s overall performance status is very important.13 We need to ask: How frail is the patient? Can he or she perform the activities of daily life independently? Does he or she require considerable assistance moving around the house or yard? The answers to these questions can help to determine a patient’s ability to tolerate HDT/ASCT. The next step in patient selection is assessment of comorbidities and organ function. Patients 60 years of age or older are at increased risk for chronic diseases, such as type 2 diabetes, cardiovascular disease, and chronic obstructive pulmonary disease. These conditions reduce organ function and can advance a patient’s physiologic age beyond their chronological age.

Once we decide to proceed to transplantation in an older patient, we may have to stratify risk and, if warranted, use a slightly lower dose of melphalan for conditioning. The dose is still high and effective, but it is scaled back a bit to get these older patients through the procedure more easily. One study has demonstrated the efficacy of a reduced-intensity, high-dose conditioning regimen of melphalan dosed at 100 mg/m2 in elderly patients (instead of the usual dose of 200 mg/m2), followed by stem cell reinfusion (Figure).14 As with any transplant candidate, older patients require individualized care. Although all patients with MM share the common goal of prolonged survival with good QoL, each one is unique and has his or her own path to that goal. As nurses, it is our job to help each patient walk that path. ♦ References

1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520.

2. Attal M, Harousseau J-L, Stoppa A-M, et al; Intergroupe Français du Myélome. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335:91-97.

3. Fermand J-P, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005;23:9227-9233.

4. Nazha A, Cook R, Vogl DT, et al. Stem cell collection in patients with multiple myeloma: impact of induction therapy and mobilization regimen. Bone Marrow Transplant. 2011; 46:59-63.

5. Cavallo F, Bringhen S, Milone G, et al. Stem cell mobilization in patients with newly diagnosed multiple myeloma after lenalidomide induction therapy. Leukemia. 2011;25:1627-1631.

6. Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia. 2007;21:2035-2042.

7. Bhutani D, Zonder J, Valent J, et al. Evaluating the effects of lenalidomide induction therapy on peripheral stem cells collection in patients undergoing autologous stem cell transplant for multiple myeloma. Support Care Cancer. 2013;21:2437-2442.

8. Grulke N, Albani C, Bailer H. Quality of life in patients before and after haematopoietic stem cell transplantation measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire QLQ-C30.

Bone Marrow Transplant. 2012;47:473-482.

9. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Multiple Myeloma, Version 2.2013. http://www.nccn. org. Accessed June 2, 2013.

10. Sheldon LK, Kazmi M, Klein C, Berry DL. Concerns of stem cell transplant patients during routine ambulatory assessment. Patient Prefer Adherence. 2013;7:15-20.

11. Stephens M. The lived experience post-autologous haematopoietic stem cell transplant (HSCT): a phenomenological study. Eur J Oncol Nurs. 2005;9:204-215.

12. Bevans M, Tierney DK, Bruch C, et al. Hematopoietic stem cell transplantation nursing: a practice variation study. Oncol Nurs Forum. 2009;36:E317-E325.

13. Palumbo A, Bringhen S, Ludwig H, et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood. 2011;118:4519-4529.

14. Palumbo A, Triolo S, Argentino C, et al. Dose-intensive melphalan with stem cell support (MEL100) is superior to standard treatment in elderly myeloma patients. Blood.

1999;94:1248-1253.

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Pharmacologic Considerations in the Transplant Setting for Myeloma Alex Ganetsky, PharmD, BCOP

Hematology/Oncology Clinical Pharmacy Specialist Abramson Cancer Center, University of Pennsylvania Philadelphia, PA

Introduction Over the past 2 decades, research has delineated the molecular biology of multiple myeloma (MM). These discoveries have given clinicians the ability to stratify risk in the disease and have also led to the development of more effective antimyeloma agents. Frontline regimens that include these novel targeted therapies produce high rates of response prior to high-dose therapy/autologous stem cell transplantation (HDT/ASCT). Induction therapy plus HDT/ASCT consistently yields favorable outcomes. In this article, Alex Ganetsky, PharmD, BCOP, describes the current paradigm for risk stratification and treatment selection in MM.

What is the role of risk stratification in the selection of induction therapy for transplant-eligible patients?

Risk stratification is a relatively new approach that derives from a more thorough knowledge of myeloma biology. Historically, we had a limited understanding of the pathophysiology of the disease and didn’t realize just how heterogeneous it was. As a result, most patients were treated very similarly.

In the past 10 to 15 years, however, there have been significant advances in our understanding of the molecular biology of MM, with a corresponding advent of new molecularly targeted drugs and combination regimens.1 We are now moving toward the goal of stratifying initial therapy based on the risk associated with different molecular characteristics of myeloma cells.

Cytogenetics—which can identify chromosomal abnormalities predictive of risk—is critically important in patient stratification.2,3 Currently, cytogenetic testing is conducted via conventional karyotyping and fluorescence in situ hybridization (FISH) testing. This testing identifies standard and high levels of risk on the basis of specific mutations.

According to current, evidence-based guidelines and consensus, patients with MM have a worse prognosis when their myeloma cells display the following abnormalities: deletion of chromosome 13 [del(13q)], deletion at the locus of the tumor suppressor gene p53 [del(17p13)], the chromosomal translocations t(4;14) and t(14;16), and an amplification at chromosome 1q21.4 FISHdetected del(17p), t(4;14), and t(14;16) have been associated with a particularly high level of risk,3-6 although there is some evidence that t(14;16) may not confer as high a risk as the other 2 abnormalities.6 While data have suggested that translocation t(11;14) may have a positive prognostic impact,7 evidence for this is not yet sufficient. Clinicians must err on the side of caution whenever a cytogenetic abnormality is detected in a patient with MM. Some experts assert that any cytogenetic abnormality may indicate higher-risk disease.5 In assessing risk, we also evaluate tumor burden and extramedullary disease, as high tumor burden and the finding of malignant plasma cells in soft tissue/visceral organ sites both confer a poorer prognosis.5,6,8 Whether a clinician relies on Durie-Salmon or International Staging System criteria to stage a patient, both methods link a greater tumor burden to a higher stage.4 We also look at a patient’s age, renal and other organ function, and overall health status in rounding out our risk assessment. Once we stratify a patient’s risk, we can use this information to select induction therapy. This is far from an exact science, but risk assessment does give us a good deal of guidance.

For a transplant-eligible patient with standard-risk myeloma—most impor-

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tantly, with normal cytogenetic findings—we may select an effective but not exceedingly aggressive therapy. We might consider patient preferences for an oral regimen or their concerns regarding adverse events (AEs). Oftentimes, in this patient type, we will use 4 cycles of lenalidomide and low-dose dexamethasone (Rd) before proceeding to HDT/ASCT. There is good clinical evidence for this regimen from a randomized trial, which showed that four 28-day cycles of Rd (oral lenalidomide 25 mg/day on days 1-21 plus low-dose dexamethasone 40 mg on days 1, 8, 15, and 22) produced better 1-year survival with lower toxicity than a regimen of the same length and lenalidomide dose but incorporating high-dose dexamethasone (40 mg on days 1-4, 9-12, and 17-20), referred to as the RD regimen.9 Overall, 1-year survival was 96% with Rd, compared with 87% with RD (P=.0002). After 4 cycles of treatment, the incidence of grade 3 or higher AEs was 35% with Rd and 52% with RD (P<.001).

For a clinician who prefers to use a bortezomib-based regimen, acceptable induction therapy for the patient at standard risk is cyclophosphamide, bortezomib, and dexamethasone (CyBorD). Historically, this regimen included twice-weekly intravenous (IV) bortezomib, but a clinical trial has shown that CyBorD using only once-weekly bortezomib also had good efficacy with manageable toxicity. Among patients whose CyBorD included once-weekly IV bortezomib (1.5 mg/m2 on days 1, 8, 15, and 22), overall response rates (ORRs) and rates of very good partial response or better (≥VGPR) to induction were comparable to those seen with CyBorD that included twice-weekly IV bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11): ORR 93% versus 88% and ≥VGPR 60% versus 61%, respectively. In addition, grade 3 or higher AEs were lower in the once-weekly bortezomib cohort than in the twice-weekly cohort (37% vs 48%, respectively).10 In a patient with intermediate-risk disease (ie, with some cytogenetic abnormalities but negative for del[17p13] or t[4;14]), CyBorD and Rd remain good choices. At this time, although we have markers that enable us to stratify patients into risk groups, we do not have the ability to make certain treatment recommendations for each group—with the possible exception of 2 high-risk groups: patients who exhibit t(4;14) and those who exhibit del(17p13).6 Bortezomib-based therapy is appropriate in these patients, because data suggest that this agent improves outcomes in patients with t(4;14).

Studies have shown that the addition of bortezomib to induction therapy enhances survival in patients with t(4;14).11,12 Recent evidence also suggests that lenalidomide has some ability to mitigate the effect of t(4;14) but with less favorable effect than bortezomib.13 Thus, bortezomib is an especially prudent choice for the t(4;14) population.

Results have been somewhat mixed, however, regarding the ability of bortezomib to overcome the adverse effect of del(17p13). For example, data from a 2010 trial suggested that outcomes in patients with this high-risk feature could not be improved with 4 cycles of bortezomib-based therapy prior to HDT/ASCT (with no maintenance).12 However, recent data from the HOVON-65 trial reported that patients with del(17p13) attained significantly higher rates of progression-free survival (PFS) and overall survival (OS) when bortezomib was included in their pretransplant induction and posttransplant maintenance regimens (Figure).14 Lenalidomide, on the other hand, has not been shown to improve poor prognosis associated with del(17p13).15 However, as an effective antimyeloma agent, it can be part of a multidrug combination for high-risk patients.

Aggressive 3-drug regimens that contain bortezomib are appropriate as induction for high-risk patients. One of these regimens—lenalidomide, bortezomib, and dexamethasone (RVD)—has shown very good results in newly diagnosed patients.16 In a phase 1/2 trial, RVD produced a 97% rate of 18month OS, with promising survival rates reported in the small number of patients with FISH-detected del(17p) and t(4;14).16 There may be no gain in adding a fourth drug to the regimen, as shown by a recent trial in which cyclophosphamide added to RVD provided no advan-

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Figure. 3-year overall survival in 37 patients with del(17p13) treated with and without bortezomib in the HOVON-65 trial.14

80

69%*

Patients (%)

70 60 50 40

Placebo + G-CSF

P Value

Patients achieving collection of ≥6 × 106 CD34+ cells/kg in ≤2 days

71.6%

34.4%

<.001

Median number of apheresis days required to collect ≥6 × 106 CD34+ cells/kg

1 day

4 days

<.001

Injection site reaction

20.4%

3.3%

NR

10

Diarrhea

18.4%

5.3%

NR

0

Nausea

16.3%

7.3%

NR

Bone pain

9.5%

7.9%

NR

Fatigue

8.2%

3.3%

NR

20

17%

Treatment without bortezomib

Bortezomib-based treatment

tage in response or 1-year PFS compared with RVD or CyBorD in transplant-eligible patients; all patients received bortezomib maintenance therapy.17 A caveat here is that individuals in this study were predominantly classified as standard risk; data are not sufficient to predict the utility of a 4-drug regimen in high-risk MM. What strategies can be used to optimize stem-cell mobilization prior to transplant?

There are 3 key strategies for stem cell mobilization. The first and historical strategy is to use growth factor support with filgrastim. The second is combination therapy with growth factor and chemotherapy. The third is combination therapy with growth factor plus the chemokine receptor CXCR4 antagonist plerixafor. There are advantages and disadvantages to each approach.

First, if you mobilize with growth factor alone, you can do this in the outpatient setting. Toxicity is low; the most common AE associated with filgrastim is bone pain,18 which is relatively manageable. Also, the timing for apheresis is more predictable with this method. The disadvantages of mobilizing with growth factor alone are that stem cell yields are lower than with the other 2 methods, more apheresis sessions are required, and there is no antitumor effect.

The second type of mobilization strategy—growth factor plus chemotherapy—produces a higher stem cell collection yield than does growth factor alone.19 This technique also provides cytoreduction of the malignancy via the chemotherapy drug. For MM, the most common chemotherapeutic agent to use for mobilization is cyclophosphamide. One of the disadvantages of this second strategy is that there is actually quite a bit of variability in peak CD34+ cell counts, which renders timing of apheresis sessions unpredictable. Another issue is that adding chemotherapy increases toxicity. Nevertheless, a recent retrospective study reported that the combination of chemotherapy plus a growth factor produced higher CD34+ cell yields and required fewer days of apheresis than did the use of a growth factor alone.20 Although rates of febrile neutropenia were higher with the chemotherapy–growth factor combination than with growth factor alone (17% vs 2%; P<.05), rates of other AEs were comparable between groups. Cost for chemotherapy plus growth factor mobilization was significantly higher than for growth factor alone, predominantly because of hospital admissions in the former group; febrile neutropenia often requires immediate hospitalization for a few days for IV antibiotics.

The final mobilization strategy—growth factor plus plerixafor—has been shown to improve stem cell collection.21 In a phase 3 trial, the combination of these agents significantly increased the likelihood that patients with MM would achieve adequate stem cell harvest in 2 days or less of apheresis com-

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Plerixafor + G-CSF

Incidence of most common adverse events:

30

*P=.028.

Treatment without bortezomib: 3 cycles of induction with vincristine 0.4 mg IV on days 1-4; doxorubicin 9 mg/m2 IV on days 1-4; and dexamethasone 40 mg PO on days 1-4, 9-12, and 17-20/HDT/ ASCT/2 years of thalidomide maintenance (50 mg/day PO).

Bortezomib-based treatment: Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11; doxorubicin 9 mg/m2 IV on days 1-4; and dexamethasone 40 mg PO on days 1-4, 9-12, and 17-20/HDT/ASCT/2 years of bortezomib maintenance (1.3 mg/m2 IV once every 2 weeks).

HDT/ASCT indicates high-dose therapy/autologous stem cell transplantation; IV, intravenously; PO, orally.

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Table. Stem-Cell Mobilization with Plerixafor + G-CSF vs Placebo + G-CSF: Efficacy and Tolerability21

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G-CSF indicates granulocyte colony-stimulating factor; NR, not reported.

pared with growth factor alone (Table).21 Plerixafor is very well tolerated; the most common AEs are gastrointestinal complaints, fatigue, and subcutaneous injection site reaction (Table). The disadvantages of plerixafor are timing of administration (it must be given 11 hours prior to initiation of apheresis)22 and cost. There have actually been a few studies to address these 2 disadvantages. A recent study suggested that the drug can be given 17 hours prior to apheresis with no untoward effect, which would improve the convenience factor.22 Costs of plerixafor can be contained by using it selectively, with a risk-adapted approach, in which preemptive plerixafor is given to patients with low CD34+ cell counts on day 4 of apheresis.23 At our center, we use multiple approaches, based on the patients’ needs.

Patients with active myeloma who can benefit from additional cytoreductive therapy are good candidates for mobilization with growth factor plus chemotherapy. Patients in ≥VGPR who appear to have good cellularity in bone marrow may be candidates for mobilization with growth factor alone. In patients suspected to be poor mobilizers (ie, heavily pretreated, with poor cellularity on a bone marrow exam, or with low peripheral CD34+ cell counts), we like to administer filgrastim plus plerixafor.

The next step in mobilization may be to combine all 3 strategies: growth factor, chemotherapy, and plerixafor. This approach has been studied in a small trial and was found safe in poor mobilizers.24 ♦ References

1. Lombardi L, Poretti G, Mattioli M, et al. Molecular characterization of human multiple myeloma cell lines by integrative genomics: insights into the biology of the disease. Genes Chromosom Cancer. 2007;46:226-238.

2. Stewart AK, Fonseca R. Prognostic and therapeutic significance of myeloma genetics and gene expression profiling. J Clin Oncol. 2005;23:6339-6344.

3. Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc. 2009;84:1095-1110.

4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. Version 2.2013. http://www.nccn.org. Accessed June 2, 2013.

5. Munshi NC, Anderson KC, Bergsagel L, et al; on behalf of the International Myeloma Workshop Consensus Panel 2. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood. 2011;117: 4696-4700.

6. Chng W-J, Dispenzieri A, Chim CS, et al; on behalf of the International Myeloma Working Group. IMWG consensus on risk stratification in multiple myeloma [published online ahead of print August 26, 2013]. Leukemia. doi:10.1038/leu.2013.247.

7. Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004;64:1546-1558.

8. Usmani SZ, Heuck C, Mitchell A, et al. Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents.

Haematologica. 2012;97:1761-1767.

9. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37.

10. Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115:3416-3417.

11. Cavo M, Tacchetti P, Patriarca F, et al; for the GIMEMA Italian Myeloma Network.

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Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.

Lancet. 2010;376:2075-2085.

12. Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p).

J Clin Oncol. 2010;28:4630-4634.

13. Kalff A, Spencer A. The t(4;14) translocation and FGFR3 overexpression in multiple myeloma: prognostic implications and current clinical strategies. Blood Cancer J. 2012;2:e89.

14. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119:940-948.

15. Reece D, Song KW, Fu T, et al. Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13. Blood. 2009;114:522-525.

16. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686.

17. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012;119:4375-4382.

18. Pulsipher MA, Chitphakdithai P, Miller JP, et al. Adverse events among 2408 unrelated donors of peripheral blood stem cells: results of a prospective trial from the National Marrow Donor Program. Blood. 2009;113:3604-3611.

19. Pusic I, Jiang SY, Landua S, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant. 2008;14:1045-1056.

20. Sung AD, Grima DT, Bernard LM, et al. Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G-CSF vs G-CSF alone [published online ahead of print June 10, 2013]. Bone Marrow Transplant. doi:10.1038/bmt.2013.80.

21. DiPersio JF, Stadtmauer EA, Nademanee A, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009;113:5720-5726.

22. Harvey RD, Kaufman JL, Johnson HR, et al. Temporal changes in plerixafor administration and hematopoietic stem cell mobilization efficacy: results of a prospective clinical trial in multiple myeloma. Biol Blood Marrow Transplant. 2013;19:1393-1395.

23. Chen AI, Bains T, Murray S, et al. Clinical experience with a simple algorithm for plerixafor utilization in autologous stem cell mobilization. Bone Marrow Transplant. 2012;47:1526-1529.

24. Attolico I, Pavone V, Ostuni A, et al. Plerixafor added to chemotherapy plus G-CSF is safe and allows adequate PBSC collected in predicted poor mobilizer patients with multiple myeloma or lymphoma. Biol Blood Marrow Transplant. 2012;18:241-249.

The Role of Transplantation in Improving Patient Outcomes in Multiple Myeloma

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2005-02 studies, approximately 8% of patients who received lenalidomide maintenance developed SPMs, compared with 3% to 4% of those who received placebo. Fortunately, many types of SPMs are treatable. Furthermore, development of an SPM does not appear to erode the significant survival benefit derived from continuing or utilizing lenalidomide maintenance.17,18 Based on the strength of this evidence, lenalidomide is emerging as a standard of care for posttransplant maintenance therapy in patients with MM. Thalidomide maintenance, although effective, is limited by the development of neurotoxicity and fatigue.19 In a recent study in which our center participated, only about 15% of the patients who were assigned to thalidomide were able to continue taking the agent for 1 year.20 Bortezomib also has demonstrated efficacy as maintenance therapy following HDT/ASCT, with particular utility in patients with the high-risk cytogenetic abnormality deletion 17p (del 17p).21,22 Bortezomib is usually dosed once every 2 weeks as maintenance therapy; in the HOVON-65 trial, the agent was administered for approximately 2 years.21 The appropriate duration of this maintenance program has not been as well studied as the program for lenalidomide; however, 1 year of bortezomib maintenance is a reasonable estimate for treatment duration. The use of bortezomib with thalidomide plus a corticosteroid as induction prior to HDT/ASCT and as consolidation/maintenance following remission both in transplant-eligible and -ineligible patients improved outcomes compared with thalidomide plus dexamethasone or bortezomib plus prednisone.15,23 These results further suggest that bortezomib in combination with an immunomodulator may be useful as maintenance therapy following HDT/ASCT. ♦ References

1. Cavo M, Rajkumar SV, Palumbo A, et al; International Myeloma Working Group. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood. 2011;117:6063-6073.

2. Dunavin NC, Wei L, Elder P, et al. Early versus delayed autologous stem cell transplantation in patients receiving novel therapies for multiple myeloma. Leuk Lymphoma. 2013;54:1658-1664.

3. Kumar S, Lacy MQ, Dispenzieri A, et al. Early versus delayed autologous transplantation following IMiD-based induction therapy in patients with newly diagnosed multiple myeloma.

Cancer. 2012;118:1585-1592.

4. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520.

5. Attal M, Harousseau J-L, Stoppa A-M, et al; Intergroupe Français du Myélome. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335:91-97.

6. Fermand J-P, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe.

J Clin Oncol. 2005;23:9227-9233.

7. Child JA, Morgan GJ, Davies FE, et al; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma.

N Engl J Med. 2003;348:1875-1883.

8. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combina-

tion therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686.

9. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up. J Clin Oncol (ASCO Annual Meeting Abstracts).

2013;31(suppl):Abstract 8543.

10. Palumbo A, Cavallo F, Hardan I, et al. Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) in newly diagnosed multiple myeloma (MM) patients <65 years: results of a randomized phase III study. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3069.

11. Boccadoro M, Cavallo F, Gay FM, et al. Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) plus lenalidomide maintenance or no maintenance in newly diagnosed multiple myeloma (MM) patients. J Clin Oncol.

2013;31(suppl);Abstact 8509.

12. US National Institutes of Health. ClinicalTrials.gov. Study comparing conventional dose combination RVD to high-dose treatment with ASCT in the initial myeloma up to 65 years (IFM/DCFI2009) [NCT01191060]. http://clinicaltrials.gov/show/NCT01191060. Accessed September 27, 2013.

13. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Multiple Myeloma. Version 2.2013. http://www.nccn.org.

Accessed June 2, 2013.

14. Harousseau J-L, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621-4629.

15. Cavo M, Tacchetti P, Patriarca F, et al; for the GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet.

2010;376:2075-2085.

16. Harousseau J-L, Avet-Loiseau H, Attal M, et al. Achievement of at least a very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol. 2009; 27:5720-5726.

17. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-1781.

18. Attal M, Lauwers-Cances V, Marit G, et al; IFM Investigators. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791.

19. Attal M, Harousseau J-L, Leyvraz S, et al; Inter-Groupe Francophone du Myélome (IFM).

Maintenance therapy with thalidomide improves survival in patients with multiple myeloma.

Blood. 2006;108:3289-3294.

20. Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol.

2011;12:1195-1203.

21. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30:2946-2955.

22. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119:940-948.

23. Mateos MV, Oriol A, Martínez-López J, Gutiérrez N. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012;120:2581-2588.

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Multiplex Genetic Assays Identify Mutations Beyond BRCA1/2 in 10% of Patients at Risk for Breast Cancer

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ne of 10 patients referred for BRCA1/2 mutation testing have pathogenic mutations in other genes, and these often prompt a change in care, according to Stanford University researchers who used a novel cancer gene sequencing panel to fully assess germline mutations in patients at risk for breast cancer.

“Multiple-gene sequencing panels are entering clinical practice. We are reporting on research testing with a custom sequencing panel (InVitae Corporation, San Francisco) in patients referred for assessment of hereditary breast and ovarian cancer risk,” said Allison W. Kurian, MD, MSc, who presented the findings at the 2013 Breast Cancer Symposium.

In the most notable case, one 53-year-old patient with a personal history of breast and endometrial cancers was found to carry a pathogenic MLH1 mutation.

Patients were referred to the Stanford Cancer Genetics Program for clinical BRCA1 and BRCA2 mutation testing between 2002 and 2012. In blood samples from these patients, the entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 43 genes that have published associations with a risk for breast, ovarian, and other cancers. An additional 32 cancer-associated variants were also sequenced. Ultimately, they derived a set of 41 fully sequenced genes and 23 single nucleotide polymorphisms.

The researchers disclosed the results to the participants, and if they were clinically actionable (ie, an approved or investigational targeted agent was available,) these patients were invited to counseling.

Of 198 patients, 141 women had breast cancer and 57 carried a known BRCA1/2 mutation. Interestingly, a pathogenic variant in a gene other than BRCA1/2 was found in 21 patients. These included mutations in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4, Kurian reported.

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Of these, 15 were actionable and 6 were not. Of the 15 patients with actionable genes, 3 were lost to follow-up, yielding 12 patients to be contacted by the researchers for follow-up care.

Of these 12 patients, 10 warranted new screening or prevention recommendations. In the most notable case, she said, “One 53-year-old patient with a personal history of breast and endometrial cancers was found to carry a pathogenic MLH1 mutation. She underwent risk-reducing salpingo-oophorectomy and colonoscopy, with removal of a tubular adenoma.”

Six patients underwent discussions of more intensive breast surveillance, and 6 chose to have more intensive gastrointestinal surveillance.

Discussing the study, Lajos Pusztai, MD, PhD, professor of medicine, Yale University, and codirector of the Yale Cancer Genetics Research Program, commented on the value of this cancer gene sequencing panel for hereditary risk assessment.

“This is very exciting research,” he said. “More than 10% of patients had a pathogenic mutation beyond BRCA1/2, and up to 12% of them had a clinically actionable finding. But the test also detected many variants of uncertain significance, averaging 76 per patient across 41 genes, and these did not contribute to patient care.”

“The study also showed the feasibility of patient notification and intervention. Most patients could be reached up to 10 years postenrollment. To date, early colonoscopy has likely prevented 1 cancer. Larger population-based studies should follow.”

More broadly, Pusztai commented on where the field is moving. “We are entering a new era of cancer risk prediction. Next-generation sequencing of a large number of risk alleles or whole exome sequencing can cast a much broader net to find disease-predisposing variants,” he said.

“Most ‘high-risk genetic screening clinics’ have adopt­ ed multiplexed assays, either in-house or commercially.

Moving forward, we must acknowledge 3 important challenges,” he added. “We must be able to functionally characterize the variants of unknown significance, quantify hazards more accurately, and test the value of our preventive interventions.” u

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ASCO BREAST CANCER SYMPOSIUM EDITORIAL

Molecular Profiling in Breast Cancer: Still Not Ready for the Clinic

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he “new taxonomy” of breast cancer and molecular subtyping of tumors are “making clinical sense” to oncologists, but molecular tools that describe these cancers are still not ready for routine use, according to Joyce O’Shaughnessy, MD, of Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, Texas.

At the 2013 Breast Cancer Symposium, O’Shaughnessy described the latest research to truly personalize breast cancer treatment by molecular profiling but cautioned that these tests should not be driving treatment outside of clinical trials.

Inhibition of what appear to be “clear targets” can be ineffective due to de novo or acquired resistance or alternative pathway activation.

“Clinicians are mainly still using routine pathology and immunohistochemistry, but we can see the future, where there will be a new taxonomy for many cancers based on pathway activation, the tumor microenvironment, and the presence of cytokines, immune-based mediators, and the like,” she said. “There is likely to be a different taxonomy for breast cancer than what we use today, but we are at the infancy of this process.”

Best Use of Molecular Tools: Triaging Patients to Clinical Trials “We all agree that to stem the spiraling cost of cancer treatment, concerted efforts are needed to develop molecular diagnostics that will better identify patients who will respond to expensive therapies,” O’Shaughnessy said. “My own opinion is that in today’s clinical practice, next-generation sequencing and other molecular tools have most utility in triaging our patients to clinical trials, a number of which are selecting participants based on molecular characteristics.”

She pointed out that targeted therapy based on a single gene marker is unlikely to be of high clinical utility at this time. Inhibition of what appear to be “clear targets” can be ineffective due to de novo or acquired resistance or alternative pathway activation. “These are the pitfalls we face

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if we try to match molecular abnormalities with targeted agents, off label,” she said. The off-label use of targeted agents, therefore, is not recommended.

Looking to the Future “We are just beginning to have a few data sets to give insights into how molecular profiling tools can help us in practice,” she said.

One is the Caris Life Sciences database of more than 35,000 tumors (all the common tumors, some rare tumors), for which driver gene mutations, copy number alterations, and protein expression patterns were described. Numerous targets were discovered that had the potential to be treated with targeted therapy not usually considered for the cancer type.1 “This is a rich data set that has yielded several key findings,” she said. “For our patients who have proven unresponsive to standard therapy, these kinds of tests can help us understand whether the patient might benefit from, for example, a cMET inhibitor trial. The real power of such a test, again, is to understand which patients might benefit from a particular clinical trial.”

Daniel Von Hoff, MD, director of translational research at the Translational Genomics Research Institute in Phoenix, Arizona, and colleagues reported the potential clinical utility of this broad molecular profiling in 66 metastatic patients.2 They compared progression-free survival (PFS) using a treatment selected by molecular profiling of the tumor with PFS from the patient’s most recent regimen. Of these patients, 27% had a PFS that was at least 30% longer than their last unselected treatment. A follow-up study in metastatic breast cancer is under way.

Foundation Medicine has also used next-generation sequencing to study actionable mutations (for which there are approved or investigational matched agents) in 169 breast cancer patients. They found that 90% of patients had actionable mutations, averaging 1.9 per patient.3 “This is our first view into what is found if next-generation sequencing is done on paraffin tissues of metastatic breast cancer patients in the community,” O’Shaughnessy noted.

Other work by this group in 44 metastatic breast cancer patients found at least 1 molecular alteration in 98% of patients; about a dozen common mutations were identified, while dozens of rare mutations were observed in small percentages of patients. A phase 1 targeted agent was

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given to 73% of the patients with mutations, and 44% of these patients achieved a response or stable disease.4 Finally, O’Shaughnessy said she is especially interested in the concept of the “exceptional responder” and how these patients might guide treatment. The National Cancer Institute is leading an effort to locate trial participants who respond exceptionally well to the study agent, and then genotype those individuals.

“An ‘N of 1’ could be hypothesis-generating,” she said. The identification of the responding phenotype could lead to the description of the genotype, and this could be used not only to select patients for clinical trials of new agents but also in the clinic, she suggested.

“Over time, with larger numbers of patients, this

could identify which mutations are essential to the exceptional responder genotype and could ultimately identify high-value therapies,” she said. u

References

1. Gatalica Z, Millis S, Chen S, et al. Integrating molecular profiling into cancer treatment decision making: experience with over 35,000 cases. J Clin Oncol. 2013;31(suppl).

Abstract 11001.

2. Von Hoff DD, Stephenson JJ Jr, Rosen P, et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010;33:4877-4883.

3. Ross JS, Cristofanilli M, Downing S, et al. Use of the FoundationOne next-generation sequencing (NGS) assay to detect actionable alterations leading to clinical benefit of targeted therapies for relapsed and refractory breast cancer. J Clin Oncol.

2013;31(suppl). Abstract 1009.

4. Miller VA, Ross JS, Wang K, et al. Use of next-generation sequencing (NGS) to identify actionable genomic alterations (GA) in diverse solid tumor types: the Foundation Medicine (FMI) experience with 2,200+ clinical samples. J Clin Oncol.

2013;31(suppl). Abstract 11020.

Role of Radiation and Imaging in DCIS Explained

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anagement of ductal carcinoma in situ (DCIS) was the focus of 2 studies highlighted at a premeeting Press Cast for the American Society of Clinical Oncology (ASCO) Breast Cancer Symposium held in San Francisco, California, September 7-9, 2013.1,2 The studies showed: • Radiation to the breast as part of treatment of DCIS does not appear to increase cardiovascular toxicity, including risk of cardiovascular disease (CVD) and death from CVD or other causes • Perioperative MRI does not reduce the risk of locoregional recurrence (LLR) or contralateral breast cancer in patients with DCIS undergoing surgery as part of their treatment program Women and their physicians can gain reassurance from the first study that radiation for DCIS does not increase cardiotoxicity, and the second study suggests that MRI should not be part of routine presurgical or surgical planning.

Radiation for DCIS DCIS is a lesion that may progress to invasive cancer in a small percentage of patients if left untreated. At present there is no way to identify which patients with DCIS are at risk of progression, so DCIS is typically treated with surgery with or without radiation to reduce the risk of LLR. Concern has been raised about increased cardiotoxic-

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ity with radiation to the breast area, and modern protocols have been adjusted to reduce exposure to the breast.

Using modern techniques, the risk of CVD was not increased in women with DCIS treated with radiotherapy in a large population-based study in the Netherlands when compared with women treated with surgery alone and with women in the general population.

According to the authors, this is the first large study to evaluate long-term effects of radiotherapy for DCIS on both the incidence of CVD and associated deaths.

However, longer follow-up is needed to establish the cardiovascular safety of radiation with certainty in patients with DCIS, said lead author Naomi B. Boekel, MSc, a PhD student at the Netherlands Cancer Institute in Amsterdam. She said that 5 to 10 more years of follow-up should be sufficient.

The study included 10,468 women younger than 75 years diagnosed with DCIS between 1989 and 2004.

About 71% had surgery only (43% had mastectomy and the remaining women had lumpectomy), and 28% underwent both surgery and radiotherapy. DCIS survivors had similar death rates as well as a 30% lower risk of dying of CVD compared with the general population.

Patients treated with surgery alone had a similar risk of developing CVD as those treated with both surgery and radiotherapy (9% vs 8%, respectively); no difference in risk of CVD was observed between patients who received left-sided radiotherapy (which includes a portion of the

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heart in the radiation field) or right-sided radiotherapy (which does not include the heart in the radiation field); in these subgroups, the incidence of CVD was 7% versus 8%, respectively.

It is not clear why DCIS survivors had a slightly lower risk of CVD compared with the general population, but Boekel suggested that cancer survivors may be more concerned about a healthy lifestyle than the general population.

MRI in DCIS Perioperative MRI may not be necessary in all patients undergoing surgery for DCIS, according to results from the second study featured at the Press Cast. The risk of LRR or contralateral breast cancer (CBC) was not lower in women who underwent MRI around the time of surgery, according to a retrospective study conducted at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City.

Although no official guidelines for MRI in DCIS are available, many medical centers routinely order perioperative MRI in the hope of improving outcomes by finding additional cancers not detected by mammograms or other imaging studies. “Our findings indicate that MRI is not necessary for every patient with DCIS,” stated first author Melissa L. Pilewskie, MD, MSKCC in New York City and Commack, New York. She noted that periop-

erative MRI may be useful in specific patients with DCIS, such as those with a palpable mass and nipple discharge not found on mammography screening.

The study analyzed rates of LRR and CBC in 2321 women who underwent a lumpectomy between 1997 and 2010 at MSKCC; 596 had an MRI before or immediately following surgery and 1725 did not. At a median follow-up of 57 months, 5-year LRR rates were 8.5% in those who had an MRI versus 7.2% for those who did not. After adjusting for patient characteristics and risk factors associated with recurrence, MRI was still not associated with lower rates of LRR. Additionally, no significant differences were seen in the 5-year rates of CBC (3.5 years in both groups).

At 8 years, the rate of LRR was 14.6% for those who had an MRI versus 10.2% for those who did not. The rate of CBC at 8 years was 3.5% and 5.1%, respectively.

MRIs are typically ordered for women who have risk factors for breast cancer, such as younger age or family history. Pilewskie said that this might explain the higher recurrence rates in that group. u

References

1. Boekel NB, Schaapveld M, Gietema JA, et al. Cardiovascular morbidity and mortality in patients treated for ductal carcinoma in situ of the breast. J Clin Oncol.

2013;31(suppl 26). Abstract 58.

2. Pilewskie ML, Olcese C, Eaton A, et al. Association of MRI and locoregional recurrence (LRR) rates in ductal carcinoma in situ (DCIS) patients treated with or without radiation therapy (RT). J Clin Oncol. 2013;31(suppl 26). Abstract 57.

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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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Discussions in Personalized Treatment for Lymphoma: Do We Have Consensus?

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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

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NSCLC CASE STUDY

Personalizing Therapy in the Management of Recurrent Non–Small Cell Lung Cancer: Case Study of a Patient With an EGFR Mutation At the 2013 conference of the Global Biomarkers Consortium, which took place October 4-6, 2013, in Boston, Massachusetts, Roy S. Herbst, MD, PhD, from the Yale Comprehensive Cancer Center in New Haven, Connecticut, discussed the use of personalizing therapy in the management of recurrent non–small cell lung cancer.

A

ceiling for cytotoxic chemotherapy for lung cancer was reached in 2002. Shortly thereafter, a mutation in epidermal growth factor receptor (EGFR) was discovered as a driver mutation in advanced non–small cell lung cancer (NSCLC), and therapies targeting this mutation were developed. This mutation is present in up to 40% of Asians with NSCLC.

Case: Recurrence of NSCLC Suspected A 41-year-old Chinese American female presents with right-sided chest wall pain and right abdominal pain. She has never smoked. Her performance status is 1. In 2011, she had stage 1B (pT2a N0 M0) NSCLC with squamous histology treated with right upper lobectomy with no adjuvant treatment.

The benefits of adjuvant therapy in lung cancer are real but small. On this latest follow-up, a recurrence was suspected based on her symptoms and history. A CT scan of the chest and abdomen revealed multiple heterogeneous masses in the liver and spleen and extensive abdominal lymphadenopathy. These findings are compatible with tumor spread within the right pleural space and involving the right hemidiaphragm (Figure).

In lung cancer, even with therapies to target EGFR mutations and ALK rearrangements, the median time to regression is still only 1 year.

asses in• CT Findings gnostic: scancompatible of the with tumor spread

A PET/CT scan is performed and shows hypermetabolic metastatic masses above and below the diaphragm; a large hypermetabolic mass in the right costophrenic angle extending to the right hepatic lobe; hypermetabolic lymph nodes in the left paratracheal, left hilar, hepatic, and retroperitoneal region; hypermetabolic right pleural effusion; and hypermetabolic bony disease.

The findings represent profound recurrence 2 years later. “That’s the problem with lung cancer; even when you think you’ve cured it in stage 1B disease, there’s a 40% chance that it will come back,” said Roy S. Herbst, MD, PhD, director of the Thoracic Oncology Research Program and associate director of Translational Research, Yale Comprehensive Cancer Center, New Haven, Connecticut.

ultiple heterogeneous masses in ver and spleen tumor xtensive abdominal ural mphadenopathy ght indings compatible with tumor pread within the right pleural pace and involving the right emidiaphragm

Assuming equal procedure risk, which lesion should be biopsied to establish the diagnosis of recurrent cancer?

Mediastinal lymph node Liver Bone Any site; it does not make a difference “We ask the radiologist what he or she wants,” said Herbst. “The one thing you don’t want to do is bone.

With personalized therapy and biopsy becoming so common in lung cancer, the radiologists are working more closely with us on the biopsies. In this electronic

t’d) Figure urrence

Suspected Recurrence: CT scan

Diagnostic: CT scan of the chest, Case 2 (Cont’d) abdomen e • Multiple heterogeneous masses in liver Suspected Recurrence and spleen

• Extensive abdominal lymphadenopathy within the right pleural space and in-

volving the right hemidiaphragm st, abdomen

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age, you can e-mail them a record, and they look at it.”

The pathology in the liver on ultrasound-guided fine-needle aspiration is poorly differentiated squamous cell carcinoma. The malignant cells are cytologically similar to the patient’s prior lung squamous cell carcinoma.

Would you recommend tumor genotyping before initiating systemic therapy for EGFR mutation and ALK fusion?

“In this era of molecular pathology, I would do profiling,” he said. “EGFR mutations have been described now as we look more in squamous, and molecular pathology is now an added tool to histological pathology.”

The EGFR mutation was positive for L858R. What is recommended first-line therapy in this never-

smoking Chinese American patient with lung squamous cell carcinoma and EGFR mutation?

Erlotinib or gefitinib based on EGFR mutation testing Afatinib Ignore EGFR mutation testing since this is squamous cell carcinoma. Give a platinum-based doublet Erlotinib or gefitinib would be the choice until more data with afatinib become available, said Herbst. In lung cancer, even with therapies to target EGFR mutations and ALK rearrangements, the median time to regression is still only 1 year. “Most every patient will become resistant,” he said. “The longest patient I ever had who was treated with an EGFR inhibitor on an off, was about 8.5 years. These are not curative therapies. The tumor will have either preexisting resistance or will develop resistance.” u

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Challenges Patients Face in Cancer Care: Implications for the Healthcare Team Lea Ann Hansen, PharmD, BCOP Associate Professor, Virginia Commonwealth University

cancer.1 More than half are living well beyond 5 years ancer is an illness associated with substantial physical, emotional, social, and financial ramafter diagnosis. Women comprise a majority of longifications for affected individuals and their term survivors due to the favorable outcomes with families. In a significant number of cases, the diagnosis breast, cervical, and uterine cancers.2 The number of of cancer is either preceded by a period people living with a history of cancer

of gradual, nonspecific symptoms or is projected to grow considerably over

discovered by routine screening, and the next 20 years for 2 major reasons. individuals are then thrust into a First, the number of Americans over whirlwind of diagnostic testing, inage 65 is predicted to double between vasive procedures, and complicated the years 2000 and 2030.3 Consetreatments with very little warning or Lea Ann Han quently, as a disease primarily of older sen Associate , Pha opportunity to assimilate their circumProfessor, rmD, BCOP adults, cancer will also increase. SecVirginia Commond, stances. Frequently, a multidisciplinary as the effectiveness of cancer onweal versity â&#x201E;˘ th Uni approach to treatment is necessary, retreatments improves, the number of he past dec ade has seen quiring patients to engage with numerthe utilizat a drapatients matic upscured of the disease will in

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EDITORIAL THE LAST WORD

To PARP or Not to PARP – What Is the Question? Part 2

Perspective on the First “Disappointment” With a New Drug Class

I

n the first article on this topic, appearing in the last issue of PMO, we looked at a sequence of events surrounding an attempt to achieve quick consensus concerning the treatment of metastatic triple-negative breast cancer (TNBC) with a PARP inhibitor. O’Shaughnessy et al selected iniparib as the PARP inhibitor to study, and after a phase 2 study produced encouraging outcomes, she attempted to replicate them in an eagerly awaited phase 3 trial.1 Expectations in the oncology community were high, and so, when the phase 3 results were poor, profound disappointment ensued. PARP inhibitors had been so thoroughly documented to reverse TNBC that these results stunned many. There was almost a sense that these phase 2 and phase 3 trials were simply necessary preludes to an inevitable ceremonial coronation of a winner, rather than empirical trials requiring rigor and assuming nothing but additional understanding of a highly complex disease state and equally complex pharmacologic class of agents for it. The need for an explanation of the failed phase 3 study was acute.

It was not long in coming.

A pharmacologic fact lurking in the shadows of these 2 trials explained the problem and quickly restored confidence in PARP inhibitors for TNBC. As Metzger-Filho et al blandly state, “Iniparib (BSI-201) was initially thought to be a PARP inhibitor, but recent data indicate that iniparib does not possess characteristics typical of this class.”2 In short, the trials were studying a drug that is not a PARP inhibitor.

Oops. Mistaking a drug’s class and function is not unprecedented – it has happened before. It tends to occur in new drug classes, reflecting the subtlety and the perils of cutting-edge research, which can become bleeding-edge research when any of the subtle pharmacologic qualities of the drug are overlooked. The good news is that it has not slowed work on several new PARP inhibitors. Had politics ruled medicine, the failed phase 3 trial would have consigned PARP inhibitors to the fast-fail drug heap, depriving TNBC patients of their best hope.

The issue involves the immense complexities of both PARP inhibitors and TNBC. Metzger-Filho et al provide a useful summary perspective of these conjoined issues: TNBC is a challenging disease that has lacked a

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standardized treatment approach both in the early and advanced settings. Available evidence suggests that among patients with TNBC, prognosis seems to vary according to factors such as age and pathologic subtype. Several research groups have provided important insights into TNBC heterogeneity. Genes related Robert E. Henry to immune response have been shown to be of prognostic and predictive value, but validation is needed. PARP inhibitors have demonstrated impressive results in studies in the BRCA1/2 BC [breast cancer] subpopulation, but the identification of nonmutant TNBC likely to derive the same magnitude of benefit remains challenging. Prospective clinical trials coupled with integrated adequately powered translational research questions are likely to improve the outcome of patients with TNBC and should be our priority.2

Had politics ruled medicine, the failed phase 3 trial would have consigned PARP inhibitors to the fast-fail drug heap, depriving TNBC patients of their best hope.

Personalized medicine is a perfect model for understanding how to combat TNBC with PARP inhibitors.

But like any recently understood disease entity, TNBC requires oncologists to go past the punch lines of clinical trials and understand its biology and a drug’s pharmacodynamics in minute detail. We are dealing with a heterogeneous disease state – a textbook environment for an iterative process of understanding diagnostic and treatment nuances: “The lack of a consensus definition for stratifying TNBCs into subtypes attests to the molecular complexity of basal tumors, underscoring the need for comprehensive translational research efforts in this field.”2 Just how heterogeneic is the disease that iniparib was sent out to treat? The overview by Metzger-Filho et al cuts to the chase with their article’s title: Dissecting the

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Heterogeneity of Triple-Negative Breast Cancer. It puts us on notice that this disease state is fiercely complex and has a lot of moving parts that cannot be oversimplified by clinician or researcher: “As the heterogeneity of TNBC is better defined, potential therapeutic targets are likely to emerge. A better understanding of the immune system is likely to foster new therapies designed to modulate immune response. For the time being, studies in TNBC are focused on evaluating the role of novel cytotoxics or available cytotoxics in combination with known target agents.”2 A major consideration is patient selection: “In clinical practice, patients are selected for treatment based on clinical stage, tumor histology, and biomarkers with the ability to predict response to treatment.”2 A heterogeneous disease state is a textbook environment for obstacles in attaining the precision in diagnostics and treatment. HER2 receptor assessment follows a standardized definition according to guidelines, but hormone receptor assessment varies across different countries, and different immunohistochemistry (IHC) cutoffs are used to define positivity. The American Society of Clinical Oncology/College of American Pathologists guidelines for IHC testing for estrogen receptors and progesterone receptors recommend that assays be considered positive if there is at least 1% of positive tumor cells in the sample.3 If this description connotes nothing else, it is the demand for attention to detail in high science.

So the oncologist treating TNBC must dig beneath the succinct definition of PARP inhibitors, neatly described as “...a family of nuclear enzymes that polymerize poly(adenosine diphosphate–ribose) on substrate proteins to regulate processes such as DNA repair, gene transcription, and chromatin architecture.”4 They work in concert with conventional chemotherapy and radiation interventions that seek to break a tumor’s DNA double-strands. The body responds by attempting to repair the double-strand break that would kill the tumor cells, by “...a BRCA1/2-dependent, high-fidelity process in which the homologous sequence is used to

REPRINTS

precisely repair the break.”4 A definition is by no means a guide to treatment; the answers will lie in the details, and they are legion.

Translational research...personalized medicine depends on it, feeds on it, this intersection between research and clinical practice. O’Shaughnessy and colleagues did not dislodge research into PARP inhibitors, but if anything accelerated it by forcing a deeper look into the pharmacologic distinctions between iniparib and the real PARP inhibitors. The phase 3 research “failure” speaks to the need for cultivating a sense of what is on or off track in charting a treatment course in any newly delineated disease state – and TNBC is less than a decade old, PARP inhibitors younger.

Disappointment with clinical trial results also cultivates patience rather than a precipitous dismissal of new agents when survival is only nominally improved. We will examine this fascinating matter in our next column, for within it lays another component of personalized medicine: things are not always what they seem, and limited survival improvements may not always signal retreat. It involves the matter of proof of concept, and it is part of the exotic biological jungle we have entered when we accepted the challenge to confront cancer with personalized medicine. u

Robert E. Henry

References

1. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol. 2011;29(suppl). Abstract 1007.

2. Metzger-Filho O, Tutt A, de Azambuja E, et al. Dissecting the heterogeneity of triple-negative breast cancer. J Clin Oncol. 2012;30:1879-1887.

3. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol.

2010;28:2784-2795.

4. Carey L, Sharpless N. PARP and cancer – if it’s broke, don’t fix it. N Engl J Med. 2011;364:277-279.

Personalized Medicine in Oncology ™ offers reprints of individual articles in printed or electronic form to increase awareness of your product or company.

ORDER TODAY! Russell Hennessy • 732.992.1888 • russell@greenhillhc.com 414

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PM O

Interview With the Innovators A PMO Exclusive Series The world of personalized medicine is a rapidly changing, ever-evolving state involving many stakeholders on the front lines of its creation: physicians, industry, researchers, patient advocates, and payers.

PMO seeks out the leaders in these sectors and brings you their game-changing strategies, missions, and impact on personalizing oncology care.

To view Interview With the Innovators, or to nominate an interviewee, visit us at

www.personalizedmedonc.com

PMO Interviewees include:

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

Edith Perez, MD Mayo Clinic

Kimberly Popovits Genomic Health

Edward Abrahams, PhD Personalized Medicine Coalition

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

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

Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

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

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

NCT#01889186 Reference: ClinicalTrials.gov.

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

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