Personalized Medicine in Oncology February 2015

A Peer-Reviewed Journal

February 2015 • Volume 4 • Number 1

PM O

BIOMARKERS • TARGETED THERAPIES • DIAGNOSTICS

Personalized Medicine in Oncology TM

HEMATOLOGIC MALIGNANCIES Novel Therapeutics Targeting CD19 and CD22 in Adult Acute Lymphoblastic Leukemia.................Page 14

LUNG CANCER CME Faculty Perspectives: Latest Treatment Advances for Individualized Care of NSCLC................... Page 22

COLORECTAL CANCER CME Faculty Perspectives: Latest Treatment Advances for Individualized Care of CRC..........................Page 34

WORLD CUTANEOUS MALIGNANCIES CONGRESS Case Presentation: International Focus on the Management of Acral Lentiginous Melanoma..................Page 42

PMO LIVE Case Report: Intense Maintenance in a Woman with High-Risk Multiple Myeloma.................... Page 48

THE LAST WORD To Regulate or Not Regulate LaboratoryDeveloped Tests, That Is the Question........... Page 58

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

The official publication of

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

WORLD CUTANEOUS MALIGNANCIES CONGRESS

© 2015 Green Hill Healthcare Communications, LLC An affiliation of The Lynx Group

WORLD CUTANEOUS

In partnership with

™

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.

ISTODAX FOR THE 2ND-LINE TREATMENT OF PTCL

Important Safety Information WARNINGS AND PRECAUTIONS • Myelosuppression: ISTODAX® (romidepsin) can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; monitor blood counts regularly during treatment with ISTODAX; interrupt and/or modify the dose as necessary • Infections: Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses, have been reported during and within 30 days after treatment with ISTODAX in clinical trials. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow. Reactivation of Epstein Barr viral infection led to liver failure.

Consider monitoring for reactivation and antiviral prophylaxis in patients with evidence of prior hepatitis B infection. Ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation in one case • Electrocardiographic (ECG) changes: 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, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment. Confirm that potassium and magnesium levels are within the normal range before administration of ISTODAX • Tumor lysis syndrome: TLS (Tumor lysis syndrome) has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden are at greater risk and should be closely monitored and managed as appropriate • Embryo-fetal toxicity: ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women of potential hazard to the fetus and to avoid pregnancy while receiving ISTODAX

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. © 2014 Celgene Corporation 10/14 US-IST140021

www.istodax.com

ISTODAX demonstrated efficacy in PTCL after at least one prior therapy1 Efficacy and safety evaluated in the largest prospective single-arm PTCL study (Study 3, N=131) in a pretreated, histologically diverse PTCL population. All patients received prior systemic therapy for PTCL. Patients could be treated until disease progression at their discretion and that of the investigator.

60% (12/20) of complete responses were known to exceed

26% ORR

11.6 Months

(34/130)

(CR + CRu + PR) [95% CI: 18.8, 34.6a]

15% CR/CRu

(20/130)

Primary End Point

(CR + CRu) [95% CI: 9.7, 22.8a] 0

2

4

6

8

10

12

14

16

Months

• Follow-up on the remaining 8 patients was

56 days

(1.8 months, n=34)

median time to objective disease response2

discontinued prior to 8.5 months

a95% confidence interval. Response rates above are rounded to the nearest whole number.

CR=complete response; CRu=complete response unconfirmed; ORR=overall disease response rate.

Infections were the most common type of serious adverse event reported in Study 3 (N=131) and Study 4 (N=47).

In Study 3, 26 patients (20%) experienced a serious infection, including 6 patients (5%) with serious treatmentrelated 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 more frequently prothrombin time and International Normalized Ratio in patients concurrently administered ISTODAX and warfarin or coumarin 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 (romidepsin) 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 • Pregnancy Category D: 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 • 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.

References: 1. ISTODAX [package insert]. Summit, NJ: Celgene Corp; 2014.

2. Data on file, Celgene Corporation, Summit, NJ.

10-MG SINGLE-USE VIAL

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NK/T-cell lymphoma. In one case, ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation.

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, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment.

Confirm that potassium and magnesium levels are within 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 may be at greater risk, should be closely monitored, and managed as appropriate.

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 The following adverse reactions are described in more detail in other sections of the prescribing information.

• Myelosuppression [see Warnings and Precautions (5.1)] • Infection [see Warnings and Precautions (5.2)] • Electrocardiographic Changes [see Warnings and Precautions (5.3)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.4)] 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 were 5.6 months and 6 cycles in Study 3 and 9.6 months and 8 cycles in Study 4.

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) Adverse Reactions n (%) All grades Grade 3 or 4 All grades Grade 3 or 4 Any adverse reactions 128 (97) 88 (67) 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 14 (11) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 8 (6) 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 33 (25) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) (continued)

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ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a Brief Summary only; see full Prescribing Information for complete product information.

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.

These indications are 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 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 is a cytotoxic drug. Use appropriate handling procedures.

ISTODAX must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium Chloride Injection, USP before intravenous infusion.

• Each 10 mg single-use vial of ISTODAX (romidepsin) must be reconstituted with 2 mL of the supplied diluent. With a suitable syringe, aseptically withdraw 2 mL from the supplied diluent vial, and slowly inject it into the ISTODAX (romidepsin) for injection vial. Swirl the contents of the vial until there are no visible particles in the resulting solution. The reconstituted solution will contain ISTODAX 5 mg/mL. The reconstituted ISTODAX solution is chemically stable for up to 8 hours at room temperature.

• Extract the appropriate amount of ISTODAX from the vials to deliver the desired dose, using proper aseptic technique. Before intravenous infusion, further dilute ISTODAX in 500 mL 0.9% Sodium Chloride Injection, USP. • Infuse over 4 hours.

The diluted solution is compatible with polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyethylene (PE) infusion bags as well as glass bottles, and is chemically stable for up to 24 hours when stored at room temperature.

However, it should be administered as soon after dilution as possible.

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia. Monitor blood counts regularly during treatment with ISTODAX, and modify the dose as necessary [see Dosage and Administration (2.2) and Adverse Reactions (6)].

5.2 Infections Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow [see Adverse Reactions (6)].

Reactivation of hepatitis B virus infection has occurred in 1% of PTCL patients in clinical trials in Western populations [see Adverse Reactions (6)]. In patients with evidence of prior hepatitis B infection, consider monitoring for reactivation, and consider antiviral prophylaxis.

Reactivation of Epstein Barr viral infection leading to liver failure has occurred in a trial of patients with relapsed or refractory extranodal

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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) Adverse Reactions n (%) All grades Grade 3 or 4 All grades Grade 3 or 4 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 14 (11) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

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 © 2010-2014 Celgene Corporation. All Rights Reserved.

Pat.www.celgene.com/therapies IST_PTCL_BSv006 10/2014

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Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 26 patients (20%) 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 (8%), 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%).

Reactivation of hepatitis B virus infection has occurred in 1% of patients with PTCL patients in clinical trials in Western population enrolled in Study 3 and Study 4 [see Warnings and Precautions (5.2)].

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.

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%).

6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience.

7 DRUG INTERACTIONS 7.1 Warfarin or Coumarin 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 warfarin has not been formally studied, monitor PT and INR more frequently in patients concurrently receiving ISTODAX and warfarin.

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%.

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. 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. 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.

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

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.

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.

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 heartbeat, 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.

FEBRUARY 2015

VOLUME 4, NUMBER 1 PUBLISHING STAFF Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Manager, Client Services Travis Sullivan tsullivan@the-lynx-group.com Editorial Director Kristin Siyahian ksiyahian@the-lynx-group.com Strategic Editor Robert E. Henry Senior Copyeditor BJ Hansen Copyeditor Rosemary Hansen Production Manager Marie RS Borrelli

TABLE OF CONTENTS HEMATOLOGIC MALIGNANCIES

14 Novel Therapeutics Targeting CD19 and CD22 in Adult Acute Lymphoblastic Leukemia

Shira N. Dinner, MD; Olga Frankfurt, MD; Jessica K. Altman, MD The authors focus on monoclonal antibodies, antibody-drug conjugates, bispecific T-cell–engaging antibodies, and chimeric antigen receptors that specifically target CD19 and/or CD22.

LUNG CANCER CME

22

Faculty Perspectives: Latest Treatment Advances for Individualized Care of NSCLC

Roy S. Herbst, MD, PhD; Marianne Davies, RN, MSN, ACNP, AOCN; James T. Kenney Jr, RPh, MBA The faculty provide an overview of data from key clinical trials in EGFR- and ALK- positive NSCLC presented at the recent ASCO and ESMO meetings.

COLORECTAL CANCER CME

34

Faculty Perspectives: Latest Treatment Advances for Individualized Care of CRC

Leonard Saltz, MD; Ellen M. Hollywood, MSN, RN, OCN; James T. Kenney Jr, RPh, MBA The faculty of this continuing educational activity review emerging data in colorectal cancer from ASCO and ESMO and discuss the clinical relevance of these advances.

WORLD CUTANEOUS MALIGNANCIES CONGRESS

42 Case Presentation: International Focus on the Management of Acral Lentiginous Melanoma

Héctor Martínez-Said, MD; Axel Hauschild, MD, PhD; and Sanjiv S. Agarwala, MD, representing Latin America, Europe, and the United States, respectively, discussed the management of melanoma through a presentation of a case study at the Third Annual World Cutaneous Malignancies Congress.

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

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

6

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Personalized Medicine in Oncology

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www.PersonalizedMedOnc.com

The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Wayne Williams Director, Digital Media Anthony Romano Jr Digital Media Specialist Charles Easton IV Web Content Manager Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Mezzacappa Senior Project Managers Alyson Bruni Jini Gopalaswamy Project Manager Deanna Martinez Project Coordinator Mike Kodada IT Manager Kashif Javaid Administrative Team Leaders Rachael Baranoski Allison Ingram Administrative Assistant Amanda Hedman 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

February 2015

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Vol 4, No 1

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FEBRUARY 2015

VOLUME 4, NUMBER 1

RegisteR today TABLE OF CONTENTS

M ay 3-6, 2015

(Continued)

PMO LIVE

48 Case Report: Intense Maintenance in a Woman with High-Risk Multiple Myeloma

A case report presented at PMO Live, the only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology.

AnnuAl ConferenCe

NEWS FROM THE AMERICAN SOCIETY OF HEMATOLOGY

50 51

Personalizing Myeloma Treatment Can Limit the Use of Expensive Drugs Genomic Panel Likely to Be Cost-effective in AML

TH

AN

RSARY VE NI

NEWS FROM THE CHEMOTHERAPY FOUNDATION

52 53 54

Scientific Exploration of Obesity and Breast Cancer Link PARP Inhibitors in Gynecologic Cancer: More Questions Than Answers Basket Trials Based on Genomics Hold Promise

EDITORIAL

56

FACT SHEET: President Obama’s Precision Medicine Initiative The White House unveils details about the Precision Medicine Initiative, a bold new research effort to revolutionize how we improve health and treat disease.

Omni Shoreham Hotel Washington, DC

THE LAST WORD

58

To Regulate or Not Regulate Laboratory-Developed Tests, That Is the Question Edward Abrahams, PhD Dr Abrahams explores the hotly debated topic of regulating diagnostic tests – how best to protect the public’s health while encouraging innovation in diagnostics.

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

Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 6 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copy­right ©2015 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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Immunotherapy in

oncology A 6-PART SERIES

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EDITORIAL BOARD

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

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

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

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

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

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

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

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

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

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

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THE bioT3 METASTATIC CANCER SOLUTION ACTIONABLE GENOMIC INFORMATION TO HELP WITH ACCURATE DIAGNOSIS AND TREATMENT OF METASTATIC CANCER PATIENTS

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FOR MORE INFORMATION VISIT WWW.METASTATICCANCERSOLUTION.COM bioTheranostics, Inc. | 9640 Towne Centre Drive | Suite 200 | San Diego, CA 92121 | bioTheranostics.com Client Services: +1 (877) 886-6739 Fax: +1 (858) 587-5874 © 2014 bioTheranostics, Inc. CancerTYPE ID is a registered trademark of bioTheranostics, Inc. Indications for use and limitations available at www.biotheranostics.com

LETTER TO OUR READERS

Enthusiasm Mounts in the Personalized Medicine Movement Dear Colleague,

I Al B. Benson III, MD, FACP, FASCO

t is my pleasure to welcome you to the 2015 volume of Personalized Medicine in Oncology (PMO). We are extremely enthusiastic about the forthcoming, much anticipated advances in the personalized medicine movement this year. And we’re not the only ones. Of course, those of us in the oncology community are acutely aware of the vast amount of research that has gone into establishing personalized medicine as the goal of oncology care, but now the nation at large has become aware of the promise of personalized medicine too, as exemplified even in the president’s State of the Union address last month.

More than ever, we are marching toward a future where the combination of past progress and current technologies promises to advance our ability to provide the most effective, including cost-effective, care for our patients with cancer. All of which are reflected in our pages. This year, you will note the following in PMO: • Interview with the Innovators 2015 series: We will present eye-opening, provocative, and informative interviews with those who are shaping the landscape of personalized care in oncology • Innovator of the Year award: Meet the current Innovator of the Year, recognized by PMO for his incredible contributions to the personalized medicine movement (page 13) • Personalized Medicine Coalition (PMC): Our collaboration with PMC continues with the column by Dr Edward Abrahams, The Last Word (page 58) In addition, we are delighted to announce a 2015 volume of our sister publication, Immunotherapy in Oncology, to specifically cover advances in this timely and exciting realm of oncology.

Thank you for sharing our enthusiasm in the quest to personalize care by being part of our reading community. We are looking forward to a bright future in which we are able to improve the lives of our patients.

Sincerely,

Al B. Benson III, MD, FACP, FASCO Coeditor in Chief Personalized Medicine in Oncology

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BIOMARKERS • IMMUNOTHERAPY • TARGETED THERAPIES • DIAGNOSTICS

Interview with the Innovators

INNOVATOR OF THE

YEAR AWARD

James Allison, PhD The University of Texas MD Anderson Cancer Center

The world of personalized medicine is a rapidly changing, ever-evolving state involving many stakeholders on the frontlines of its creation: physicians, industry, researchers, patient advocates, and payers. The publishers of PMO have the distinct honor of interviewing leaders in these sectors to bring you their game-changing strategies, missions, and impact on personalized oncology care.

Each year, we select the innovator whose contribution to the field of oncology represents the most profound impact on patient care. For 2015, it is our pleasure to award the distinction of Innovator of the Year to James Allison, PhD, of The University of Texas MD Anderson Cancer Center.

Dr Allison is the chairman of the Immunology Department and executive director of the immunology platform for the Moon Shots Program at MD Anderson in Houston.

He is the recipient of numerous honors for biomedical research, including the inaugural AACR-CRI Lloyd J. Old Award in Cancer Immunology, the 2013 Innovations Award for Bioscience from The Economist, and a 2014 Breakthrough Prize in Life Sciences. He also coleads a Stand Up to Cancer Dream Team research project in immunotherapy.

Dr Allison is on a quest to train the immune system to attack cancer cells, eliminate tumors, and protect against recurrence. The strategy being employed is a new paradigm for cancer treatment called immune checkpoint targeting. This approach has proved effective in treating many different types of cancer and is now a standard of care for metastatic melanoma. To see our interview with Dr Allison, please visit us at www.PersonalizedMedOnc.com.

INNOVA NOVATOR NOVA VATOR OF THE YEAR

2015

It is our pleasure to congratulate Dr Allison on his work to date and the profound impact it has had on the lives of patients. We wish him continued success in his quest to harness the power of the immune system to combat cancer.

GLOBAL BIOMARKERS www.PersonalizedMedOnc.com CONSORTIUM ™

Clinical Approaches to Targeted Technologies

The official publication of

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

In partnership with

WORLD CUTANEOUS MALIGNANCIES CONGRESS

™

PMOinnovatorAsize 020515

ACUTE LYMPHOBLASTIC LEUKEMIA

Novel Therapeutics Targeting CD19 and CD22 in Adult Acute Lymphoblastic Leukemia Shira N. Dinner, MD; Olga Frankfurt, MD; Jessica K. Altman, MD Northwestern University Feinberg School of Medicine Robert H. Lurie Comprehensive Cancer Center Chicago, IL

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utcomes in adult acute lymphoblastic leukemia (ALL) remain poor, with long-term disease-free survival (DFS) rates of 30% to 40%.1 Salvage chemotherapy regimens demonstrate limited success in inducing and maintaining a second remission, and consequently overall survival (OS) at 5 years after relapse is as low as 7%.2 Therefore, novel Shira N. Dinner, agents with alternative mechanisms of action MD are essential for improving outcomes in both newly diagnosed and relapsed/refractory disease. Because the cell surface antigen CD19 is expressed on up to 100% of B-lineage ALL (B-ALL) blast cells and CD22 is expressed on up to 90% of B-ALL blasts, they have become highly investigated targets for immunotherapies.3 This review will focus on monoclonal antibodies, antibody-drug conjugates, bispecific T-cellâ&#x20AC;&#x201C;engaging antibodies, and chimeric antigen receptors that specifically target CD19 and/or CD22.

CD19 CD19 expression on the B-cell surface continues from the time of B-lineage commitment during hematopoietic stem cell differentiation until it is downreguDr Dinner is an Assistant Professor of Medicine in the Division of Hematology/Oncology at Northwestern University focused on the development of early-phase clinical trials and correlative translational studies for the treatment of acute leukemias, in particular acute lymphoblastic leukemia.

Dr Frankfurt is an Associate Professor of Medicine in the Division of Hematology/Oncology at Northwestern University with an interest in acute leukemias, myelodysplastic syndromes, and stem cell transplantation. She leads the Cord Blood Transplantation Program at Northwestern University.

Dr Altman is an Associate Professor of Medicine in the Division of Hematology/Oncology at Northwestern University. She is the Director of the Leukemia Program for Northwestern Medicine Developmental Therapeutics Institute. She focuses her career on translational research in acute myeloid leukemia with a specific interest in signal transduction and the development of early-phase clinical trials.

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lated during terminal differentiation into plasma cells.

CD19 expression is maintained in B-lineage cells that have undergone neoplastic transformation and has a high density of expression, making it an ideal target for immunotherapies.3,4 CD19 Monoclonal Antibody (Table) MEDI-551 is a humanized monoclonal anti-CD19 antibody that is known to have antileukemic activity both in vitro and in clinical trials via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis in chronic lymphocytic leukemia.5,6 In vitro studies in B-ALL cell lines demonstrate interaction between anti-CD19â&#x20AC;&#x201C;bound target leukemia cells and effector cells, resulting in recruitment of natural killer (NK) cells and macrophages to induce NK-mediated killing and macrophage phagocytosis of blasts. In a xenograft ALL model, treatment with MEDI-551 resulted in decreased disease burden and prolonged survival.7 Therefore, this drug should be investigated further in early-phase clinical trials in B-ALL. CD19 Antibody-Drug Conjugate (Table) SAR3419 is a humanized monoclonal IgG1 antibody attached to the tubulin inhibitor maytansinoid DM4 by the cleavable linker N-succinimidyl-4-butyrate.8 DM4 is similar to vinca alkaloids but with over 100-fold higher potency.8 After SAR3419 binds to the CD19 antigen on the B-cell surface, it is endocytosed and routed to the lysosomes and cytoplasm for degradation and release of the DM4 toxin.8 Early-phase studies of SAR3419 in relapsed/refractory B-cell non-Hodgkin lymphomas (NHLs) demonstrated safety and efficacy with weekly dosing.9 This prompted preclinical investigation in ALL. In vivo SAR3419 delayed tumor progression and produced objective responses in ALL xenograft models, including those with chemoresistant disease. In untreated ALL xenograft models, SAR3419 enhanced the antileukemia effects of vincristine, dexamethasone, and asparaginase induction therapy. Further, when administered after attainment of remission, SAR3419 prevented disease recurrence.10

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CD19 Bispecific T-Cell–Engaging Antibody (Table) Blinatumomab is a bispecific T-cell–engaging antibody that combines 2 single-chain antibodies directed against CD19 and CD3.11 While targeting the CD19expressing B cells, it is able to recruit CD3-expressing cytotoxic T cells, thus directing T cells to malignant B cells for perforin-mediated cell death. Binding both CD19 and CD3 is required for T-cell activation and prevents uncontrolled cell lysis.12 The first reports of blinatumomab safety and activity were in relapsed NHLs with a dose of 15 μg/m2/24 hours IV administered continuously for 4 weeks, resulting in elimination of tumor cells from the bone marrow.12 The same dose and schedule was therefore used in patients who never achieved minimal residual disease (MRD) negativity or molecularly relapsed B-ALL. MRD positivity was defined as a quantifiable MRD load of ≥1×10-4 by quantitative reverse transcriptase-polymerase chain reaction.

Eighty percent of patients became MRD negative, including 57% of patients who were molecularly refractory to prior chemotherapy. Lymphopenia was the most common toxicity grade ≥3. Additional common adverse events (AEs) included pyrexia, chills, decreased blood immunoglobulin, and hypokalemia.13 Follow-up of this study after a median of 33 months was significant for a hematologic relapse-free survival (RFS) of 61% for the entire evaluable study cohort of 20 patients. The hematologic RFS of the 9 patients who received an allogeneic hematopoietic stem cell transplant (HSCT) after blinatumomab treatment was 65% after a median follow-up of 33 months. Notably, 67% of Philadelphia chromosome (Ph)-negative MRD responders with no further therapy after blinatumomab remained in hematologic and molecular remission after a median follow-up of 30 months, demonstrating similar rates of long-term DFS in patients who did or did not undergo HSCT. This is one of the first novel agents showing the ability to induce a long-lasting complete remission (CR) in ALL refractory to chemotherapy, suggesting it may be beneficial for the frontline treatment of ALL.14 The recently opened United States Intergroup Trial, ECOG 1910, is comparing blinatumomab plus chemotherapy with chemotherapy alone in adults with newly diagnosed B-ALL (NCT02003222).

Analysis of serum samples from the clinical trial for MRD-positive patients confirmed on-target activity of blinatumomab by depleting CD19-expressing B cells both during and between treatment cycles. Cytokine levels, including interleukin (IL)-2, IL-6, IL-10, interferon-gamma, and tumor necrosis factor-alpha, increased early in the first cycle with a high interpatient variability and were no longer detected after beginning cycle 2, suggesting that cytokine-release syndrome (CRS) may

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KEY POINTS The majority of malignant B cells in acute lymphoblastic leukemia (ALL) maintain CD19 and CD22 cell surface expression at high levels, making them excellent targets for novel therapies ➤ The anti-CD22 monoclonal antibody, epratuzumab, demonstrated limited single-agent activity in ALL but caused minimal toxicities and was more effective in combination with chemotherapy. The antiCD19 monoclonal antibody, MEDI-551, produced promising antileukemia activity in preclinical models but has not yet been investigated in earlyphase clinical trials in ALL as a single agent or with chemotherapy ➤ Antibody-drug conjugates improve upon monoclonal antibody cytotoxicity by delivering an immunotoxin to the ALL cell for endocytosis.

The CD22-targeted agent, inotuzumab ozogamicin, showed particular promise as a single agent in relapsed/refractory ALL ➤ T-cell–engaging bispecific single-chain antibodies such as CD19-targeted blinatumomab recruit and activate T cells to attack B-ALL cells. Clinically, blinatumomab is highly effective in eliminating minimal residual disease, as well as relapsed/ refractory ALL ➤ Chimeric antigen receptor (CAR) T cells targeting CD19 represent a promising novel approach in ALL that directs and activates T cells against the ALL cells while also expanding and maintaining CAR T-cell proliferation for ongoing antileukemia activity ➤

be most prevalent with the first cycle of treatment.

While peripheral T-cell counts initially dropped with treatment, likely due to rapid cell redistribution, they recovered within several days and expanded above baseline counts. Additionally, a large proportion of recovering T cells demonstrated increased expression of the activation marker CD69. Patients who did not respond to treatment also had evidence of T-cell expansion and activation. Further, the degree of CD19-positive B-cell disease burden in the bone marrow did not correlate with response. This may be due to molecular abnormalities or mechanisms of resistance to blinatumomab in the leukemia cells that have not yet been identified.15 The same group investigated blinatumomab in 36 patients with relapsed/refractory B-ALL in a phase 1 dose-escalation trial. Seventy-two percent of patients achieved a CR or CR with incomplete blood count re-

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Table CD19 and CD22 Clinical Trials Cell Surface Antigen CD19

Targeted Therapy

CD19 and CD22

Disease Status

n

CR (%)

Survival Outcomes

MEDI-551

Monoclonal antibody

SAR3419

Antibody-drug conjugate

Previously untreated and RR xenograft models

Blinatumomab

Bispecific T-cellâ&#x20AC;&#x201C;engaging antibody

MRD+ or relapsed13,14

21

16 (80)

Relapse-free survival 61% at 33 months

RR16

36

26 (72)

Median OS 14.1 months

Pediatric RR42

2

2 (100)

Patient 1: CR at 11 months Patient 2: Relapse at 2 months

Pediatric and adult RR

17

14 (82)

RR44

5

5 (100)

RR45

13

10 (77)

Pediatric RR46

7

5 (71)

Epratuzumab

Monoclonal antibody Pediatric RR21

14

1 (7)

Epratuzumab + chemotherapy

Monoclonal antibody Pediatric RR

98

64 (66)

Epratuzumab + clofarabine, cytarabine

Monoclonal antibody RR23

29

13 (45)

BL22

Antibody-drug conjugate

Pediatric RR25

23

0 (0)

Moxetumomab pasudotox

Antibody-drug conjugate

Pediatric RR28

12

3 (25)

Inotuzumab ozogamicin

Antibody-drug conjugate

RR31

49

28 (57)

Median DOR 6.3 months Median OS 7.9 months

RR32

34

18 (53)

Median OS 6.3 months

RR33

11

9 (82)

Pediatric RR ALL37

17

3 (35)

Adult RR ALL38

17

0 (0)

CAR T cells

CD22

Class

Combotox

CAR T cell

Prolonged survival and decreased disease burden in vivo7

22

Combined antibodydrug conjugate

Enhanced antileukemia effects of chemotherapy and prevented disease recurrence10

1 patient relapsed at 3 months 1 patient post-HSCT died of pulmonary embolism

70% had peripheral blast reduction, bone marrow blast reduction, or recovery of blood counts, but no improvement in OS

Xenograft models demonstrate survival benefit

ALL indicates acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CR, complete remission; DOR, duration of response; HSCT, hematopoietic stem cell transplant; MRD, minimal residual disease; OS, overall survival; pediatric RR, relapsed/ refractory pediatric B-cell acute lymphoblastic leukemia; RR, relapsed/refractory adult B-cell acute lymphoblastic leukemia.

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covery (CRi), and 92% of these also achieved a molecular response. Ninety-five percent of patients in first relapse responded, whereas only 40% of the remaining patients achieved a CR. Thirteen of 26 responders went on to transplant. Eight of the remaining 13 responders relapsed. The median OS for patients who achieved a CR was 14.1 months. CRS, characterized by pyrexia, rigors, and hypotension, as well as central nervous system (CNS) events, was the most common clinically significant AE. The doses of 5 Îźg/m2/day in week 1 and 15 Îźg/ m2/day for the remaining treatment of a 28-day cycle were selected for further investigation in the extension cohort. The lower starting dose likely reduces the risk of CRS associated with higher disease burden.16 Given that blinatumomab was generally tolerable, produced high complete hematologic and molecular remission rates, and improved survival in this and a larger multicenter phase 2 study in relapsed/refractory ALL, the drug was recently approved by the FDA in December of 2014.17

CD22 CD22 is a B-cellâ&#x20AC;&#x201C;specific cell surface glycoprotein of the immunoglobulin superfamily thought to be involved in B-cell survival, activation, proliferation, migration, and interaction with T cells and antigen-presenting cells through both ligand-dependent and -independent mechanisms.18 CD22 is expressed on up to 93% of B-lymphoblasts in ALL. Because B cells internalize CD22 after binding the ligand or antibody, it provides a convenient means for cytotoxic drug delivery by antibody-drug conjugates.3 Clinical data showed a positive correlation between CD22 expression and OS, suggesting it may play an important role in leukemogenesis that can be effectively treated.19 CD22 Monoclonal Antibody (Table) Epratuzumab is a humanized anti-CD22 monoclonal antibody that modulates B-cell activation and signaling and induces cell lysis by ADCC.20 A pediatric relapsed/ refractory ALL pilot study of epratuzumab, followed by epratuzumab with chemotherapy, demonstrated that it was tolerable as a single agent and when combined with chemotherapy. Grade 1 or 2 infusion reactions were observed in 10 of 15 patients with the initial epratuzumab infusion. Two patients experienced dose-limiting toxicities (DLTs), including grade 4 seizure with epratuzumab and grade 3 transaminase elevation with epratuzumab in combination with chemotherapy. After single-agent epratuzumab, 1 patient (7%) achieved a partial response.

Nine patients (60%) achieved a CR after chemoimmunotherapy, 7 of whom were MRD negative. In all but 1 patient, surface CD22 was not detected by flow cytometry on peripheral blood leukemic blasts within 24 hours

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of drug administration, indicating effective targeting of leukemic cells by epratuzumab.21 Based on these results, the regimen was evaluated further in a pediatric phase 2 trial of chemotherapy and epratuzumab concurrently.

Sixty-six percent of 108 patients evaluable for response achieved a CR, and among 62 of these patients with available MRD data, 42% were MRD negative, which was significantly higher than the historical control of chemotherapy alone. Further follow-up data will be required to evaluate the impact this has on duration of response (DOR) and OS.22

Given that blinatumomab was generally tolerable, produced high complete hematologic and molecular remission rates, and improved survival, it was recently approved by the FDA for relapsed/refractory B-ALL in adult patients.

In adult patients, epratzumab was combined with cytarabine and clofarabine in relapsed/refractory B-ALL in a phase 2 trial. Seventeen percent of patients experienced grade 4 nonhematologic toxicities, including hypercalcemia, elevated transaminases, febrile neutropenia, acute kidney injury, hepatic failure, pneumonia, hypoxia, and respiratory failure. Among 29 evaluable patients, the response rate was 45%, including 8 patients with a CR and 5 with a CRi. Only 5 of these patients had MRD assessments, of which 1 achieved a significant MRD response.23 Compared with a historical control of clofarabine and cytarabine (SWOG S0530), the response rate and MRD negativity suggest an added benefit to chemoimmunotherapy with epratuzumab; however, as with the pediatric studies, further studies are necessary to determine the effect on DOR and OS.24

CD22 Antibody-Drug Conjugate (Table) BL22 BL22 is an antibody-drug conjugate made up of the variable domains of the anti-CD22 monoclonal antibody RFB4 fused to a fragment of Pseudomonas aeruginosa exotoxin A. BL22 caused cell death in vitro in ALL blasts and prolonged leukemia-free survival in ALL xenograft models in vivo. In a phase 1 clinical trial of BL22 in pediatric relapsed/refractory ALL, grade 1-2 liver function test abnormalities were the most common AEs. Two patients experienced grade 4 ALT elevation; however, this was reversible. Whereas no patients met remission criteria, 16 of 23 subjects (70%) had peripheral blast re-

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duction, bone marrow blast reduction, or recovery of blood counts.25 Moxetumomab Pasudotox Given limited efficacy, the latter trial was closed and high-affinity BL22 (also known as HA22, CAT-8015, or moxetumomab pasudotox [MP]), a BL22 construct with 14-fold higher antibody affinity for CD22, was investigated further. In vitro data for MP demonstrated cytotoxic activity in blasts from ALL patients with newly diagnosed and relapsed disease.26 The level of CD22 surface expression did not correlate with MP cytotoxicity in vitro. However, the binding and internalization of MP correlated with response. Additionally, cleavage of MP to an active toxin intracellularly correlated with cellular uptake and inhibition of protein synthesis. This suggests that resistance to MP may be related to heterogeneity of blasts binding and internalizing the drug. Further studies will need to investigate the role of MP cleavage and trafficking within the cell to further elucidate mechanisms of action and resistance.27

MP is currently under investigation in children and young adults with relapsed/ refractoy CD22-positive ALL or NHL, as well as adults with relapsed/refractory ALL. In the phase 1 trial of MP in relapsed/refractory pediatric ALL, 3 of 12 patients (25%) achieved a CR by morphology and flow cytometry, 5 (42%) had blood count improvement or blast reduction, and 3 (25%) had stable disease.28 Therefore, MP is currently under investigation in children and young adults with relapsed/ refractory CD22-positive ALL or NHL, as well as adults with relapsed/refractory ALL (NCT00659425, NCT01891981).

Inotuzumab Ozogamicin Inotuzumab ozogamicin (IO) is a humanized antiCD22 antibody conjugated at the Fc portion to calicheamicin, a cytotoxic agent that cleaves double-stranded DNA. In vitro, IO inhibited ALL cell growth, and in vivo, it resulted in tumor regression and cure in tumor-bearing mice.29 Another in vitro study with pediatric B-ALL cells demonstrated that CD22 expression was essential for uptake of IO. However, complete and prolonged CD22 saturation and inhibition were not required for apoptosis; therefore, patients may benefit from multiple low IO dosages.30 Based on safety and efficacy in lymphoma, a phase 2

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trial of IO 1.8 mg/m2 IV every 3 to 4 weeks was conducted in 49 children and adults with relapsed/refractory ALL. CD22 was expressed on more than 50% of blasts in all patients. Eighteen percent of patients achieved a CR, and 39% a CRi; however, the median DOR was limited to 6.3 months. Although a relatively high number of patients (33%) went on to transplant, this did not provide additional survival benefit, with a median OS in all responders of 7.9 months versus a median OS in HSCT patients of 5.2 months. In addition to high rates of fever (59%) associated with drug infusion, increased liver enzymes occurred in 28 patients (57%), and 14 patients (28%) experienced increases in bilirubin concentrations.31 An additional 34 patients were treated with IO weekly, which was equally effective (CR 53%, median OS 6.3 months) and less hepatotoxic than the single-dose schedule. In patients who went on to HSCT, veno-occlusive disease was observed in 5 of 22 patients (23%) with single-dose IO and in 1 of 9 patients (11%) with weekly dose IO.32 Another phase 2 trial evaluated a similar IO weekly dosing regimen and found the most frequent treatment-related AEs were cytopenias and transaminitis.

One DLT of grade 4 lipase elevation occurred. The overall response rate (ORR) was impressive at 82% (9 of 11 evaluable patients), including 36% with CR and 45% with CRi. Six of 9 responders (67%) also achieved negative MRD.33 This confirmed promising response rates with IO as a single agent in the adult relapsed/refractory B-ALL population. Further follow-up data are expected from these trials regarding DOR and OS. Preliminary results from a phase 1/2 trial investigating IO combined with low-dose chemotherapy (cyclophosphamide, vincristine, cytarabine, methotrexate, dexamethasone, and rituximab) in newly diagnosed elderly (>60 years of age) ALL patients showed activity with IO in the frontline setting. Of 14 evaluable patients, 12 achieved CR and 1 CRi (ORR 93%), as well as molecular remissions. After a median follow-up of 10.8 months, 1-year DFS and OS were 83% and 93%, respectively. Six patients discontinued induction chemotherapy due to thrombocytopenia, but no DLTs occurred, suggesting that this may be a promising regimen in elderly patients.34 Trials are currently ongoing to evaluate the role of IO in the context of allogeneic HSCT, as well as efficacy and survival benefit in a randomized phase 3 trial comparing IO with salvage chemotherapy in patients with relapsed/refractory ALL (NCT01664910, NCT01564784).

Combination Antibody-Drug Conjugate (Table) Combotox is a novel agent that combines 2 antibody-drug conjugates, consisting of one murine IgG

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monoclonal antibody targeting CD19 (HD37) and another targeting CD22 (RFB4) conjugated to the toxin deglycosylated ricin A chain (dgRTA) in a 1:1 ratio.

HD37-dgRTA, RFB4-dgRTA, and Combotox all resulted in cytotoxicity in a dose-dependent fashion in ALL cell lines. When tested in pediatric B-ALL blast samples, the individual immunotoxins were effective; however, Combotox caused the highest rate of cell death compared with either immunotoxin alone.35 Similar findings were noted in vivo, particularly in limited-stage disease, and resulted in decreased disease burden and improved survival.36 A phase 1 clinical trial with Combotox in 17 patients with relapsed/refractory pediatric pre–B-ALL reported an 18% CR rate; however, 35% had a >95% decrease in their peripheral blood blast counts, and 1 patient had a 75% decrease in peripheral blood blast count. Severe toxicities possibly related to Combotox included grade 3 pancreatitis, grade 3 anaphylaxis, and grade 4 graft-versus-host disease (GVHD), each in 1 patient.37 A subsequent phase 1 trial in 17 adult patients with relapsed/ refractory B-ALL identified vascular leak syndrome as the DLT. Two other patients experienced grade 3 transaminitis that was reversible. One patient had 80% involvement of the bone marrow with blasts, which decreased to 10% after Combotox treatment, suggesting a partial response, and subsequently underwent allogeneic HSCT. All patients with peripheral blood blasts demonstrated decreased blast counts after Combotox.38 Whereas Combotox reduced the leukemic disease burden in all patients, it may require more frequent or extended treatments to achieve a higher degree of response. In particular, blasts increased quickly after completing the final Combotox dose, suggesting continuous dosing may be beneficial.

In a xenograft B-ALL model, a survival benefit was seen in mice treated with Combotox and cytarabine together, in particular when administered sequentially after cytarabine, reflective of synergistic activity.39 Based on these findings, cytarabine and Combotox are currently under investigation in a phase 1 trial in adults with relapsed/refractory ALL (NCT01408160).

Chimeric Antigen Receptor T Cells (Table) Chimeric antigen receptors (CARs) are composed of antibody-binding domains of single-chain variable fragments linked to T-cell–stimulating moieties, most commonly CD3-zeta. The chimeric receptor CTL019 binds CD19 on malignant B cells and leads to tyrosine kinase–mediated activation of the T cell through the CD3-zeta chain portion of the chimeric receptor and costimulatory activity of normal CD137. In chronic lymphocytic leukemia (CLL), CAR T cells expanded

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>1000-fold in vivo, trafficked to bone marrow, continued to be expressed at high levels for at least 6 months, and persisted as memory CAR T cells. Common AEs, but also evidence for on-target toxicity, included B-cell aplasia, decreased numbers of plasma cells, and hypo­ gammaglobulinemia.40,41 Subsequently, 2 children with relapsed/refractory B-ALL received infusions of CTL019 CAR T cells. One patient had chemotherapy-refractory disease, and the other patient relapsed after allogeneic cord blood transplant and did not respond to blinatumomab. Similar to the CLL experience, the CAR T cells expanded >1000fold in vivo and were identified in the bone marrow as well as cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. This migration of CAR T cells into the CSF suggests a potential prophylactic CNS therapy for ALL. Both patients developed CRS and B-cell aplasia. CRS management with etanercept and tocilizumab to inhibit the cytokines did not impede expansion of CAR T cells or antileukemic efficacy. CR was observed in both patients by morphology and MRD negativity. CR was ongoing in the first patient 11 months after treatment. The other patient relapsed, with CD19-negative blast cells 2 months after treatment.42

CARs are composed of antibody-binding domains of single-chain variable fragments linked to T-cell–stimulating moieties, most commonly CD3-zeta.

Longer follow-up data from pilot studies by these investigators, including 16 pediatric and 4 adult patients with relapsed/refractory ALL, showed a CR rate of 82% (14 of 17 evaluable patients), including 1 patient with CD19-positive T-cell ALL. The targeted T-cell dose in adults was 5×109 cells divided over 3 days. All responding patients experienced CRS, which correlated with peak T-cell expansion. Eleven patients received CTL019 cells after allogeneic stem cell transplant with T cells of donor origin; however, no GVHD occurred. B-cell aplasia continued as long as CTL019 cells persisted, up to 15 months in some patients. Patients were treated with IV immunoglobulin, and no severe infectious complications were reported.43 Another group treated 5 relapsed adult B-ALL patients with morphologic or MRD-positive disease and no prior HSCT with a dose of 3×106 autologous T cells expressing a CD19-specific CD28/CD3-zeta second-generation dual-signaling CAR. Three patients remain in CR post HSCT; however, 1 died of a suspected pulmonary

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embolism. The 1 patient who was ineligible for further therapy relapsed with CD19-positive blasts 90 days after treatment in the setting of steroid therapy for cytokine-mediated toxicities, which may have limited CAR-modified T-cell persistence. Similar to the other studies, patients experienced CRS, worst in patients with the greatest tumor burden, which was also associated with the largest number of detectable CAR T cells.

Whereas initial expansion of CAR T cells was observed in all patients, recovery of normal B-cell clones was also seen, consistent with waning persistence of CAR-modified T cells and, importantly, recovery of normal B-cell lymphopoiesis.44

These studies showed that CAR T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells and may prolong remission and survival...

Longer follow-up of this study showed results for an additional 8 patients enrolled (n=13). Five of 7 patients with morphologic disease relapse (>5% to 70% blasts in bone marrow) at the time of CAR T-cell infusion achieved a molecular remission with MRD negativity.

Five of 6 patients with MRD at the time of CAR T-cell infusion became MRD negative. Molecular remission was observed as early as 7 to 14 days after T-cell infusion. Additionally, among these patients 3 were Phpositive B-ALL, demonstrating activity in ALL with the worst prognosis.45 In another study of anti–CD19-CD28/CD3-zeta CAR T cells in pediatric relapsed/refractory B-ALL, 5 of 7 patients (71%) achieved a CR, including 3 who became MRD negative. One patient with CNS involvement cleared all blasts from the CSF without further intrathecal chemotherapy after receiving CAR T cells. At the time of day 28 restaging, 4 of 5 responding patients had detectable CD19-positive hematogones, suggesting that T-cell expansion and antileukemia effects can be maintained without chronic B-cell aplasia. GVHD was not seen in patients with prior HSCT who received donor-derived T cells.46 These studies showed that CAR T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells and may prolong remission and survival via bridge to transplant or repeat infusion and maintenance therapy.

Conclusion Several CD19 and CD22 antigen-targeted immunotherapies show great potential in B-ALL. The ability of

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these agents to induce molecular remissions in relapsed and refractory disease has the promise of improving survival outcomes in ALL. As well, this implies that there may be benefit to utilizing these agents in induction regimens for newly diagnosed B-ALL for greater depth of response to prevent relapse. Future trials will need to address how to effectively combine these agents with standard chemotherapy and other novel drugs as our understanding of the disease biology improves. u

References

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14. Topp MS, Gökbuget N, Zugmaier G, et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012;120:5185-5187.

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17. Topp MS, Gökbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16:57-66.

18. Poe JC, Fujimoto Y, Hasegawa M, et al. CD22 regulates B lymphocyte function in vivo through both ligand-dependent and ligand-independent mechanisms. Nat Immunol. 2004;5:1078-1087.

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Abstract 1907.

20. Shih LB, Lu HH, Xuan H, et al. Internalization and intracellular processing of an anti-B-cell lymphoma monoclonal antibody, LL2. Int J Cancer. 1994;56:538-545.

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21. Raetz EA, Cairo MS, Borowitz MJ, et al. Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a Children’s Oncology Group Pilot Study. J Clin Oncol. 2008;26:3756-3762.

22. Raetz EA, Cairo MS, Borowitz MJ, et al. Reinduction chemoimmunotherapy with epratuzumab in relapsed acute lymphoblastic leukemia (ALL) in children, adolescents and young adults: results from Children’s Oncology Group Study ADVL04P2. Blood. 2011;118. Abstract 573.

23. Advani A, McDonough S, Coutre S, et al. Southwest Oncology Group Study S0910: a phase 2 trial of clofarabine/cytarabine/epratuzumab for relapsed/refractory acute lymphocytic leukemia. Blood. 2012;120. Abstract 2603.

24. Advani A, Gundacker HM, Sala-Torra O, et al. Southwest Oncology Group Study S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukemia. Br J Haematol. 2010;151:430-434.

25. Wayne AS, Kreitman RJ, Findley HW, et al. Anti-CD22 immunotoxin RFB4 (dsFv)-PE38 (BL22) for CD22-positive hematologic malignancies of childhood: preclinical studies and phase I clinical trial. Clin Cancer Res. 2010;16:1894-1903.

26. Mussai F, Campana D, Bhojwani D, et al. Cytotoxicity of the anti-CD22 immunotoxin HA22 (CAT-8015) against paediatric acute lymphoblastic leukaemia. Br J Haematol. 2010;150:352-358.

27. Matlawska-Wasowska K, Nickl CK, Winter SS, et al. Variability in precursor B ALL killing with moxetumomab pasudotox (CAT-8015) linked to differential binding and endocytic trafficking. Blood. 2013;122. Abstract 5022.

28. Wayne A, Bhojwani D, Richards K, et al. Complete remissions in 3 of 12 patients with pediatric acute lymphoblastic leukemia (ALL) during phase I testing of the antiCD22 immunotoxin moxetumomab pasudotox. Blood. 2010;116. Abstract 3246.

29. Dijoseph JF, Dougher MM, Armellino DC, et al. Therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin (CMC-544) for the treatment of acute lymphoblastic leukemia. Leukemia.

2007;21:2240-2245.

30. de Vries JF, Zwaan CM, De Bie M, et al. The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells. Leukemia. 2012;26:255-264.

31. Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, an antiCD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012;13:403-411.

32. O’Brien S, Thomas DA, Jorgensen JL, et al. Experience with 2 dose schedules of inotuzumab ozogamicin, single dose, and weekly, in refractory-relapsed acute lymphocytic leukemia (ALL). Blood. 2012;120. Abstract 671.

33. DeAngelo D, Stock W, Petersdorf S, et al. Weekly inotuzumab ozogamicin in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia. Blood. 2012;120. Abstract 2612.

34. Jain N, O’Brien S, Thomas DA, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy (Mini-hyper-CVD) as frontline therapy for older patients (≥60 years) with acute lymphoblastic leukemia (ALL). Blood. 2013;122.

Abstract 1432.

35. Herrera L, Farah RA, Pellegrini VA, et al. Immunotoxins against CD19 and CD22 are effective in killing precursor-B acute lymphoblastic leukemia cells in vitro.

Leukemia. 2000;14:853-858.

36. Herrera L, Yarbrough S, Ghetie V, et al. Treatment of SCID/human B cell precursor ALL with anti-CD19 and anti-CD22 immunotoxins. Leukemia. 2003;17:334-338.

37. Herrera L, Bostrom B, Gore L, et al. A phase 1 study of Combotox in pediatric patients with refractory B-lineage acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2009;31:936-941.

38. Schindler J, Gajavelli S, Ravandi F, et al. A phase I study of a combination of anti-CD19 and anti-CD22 immunotoxins (Combotox) in adult patients with refractory B-lineage acute lymphoblastic leukaemia. Br J Haematol. 2011;154:471-476.

39. Barta S, Zou Y, Schindler J, et al. Synergy of sequential administration of a deglycosylated ricin A chain-containing combined anti-CD19 and anti-CD22 immunotoxin (Combotox) and cytarabine in a murine model of advanced acute lymphoblastic leukemia. Leuk Lymphoma. 2012;53:1999-2003.

40. Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725-733.

41. Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3:95ra73.

42. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509-1518.

43. Grupp SA, Frey NV, Aplenc R, et al. T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) produce significant in vivo proliferation, complete responses and long-term persistence without GVHD in children and adults with relapsed, refractory ALL. Blood. 2013;122. Abstract 67.

44. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5:177ra38.

45. Davilla ML, Riviere I, Wang X, et al. Safe and effective re-induction of complete remissions in adults with relapsed B-ALL using 19-28z CAR CD19-targeted T cell therapy. Blood. 2013;122. Abstract 69.

46. Lee DW, Shah NN, Stetler-Stevenson M, et al. Anti-CD19 chimeric antigen receptor (CAR) T cells produce complete responses with acceptable toxicity but without chronic B-cell aplasia in children with relapsed or refractory acute lymphoblastic leukemia (ALL) even after allogeneic hematopoietic stem cell transplantation (HSCT). Blood. 2013;122. Abstract 68.

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CONTINUING EDUCATION

Faculty Perspectives

JANUARY 2015 • VOLUME 6 • NUMBER 1

™

LATEST TREATMENT ADVANCES FOR INDIVIDUALIZED CARE OF NSCLC PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copyeditor BJ Hansen Copyeditors Dana Delibovi Rosemary Hansen The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale

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

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

FACULTY

Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede

Roy S. Herbst, MD, PhD Chief of Medical Oncology Professor, Medicine and Pharmacology Yale Comprehensive Cancer Center New Haven, CT

Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Jr Digital Media Specialist Charles Easton IV Web Content Manager Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Alyson Bruni Jini Gopalaswamy

Marianne Davies, RN, MSN, ACNP, AOCN Smilow Cancer Hospital Yale School of Nursing Greenwich, CT

James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

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This activity is jointly provided by Global Education Group and Center of Excellence Media, LLC.

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Supported by an educational grant from Boehringer Ingelheim.

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

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

Educational Objectives After completing this activity, the participant should be better able to: • Assess emerging data from ASCO 2014 and ESMO 2014 on the discovery of molecular biomarkers and their impact on the management of patients with solid tumors • Discuss the advances from ASCO 2014 and ESMO 2014 on the personalized therapy for patients with solid tumors • Outline the practical aspects of integrating molecular biomarkers and emerging targeted agents into everyday clinical practice in the personalized treatment of cancer patients Faculty Roy S. Herbst, MD, PhD Chief of Medical Oncology Professor, Medicine and Pharmacology Yale Comprehensive Cancer Center, New Haven, CT Marianne Davies, RN, MSN, ACNP, AOCN Smilow Cancer Hospital Yale School of Nursing, Greenwich, CT James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care, Wellesley, MA Term of Offering Estimated time to complete activity: 1.0 hour Date of initial release: December 24, 2014 Valid for CME/CPE/CE credit through: December 24, 2015 Physician Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Center of Excellence Media, LLC. Global is accredited by the ACCME to provide continuing medical education for physicians.

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Scientific advisory board member for Biothera, Diatech, Genentech, and Koltan; consultant for Genentech/Roche and Merck; clinical trial support from Genentech

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Speaker’s bureau for Genentech and Novartis

James T. Kenney, Jr, RPh, MBA

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Updates from ASCO 2014 and ESMO 2014 INTRODUCTION The past decade has witnessed the emergence of targeted therapies in non–small-cell lung cancer (NSCLC), representing a huge paradigm shift in the management of this disease. These advances have been spurred by an improved understanding of the pathobiology of NSCLC, which has led to the molecular characterization of distinct NSCLC subtypes and the development of rational therapeutic agents specific to these subtypes. The presence of epidermal growth factor receptor (EGFR) mutations, which promote an oncogenic phenotype, defines one NSCLC subtype that is exquisitely sensitive to EGFR-tyrosine kinase inhibitor (TKI) therapy. Anaplastic lymphoma kinase (ALK)–positive NSCLC is another molecular subtype that is sensitive to treatment with ALK inhibitors. Unfortunately, many patients inevitably progress on EGFR-TKI and ALK inhibitor therapy. Responding to the urgent need for novel therapeutic improvements, current clinical research efforts are focused on evaluating EGFR-TKIs in combination with other active agents, novel agents directed toward common EGFR resistance mutations, ALK inhibitors in the first-line setting, and novel ALK inhibitors for use in the ALK inhibitor–resistant disease setting. In addition, several novel agents directed toward rational molecular targets, such as mutational variants of the human epidermal growth factor receptor 2 (HER2) and BRAF genes, as well as immunotherapy with vaccines and inhibitors of immune checkpoint regulators, are being evaluated in patients with NSCLC. Results of key clinical trials in EGFR- and ALK-positive NSCLC were reported at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), held in Chicago, Illinois, May 30-June 3, 2014, and at the 39th European Society for Medical Oncology (ESMO) Congress, held in Madrid, Spain, September 26-30, 2014. This supplement will provide an overview of these data, as well as key take-home messages from Roy S. Herbst, MD, PhD, Yale Comprehensive Cancer Center; Marianne Davies, RN, MSN, ACNP, AOCN, Smilow Cancer Hospital, Yale School of Nursing; and James T. Kenney, Jr, RPh, MBA, Harvard Pilgrim Health Care.

EGFR-TKI THERAPY IN EGFR MUTATION–POSITIVE NSCLC

EGFR-sensitizing mutations are detected in approximately 10% of all NSCLCs in the Caucasian patient population and at higher rates in the Asian population.1 Several randomized trials have demonstrated significant prolongation of progression-free survival (PFS) with first-line EGFR-TKI

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therapy (erlotinib or gefitinib) compared with chemotherapy in EGFR mutation–positive advanced NSCLC.2-5 Based on these pivotal results, erlotinib and gefitinib are currently indicated as first-line therapy for patients with advanced NSCLC harboring EGFR-sensitizing mutations.1 The prolongation in PFS with EGFR-TKIs is suboptimal, however, and acquired

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CONTINUING EDUCATION resistance to these agents is common.6 Moreover, the role played by EGFRTKI therapy in early-stage EGFR mutation–positive NSCLC is currently unknown; only limited clinical trial data evaluating EGFR-TKIs in the adjuvant setting or in EGFR mutation–positive disease are available.

The National Cancer Institute of Canada Clinical Trials Group (NCIC) BR19 randomized trial, which evaluated adjuvant gefitinib versus placebo in 503 patients with completely resected NSCLC, was closed prematurely because of futility, since no differences in disease-free survival (DFS) and overall survival (OS) were observed in the unselected, and EGFR wild-type (WT) or EGFR mutation–positive patient populations, albeit in only 15 patients in the EGFR mutation–positive cohort.7 The SWOG (Southwest Oncology Group) S0023 trial was initiated in 2001 to compare adjuvant gefitinib versus placebo in unresectable patients with stage IIIA or IIIB NSCLC following concurrent chemotherapy and radiation therapy; however, this trial was also stopped early.8 Unplanned analysis did not show a PFS benefit for patients treated with gefitinib versus placebo8; no information was available on EGFR-mutation status.

Single-Arm Phase 2 Trial of Adjuvant Erlotinib in EGFR Mutation– Positive NSCLC A retrospective study revealed that TKIs may prolong DFS in patients with EGFR mutation–positive tumors.9 In 286 patients with EGFR-positive mutations, treatment with adjuvant erlotinib or gefitinib was associated with a 57% reduced risk for recurrence or death (hazard ratio [HR], 0.43; P = .001) and a trend toward improved OS.9 At ASCO 2014, Pennell and colleagues presented the results of the single-arm, multicenter, phase 2 SELECT trial, which is prospectively evaluating the efficacy of adjuvant erlotinib in patients with EGFR mutation–positive NSCLC.10 Patients enrolled in the trial had surgically resected stage IA-IIIA NSCLC harboring a TKI-sensitizing EGFR mutation and had completed routine adjuvant chemotherapy and/or radiotherapy. Eligible patients were treated with erlotinib 150 mg/day for 2 years. Of the 100 patients enrolled at 7 sites, 89 participants have reached the 2-year follow-up at the time of this analysis. The safety profile was typical of erlotinib, with no grade 4/5 adverse events (AEs) reported and 1 case of grade 2 pulmonary fibrosis.

Dose reductions to 100 mg/day were required in 40% of patients, whereas 2 dose reductions to 50 mg/day were needed in 16% of patients. Overall, 69% of patients completed at least 22 months of erlotinib treatment.10

The use of targeted therapies has provided true benefit to select patients with NSCLC. It is imperative that all patients are screened for the most common mutations and are educated about the implications of the results.

After a median follow-up of 3 years, the 2-year DFS for the total cohort was 90% (97%, 73%, and 92% in patients with stage 1, stage 2, and stage 3 disease, respectively).10 At the time of this report, median DFS and OS had not been reached. A total of 24 patients showed evidence of disease recurrence; 22 of the cases occurred after stopping erlotinib, with a median time to recurrence of 12 months, indicating that patients may benefit from longer duration of adjuvant treatment. Of those who experienced disease recurrence, 15 patients (63%) underwent repeat biopsy and only 1 case of a EGFR T790M mutation was detected; 17 (71%) of recurrent patients were retreated with erlotinib. Currently, 10 patients remain on erlotinib therapy, with treatment ranging from 2 to 42 months, suggesting that patients continue to be sensitive to EGFR-TKIs after first disease recurrence.10 Perspectives The results of the SELECT trial are intriguing and suggest a possible use for EGFR-TKIs in the adjuvant setting. However, this experience is only a singlearm study and larger randomized studies will be needed to more fully answer this question.

-Roy S. Herbst, MD, PhD

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The use of targeted therapies has provided true benefit to select patients with NSCLC. It is imperative that all patients are screened for the most common mutations and are educated about the implications of the results. The SELECT trial highlights the benefit of continued therapy with the orally administered TKI erlotinib. However, providers must remain vigilant in assessing for specific toxicities associated with this agent. As shown in this trial, >50 % of patients required a dose reduction. However, I think that with proper dose adjustment and successful management of toxicities, patients can benefit from an extended course of this therapy.

-Marianne Davies, RN, MSN, ACNP, AOCN The concept of personalized medicine has real application in the treatment of cancer, and health plans are challenged with the task of managing multiple complex and expensive diagnostics and the appropriate drug therapies targeted for specific cancers. The SELECT trial demonstrates the value of targeted adjuvant treatment with erlotinib for NSCLC and the potential for improved outcomes over the standard of care. A key challenge for health plans will be the appropriate targeting of patients to ensure that the best drug treatment regimen is applied to the ideal population in order to achieve favorable clinical outcomes.

-James T. Kenney, Jr, RPh, MBA

Exploratory Analysis of Adjuvant Erlotinib versus Placebo in an EGFR Mutation–Positive Subgroup The RADIANT trial also assessed the role played by erlotinib as adjuvant therapy in patients with EGFR-expressing (immunohistochemistry+ and/or fluorescence in situ hybridization [FISH]+) completely resected stage IB-IIIA NSCLC. In this trial, 973 patients who had undergone complete surgical resection and randomization to either erlotinib or no platinum-based doublet chemotherapy went on to a second 2:1 randomization, at which time they received erlotinib 150 mg/day (n = 623) or placebo (n = 350) for up to 2 years.11 The trial, however, failed to meet the primary end point of prolonged DFS (HR, 0.9; P = .3). Subsequently, a prospectively specified subgroup analysis was conducted to evaluate the efficacy of adjuvant erlotinib therapy in the subgroup of patients with EGFR mutation–positive NSCLC. Shepherd and colleagues presented the results of this exploratory subgroup analysis of the RADIANT trial at ASCO 2014.11 In the current analysis, 161 (17%) of the 973 patients randomized to the RADIANT trial had mutations (exon 19 deletion: 55%; exon 21 L858R: 45%).11 Although the treatment arms were well balanced with respect to gender, age, ethnicity, smoking history, tumor histology, EGFR FISHpositivity, and mutation type, patients in the erlotinib group had received less chemotherapy and had lower-stage disease, whereas those in the placebo group had smaller tumors.

The median duration of treatment was 21.2 months with erlotinib and 21.9 months with placebo. Patients who received adjuvant erlotinib therapy achieved a longer DFS compared with those who received placebo (median: 46.4 months vs 28.5 months, respectively; P = .039); this was not statistically significant, however, because of the hierarchal testing procedure. The DFS effects were reproduced using an exploratory multivariate Cox model after adjusting for other prognostic variables (HR, 0.60; P = .046).11 A lower percentage of erlotinib-treated patients compared with patients receiving placebo relapsed (34.3% vs 52.5%, respectively). Notably, there was a higher incidence of brain relapses (40.0% vs 12.9%, respectively) and a lower incidence of bone relapses (14.3% vs 29.0%, respectively) among patients in the erlotinib cohort compared with those in the placebo cohort. No significant difference in OS was reported (OS median not reached in either treatment arm; HR, 1.09; P = .8153).

In the EGFR mutation–positive cohort, grade 3/4 rash (19% vs 0%, respectively) and diarrhea (5% vs 0%, respectively) were higher in the erlotinib arm compared with the placebo arm. Overall, the rate of treatment discontinuations due to AEs was higher with erlotinib therapy (25%) than with placebo (0%).

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FACULTY PERSPECTIVES Perspectives This trial suggests the benefit of erlotinib in EGFR mutation–positive tumors.

However, the small percentage of patients with this mutation and the imbalances of the arms make the data somewhat difficult to interpret.

-Roy S. Herbst, MD, PhD The subgroup analysis of the RADIANT trial revealed prolonged DFS in the arm treated with erlotinib. The patients in this group also experienced lower rates of relapse. These results may be partially explained by the fact that erlotinib-treated patients had lower-stage disease. Adjuvant therapy with erlotinib may be more beneficial for patients with high stage of disease at resection.

-Marianne Davies, RN, MSN, ACNP, AOCN Managing oncology drugs requires a combination of clinical expertise from oncology specialists and general knowledge of treatment options by the Pharmacy and Therapeutics (P&T) committees of the various health plans. The P&T Committee has to assess value from clinical data even when primary end points are not reached and determine where to place specific drugs on the formulary for coverage. The RADIANT trial demonstrates close to 2 years of DFS benefit compared with placebo as well as lower relapse rates in the erlotinib arm. Although the results did not reach statistical significance, these data may support a positive response from a health plan P&T Committee.

-James T. Kenney, Jr, RPh, MBA

Erlotinib plus Bevacizumab versus Erlotinib Although EGFR-TKIs improve PFS significantly compared with standard chemotherapy, the median PFS achieved is only approximately 9.2 to 13.1 months in patients with EGFR mutation–positive NSCLC.2-5 In order to further improve PFS rates, research efforts have focused on the addition of other active agents to EGFR-TKIs. Results from the phase 3 BeTa Lung study in a subgroup of patients with EGFR-positive mutations suggest that erlotinib-plus-bevacizumab combination therapy may prolong PFS.12 At ASCO 2014, Kato and colleagues presented the results of an openlabel, randomized trial evaluating erlotinib plus bevacizumab in chemotherapy-naïve patients with stage IIIb/IV or recurrent nonsquamous EGFR mutation–positive NSCLC.13 Activating EGFR mutations included exon 19 deletion and exon 21 L858R; patients with T790 mutations were excluded from the study. Stratification factors included gender, smoking status, clinical stage, and EGFR mutation type. Eligible patients were randomized to receive erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day alone until disease progression or unacceptable toxicity.13 The primary end point was PFS by Response Evaluation Criteria in Solid Tumors (RECIST) and independent review committee; secondary end points included OS, objective response rate (ORR), safety, and quality of life.13 The addition of bevacizumab to erlotinib treatment was associated with a statistically significant 46% reduction in the risk for progression compared with the use of erlotinib alone (HR, 0.54; log-rank, P = .0015). Median PFS was 16.0 months with erlotinib plus bevacizumab versus 9.7 months with erlotinib alone.13 The subgroup of patients with EGFR exon 19 deletion benefited more from erlotinib-plus-bevacizumab therapy than did those with exon 21 L858R, with a median PFS of 18.0 months (vs 10.3 months with erlotinib alone; HR, 0.41) and 13.9 months (vs 7.1 months with erlotinib alone; HR, 0.67), respectively.13 ORR did not differ significantly between the 2 treatment groups (69.3% with erlotinib plus bevacizumab vs 63.6% with erlotinib alone; P = .4951).

A higher incidence of grade 3/4 AEs was reported in the combination group (91%) than in the erlotinib monotherapy group (53%), driven mostly by hypertension events related to bevacizumab therapy (60% with bevacizumab plus erlotinib vs 10% with erlotinib alone). The incidence of serious AEs was similar between the 2 treatment arms. Proteinuria (all grades) was also higher in the combination treatment group compared with the er-

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Table 1. Combined OS Analysis of LUX-Lung 3 and LUX-Lung 6 Trials: Afatinib versus Chemotherapy16 Afatinib versus chemotherapy Population

Median OS, months

Hazard ratio; P value

All common mutations (N = 631)

27.3 vs 24.3

0.81; .0374

Exon 19 deletion (n = 355)

31.7 vs 20.7

0.59; < .001

Exon 21 L858R mutation (n = 276)

22.1 vs 26.9

1.25; .1600

OS indicates overall survival.

lotinib monotherapy group (52% vs 4%, respectively) and was the reason for discontinuation of bevacizumab in 15% of the patients.13 Perspectives This Japanese study is quite exciting and confirms our work in EGFR mutation–positive patients in the BeTa trial. Clearly, this combination therapy seems to have an effect on preventing resistance and should be analyzed in future studies.

-Roy S. Herbst, MD, PhD Combination regimens challenge providers to screen for and manage a broader range of side effects. Collaboration with onco-cardiologists may help screen patients at risk for hypertension and may allow for early management of this condition. Patients need to be well educated about the increased toxicity profile of certain regimens and strategies for effective management.

-Marianne Davies, RN, MSN, ACNP, AOCN A 46% reduction in the risk of progression is a compelling result that would support coverage of this combination of erlotinib plus bevacizumab in the treatment of patients with NSCLC. Combining injectable and oral therapies may present management challenges for health plans due to the application of separate benefits for the coverage of each agent.

Coordination of the pharmacy and medical benefits is needed to effectively monitor and coordinate care. Differences in the out-of-pocket costs across the 2 benefits may present challenges for providers in ensuring that patients can afford, and will comply with, complex treatment regimens.

-James T. Kenney, Jr, RPh, MBA

Afatinib versus Chemotherapy: Pooled Analysis of LUX-Lung 3 and LUX-Lung 6 Trials Afatinib is an oral, irreversible pan-ErbB TKI that inhibits signaling via the ErbB family members, including EGFR, HER2, ErbB3, and ErbB4. In the United States, afatinib is indicated for previously untreated patients with advanced NSCLC harboring common EGFR mutations (exon 19 deletion/exon 21 L858R).1 Two large, randomized, phase 3 trials—LUX-Lung 3 (LL3)14 and LUXLung 6 (LL6)15—compared afatinib with cisplatin plus pemetrexed and cisplatin plus gemcitabine, respectively, in 345 patients recruited globally14 and 364 Asian patients,15 respectively. The primary analyses for both of these trials showed significant prolongation of PFS with afatinib versus standard first-line therapy in the overall EGFR mutation–positive population (LL3: 11.1 months vs 6.9 months, respectively; HR, 0.58; P = .00114; LL6: 11.0 months vs 5.6 months, respectively; HR, 0.28; P < .000115). However, this did not translate into improvement in OS in either of the studies (LL3: 28.2 months vs 28.2 months, respectively; HR, 0.88; P = .385014; LL6: 23.1 months vs 23.5 months, respectively; HR, 0.93; P = .613715).

At ASCO 2014, Yang and colleagues presented a pooled analysis of mature OS data from the LL3 and LL6 studies.16 Eligible patients enrolled in these trials were randomized in a 2:1 ratio to afatinib 40 mg or up to 6 cycles

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Table 2. Results of the LUX-Lung 8 Trial: Afatinib versus Erlotinib17 P value

Efficacy end point

Afatinib (n = 335)

Erlotinib (n = 334)

Median PFS (IRR)

2.4 months

1.9 months

.043

Median PFS (IR)

2.7 months

1.9 months

.005

DCR

45.7%

36.8%

.020

ORR

4.8%

3.0%

.233

DCR indicates disease control rate; IR, investigator review; IRR, independent radiological review; ORR, objective response rate; PFS, progression-free survival.

of standard chemotherapy. The pooled analysis included 631 and 709 patients with the common exon 19 deletion/exon 21 L858R EGFR mutations who were randomized into the LL3 and LL6 trials, respectively. At a median follow-up of 36.5 months, OS was significantly improved with afatinib versus chemotherapy (median: 27.3 months vs 24.3 months; HR, 0.81; P = .0374) (Table 1).16 Patients with the exon 19 deletion derived a particular benefit from afatinib therapy, with a 41% reduction in the risk for death compared with chemotherapy and a median OS of 31.7 months versus 20.7 months, respectively (HR, 0.59; P < .001). In contrast, there was no significant difference in OS among patients with exon 21 L858R mutations (HR, 1.25; P = .1600).16

The EGFR T790M resistance mutation is detected in approximately 60% of TKI-resistant patients, with no approved treatments directed toward this common mutation currently available.

Perspectives These findings, which demonstrate a survival benefit in patients with the exon 19 deletion, are compelling, and make a case for the use of afatinib in this population. Certainly, one might expect similar results in these patients with the use of other EGFR inhibitors, although such data remain to be reported.

-Roy S. Herbst, MD, PhD Afatinib should perhaps be considered as frontline treatment for patients with select exon 19 deletions. In patients with exon 21 L858R, the treatment selection should consider toxicity profile, ability to adhere to a daily regimen, and quality of life.

-Marianne Davies, RN, MSN, ACNP, AOCN These trials highlight the challenges faced by health plans in trying to interpret and appreciate the clinical value of trials with mixed results. OS is the gold standard for P&T Committee evaluation of oncology treatments and PFS is used when OS data are not available. The results highlight the complexity of evaluating targeted therapies in patients with unique genetic profiles and determining the true value of the products.

-James T. Kenney, Jr, RPh, MBA

Afatinib versus Erlotinib: LUX-Lung 8 Trial At ESMO 2014, Goss and colleagues presented results of the global, randomized, phase 3 LUX-Lung 8 (LL8) study, which compared afatinib versus erlotinib in patients with stage III/IV relapsed/refractory squamous cell carcinoma of the lung following failure of first-line chemotherapy.17 The primary analysis of the trial (based on 414 PFS events by independent radiological review [IRR] in the first 669 patients randomized) showed that afatinib therapy was associated with significant improvements in PFS (IRR: 2.4 months vs 1.9 months; P = .043) and disease control rate (45.7% vs 36.8%; P = .020) compared with erlotinib treatment (Table 2).17 Although the ORRs were

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numerically higher with afatinib than with erlotinib (4.8% vs 3.0%, respectively; P = .233), they did not reach statistical significance. This safety analysis demonstrated that the AE profile was comparable between the 2 treatment arms and was typical of that seen with EGFR inhibitors. Afatinib-treated patients experienced a higher incidence of treatment-related grade 3/4 diarrhea (9.7% vs 2.4%) and stomatitis (3.3% vs 0.0%), whereas erlotinib-treated patients reported a higher incidence of grade 3 rash/acne (5.5% vs 9.0%).

Perspectives It is my belief that afatinib and erlotinib, for the most part, should be reserved for EGFR mutantâ&#x20AC;&#x201C;positive patients with NSCLC. -Roy S. Herbst, MD, PhD Diarrhea is an anticipated side effect associated with afatinib-based therapy. Most often, this is managed with an anti-diarrheal; however, dose reduction may be required in some individuals. Patients may choose to receive erlotinib or afatinib based on the toxicity profiles of these agents.

A shared decision-making approach regarding treatment selection may support improved adherence to therapy.

-Marianne Davies, RN, MSN, ACNP, AOCN This trial presents a common question for the health plan clinical team regarding statistical significance from clinical trials and whether or not the results are clinically meaningful. The challenge for reviewers will be to determine whether the PFS increase of 0.5 months is worth any decrease in quality of life due to adverse drug effects.

-James T. Kenney, Jr, RPh, MBA

Treatment of EGFR Inhibitorâ&#x20AC;&#x201C;Resistant NSCLC Although first-line EGFR-TKI therapy significantly improves clinical outcomes, including PFS, compared with standard chemotherapy, the effects are not long-lasting, with the majority of patients developing resistance, driven mostly by the acquisition of secondary mutations.6 The EGFR T790M resistance mutation is detected in approximately 60% of TKIresistant patients, with no approved treatments directed toward this common mutation currently available.6 Gefitinib Plus Chemotherapy versus Chemotherapy Alone At ESMO 2014, Mok and colleagues presented results of the phase 3, double-blind IRESSA Mutation Positive Multicentre Treatment Beyond ProgRESsion Study (IMPRESS), which evaluated the efficacy and safety of continuing gefitinib plus cisplatin/pemetrexed therapy versus placebo plus cisplatin/pemetrexed therapy in 265 patients with gefitinib-resistant NSCLC.18 Second-line gefitinib plus chemotherapy did not provide a statistically significant improvement in PFS (median PFS: 5.4 months in both arms; HR, 0.86; P = .273) or ORR compared with chemotherapy alone. OS was immature (33% of patients had died), with better OS for placebo plus cisplatin/pemetrexed versus gefitinib plus cisplatin/pemetrexed suggested (statistically significant difference: HR, 1.62; confidence interval [CI], 1.052.52; P = .029).18 The safety profiles of both arms were consistent with those already described, with gefitinib combination therapy associated with increased grade 1/2 gastrointestinal toxicities. These results suggest that continuation of gefitinib plus chemotherapy provided no additional clinical benefit compared with chemotherapy alone in patients with acquired resistance to first-line gefitinib.18 Perspectives Results from this study will affect my treatment approach, as I am now much less likely to continue using an EGFR inhibitor with chemotherapy upon the emergence of refractory disease, which had been my practice.

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-Roy S. Herbst, MD, PhD

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FACULTY PERSPECTIVES It is difficult to discontinue therapy for a patient with a cancer diagnosis when there is no demonstrated clinical benefit to a particular treatment regimen. Health plans rely heavily on oncologists to make the decision to avoid additional treatment and subsequent AEs in an effort to reduce unnecessary clinical and financial costs to the healthcare system.

-James T. Kenney, Jr, RPh, MBA

Table 3. Objective Response Rates Associated with AZD9291 Therapy in EGFR-Resistant NSCLC20 All doses

20 mg

40 mg

80 mg

160 mg

Overall population (N = 157)

53%

55%

44%

54%

58%

67%

T790M-positive (n = 107)

64%

50%

62%

68%

64%

83%

T790M-negative (n = 50)

22%

67%

12%

24%

23%

0%

EGFR indicates epidermal growth factor receptor; NSCLC, non–small-cell lung cancer.

Phase 1/2 Study of AZD9291 AZD9291 is an oral, irreversible, selective third-generation EGFR TKI that has demonstrated clinical activity against both EGFR-TKI sensitizing and resistant T790M mutations, while showing less activity against WT-EGFR, in preclinical experimental models.19 At ASCO 2014, Janne and colleagues presented preliminary results of a phase 1/2 dose-escalation and dose-expansion cohort study of AZD9291 in Asian and Caucasian patients with EGFR mutation–positive advanced NSCLC who have documented radiologic progression on EGFR-TKI therapy.20 In the dose-escalation phase, a total of 31 patients in 5 cohorts received AZD9291 at a dose of 20 to 240 mg once daily.

In the 201 patients in the dose-expansion cohort, confirmation of tumor T790M mutation status from a new biopsy sample was required.

Among the 205 patients evaluable for efficacy analysis in the total cohort, the ORR was 53% (Table 3).20 The longest duration of response was >9 months ongoing at the time of data cutoff. Importantly, the ORR was 64% among 107 patients from the expansion cohort with centrally confirmed T790M-positive NSCLC, but was only 22% in patients with T790Mnegative NSCLC. Consistently, the PFS in patients with T790M-positive NSCLC was prolonged compared with those who had T790M-negative disease. No clear dose-response relationship was observed in any of the subgroups tested. The highest ORR (67%) in the total cohort was achieved in the 240-mg dose group, followed by 58% in the 160-mg dose group; the lowest ORR was reported in the 40-mg dose group. The phase 2 dose of 80 mg once daily was selected, based on both antitumor activity and incidence of toxicity reported in patients with T790M-positive NSCLC.20 No dose-limiting toxicities were observed, and the maximum tolerated dose (MTD) has not been defined. In the total patient population, common AEs of any grade were reported in 93% of patients, including diarrhea, rash, nausea, dry skin, pruritus, decreased appetite, and fatigue; however, AEs leading to treatment discontinuation were reported in only 4% of patients.

Grade 3/4 AEs occurred in 24% of patients.20 Perspectives These next-generation EGFR inhibitors are game changing. We now have effective therapy for the 50% of patients with NSCLC who develop T790M mutation–positive disease.

-Roy S. Herbst, MD, PhD AZD9291 offers next-line therapy for patients who develop resistance to first-line TKIs, and this agent appears to be well tolerated in most patients.

Re-biopsy of tumors to test for new mutations is a paradigm shift in the decision-making process. Patients, caregivers, and providers need to be educated about the importance and significance of this approach to treatment.

-Marianne Davies, RN, MSN, ACNP, AOCN Early trial data can be encouraging for select patient groups with specific genetic profiles. However, because there are ongoing clinical trials of more than 900 oncology therapies, health plans typically wait until approval and launch of a drug before expending significant effort and energy on potential new compounds, as the approved product list is formidable enough to challenge the scarce clinical resources available to manage and monitor the current FDA-approved oncology products.

-James T. Kenney, Jr, RPh, MBA

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240 mg

Dose-Finding Study of CO-1686 CO-1686 is a selective, potent oral TKI that targets key activating EGFR mutations and the common T790M resistance mutation, while sparing WTEGFR signaling. At ASCO 2014, Sequist and colleagues presented the results of an ongoing dose-finding study in patients with EGFR who had mutated advanced or recurrent NSCLC. Eligible patients must have documented activating EGFR mutation and must have been previously treated with EGFR-TKI therapy.21 Of the 88 patients who were treated with CO-1686, 57 received CO-1686 free base (up to 900 mg twice daily) and 31 received CO-1686 hydrogen bromide (HBr) salt formulation (500-1000 mg twice daily); 10 patients transitioned from the free base to the HBr formulation.21 In this report, 72 patients treated at efficacious doses were included in the analysis. The ORR for 40 patients with EGFR T790M mutation–positive disease within the therapeutic dosing range was 58%; responses were observed across all dose levels.21 The current estimate of PFS exceeds 12 months; the median PFS has not yet been reached.21

In the pharmacokinetic analysis, CO-1686 demonstrated dose-linearity across the dose ranges tested; the half-life of the agent was suitable for a twice-daily dosing regimen.

Common AEs (all grades) occurring in >10% patients included nausea (34%), impaired glucose tolerance (IGT)/hyperglycemia (52%), diarrhea (23%), vomiting (17%), decreased appetite (21%), myalgia (11%), and QTc prolongation (15%). Grade 3 IGT/hyperglycemia occurred in 22% of patients but was manageable with oral hypoglycemics and/or dose reduction.

Dose-related WT-EGFR–driven diarrhea and rash have not been observed.

A recommended phase 2 dose of 750 mg twice daily was selected.21 In the pharmacokinetic analysis, CO-1686 demonstrated dose-linearity across the dose ranges tested; the half-life of the agent was suitable for a twice-daily dosing regimen. Moreover, the HBr formulation demonstrated 3 times greater exposure than did the equivalent free base dose.21 Perspectives CO-1686 is clearly active in EGFR T790M mutation–positive NSCLC. However, the toxicities of hyperglycemia and QTc prolongation could be an issue in a reasonable number of our patients.

-Roy S. Herbst, MD, PhD The overall response and PFS rates associated with the use of CO-1686 in this trial are encouraging. However, the toxicity profile of targeted agents is not benign. Providers must be diligent in closely monitoring patients for AEs and implementing effective intervention and management strategies to ensure adherence to therapy.

-Marianne Davies, RN, MSN, ACNP, AOCN A potent targeted therapy may offer promise for a select subset of patients with NSCLC. Agents with the potential for predictable responses based on a patient with specific EGFR mutations can offer greater value for the dollars spent on the therapy. A key goal of health plan pharmacy

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CONTINUING EDUCATION cisplatin 75 mg/m2 or carboplatin area under the curve 5-6 every 3 weeks for ≤6 cycles; n = 171). The primary end Chemotherapy point of the study was PFS; secondary end points included Efficacy end point Crizotinib (n = 172) (n = 171) Hazard ratio; P value ORR, OS, safety, and patient-reported outcomes.27 Median PFS 10.9 months 7.0 months 0.454; < .0001 At this interim analysis, crizotinib was associated with significantly prolonged PFS (median: 10.9 months vs 7.0 ORR 74% 45% < .0001 months with chemotherapy) and reduced the risk for proMedian DOR 49.0 weeks 22.9 weeks gression by 54% (HR, 0.454; 95% CI, 0.346-0.596; P < Onset of response 6.1 weeks 12.1 weeks .0001; Table 4).27 The ORR was significantly higher with DOR indicates duration of response; ORR, objective response rate; PFS, progression-free survival. crizotinib than with chemotherapy (74% vs 45%, respectively; P < .0001).27 Use of crizotinib was associated with a longer duration of response (median: 49.0 weeks vs 22.9 weeks) and a more management is to avoid use in patients in whom a response is not supported by the evidence presented in the trial data. rapid onset of response (median: 6.1 weeks vs 12.1 weeks) compared with the use of pemetrexed plus platinum-based chemotherapy. With 68% of patients still in follow-up, a median OS was not reached. At the time of data -James T. Kenney, Jr, RPh, MBA cutoff, 109 patients had crossed over to the crizotinib arm.27 AEs with crizotinib were consistent with those previously reported in patients with advanced ALK-positive NSCLC. Common AEs associated ALK-Positive Advanced NSCLC with crizotinib therapy versus chemotherapy, respectively, included vision ALK is a receptor tyrosine kinase that is constitutively activated in 2% to disorders (71% vs 14%), diarrhea (61% vs 17%), edema (49% vs 13%), 7% of all NSCLCs by chromosomal rearrangement due to generation of an vomiting (46% vs 40%), constipation (43% vs 31%), and elevated transamaberrant oncogenic EML4-ALK fusion gene.22 Crizotinib is an ALK inhibiinases (36% vs 13%). tor that has demonstrated efficacy in this disease subgroup, and was approved by the US Food and Drug Administration (FDA) for the treatment 23-25 Phase1 Study of Ceritinib of patients with ALK-positive NSCLC in November 2013.

In a phase 1 At ASCO 2014, Kim and colleagues presented updated results of the study, treatment with crizotinib monotherapy was associated with an ORR ongoing ASCEND-1 trial, which followed the enrollment of 246 patients of 60.8%, a median duration of response of 49.1 weeks, a median PFS of 9.7 across 11 countries who were treated with a ceritinib MTD of 750 mg/ months, and an estimated 1-year OS rate of 74.8%.23 In a phase 3, randomday.28 Of the enrolled patients, 163 had previously received crizotinib ized, open-label study of 347 patients with ALK-positive NSCLC who had received 1 prior platinum-based regimen, crizotinib demonstrated superior therapy and 83 were ALK inhibitor–naïve. Ceritinib 750 mg/day was assoefficacy compared with standard second-line chemotherapy (pemetrexed or ciated with high antitumor activity, regardless of prior treatment with docetaxel), reducing the risk for progression by 51% (HR, 0.49; P < .001).

ALK inhibitors. The ORR in the total cohort was 58.5%, with ORRs in The median PFS was 7.7 months in the crizotinib arm versus 3.0 months in the ALK inhibitor–treated patients and ALK inhibitor–naïve patients of the chemotherapy arm; the ORR was higher with crizotinib than with che54.6% and 66.3%, respectively (Table 5).28 The median duration of motherapy (65% vs 20%, respectively; P < .001).24 Crizotinib-treated paresponse in patients with a confirmed complete response or a partial response was 9.69 months in the total cohort, 7.39 months in the ALK tients invariably relapse, however, typically within 1 year, because of the 25 inhibitor–treated arm, and not estimable in the ALK inhibitor–naïve arm. development of drug resistance.

The median PFS was 8.21 months in the total cohort, 6.90 months in the ALK inhibitor–treated group, and not estimable in the ALK inhibitor– A subset analysis of 124 patients with clinically and naïve group.28 In the 255 patients evaluable for the safety analysis, the most common neurologically stable brain metastases at baseline AEs and laboratory abnormalities (all grades) were diarrhea (86%), nausea showed a high rate of responses and prolonged PFS. (80%), vomiting (60%), abdominal pain (54%), fatigue (52%), alanine transaminase (ALT) increased (80%), and aspartate transaminase (AST) increased (75%). Of these, grade 3/4 AEs and laboratory abnormalities inCeritinib (LDK378) is a potent, selective ALK inhibitor that was evalucluded elevations in ALT (27%), elevations in AST (13%), elevations in ated in a dose-escalation phase 1 study (ASCEND-1), in which 59 patients glucose (13%), and diarrhea (6%).28 At the 750-mg/day dosage, at least 1 with advanced ALK-positive NSCLC received ceritinib at doses of 50 to 750 mg/day.26 The MTD of ceritinib was established at 750 mg/day, with dose reduction due to an AE was reported in 59% of patients and treatment discontinuation due to an AE was reported in 9.4% of patients.28 Overall, 10 dose-limiting toxicities, including diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia.26 An expansion phase folpatients developed interstitial lung disease/pneumonitis, 3 of whom discontinued ceritinib treatment, including 1 fatal case; the remaining cases were lowed in which an additional 71 patients received treatment with ceritinib, managed by dose adjustments and/or interruptions.28 for a total of 130 patients overall. Of 114 patients with NSCLC who received ceritinib doses ≥400 mg, the ORR was 58%. Among 80 patients who A subset analysis of 124 patients with clinically and neurologically stable had progressed on crizotinib, the ORR was 56%.26 Based on the results of the brain metastases at baseline showed a high rate of responses and prolonged PFS. The ORR in the total subset of patients with brain metastases was ASCEND-1 trial, ceritinib received FDA approval in April 2014 for the 54.0%, with responses achieved in both ALK inhibitor–treated (n = 98; treatment of the ALK-positive nonsquamous subset of patients with NSCLC 50.0%) and ALK inhibitor–naïve (n = 26; 69.2%) groups. Median PFS was who had failed prior ALK inhibitor therapy.

6.90 months, 6.70 months, and 8.31 months, respectively, in the total subset, ALK inhibitor–treated arm, and ALK inhibitor–naïve arm. In the 14 First-Line Crizotinib Pemetrexed plus Cisplatin or Pemetrexed plus patients with measurable brain metastases at baseline, the overall intracraCarboplatin nial response rate was 50.0%.28 The efficacy and safety of crizotinib compared with chemotherapy as firstline treatment for patients with ALK-positive NSCLC is currently unknown. At ASCO 2014, Mok and colleagues presented results of the multicenter, open-label, randomized, crossover, phase 3 PROFILE 1014 trial, Perspectives which compared the efficacy and safety of crizotinib versus pemetrexed plus All TKIs will produce resistance. These new agents are potent in NSCLC platinum-based chemotherapy in the front-line setting.27 In this trial, a total and have demonstrated activity in patients with brain metastasis, which offers new hope against this disease. of 343 patients with previously untreated, advanced nonsquamous ALKpositive NSCLC were randomized in a 1:1 ratio to receive crizotinib 250 mg 2 -Roy S. Herbst, MD, PhD twice daily (n = 172) or chemotherapy (pemetrexed 500 mg/m plus either Table 4. Efficacy Analysis of Crizotinib in the PROFILE 1014 Trial27

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FACULTY PERSPECTIVES Crizotinib and ceritinib offer options for the small subTable 5. Efficacy Analysis of Ceritinib Therapy in the ASCEND-1 Trial28 population of patients with ALK-positive NSCLC. The ALK inhibitor–treated ALK inhibitor–naïve All patients ASCEND-1 trial supports the use of ceritinib as first-line Efficacy end point (n = 163) (n = 83) (N = 246) treatment in patients with known brain metastases.

ORR 54.6% 66.3% 58.5% Current recommendations are for both agents to be taken on an empty stomach. This likely contributes to DOR 7.39 months Not estimable 9.69 months the gastrointestinal toxicities reported. Further studies on Median PFS 6.90 months Not estimable 8.21 months taking these agents with food may help decrease the 12-month PFS rate 28.4% 61.3% 39.1% incidence of toxicities. All patients who are treated with ALK indicates anaplastic lymphoma kinase; DOR, duration of response; ORR, objective response rate; crizotinib should have baseline and ongoing ophthalmolPFS, progression-free survival. ogy examinations. Providers also need to monitor glucose and transaminases levels closely, and should anticipate the need for dose reductions in order to successfully manage AEs. the efficacy of the agent for a particular cancer.

-Marianne Davies, RN, MSN, ACNP, AOCN

-James T. Kenney, Jr, RPh, MBA

The high relapse rates of patients on crizotinib after 1 year supports the need for additional treatment options in ALK-positive patients. This early data from the ASCEND-1 trial suggests the potential value of ceritinib in patients with brain metastases, notably an ORR of 54%. Concerns regarding resistance will need to be evaluated as newer agents progress through clinical trials. In particular, we will need to look at data that may support use in patients with resistance to first-generation ALK-positive treatments.

Neratinib in HER2-Positive NSCLC Somatic HER2 mutations are detected in approximately 2% of patients with NSCLC and appear to be mutually exclusive of such other genetic aberrations as KRAS, EGFR, and ALK in NSCLC.32,33 Preclinical and early clinical trial evidence suggests that combined HER2/mTOR inhibition has synergistic effects on HER2-driven lung tumors.34 Based on these results, a phase 2, multicenter, randomized, 2-stage study was conducted to compare the irreversible pan-HER TKI neratinib with or without temsirolimus in patients with stage IIIB/IV HER2 mutation–positive NSCLC. The results of the stage I component of the trial (n = 27) were presented by Besse and colleagues at ESMO 2014.35 In stage I of this study, neratinib plus temsirolimus therapy was associated with an ORR of 21%, compared with 0% with the use of neratinib alone; partial responses were observed in 3 patients and 0 patients, respectively. A median PFS of 4.0 months was reported in the neratinib-plus-temsirolimus arm versus 2.9 months in the neratinib-only arm. In terms of safety, grade 3 AEs in the neratinib-plus-temsirolimus group versus the neratinib-alone group, respectively, included dyspnea (14% vs 8%), diarrhea (14% vs 8%), vomiting (21% vs 0%), and nausea (14% vs 0%).35 One grade 4 event each of dyspnea, blood uric acid elevation, and cardiorespiratory arrest occurred; 3 deaths were reported due to pleural effusion, cerebrovascular accident, and respiratory failure. All grade 4 and 5 events reported were considered to be unrelated to neratinib. The use of neratinib plus temsirolimus combination therapy has now been expanded into the stage II part of the study following fulfillment of efficacy criteria in stage I.35

-James T. Kenney, Jr, RPh, MBA

NOVEL TARGETED APPROACHES IN NSCLC

Dabrafenib in BRAF V600E Mutation–Positive NSCLC Activating BRAF mutations are present in approximately 2% of lung carcinomas, and are associated with shorter disease-free survival and OS rates.29,30 Since approximately 80% of these are BRAF V600E mutations,30 a multicenter, open-label, phase 2 study evaluated the BRAF TKI dabrafenib in 78 patients with BRAF V600E mutation–positive NSCLC.31 Planchard and colleagues presented the results of this trial at ESMO 2014. After 12 weeks of dabrafenib treatment, an ORR of 32% was achieved in patients who had previously received ≥1 prior treatments, with a disease control rate of 56%.The median duration of response was 11.8 months.31 The most common AEs reported included pyrexia (36%), asthenia (30%), hyperkeratosis (30%), loss of appetite (29%), nausea (27%), cough (26%), fatigue (26%), and skin papilloma (26%). Cutaneous squamous cell carcinomas, including keratoacanthoma, were reported in 18% of patients.31

Perspectives

Perspectives As we seek more personalized care of our patients, dabrafenib offers a good option for those with BRAF V600E–positive disease. However, the side effects will need to be managed effectively.

-Roy S. Herbst, MD, PhD

Neratinib is yet another option in a small subgroup of patients with advanced NSCLC. -Roy S. Herbst, MD, PhD

Dabrafenib offers a treatment option for patients with BRAF V600E mutations. However, there are significant dermatologic and gastrointestinal toxicities associated with this therapy. Twice-daily dosing on an empty stomach and associated gastrointestinal AEs may influence adherence to the treatment regimen and hence impact outcomes. Consultation and collaboration with dermatologists who have expertise in targeted therapeutics should be recommended.

These early data are focused on combining HER2/mTOR inhibition as a potential target for a small subset of patients with NSCLC. A new mechanism of action (MOA) is always an exciting option for the pharmacy program, as patients without good clinical options may benefit from a new targeted treatment approach. The minimal efficacy improvement is not sufficient at this time to suggest that this could be a key treatment approach in the future. Additional studies will need to focus on the potential to target additional subsets of the overall population that may achieve clinical benefit from neratinib.

-Marianne Davies, RN, MSN, ACNP, AOCN

-James T. Kenney, Jr, RPh, MBA

Although select therapies may present compelling clinical trial results, AE rates may severely limit the value of them in treatment protocols. A balance of efficacy, safety, and tolerability are key pharmacologic criteria that must be evaluated to assess the true value of a new oncology agent.

The oncologist must assess the risk-benefit options in selecting an appropriate therapy for a patient based on genetics, prior treatment history, and

Pembrolizumab in NSCLC Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors cytotoxic T-lymphocyte–associated protein 4, (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) has emerged as a successful treatment approach for patients with advanced melanoma.36 Pembrolizumab, a humanized antibody that exerts

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CONTINUING EDUCATION dual blockade of the immune checkpoint receptor PD-1 to overcome tumormediated immunosuppression, is in clinical development for various types of cancer. At ESMO 2014, Garon and colleagues reported efficacy and safety results from the phase 1b KEYNOTE-001 study of pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks in 282 patients with advanced NSCLC, who were either treatment-naïve or had failed prior EGFR and ALK TKI therapy.37 At a median follow-up of 5.4 months, ORRs per RECIST v1.1 by central review and per immune-related response criteria by investigator review in the overall population were 21% and 23%, respectively.37 Pooled data analysis yielded a median PFS of 13 weeks, 24-week PFS rate of 30%, median OS of 8.2 months, and 6-month OS rate of 64%. In the treatment-naïve cohort of patients, the ORR was 26%, median PFS was 27 weeks, 24-week PFS rate was 51%, median OS was not yet reached, and 6-month OS rate was 86%. In previously treated patients, however, these efficacy end points were lower, with median PFS of 10 weeks, 24-week PFS rate of 26%, median OS of 8.2 months, and 6-month OS rate of 59%. Grades 3 to 5 drug-related AEs were reported in 24 patients (9%), most commonly pneumonitis.37

These results indicate that immunotherapy with MAGE-A3 in the adjuvant setting is not yet a feasible strategy in NSCLC with current technology.

Perspectives

The immune checkpoint inhibitors have transformed our view of lung cancer treatment, based on their specific and durable responses and side effect profiles that are much more favorable than those associated with standard chemotherapy.

-Roy S. Herbst, MD, PhD Immune checkpoint inhibitors have demonstrated promising outcomes in terms of PFS, OS, and ORR for patients with advanced NSCLC. Assessing for PDL-1 expression in the tumor at baseline and at time of progression is of uncertain value in selecting patients who may benefit from targeting the PD-1 pathway. Combination blockade may be useful. Immune-related AEs may be observed with this class of drug; early identification and management of these events are necessary for successful continued treatment.

-Marianne Davies, RN, MSN, ACNP, AOCN

The PD-1 target is gaining a lot of attention in drug development and clinical trials and offers a new MOA that may yield valuable clinical results in treatment-naïve and previously treated patients. Data on OS, PFS, and ORR suggests the potential clinical value of this new monoclonal antibody in NSCLC and many other cancers.

-James T. Kenney, Jr, RPh, MBA

recMAGE-A3 + AS15 as Adjuvant Therapy in Resected MAGE-A3– Positive NSCLC At ESMO 2014, Vansteenkiste and colleagues discussed results of the randomized, double-blind, placebo-controlled, phase 3 MAGRIT trial, which evaluated recMAGE-A3 + AS15 immunotherapeutic (MAGE-A3 CI) as adjuvant treatment in 2272 patients with resected MAGE-A3–positive NSCLC regardless of the use of prior adjuvant chemotherapy.38 Patients were randomized in a 1:1 ratio to receive 13 intramuscular injections of MAGE-A3 CI or placebo over a 27-month treatment period. At a median follow-up of 38.8 months, administration of 13 injections of MAGE-A3 CI over a 27-month treatment period was not associated with any significant difference in median DFS compared with placebo treatment

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(60.5 vs 57.9 months, respectively; HR, 1.024; P = .7379).38 Consistently, no improvement in OS was reported between the 2 treatment arms. Subset analysis also did not reveal any survival benefit for any patient subgroups analyzed, including by age, disease stage, histopathology, chemotherapy, tumor region, and MAGE-A3 quantitative expression. Common AEs, which were mostly grade 1/2 in severity, included pyrexia, injection-site pain, injection-site reaction, fatigue, pain, influenza-like illness, and myalgia. These results indicate that immunotherapy with MAGE-A3 in the adjuvant setting is not yet a feasible strategy in NSCLC with current technology.38 References 1. Peters S, Adjei AA, Gridelli C, et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.

2012;23(suppl 7):vii56-vii64.

2. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380-2388.

3. Mitsudomi T, Morita S, Yatabe Y, et al; West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121-128.

4. Rosell R, Carcereny E, Gervais R, et al; on behalf of the Spanish Lung Cancer Group in collaboration with the Groupe Français de Pneumo-Cancérologie and the Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol.

2012;13:239-246.

5. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol.

2011;12:735-742.

6. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.

Clin Cancer Res. 2013;19:2240-2247.

7. Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non–small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013; 31:3320-3326.

8. Kelly K, Chansky K, Gaspar LE, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non–small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008;26:2450-2456.

9. D’Angelo SP, Janjigian YY, Ahye N, et al. Distinct clinical course of EGFR-mutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib. J Thorac Oncol. 2012;7:1815-1822.

10. Pennell NA, Neal JW, Chaft JE, et al. SELECT: a multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 7514.

11. Shepherd FA, Altorki NK, Eberhardt WEE, et al. Adjuvant erlotinib (E) versus placebo (P) in non-small cell lung cancer (NSCLC) patients (pts) with tumors carrying EGFRsensitizing mutations from the RADIANT trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 7513.

12. Herbst RS, Ansari R, Bustin F, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011;377:1846-1854.

13. Kato T, Seto T, Nishio M, et al. Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation–positive nonsquamous non-small cell lung cancer (NSCLC): an open-label randomized trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 8005.

14. Sequist LV, Yang JC-H, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334.

15. Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014; 15:213-222.

16. Yang JC-H, Sequist LV, Schuler MH, et al. Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy (CT). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 8004.

17. Goss G, Felip E, Cobo M, et al. A randomized, open-label, phase III trial of afatinib (A) vs erlotinib (E) as second-line treatment of patients (pts) with advanced squamous cell carcinoma (SCC) of the lung following first-line platinum-based chemotherapy: LUXLung 8 (LL8). Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract 1222O. 18. Mok TS, Wu Y-L, Nakagawa K, et al. LBA2_PR - Gefitinib/chemotherapy vs chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer

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FACULTY PERSPECTIVES (NSCLC) after progression on first-line gefitinib: the phase III, randomised IMPRESS study.

Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract LBA2_PR. 19. Cross DAE, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov.

2014;4:1046-1061.

20. Janne PA, Ramalingam SS, Yang JC-H, et al. Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32 (suppl):Abstract 8009.

21. Sequist LV, Soria J-C, Gadgeel SM, et al. First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 8010.

22. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non– small-cell lung cancer. N Engl J Med. 2010;363:1693-1703.

23. Camidge DR, Bang Y-J, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13:1011-1019.

24. Shaw AT, Kim D-W, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385-2394.

25. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4:120ra17.

26. Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALK-rearranged non–small-cell lung cancer. N Engl J Med. 2014;370:1189-1197.

27. Mok T, Kim D-W, Wu Y-L, et al. First-line crizotinib versus pemetrexed–cisplatin or pemetrexed–carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 8002.

28. Kim D-W, Mehra R, Tan DS-W, et al. Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): results of the ASCEND-1 trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl): Abstract 8003.

29. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311:1998-2006.

30. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non–small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011;29:3574-3579.

31. Planchard D, Kim TM, Mazieres J, et al. Dabrafenib in patients with BRAF V600E-mutant advanced non-small cell lung cancer (NSCLC): a multicenter, open-label, phase 2 trial (BRF113928). Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract LBA38_PR. 32. Mazières J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol. 2013;31:1997-2003.

33. The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543-550.

34. Gandhi L, Bahleda R, Tolaney SM, et al. Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2–dependent and other solid tumors. J Clin Oncol. 2014;32:68-75.

35. Besse B, Soria J-C, Yao B, et al. Neratinib (N) with or without temsirolimus in patients (pts) with non-small cell lung cancer carrying HER2 somatic mutations: an international randomized phase II study. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract LBA39_PR. 36. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19: 5300-5309.

37. Garon EB, Gandhi L, Rizvi N, et al. Antitumor activity of pembrolizumab (Pembro; MK3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non–small cell lung carcinoma (NSCLC). Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract LBA43.

38. Vansteenkiste JF, Cho B, Vanakesa T, et al. MAGRIT, a double-blind, randomized, placebo-controlled phase III study to assess the efficacy of the recMAGE-A3 + AS15 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (NSCLC). Ann Oncol (ESMO Annual Meeting Abstracts).

2014;25(suppl 4):Abstract 11730.

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Š 2014 Genentech USA, Inc. All rights reserved. COB/091614/0001 Printed in USA.

IN METASTATIC MELANOMA, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY? Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.1 Overactivation of MAPK signaling has been implicated as a key driver of metastatic melanoma.2 Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

REFERENCES: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. 2. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.

CONTINUING EDUCATION

Faculty Perspectives

JANUARY 2015 • VOLUME 6 • NUMBER 2

™

Latest Treatment Advances for Individualized Care of CRC PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copyeditor BJ Hansen Copyeditors Dana Delibovi Rosemary Hansen The Lynx Group President/CEO Brian Tyburski

OVERVIEW This 4-part Faculty Perspectives™ series will provide readers with summaries of pivotal emerging data from 2 recent international oncology meetings—the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) and the 39th European Society for Medical Oncology (ESMO) Congress—as well as expert perspectives on the application of the data to daily patient care. The first 3 issues in this series discussed recent advances in the management of breast cancer, melanoma, and non–small-cell lung cancer. This fourth issue focuses on the latest advances in the treatment of colorectal cancer (CRC).

Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz

FACULTY

Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno

Leonard Saltz, MD Chief, Gastrointestinal Oncology Service Head, Colorectal Oncology Section Memorial Sloan Kettering Cancer Center New York, NY

Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Jr Digital Media Specialist Charles Easton IV Web Content Manager Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito

Ellen M. Hollywood, MSN, RN, OCN Clinical Research Nurse Gastrointestinal Medical Oncology Service Memorial Sloan Kettering Cancer Center New York, NY

James T. Kenney, Jr, RPh, MBA Manager, Specialty and Pharmacy Contracts Harvard Pilgrim Health Care Wellesley, MA

Senior Project Managers Alyson Bruni Jini Gopalaswamy Project Manager Deanna Martinez Project Coordinator Mike Kodada IT Manager Kashif Javaid

This activity is jointly provided by Global Education Group and Center of Excellence Media, LLC.

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

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

Educational Objectives After completing this activity, the participant should be better able to: • Assess emerging data from ASCO 2014 and ESMO 2014 on the discovery of molecular biomarkers and their impact on the management of patients with solid tumors • Discuss the advances from ASCO 2014 and ESMO 2014 on the personalized therapy for patients with solid tumors • Outline the practical aspects of integrating molecular biomarkers and emerging targeted agents into everyday clinical practice in the personalized treatment of cancer patients Faculty Leonard Saltz, MD Chief, Gastrointestinal Oncology Service Head, Colorectal Oncology Section Memorial Sloan Kettering Cancer Center New York, NY Ellen M. Hollywood, MSN, RN, OCN Clinical Research Nurse Gastrointestinal Medical Oncology Service Memorial Sloan Kettering Cancer Center New York, NY James T. Kenney, Jr, RPh, MBA Manager, Specialty and Pharmacy Contracts Harvard Pilgrim Health Care, Wellesley, MA Term of Offering Estimated time to complete activity: 1.0 hour Date of initial release: January 20, 2015 Valid for CME/CPE/CE credit through: January 20, 2016 Physician Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Center of Excellence Media, LLC. Global is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation Global Education Group designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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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 http://ce. lynxcme.com/1807E. 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.

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The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/ CPE/CE activity: Name of Faculty or Presenter Leonard Saltz, MD

Reported Financial Relationship Consultant for Eli Lilly and Roche

Ellen M. Hollywood, MSN, RN, OCN

Nothing to disclose

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

James T. Kenney, Jr, RPh, MBA Nothing to disclose

Updates from ASCO 2014 and ESMO 2014 INTRODUCTION The 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) was held in Chicago, Illinois, May 30-June 3, 2014, and the 39th European Society for Medical Oncology (ESMO) Congress was held in Madrid, Spain, September 26-30, 2014. Both meetings brought together thousands of oncology professionals from a wide range of specialties. This supplement will address important topics in colorectal cancer (CRC) treatment presented at these meetings. Leonard Saltz, MD, and Ellen M. Hollywood, MSN, RN, OCN, of Memorial Sloan Kettering Cancer Center, and James T. Kenney, Jr, RPh, MBA, of Harvard Pilgrim Health Care, after reviewing the presented data, provide their key take-home messages for community oncology practices.

Addition of Oxaliplatin to 5-FU–Based Neoadjuvant and Adjuvant Regimens In 2004, results of the CAO/ARO/AIO-94 trial showed that use of preoperative chemoradiotherapy (CRT) versus postoperative CRT, along with total mesorectal excision (TME) surgery and adjuvant 5-fluorouracil (5-FU) chemotherapy, was associated with persistent, significant improvements in local control of advanced rectal cancer, although no effect on overall survival (OS) was reported.1 The subsequent randomized, phase 3 CAO/ARO/ AIO-04 trial sought to integrate more effective systemic treatment, and initial results of early secondary end points have already been published.2 At ASCO 2014, Rödel and colleagues presented results of the primary end point—disease-free survival (DFS) at 3 years.3 A total of 1265 patients with cT3/4 or cN+ rectal cancer were randomized into 1 of 2 treatment arms: (1) preoperative CRT 50.4 Gy plus infusional 5-FU, followed by TME surgery and 4 cycles of bolus 5-FU (arm 1; n = 637); or (2) preoperative CRT 50.4 Gy plus infusional 5-FU and oxaliplatin, followed by TME surgery and

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8 cycles of adjuvant oxaliplatin, leucovorin, and infusional 5-FU (arm 2; n = 628).3 After a median follow-up of 50 months, 198 patients in arm 1 experienced a DFS-related event versus 159 patients in arm 2 (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.64-0.98; P = .03). At 3 years, the DFS rate was 71.2% in arm 1 and 75.9% in arm 2. Grade 3/4 late overall treatment-related toxicity was reported in 23% of patients in arm 1 and 26% in arm 2 (P = .14).

Grade 3/4 sensory neuropathy was reported in 7% of patients in the oxaliplatin-containing arm during treatment, decreasing to 3% at 1 year of follow-up.3 Perspectives Interpretation of this trial is problematic for several reasons. First, the regimens of 5-FU in the 2 arms are so different that this alone could account for the modest differences reported; it also makes it impossible to interpret the potential contribution of oxaliplatin. Second, the standard biweekly infusional 5-FU/leucovorin of the postoperative 5-FU/leucovorin/oxaliplatin

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Table 1. Results from the Phase 3 AIO KRK 0207 Trial6 Median TFS, months

Median OS from start of maintenance, months

Median PFS1, months

Arm A Maintenance (fluoropyrimidines plus bevacizumab)

6.8

23.8

6.2

Arm B (bevacizumab alone)

6.5

26.2

4.6

Arm C Observation

6.1

23.1

3.6

OS indicates overall survival; PFS1, first progression; TFS, time to failure of strategy.

(FOLFOX) in the experimental arm has been shown to be superior to bolus 5-FU used in the postoperative control arm. Thus, in both preoperative and postoperative treatment, the superiority of the 5-FU regimen, in my opinion, obscures interpretation of the role of oxaliplatin. Furthermore, the addition of oxaliplatin to the preoperative CRT and the postoperative chemotherapy makes it difficult to determine the degree to which the addition of oxaliplatin to the preoperative CRT regimen is beneficial, and the use of a more toxic 5-FU control arm makes it difficult to determine how much additional toxicity can be attributed to oxaliplatin. Given the findings of the R-04 trial and the STARR studies, which have shown no benefit (but increased toxicity) for the addition of oxaliplatin to neoadjuvant CRT, and the limitation of this trial, I do not feel it would be appropriate to incorporate oxaliplatin into preoperative combined therapy for rectal cancer.

-Leonard Saltz, MD It is difficult to draw a conclusion that the addition of oxaliplatin is beneficial because of the different regimens of 5-FU. It is important to remember that less can be more. Oxaliplatin is associated with adverse events including transient peripheral neuropathy and/or laryngopharyngeal dysesthesias, cumulative neuropathy, fatigue, and hypersensitivity reactions. All of these can impact patient quality of life (QOL).

-Ellen M. Hollywood, MSN, RN, OCN This study shows a modest efficacy benefit that must be balanced with the potential for increased toxicity. These results would not prompt a plan to aggressively manage patients with either regimen.

-James T. Kenney, Jr, RPh, MBA

Preoperative Fluoropyrimidine-Based Chemotherapy plus Oxaliplatin Interim results of the PETACC-6 (Pan-European Trials in Adjuvant Colon Cancer 6) were presented at ASCO 2014 by Schmoll and colleagues.4 This trial investigated whether the addition of oxaliplatin to a preoperative regimen that included oral fluoropyrimidine-based CRT followed by postoperative adjuvant fluoropyrimidine-based chemotherapy would improve DFS in patients with locally advanced rectal cancer.

Between November 2008 and September 2011, a total of 1094 patients with rectal adenocarcinomas (within 12 cm from the anal verge; T3/4 and/or node positive, with no metastatic disease who were either considered, or were expected to become, resectable) were randomized to 1 of 2 treatment arms.4 Each arm received 5 weeks of preoperative CRT with capecitabine, followed by 6 cycles of adjuvant chemotherapy with capecitabine. Arm 2 (n = 547) also received oxaliplatin before and after surgery, whereas arm 1 (n = 547) did not.4 After a median follow-up of 31 months, 124 and 121 DFS events were reported in arm 1 and arm 2, respectively. The 3-year DFS rate was 74.5% in arm 1 versus 73.9% in arm 2. Because 440 DFS events were required for the trial to have 80% power, careful follow-up has been recommended until these DFS events have been met.4 Perspectives Results from this trial are easier to interpret, as there is really only 1 variable: the addition of oxaliplatin to pre- and postoperative capecitabine

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chemotherapy. Although further follow-up will be necessary before results are definitive, currently, this study supports the majority of the literature, which finds increased toxicity, decreased compliance, and no benefit when oxaliplatin is added to preoperative CRT. -Leonard Saltz, MD The oxaliplatin did not prove at this time to add benefit preoperatively. In addition, the toxicities caused by oxaliplatin can decrease compliance.

Sensory neuropathy associated with this agent is cumulative over time and there are no proven treatments to alleviate this complication. It is very important for nurses to have a good understanding of the toxicities related to treatment and to recognize early signs and symptoms so that appropriate interventions can be initiated.

-Ellen M. Hollywood, MSN, RN, OCN The data from this trial are not sufficient to impact the formulary discussion on these treatment options. Hopefully, results after the 440 DFS events are met will yield some actionable results.

-James T. Kenney, Jr, RPh, MBA

Adjuvant FOLFOX versus FL Updated results of the randomized, phase 2 ADORE trial were reported by Sang Hong and colleagues at ASCO 2014.5 This trial investigated the use of FOLFOX or 5-FU/leucovorin alone (FL) in patients with curatively resected rectal cancer following preoperative fluoropyrimidine-based CRT. A total of 321 patients were randomized between November 2008 and June 2012 to adjuvant chemotherapy with either the FL regimen for 4 cycles (n = 161) or the FOLFOX regimen for 8 cycles (n = 160). The primary end point was 3-year DFS. After a median follow-up of 38.2 months, the 3-year DFS rate was 71.6% in the FOLFOX arm versus 62.9% in the FL arm (HR, 0.657; 95% CI, 0.434-0.994; P = .047). Grade 3/4 adverse events did not differ significantly between the 2 treatment arms.5 Perspectives This trial also has 2 variables to contend with, making interpretation difficult. In addition to the fact that some patients received oxaliplatin while others did not, the 5-FU regimens were markedly different. The 5-FUâ&#x20AC;&#x201C;only arm used a bolus daily x 5 regimen similar to the Mayo Clinic schedule, but with doses lower than those typically recommended. As such, I do not feel that much can be determined from this trial.

-Leonard Saltz, MD A relative risk reduction of 34% in the FOLFOX arm is positive for this regimen. The comparable adverse events avoid any concerns that increased efficacy may be offset by additional toxicity. However, more data are needed to effectively use the results of this study to impact treatment protocols.

-James T. Kenney, Jr, RPh, MBA

Maintenance with Fluoropyrimidines plus Bevacizumab versus Bevacizumab Alone versus No Treatment The phase 3 AIO KRK 0207 trial was conducted in patients with metastatic colorectal cancer (mCRC) to evaluate a maintenance strategy of fluoropyrimidines plus bevacizumab, bevacizumab alone, or no treatment, following a standard 24-week induction regimen of fluoropyrimidines, oxaliplatin, and bevacizumab. Arnold and colleagues presented results from this trial at ASCO 2014.6 The objective of the trial was to determine whether no treatment or treatment with bevacizumab alone was noninferior to treatment with fluoropyrimidines plus bevacizumab. The primary end point was time to failure of strategy (TFS). Secondary end points included time to first progression (PFS1) and OS.6 Patients repeated the initial treatment if disease progression occurred.

A total of 473 patients were randomized to 1 of 3 treatment regimens: (1) arm A: standard maintenance treatment with fluoropyrimidines plus bevacizumab; (2) arm B: bevacizumab alone; and (3) arm C: no treatment. After a median follow-up of 27 months, median PFS1 was 6.2 months in arm A,

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FACULTY PERSPECTIVES 4.6 months in arm B, and 3.6 months in arm C (P < .0001 for arm A vs arm C).6 TFS favored arm A over arm C (HR, 1.31; 95% CI, 1.01-1.69; P = .038), but no significant difference was reported between arm A and arm B (HR, 1.04; 95% CI, 0.81-1.36; P = .74; Table 1). After first progression, 24% of patients in arm A repeated their initial treatment, compared with 47% in arms B and C. The preliminary OS was 23.4 months from randomization, with no significant difference among treatment arms (P = .69).6

Table 2. Results from the Phase 3 CAIRO 3 Trial7 Maintenance (capecitabine plus bevacizumab) Observation

Median PFS2, months

Median OS, months

11.7 P < .0001

21.6

8.5

18.1

OS indicates overall survival; PFS2, second progression.

Perspectives This trial uses a statistical design that I do not find appropriate, with noninferiority design employed when a superiority design would appear to be called for. The authors conclude that the use of bevacizumab maintenance is not noninferior to not using anything (no treatment). This triple-negative interpretation is based on a difference of 12 days between arms. I do not see anything in this trial that supports the use of maintenance bevacizumab.

-Leonard Saltz, MD A median PFS1 difference of less than 3 months in arm A versus arm C is not a particularly compelling result in this study. The formulary committee would want to consult with the oncologists with regard to the clinical relevance of this difference. OS is the primary measure that the committee prefers to focus on and with no significant difference in this end point between the treatment arms, an inconclusive formulary decision would be likely.

-James T. Kenney, Jr, RPh, MBA

Maintenance with Capecitabine plus Bevacizumab versus Observation Results of the randomized, phase 3 CAIRO 3 trial were presented by Koopman and colleagues at ASCO 2014.7 This trial investigated the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation in patients with mCRC who did not progress during induction therapy with capecitabine, oxaliplatin, and bevacizumab (CAPOX-B). A total of 558 patients were randomized to either observation (arm A) or maintenance treatment with capecitabine plus bevacizumab (arm B).7 Patients in both arms were to be treated with CAPOX-B upon PFS1 and until second progression (PFS2; the primary end point). Secondary end points included OS, time to second progression (TTP2), and QOL. Results showed that CAPOX-B was reintroduced in 61% of patients in arm A and 47% in arm B. A significant benefit for maintenance treatment was reported for PFS1, TTP2, and PFS2, with a median of 11.7 months versus 8.5 months for observation (HR, 0.67; P < .0001; Table 2). Results of a multivariable analysis conducted in 180 patients with synchronous metastases who had a resected primary tumor showed a significant interaction for treatment with OS (median OS, 18 months in arm A vs 25 months in arm B). QOL remained the same during maintenance treatment and was clinically noninferior compared with QOL in the observation arm.7 Perspectives This trial does show an improvement in PFS with continued versus interrupted therapy. This is expected. What is interesting to note, however, is the fact that the data do not show a detriment in OS for patients who were given a chemotherapy-free holiday. The reported difference is not statistically significant, with a P value of 0.22. This was measured from the time of randomization, which is after 4 months on study. When the difference in OS is evaluated from the start of therapy (a more traditional approach), there is even less significance to the OS difference between arms. Furthermore, comparisons of patients with and without the primary tumor resected are of little value, because the decision to resect or not resect was not randomized, and many nonrandomized clinical factors may have contributed to any apparent perception of differences.

-Leonard Saltz, MD Treatment interruptions appear to be safe and desirable. With this knowledge, nurses can counsel their patients and provide emotional support during the decision-making process.

-Ellen M. Hollywood, MSN, RN, OCN

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In this trial, maintenance therapy produced a compelling improvement in OS of 7 months compared with observation. QOL was not sacrificed for an efficacy benefit in patients and would lead to a favorable formulary decision.

-James T. Kenney, Jr, RPh, MBA

Is There Value to Maintenance Therapy? The Price of Stability In a virtual meeting at ASCO 2014, Leonard Saltz, MD, discussed the impact of incorporating a treatment-free interval into a therapeutic strategy for patients with mCRC, focusing specifically on the CAIRO 3 and AIO KRK 0207 studies, both of which examined treatment-free periods.

According to Dr Saltz, results from CAIRO 3 do not show a clear disadvantage associated with taking a treatment break. Responding patients are likely to benefit from continued treatment, at least until maximal response is achieved. Although treatment breaks for all patients at 4 months may mean too many breaks too early, treatment break strategies should not be abandoned, but rather individualized. Furthermore, although QOL remained the same during maintenance therapy in this trial, Dr Saltz noted that more specific, sensitive tools are needed to measure QOL. Findings from AIO KRK 0207 demonstrated that combination therapy with fluoropyrimidines plus bevacizumab was a better treatment strategy than bevacizumab alone in terms of TFS. Within the context of no difference in OS, and a median difference in TFS of 12 days and in PFS of 36 days, however, Dr Saltz believed that may be an overstatement of the data.

Using a benefit-to-cost ratio (with cost being defined as the price and toxicity of treatment, as well as the patient’s time), Dr Saltz calculated the price of stability on the basis of treatment with bevacizumab alone in this study.

Based on an observation period of approximately 3.6 months, or 15.5 weeks, during which time about 3100 mg of bevacizumab would have been used, he established a cost savings per patient of approximately $19,189 (according to average sales price of the drug). According to Dr Saltz, of approximately 40,000 patients with mCRC in the United States, approximately 28,000 are likely taking bevacizumab; of these, about 15,400 are likely eligible for a treatment break, translating into a drug savings of $308,000,000 per year.8 “The good news is our patients are doing better and living longer with metastatic disease; the bad news is that it is a long time to be on chemotherapy,” he said.

“In the AIO KRK 0207 study, fully one-third of patients, even on a simplified maintenance schedule, chose to come off therapy for reasons other than progression. Many patients declined to restart.” Clearly, a substantial number of patients see value in treatment breaks, and with a median TFS of 12 days between bevacizumab and observation, Dr Saltz does not believe the results from the AIO KRK 0207 study support the use of bevacizumab as single-agent maintenance therapy.8 “CAIRO 3 and AIO KRK 0207 explored the value of a treatment break versus capecitabine and bevacizumab or 5-FU/leucovorin/bevacizumab maintenance in oxaliplatin/bevacizumab-based chemotherapy. Compared with a treatment break, maintenance does delay progression and prolongs time to failure of treatment. However, no significant difference in OS was seen. In the absence of compelling negative data, treatment interruptions appear to be safe and desirable.” Emphasizing that like all cancer care, use and timing must be individualized, Dr Saltz concluded, “Personalized medicine will require understanding not only the individual molecular characteristics of the tumor, but also the personal characteristics, goals, and preferences of the patient. Appropriately timed chemotherapy-free intervals remain a viable and important treatment strategy to be further explored and understood.”8

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Table 3. Response to Cetuximab plus FOLFOX4 According to RAS Mutation Status10 RAS wild-type (all loci)

New RAS mutation

RAS mutation (any locus)

FOLFOX4 + cetuximab (n = 38)

FOLFOX4 (n = 49)

FOLFOX4 + cetuximab (n = 15)

FOLFOX4 (n = 16)

FOLFOX4 + cetuximab (n = 92)

FOLFOX4 (n = 75)

Response rate, %

57.9

28.6

53.3

43.8

37.0

50.7

Median PFS, months

12.0

5.8

7.5

7.4

5.6

7.8

Median OS, months

19.8

17.8

18.4

17.8

13.5

17.8

OS indicates overall survival; PFS, progression-free survival.

Table 4. Response to Cetuximab plus FOLFIRI According to RAS Mutation Status12 RAS wild-type (all loci)

New RAS mutation

RAS mutation (any locus)

FOLFIRI + cetuximab (n = 178)

FOLFIRI (n = 189)

FOLFIRI + cetuximab (n = 32)

FOLFIRI (n = 31)

FOLFIRI + cetuximab (n = 246)

FOLFIRI (n = 214)

Response rate, %

66.3

38.6

34.4

35.5

31.7

36.0

Median PFS, months

11.4

8.4

7.2

6.9

7.4

7.5

Median OS, months

28.4

20.2

18.2

20.7

16.4

17.7

OS indicates overall survival; PFS, progression-free survival.

Addition of Cetuximab to FOLFOX4 in Patients with RAS Wild-Type Tumors The randomized, phase 2 OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) trial previously established the efficacy of cetuximab plus FOLFOX4 as first-line treatment for patients with KRAS wild-type mCRC and confirmed KRAS mutation status as an effective predictive biomarker.9 Bokemeyer and colleagues presented recent study results at ASCO 2014, in which the investigators screened OPUS study patients for 26 tumor mutations (new RAS) in 4 additional KRAS codons (exons 3 and 4) and 6 NRAS codons (exons 2, 3, and 4) with the use of BEAMing technology.10 The outcome was assessed according to RAS mutation status (KRAS exon 2 + new RAS). The authors found new RAS mutations in 31 of 118 evaluable patients (26%) with KRAS exon 2 wild-type tumors. Results showed that the addition of cetuximab to the FOLFOX4 regimen in patients with RAS wild-type tumors was associated with a significantly improved response (Table 3). Those with new RAS tumor mutations could not be definitively assessed, and in patients with any tumor RAS mutation (KRAS exon 2 + new RAS), no benefit from the addition of cetuximab to FOLFOX4 was observed.10 Perspectives When you reduce the number of patients in this trial to those with RAS wild-type tumors, the numbers are quite small indeed. The data support what has been demonstrated convincingly in larger trials such as PRIME and CRYSTAL, which is that all-RAS genotyping is necessary for proper use of anti-EGFR agents, and the presence of any KRAS or NRAS mutation in any exon (not just exon 2 KRAS) should be regarded as an absolute contraindication to the use of anti-EGFR agents.

-Leonard Saltz, MD These results demonstrate the importance of proper use of anti-EGFR therapies in the appropriate population. For patients with any KRAS or NRAS mutations, the addition of anti-EGFR therapy will provide no benefit and will expose them to adverse events, such as an acne-like rash, fatigue, and low magnesium levels, as well as place them at risk for anaphylactic reactions.

The acne-like rash can be severe, and because it is so visible, it can be very disturbing to patients and impact their interactions with others. Management of this rash includes moisturizing the area, limiting sun exposure with sunscreen, and the use of doxycycline 100 mg twice daily at the start of therapy.

-Ellen M. Hollywood, MSN, RN, OCN The ability to more accurately target patients for a specific drug based on genetic mutations is a very encouraging area of cancer therapy. The benefits include limiting waste due to nonresponse, avoiding adverse

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events related to ineffective treatment options, and achieving more predictable outcomes when establishing treatment protocols for patients.

-James T. Kenney, Jr, RPh, MBA

FOLFIRI with and without Cetuximab in Patients with RAS Wild-Type Tumors The CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) study previously showed that patients with KRAS codon 12/13 (exon 2) wild-type mCRC experienced improvement in PFS and OS when treated with cetuximab in addition to 5-FU/ leucovorin/irinotecan (FOLFIRI) as first-line therapy.11 Patients with KRAS exon 2 tumor mutations, however, did not experience a treatment benefit.

At ASCO 2014, Ciardiello and colleagues presented results from their study in which they screened patients from CRYSTAL for 26 mutations (new RAS) in 4 additional KRAS codons (exons 3 and 4) and 6 NRAS codons (exons 2, 3, and 4) with the use of BEAMing technology.12 The outcome was assessed according to RAS mutation status (KRAS exon 2 + new RAS). The investigators evaluated mutation status in 430 of 666 patients (65%) with KRAS exon 2 wild-type tumors and detected new RAS mutations in 15% (63 of 430) of the patients. In patients with RAS wild-type tumors, a significant benefit across all end points was associated with the addition of cetuximab to FOLFIRI (Table 4).12 In those with new RAS tumor mutations, on the other hand, no difference in efficacy outcomes was observed between the treatment groups. Patients with any tumor RAS mutation (KRAS exon 2 + new RAS) did not experience any benefit from the addition of cetuximab to FOLFIRI.12 Perspectives This larger phase 3 trial confirms that all-RAS wild-type patients are the only ones who should be considered for anti-EGFR therapy at any point in their treatment plan.

-Leonard Saltz, MD Data from this trial reinforce the fact that only RAS wild-type patients are to receive anti-EGFR therapies. Nurses should educate patients and their families on this research and its implications to their treatment plan.

-Ellen M. Hollywood, MSN, RN, OCN This study demonstrates one of the challenges faced by health plans in terms of covering select genetic tests when an outcome may not be improved with further testing. In this case, additional testing did not identify an opportunity for improved outcomes with combination treatment. However, it suggests that patients with new RAS mutations will not benefit from the

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FOLFIRI or FOLFOX6 plus Bevacizumab or Cetuximab in Patients with KRAS Wild-Type Untreated mCRC At ASCO 2014, Venook and colleagues presented results of the phase 3 CALGB/SWOG (Cancer and Leukemia Group B/Southwest Oncology Group) 80405 trial, which examined FOLFIRI or FOLFOX6 plus bevacizumab or cetuximab as first-line treatment for patients with KRAS wild-type untreated mCRC.13 A total of 2334 patients with KRAS wild-type (codons 12 and 13) mCRC and a performance status (PS) of 0 to 1 received either FOLFIRI or FOLFOX6 (regimen of their choice; 26.6% selected FOLFIRI and 73.4% selected FOLFOX6), and were then randomized to either cetuximab or bevacizumab.13 Treatment continued until disease progression, death, unacceptable toxicity, or curative surgery occurred. Treatment breaks of 4 weeks were permitted. Study end points included OS and PFS, with OS analysis planned at 849 events. OS and PFS results after a median follow-up of 40 months are shown in the Figure.13 A total of 94 patients were free of disease following surgery.13 Additional analyses are under way (expanded RAS, FOLFOX vs FOLFIRI, subsequent therapies, long-term survivors, and correlates). The investigators concluded that although either regimen is appropriate as first-line treatment, patient preference for FOLFOX limited chemotherapy comparison.13 Perspectives This is the definitive trial addressing the question of using either bevacizumab or an anti-EGFR agent (in this case, cetuximab, although results can likely be extrapolated to panitumumab). The study was performed in patients with KRAS wild-type tumors, but a preliminary analysis of the all-RAS wild-type population supports the same conclusions. The authors concluded that the use of first-line cetuximab or bevacizumab is equally acceptable. However, I respectfully disagree. The dermatologic toxicity associated with cetuximab is a major deterrent to the use of this agent as front-line treatment. Maneuvers to mitigate this toxicity are marginally effective, and only those patients who develop a substantial skin rash derive benefit from cetuximab. In addition, the cost of cetuximab is approximately twice the cost of bevacizumab, an unwarranted surplus expense when there are no advantages in terms of tolerability or efficacy.

-Leonard Saltz, MD I have worked with patients who have received cetuximab as well as those who have received bevacizumab. The skin toxicity associated with cetuximab use can be severe; it often causes discomfort and may lead to lifestyle disturbances. The management tools we have for this condition are limited. Patients who are treated with bevacizumab may develop hypertension; however, this can be treated with medication. Overall, bevacizumab seems to be well tolerated. I feel that the skin toxicity related to cetuximab makes it an unacceptable option in the first-line setting.

-Ellen M. Hollywood, MSN, RN, OCN

FOLFIRI or mFOLFOX6 plus Cetuximab or Bevacizumab in Patients with Untreated mCRC: Expanded RAS Analysis An expanded analysis of the CALGB/SWOG 80405 study was presented at ESMO 2014 by Lenz and colleagues.14 Patients with RAS wild-type (codons 12 and 13) mCRC and a PS of 0 to 1 were treated with FOLFIRI or mFOLFOX6 at enrollment (patient or physician choice), then randomized to either cetuximab or bevacizumab. The original study was designed to randomize patients to cetuximab, bevacizumab, or both; the expanded analysis was amended to include only patients with KRAS wild-type tumors (codons 12 and 13). Expanded RAS was tested in all wild-type RAS exon 2 tumors with the use of BEAMing technology, including KRAS exons 3 and 4, and NRAS exons 2, 3, and 4. The primary end point was OS.14 Among a total of 3058 patients enrolled between November 2005 and March 2012, 2334 patients with KRAS wild-type tumors were randomized.

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Figure. OS and PFS for chemotherapy plus bevacizumab or cetuximab in patients with KRAS wild-type untreated metastatic colorectal cancer.13 45 40 35 Patients (%)

addition of cetuximab. This provides an opportunity to avoid additional costs and adverse events with a less intensive treatment regimen of FOLFIRI. -James T. Kenney, Jr, RPh, MBA

10.84

10.45

30 PFS (months) OS (months)

25 20 15

29.04

29.93

FOLFIRI or FOLFOX6 + bevacizumab (n=559)

FOLFIRI or FOLFOX6 + cetuximab (n=578)

10 5 0

OS indicates overall survival; PFS, progression-free survival.

The final analysis ultimately included 1137 patients, 559 of whom received bevacizumab plus chemotherapy and 578 of whom received cetuximab plus chemotherapy. Overall, 73.4% of patients were treated with the mFOLFOX6 regimen and 26.6% with the FOLFIRI regimen.14 Results showed that in the expanded RAS wild-type population, median OS exceeded 30 months; however, no significant difference was reported between the treatment groups (32.0 months for patients who received cetuximab plus chemotherapy vs 31.2 months for those who received bevacizumab plus chemotherapy). Median PFS also did not differ between the treatment groups. A higher response was observed, however, among patients in the cetuximab arm versus the bevacizumab arm in the expanded RAS population (68.6% vs 53.6%, respectively; P < .01).14 Perspectives As discussed earlier, expanded RAS testing has not demonstrated a survival benefit for one agent over another. Therefore, I feel that the use of first-line cetuximab would still be inappropriate. In the very unusual circumstance in which tumor shrinkage per se, in the absence of a survival benefit, is felt to justify the increased skin toxicity and cost increase, cetuximab could be used.

-Leonard Saltz, MD The lack of a significant difference in OS and PFS does not provide actionable data for the formulary committee. Whether or not a higher response in the cetuximab group has any value is unknown. Health plans could make the case that providers use the less expensive option in an effort to control costs in the treatment of mCRC. -James T. Kenney, Jr, RPh, MBA

CALGB/SWOG 80405: Patients with mCRC Undergoing Surgery Following Chemotherapy At ESMO 2014, Venook and colleagues reported on the results of a subset analysis of CALGB/SWOG 80405, the goal of which was to determine the characteristics and long-term outcomes of patients with mCRC who elected to undergo surgery following chemotherapy.15 Eligible patients with KRAS wild-type (codons 12 and 13) mCRC and a PS of 0 to 1 received FOLFIRI or mFOLFOX6 (physician or patient choice at study enrollment) and were then randomized to either cetuximab or bevacizumab. Treatment goals (palliative or neoadjuvant therapy as a component of a curative treatment plan) were determined by the physician.

Therapy continued until progression, death, unacceptable toxicity, or surgery with curative intent. Treatment holidays of 4 weeks were permitted. Patients who elected to have surgery were usually removed from the study. The primary end point was OS.15 A total of 3058 patients were enrolled between November 2005 and

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Table 5. Association Between MMR Status and Treatment Outcomes17 TTR: 5-year recurrence-free rate, %

5-year OS, %

dMMR

pMMR

dMMR

pMMR

Surgery alone (n = 307)

89

74

90

78

5-FU monotherapy (n = 1155)

88

83

88

87

Surgery alone (n = 264)

60

47

59

54

5-FU monotherapy (n = 2723)

72

64

77

71

Stage II

Stage III

dMMR indicates deficient mismatch repair; 5-FU, 5-fluorouracil; MMR, mismatch repair; OS, overall survival; pMMR, MMR-proficient; TTR, time to recurrence.

March 2012, of whom 2334 patients with KRAS wild-type tumors were randomized. The final analysis included 1137 patients. Median follow-up was 32 months. After receiving chemotherapy, 179 patients (15.7%) underwent surgery: 24.6% had an intact primary tumor, 36.9% had curative intent, 80% had received FOLFOX, and 58% had received cetuximab.15 According to the results, 130 of the 179 patients had no evidence of disease (NED) immediately following surgery. The median time from study entry to surgery was 6.8 months, and the median OS from randomization was 60 months. DFS among NED patients was 16.1 months from the time of surgical resection and 26.0 months from the time of randomization. A total of 96 patients are still alive after surgery, 50 of whom remain NED, after a median of 37 months’ postsurgical follow-up.15 Perspectives It is difficult to draw many conclusions from this analysis. It confirms that some patients who undergo R0 resections of metastatic disease are either cured or have long-term DFS. The numbers are too small to say anything definitive about a preference for one agent over another in this setting.

Until pretreatment scans are independently reviewed, we cannot say whether these patients were truly converted from unresectable to resectable or whether they had disease that was potentially resectable prior to starting therapy.

-Leonard Saltz, MD These results demonstrate that some patients with mCRC have potentially resectable disease and can be cured, which has always been true.

However, it is unclear whether the use of different monoclonal antibodies had an impact in this setting.

-Ellen M. Hollywood, MSN, RN, OCN This study offers evidence of the potential benefit of surgery following chemotherapy as a valid treatment approach. A protocol that requires chemotherapy prior to surgery could be applied by health plans to take advantage of this potential strategy.

-James T. Kenney, Jr, RPh, MBA

Extended RAS Analysis from the FIRE-3 Trial The FIRE-3 trial compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in patients with mCRC having 592 KRAS exon 2 wild-type tumors. Analysis from FIRE-3 was extended to KRAS and NRAS exons 2, 3, and 4 (codons 12, 13, 59, 61, 117, and 146) using pyrosequencing. Radiologic data were evaluated independently to determine tumor response, and to define early tumor shrinkage (ETS) and depth of response (DOR). Results of the study were presented at ESMO 2014 by Stintzing and colleagues.16 ETS was defined as a reduction in tumor diameter of >20% at the first tumor assessment after baseline (at week 6); DOR was defined as the maximal tumor shrinkage observed in a particular patient. Results were calculated for both the intent-to-treat (ITT) and the extended RAS wild-type populations.16

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Study results showed that within the ITT population, 475 patients (80.2%) were successfully tested for all RAS locations, 459 of whom were evaluable according to Response Evaluation Criteria in Solid Tumors criteria. The FOLFIRI-plus-cetuximab arm was also associated with postprogression survival (Bravais Pearson test; P < .0001).16 Objective response rate significantly favored the FOLFIRI-plus-cetuximab arm over the FOLFIRI-plus-bevacizumab arm (71.4% vs 56.4%, respectively; P = .015). The proportion of patients who achieved ETS was significantly greater in the FOLFIRI-plus-cetuximab–treated population versus the FOLFIRI-plus-bevacizumab–treated population (67.5% vs 47.9%, respectively; P = .0013). DOR was significantly greater in the FOLFIRI-plus-cetuximab group than in the FOLFIRI-plus-bevacizumab group (48.2 months vs 33.0 months, respectively; P = .0005). PFS was 10.3 months with FOLFIRI plus cetuximab and 10.2 months with FOLFIRI plus cetuximab; OS was 33.1 months in the FOLFIRI-plus-cetuximab arm vs 25.0 months in the FOLFIRIplus-bevacizumab arm.16 Perspective I think that one needs to be careful not to overinterpret the survival differences reported in this trial. First, the prespecified primary end point was objective response rate in the ITT population, and the trial was negative in terms of a statistically significant difference in this respect. As such, this is a negative trial, and any other comparisons should be regarded as hypothesis-generating at best. Second, we need to look at the survival curves. The first-line PFS was 10 months in each arm (chemotherapy was stopped after only 5 months in each arm) and yet the curves do not separate until 24 months. More information is necessary regarding what did or did not occur in the intervening months. Furthermore, the use of second-line anti-EGFR agents was only 28% in the ITT analysis of patients who received first-line cetuximab. It is concerning that 72% of RAS wild-type patients never received an anti-EGFR agent as second- or third-line therapy. We know from the Canadian C-017 trial that the use of third-line single-agent cetuximab in KRAS wild-type patients resulted in a 4.5-month OS benefit over placebo, and we could expect an even larger benefit in an all-RAS wild-type population. As such, it is quite likely that if patients had received an anti-EGFR agent second or third line, the survival differences in this study would not be significant, and results would be more in line with the substantially larger 80405 trial.

-Leonard Saltz, MD

Deficient Mismatch Repair in Patients with Stage II or III Disease Mismatch repair (MMR) status is known to be an important prognostic factor in patients with CRC. Using the Adjuvant Colon Cancer End Points database, Sargent and colleagues determined the association of deficient MMR (dMMR) status with clinical/pathologic features and prognosis in 7803 patients with stage II or III CRC, and presented their results at ASCO 2014.17 They examined microsatellite instability (MSI) from 14 studies and immunohistochemical analysis from 1 study for MLH1/MSH2/MLH6 proteins.17 Of the 7803 patients enrolled, 571 underwent surgery alone, 3878 received 5-FU monotherapy, 2299 were treated with 5-FU plus oxaliplatin, and 1055 received 5-FU plus irinotecan. Tumors with MSI-high or an absent protein were classified as dMMR; the remaining tumors were considered MMR-proficient (pMMR). End points of the study included OS and time to recurrence (TTR).17 After a median follow-up of 7 years, 524 of 2270 patients (23.1%) with stage II CRC and 823 of 5533 patients (14.9%) with stage III CRC exhibited dMMR. Compared with pMMR, dMMR was strongly associated with improved OS (HR, 0.27; P = .01) and TTR (HR, 0.27; P = .01) in patients with stage II disease who were treated with surgery alone (Table 5).17 MMR association was prognostic, but of attenuated impact in 5-FU–treated patients with stage II or III CRC. Significance was confined to patients with stage III disease treated with 5-FU monotherapy (HR, 0.80; P = .02 for TTR; HR, 0.79; P = .02 for OS).17 The investigators confirmed the prognostic utility of MMR status in patients with stage II CRC. Although they believe that MMR impacts outcomes in patients with stage III disease as well, MMR status currently does not alter the authors’ management of individuals with CRC.17

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FACULTY PERSPECTIVES Perspectives These findings reinforce the current practice of not treating stage II disease with adjuvant therapy, and treating stage III patients, albeit with somewhat less enthusiasm.

-Leonard Saltz, MD

This study demonstrates the value of adjuvant FOLFOX over 5-FU in terms of RFS. However, the addition of oxaliplatin to 5-FU also provides benefits. The health plan would rely on the oncology providers to determine the best option for patients when comparing these regimens based on efficacy and tolerability, as well as the option to avoid the leucovorin in the FOLFOX regimen.

-James T. Kenney, Jr, RPh, MBA

These data provide further justification for not treating stage II disease with adjuvant therapy and indicate that MMR does not influence treatment for stage III disease at this time. MMR is a prognostic indicator in CRC, and nurses should be prepared to explain this mechanism to their patients.

-Ellen M. Hollywood, MSN, RN, OCN

REFERENCES

Diagnostic screening that more effectively matches patients to a specific regimen is preferred by health plan managers when deciding on therapeutic and surgical options. MMR status could be added to the development of treatment pathways in CRC. -James T. Kenney, Jr, RPh, MBA

Adjuvant Chemotherapy with 5-FU or FOLFOX in Patients with MSI CRC MSI is detected in 12% of all CRCs and is associated with a low recurrence rate following curative surgery.18 Although adjuvant chemotherapy with 5-FU has appeared to be ineffective, small studies have recently suggested that adjuvant chemotherapy with FOLFOX may be effective.19 At ASCO 2014, Tougeron and colleagues reported the results of their multicenter, retrospective study designed to determine the efficacy of adjuvant chemotherapy with 5-FU or FOLFOX on relapse-free survival (RFS) in 433 patients with stage II or III MSI CRC.18 All participants underwent curative surgery between 2000 and 2012. Of the 433 patients analyzed, 57% had stage II disease and 43% had stage III disease. Overall, 263 patients (61%) received surgery alone, 119 (27%) were treated with adjuvant FOLFOX, and 51 (12%) received adjuvant 5-FU. Most of the patients (70%) who received adjuvant chemotherapy had stage III disease. After a median follow-up of 35 months, recurrence rates were 6% in those with stage II MSI CRC and 21% in patients with stage III MSI CRC. According to the investigators, adjuvant chemotherapy was associated with better RFS in univariate analysis in FOLFOX-treated patients (HR, 0.46; 95% CI, 0.23-0.79) but not in 5-FU–treated patients (HR, 1.02; 95% CI, 0.60-1.73). The 3-year RFS rates were 75% with surgery alone, 66% with 5-FU, and 84% with FOLFOX (P = .02).18 A multivariate analysis in which other prognostic factors were considered showed that adjuvant chemotherapy with oxaliplatin remains significantly associated with better RFS (HR, 0.29; 95% CI, 0.13-0.65; P = .003), leading the investigators to conclude that the addition of oxaliplatin to 5-FU can restore the chemosensitivity of MSI CRCs.18 Perspectives This trial further supports the use of standard fluoropyrimidine/oxaliplatin adjuvant therapy in patients with stage III dMMR tumors. It does not give enough direct information to inform the decisions regarding stage II due to small numbers and excellent outcomes; however, as noted above, use of adjuvant therapy in stage II dMMR tumors is not routinely indicated.

-Leonard Saltz, MD

1. Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30:1926-1933.

2. Rödel C, Liersch T, Becker H, et al; for German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial.

Lancet Oncol. 2012;13:679-687.

3. Rödel C, Liersch T, Fietkau R, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced rectal cancer: results of the German CAO/ARO/AIO-04 randomized phase III trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3500.

4. Schmoll H-J, Haustermans K, Price TJ, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: disease-free survival results at interim analysis. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3501.

5. Sang Hong Y, Nam B-H, Kim K-P, et al. Adjuvant chemotherapy with oxaliplatin/5-fluorouracil/leucovorin (FOLFOX) versus 5-fluorouracil/leucovorin (FL) for rectal cancer patients whose postoperative yp stage 2 or 3 after preoperative chemoradiotherapy: updated results of 3-year disease-free survival from a randomized phase II study (The ADORE). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3502.

6. Arnold D, Graeven U, Lerchenmuller CA, et al. Maintenance strategy with fluoropyrimidines (FP) plus bevacizumab (Bev), Bev alone, or no treatment, following a standard combination of FP, oxaliplatin (Ox), and Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC): a phase III non-inferiority trial (AIO KRK 0207). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3503.

7. Koopman M, Simkens L, May AM, et al. Final results and subgroup analyses of the phase 3 CAIRO3 study: maintenance treatment with capecitabine + bevacizumab versus observation after induction treatment with chemotherapy + bevacizumab in metastatic colorectal cancer (mCRC). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3504.

8. Saltz L. At what price stability? Value of maintenance therapy. Presented at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago, IL. http://meetinglibrary.asco.org/presentationBySession/6674/ 1344. Accessed November 23, 2014.

9. Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol.

2011;22:1535-1546.

10. Bokemeyer C, Kohne C-H, Ciardiello F, et al. Treatment outcome according to tumor RAS mutation status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/ without cetuximab. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3505.

11. Van Cutsem E, Köhne C-H, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408-1417.

12. Ciardiello F, Lenz H-J, Kohne C-H, et al. Treatment outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOLFIRI with/ without cetuximab. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3506.

13. Venook AP, Niedzwiecki D, Lenz H-J, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/ leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract LBA3.

14. Lenz H, Niedzwiecki D, Innocenti F, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/ leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients with expanded RAS analyses untreated metastatic adenocarcinoma of the colon or rectum (mCRC). Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract 5010.

15. Venook AP, Niedzwiecki D, Lenz H, et al. CALGB/SWOG 80405: analysis of patients undergoing surgery as part of treatment strategy. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract LBA10.

16. Stintzing S, Modest DP, von Weikersthal LF, et al. Independent radiological evaluation of objective response, early tumor shrinkage, and depth of response in FIRE-3 (AIO KRK-0306) in the final RAS evaluable population. Ann Oncol (ESMO Annual Meeting Abstracts). 2014;25(suppl 4):Abstract LBA11.

17. Sargent DJ, Shi Q, Yothers G, et al. Prognostic impact of deficient mismatch repair (dMMR) in 7,803 stage II/III colon cancer (CC) patients (pts): a pooled individual pt data analysis of 17 adjuvant trials in the ACCENT database. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3507.

18. Tougeron D, Sickersen G, Lecomte T, et al. Impact of adjuvant chemotherapy with 5-FU or FOLFOX in colon cancers with microsatellite instability: an AGEO multicenter study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2014;32(suppl):Abstract 3508.

19. Zaanan A, Fléjou J-F, Emile J-F, et al. Defective mismatch repair status as a prognostic biomarker of disease-free survival in stage III colon cancer patients treated with adjuvant FOLFOX chemotherapy. Clin Cancer Res. 2011;17:7470-7478.

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Case Presentation: International Focus on the Management of Acral Lentiginous Melanoma

WORLD CUTANEOUS MALIGNANCIES CONGRESS ™

T Axel Hauschild, MD, PhD

he management of melanoma from the perspective of 3 regions of the world was exemplified through the presentation of a case study at the Third Annual World Cutaneous Malignancies Congress.

The case, because it was managed in Latin America, was presented by Héctor MartínezSaid, MD, Melanoma Clinic and Soft Tissue Department, Instituto Nacional de Cancerología, Mexico City, Mexico, with input from Axel Hauschild, MD, PhD, professor of dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Germany, and Sanjiv S. Agarwala, MD, chief of oncology and hematology, St. Luke’s Cancer Center, Bethlehem, PA.

Case: 64-Year-Old Woman with Acral Lentiginous Melanoma Sanjiv S. A 64-year-old woman with no relevant family Agarwala, MD history or medical or surgical history presents with an increasing plantar pigmented skin mole with changes in the borders and color for 18 months. She has no other related symptoms. On examination, the lesion is 3.5 cm in diameter, with no satellites or in-transit disease. She is node negative (inguinofemoral and popliteal fossa). The rest of the physical examination was negative.

A biopsy of the lesion was performed that revealed acral lentiginous melanoma with a Breslow index of 2.2 mm, presence of ulceration, and a mitotic index of 5 mm2. The level of lactate dehydrogenase (LDH) was 169 IU/L (normal range, 119-213 IU/L), and a CT scan of the chest and abdomen/ pelvis was negative.

Treatment options are: 1) surgical margins and sentinel node biopsy; 2) reconstruction (grafts vs flaps); and 3) neoadjuvant treatment in locally advanced disease. How would you treat this patient?

European Perspective: Lymph Node Sonography “This is an exceptional case because the primary tumor was so large,” said Hauschild. The surgical excision margin would be 2 cm on a tumor this large.

Lymph node sonography is indicated, according to European guidelines. “I’m pretty sure that in a patient with

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this primary tumor, we’ll find a positive node already in the groin using lymph node sonography. In this case, we wouldn’t refer the patient for a sentinel node biopsy,” he said. “If this is clearly a positive node, we would go ahead immediately with a lymph node dissection.”

If the lymph node sonography is not suspicious, a sentinel lymph node biopsy would be performed under tumescent local anesthesia, and in Germany, it is usually performed by a dermatologist.

Flap reconstruction is preferred following resection of lesions on the sole “because otherwise the stability of the foot is not as good,” he said. An alternative is a split thickness graft to consolidate the wound bed followed by a skin transplant.

“If the patient is walking on this [plantar lesion], you need to have a rotational flap,” said Hauschild. “If it is an area without much pressure on it, you can go with skin transplant.”

Is Neoadjuvant Treatment Indicated?

The concept of neoadjuvant therapy in melanoma is still experimental, said Agarwala. “If this is resectable, and it looks like it is, we would not attempt a neoadjuvant therapy outside of a clinical trial,” he said.

Interest remains in considering neoadjuvant therapy, not only with systemic agents but with locoregional agents as well, as part of a clinical trial, said Agarwala.

Although the approach to this case in the United States would be similar to the one in Europe, the exception is the use of sonography, which has not caught on in the US as a primary way of assessing the lymph nodes.

“We would proceed with sentinel lymph node mapping of this patient,” he said.

Case Continued: Surgical Resection and Lymphadenectomy A surgical resection with a 2-cm margin and sentinel lymph node biopsy was performed, followed by reconstruction with a skin graft. The pathology report noted melanoma with a Breslow index of 2.2 mm and presence of ulceration, 1 sentinel node (23 mm) with metastasis in the cortex and medulla (pT3b N1 M0).

One week later, a completion lymphadenectomy was

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done, and the pathology report showed 3 of 14 metastatic nodes and 11 of 14 hyperplastic nodes.

After lymphadenectomy completion, would you recommend adjuvant treatment, either systemic or radiation?

Approaches to Adjuvant Therapy Adjuvant therapy is more likely than neoadjuvant therapy to be used outside of a clinical trial in the US, Agarwala indicated. Use of adjuvant therapy outside of a clinical trial depends on the center and the patient’s personal preference. “We have a very honest discussion with the patient regarding toxicity, and the benefit is, of course, modest,” he said.

In the US, adjuvant immunotherapy with pegylated interferon or high-dose interferon is approved for patients with resected node-positive disease, with modest benefit in disease-free survival and overall survival (OS). At most US centers, outside of a clinical trial, the patient preference is moving toward peg­ ylated interferon as opposed to high-dose interferon, he said. Otherwise, the patient would be a candidate for enrollment into a clinical trial of immunotherapy, such as the recently closed ECOG 1609 trial in which high-dose interferon alfa-2b is being compared with 2 different doses of ipilimumab as postoperative adjuvant therapy in patients with high-risk stage III/IV melanoma.

Use of pegylated interferon is not an option in Europe, as it is not approved in any country except Switzerland, said Hauschild.

Use of ipilimumab In Europe, outside of a clinical trial, awaits OS data from the EORTC 18071 trial, which compared ipilimumab with placebo after complete resection of stage III melanoma.

The case patient may be a candidate for enrollment into the BRIM8 trial, which is evaluating the safety and efficacy of vemurafenib in patients with completely resected BRAF mutation–positive melanoma at high risk for recurrence, Hauschild said.

Adjuvant radiation has demonstrated a 50% improvement in local disease control in the Australia-New Zealand trial, but without impact on progression-free survival and OS. European guidelines state, however, that irradiating the groin raises the risk of lymphedema of the legs. “I would explain the situation carefully to my patient, but I’m pretty sure that 90% of my patients would refuse applying radiotherapy in this situation,” he said.

Case: Follow-up 28 Months Later At 28 months, the patient develops a new skin lesion in the medial side of the thigh, with no other intralymphatic deposits.

The pathology report noted a melanoma in-transit lesion. A

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CT scan of the chest, abdomen, and pelvis was negative, and the LDH was normal (171 IU/L). There was no evidence of WORLD tumoral activity.

CUTANEOUS Would you recommend regionalMALIGNANCIES treatment (ie, isolated CONGRESS limb perfusion, isolated limb infusion, local ablative therapy, talimogene laherparepvec [T-VEC] injection) or systemic adjuvant treatment?

With multiple skin metastases that are not resectable, there is no role for adjuvant limb perfusion, said Hauschild. He prefers systemic treatment or possibly T-VEC injection, although that is not yet approved in Europe.

Tumor necrosis factor-alfa inhibition is allowed only as second-line treatment after relapse following melphalan or isolated limb perfusion, with the goal being local tumor control rather than improving OS. ™

Use of ipilimumab In Europe, outside of a clinical trial, awaits OS data from the EORTC 18071 trial, which compared ipilimumab with placebo after complete resection of stage III melanoma.

“An interesting approach would be to use T-VEC,” he said. “The benefit for the injected lesions is good with T-VEC, but on the noninjected lesions it doesn’t appear to be very high, so I would prefer to give systemic treatment in this scenario.”

Case: Pulmonary Nodule at 42 Months The patient was maintained on observation until, at 42 months, she developed a pulmonary nodule that was detected on the PET-CT scan. It was the only unique metastatic lesion. What do you recommend?

“It used to be surgery was the only option, because we had nothing else that was effective. That is changing,” said Agarwala. “With good systemic treatments available, we should go with systemic therapy here, simply because it’s likely that there is micrometastatic disease elsewhere. In some patients, you can resect a solitary lesion and have long-term, disease-free survival, but this is a patient for whom I would want to use immunotherapy. She is exactly the low-volume–disease patient in whom immunotherapy is going to be the most effective, and we would like to know the BRAF status as well.”

This patient is a clear candidate for surgery, said Hauschild. “If we look at the complete response rates of all the drugs we are discussing at the moment, the best are at 10% to 17%,” he said. The duration of these complete responses is not yet known.

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“If you resected, you’d have a 100% response...so why not postpone the decision for immunotherapy for a later WORLD situation if there’s a relapse,” he said.

CUTANEOUS “In this situation, we often do a PET scan to make MALIGNANCIES CONGRESS sure we’re not missing anything else,” said Agarwala. “If this was really easy to resect, we would get a consultation from our thoracic surgeon. I agree we could go either way [surgery or systemic therapy].” ™

Dacarbazine or other chemotherapeutics are used for the second, third, fourth line, or higher, assuming the patient has access to the drugs and also has adequate performance.

Case: Progressive Disease The lesion was resected by video-assisted thoracoscopy.

After almost 3 years following the surgery (total follow-up, 101 months), she developed progressive disease with multiple in-transit disease lesions on the leg. The popliteal fossa and inguinal area nodes were negative. She developed multiple subcutaneous nodules all over the body. The LDH was elevated at 213 IU/L. The pathology report came back showing BRAF wild-type metastatic melanoma (in transit). What are the systemic treatment options at this point?

Surgery is no longer the first option, said Hauschild. “It’s certainly a question for systemic treatment opportunities, and I would refer the patient to a clin-

ical trial, if available, to ipilimumab,” he said.

The scenario is favorable for ipilimumab, he said, because the tumor load is limited. “It’s not the exploding patient, although LDH is already elevated. Ipilimumab would be my first choice, and the other choice, because the tumor is BRAF wild-type, is chemotherapy.”

Dacarbazine is no longer on the list of frontline options in the US, said Agarwala. “If we have another option, then I would use something else,” he said.

Dacarbazine or other chemotherapeutics are used for the second, third, fourth line, or higher, assuming the patient has access to the drugs and also has adequate performance.

“If nothing else, dacarbazine is available and cheap and doesn’t cause many toxicities,” said Hauschild. “For patients who are not eligible for ipilimumab, such as those with diverticulitis or with contraindications, dacarbazine would still be an option.”

Case: Patient Receives Ipilimumab The patient received ipilimumab, 3 mg/kg for 4 cycles. At the moment, the patient has stable disease.

In Germany, administering more than 4 cycles of ipilimumab would be difficult, as it is not approved for maintenance treatment, and insurance companies would likely refrain from paying for more than 4 cycles, said Hauschild. After 4 cycles of ipilimumab, “this patient would be eligible for an early access program to 1 of the 2 anti–PD-1 antibodies, in the case of progressive disease.”

“As long as the patient is stable, we would also do 4 cycles and stop,” said Agarwala. u

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VALCHLOR® (mechlorethamine) gel is an alkylating drug indicated for the topical treatment of Stage IA and IB mycosis fungoides–type cutaneous T-cell lymphoma (MF-CTCL) in patients who have received prior skin-directed therapy WHEN IT’S TIME TO MANAGE THE CHALLENGES OF STAGE IA AND IB MF-CTCL

VALCHLOR IS ON IT The first and only FDA-approved topical formulation of mechlorethamine (commonly known as nitrogen mustard) • Proven efficacy in a 12-month study 1 • Once-daily gel (special handling and disposal procedures should be followed)

• Dependable formulation manufactured with consistent quality and potency • Comprehensive resources provided by VALCHLOR Support ™

For more information, including how to prescribe, visit www.valchlor.com or call 1-855-4-VALCHLOR (1-855-482-5245).

DOSING AND APPLICATION VALCHLOR is for topical dermatologic use only. Apply a thin film of gel once daily to affected areas of the skin. VALCHLOR is a cytotoxic drug and special handling and disposal procedures should be followed during use. Caregivers must wear disposable nitrile gloves when applying VALCHLOR. Patients and caregivers must wash hands thoroughly after handling or applying VALCHLOR.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS VALCHLOR is contraindicated in patients with known severe hypersensitivity to mechlorethamine. Hypersensitivity reactions, including anaphylaxis, have occurred with topical formulations of mechlorethamine.

WARNINGS AND PRECAUTIONS • Mucosal or eye injury: Exposure of mucous membranes to mechlorethamine such as the oral mucosa or nasal mucosa causes pain, redness, and ulceration, which may be severe.

Exposure of the eyes causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible anterior eye injury may occur. Should eye exposure or mucosal contact occur, immediately irrigate for at least 15 minutes with copious amounts of water, followed by immediate medical consultation • Secondary exposure: Avoid direct skin contact with VALCHLOR in individuals other than the patients due to risk of dermatitis, mucosal injury, and secondary cancers

• Dermatitis: Dermatitis may be moderately severe or severe.

Monitor patients for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections.

Stop treatment with VALCHLOR or reduce dose frequency • Non-melanoma skin cancer: Monitor patients during and after treatment with VALCHLOR • Embryo-fetal toxicity: Women should avoid becoming pregnant while using VALCHLOR due to the potential hazard to the fetus. For nursing mothers, discontinue use of VALCHLOR or nursing • Flammable gel: VALCHLOR is an alcohol-based gel. Avoid fire, flame, and smoking until the gel has dried

ADVERSE REACTIONS The most common adverse reactions (≥5%) were dermatitis (56%), pruritus (20%), bacterial skin infection (11%), skin ulceration or blistering (6%), and skin hyperpigmentation (5%). These reactions may be moderately severe or severe.

Elderly patients aged 65 and older may be more susceptible. Depending on severity, treatment reduction, suspension, or discontinuation may be required.

To report SUSPECTED ADVERSE REACTIONS, contact Actelion Pharmaceuticals US, Inc., at 1-855-4-VALCHLOR (1-855-482-5245) or FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

Please see Brief Summary of Prescribing Information on adjacent page.

REFERENCE: 1. VALCHLOR [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2013.

VALCHLOR®and VALCHLOR Support™ are trademarks of Actelion Pharmaceuticals Ltd. © 2014 Actelion Pharmaceuticals US, Inc. All rights reserved. VAL-00163 0814

A great idea finally gels

VALCHLOR® (mechlorethamine) gel, 0.016% For Topical Dermatological Use Only BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This brief summary does not include all the information needed to use VALCHLOR safely and effectively. See Full Prescribing Information for VALCHLOR. • INDICATIONS AND USAGE VALCHLOR is an alkylating drug indicated for the topical treatment of Stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy.

• CONTRAINDICATIONS The use of VALCHLOR is contraindicated in patients with known severe hypersensitivity to mechlorethamine. Hypersensitivity reactions, including anaphylaxis, have occurred with topical formulations of mechlorethamine.

• WARNINGS AND PRECAUTIONS >> Mucosal or Eye Injury Exposure of the eyes to mechlorethamine causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible anterior eye injury may occur. Advise patients that if eye exposure occurs, (1) immediately irrigate for at least 15 minutes with copious amounts of water, normal saline, or a balanced salt ophthalmic irrigating solution and (2) obtain immediate medical care (including ophthalmologic consultation).

Exposure of mucous membranes such as the oral mucosa or nasal mucosa causes pain, redness, and ulceration, which may be severe. Should mucosal contact occur, immediately irrigate for at least 15 minutes with copious amounts of water, followed by immediate medical consultation. >> Secondary Exposure to VALCHLOR Avoid direct skin contact with VALCHLOR in individuals other than the patient. Risks of secondary exposure include dermatitis, mucosal injury, and secondary cancers. Follow recommended application instructions to prevent secondary exposure. >> Dermatitis The most common adverse reaction was dermatitis, which occurred in 56% of the patients. Dermatitis was moderately severe or severe in 23% of patients.

Monitor patients for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections. The face, genitalia, anus, and intertriginous skin are at increased risk of dermatitis. Follow dose modification instructions for dermatitis. >> Non-Melanoma Skin Cancer Four percent (4%, 11/255) of patients developed a non-melanoma skin cancer during the clinical trial or during one year of post-treatment follow-up: 2% (3/128) of patients receiving VALCHLOR and 6% (8/127) of patients receiving the mechlorethamine ointment comparator. Some of these non-melanoma skin cancers occurred in patients who had received prior therapies known to cause non-melanoma skin cancer. Monitor patients for non-melanoma skin cancers during and after treatment with VALCHLOR. Non-melanoma skin cancer may occur on any area of the skin, including untreated areas. >> Embryo-fetal Toxicity Based on its mechanism of action, case reports in humans, and findings in animals, VALCHLOR can cause fetal harm when administered to a pregnant woman. There are case reports of children born with malformations in pregnant women systemically administered mechlorethamine. Mechlorethamine was teratogenic and embryo-lethal after a single subcutaneous administration to animals. Advise women to avoid becoming pregnant while using VALCHLOR. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. >> Flammable Gel Alcohol-based products, including VALCHLOR, are flammable. Follow recommended application instructions.

• ADVERSE REACTIONS In a randomized, observer-blinded, controlled trial, VALCHLOR 0.016% (equivalent to 0.02% mechlorethamine HCl) was compared to an Aquaphor ®-based mechlorethamine HCl 0.02% ointment (Comparator). The maximum duration of treatment was 12 months. Sixty-three percent (63%) of patients in the VALCHLOR arm and 67% in the comparator arm completed 12 months of treatment.

The body system associated with the most frequent adverse reactions was skin and subcutaneous tissue disorders. The most common adverse reactions (occurring in at least 5% of the patients) are shown in Table 1.

Table 1. Most Commonly Reported (≥5%) Cutaneous Adverse Reactions Comparator VALCHLOR N=127 N=128 % of patients % of patients Any ModeratelyAny ModeratelyGrade Severe or Severe Grade Severe or Severe Dermatitis 56 23 58 17 Pruritus 20 4 16 2 Bacterial skin infection 11 2 9 2 Skin ulceration or blistering 6 3 5 2 Skin hyperpigmentation 5 0 7 0 In the clinical trial, moderately-severe to severe skin-related adverse events were managed with treatment reduction, suspension, or discontinuation.

Discontinuations due to adverse reactions occurred in 22% of patients treated with VALCHLOR and 18% of patients treated with the comparator. Sixty-seven percent (67%) of the discontinuations for adverse reactions occurred within the first 90 days of treatment. Temporary treatment suspension occurred in 34% of patients treated with VALCHLOR and 20% of patients treated with the comparator.

Reductions in dosing frequency occurred in 23% of patients treated with VALCHLOR and 12% of patients treated with the comparator.

Reductions in hemoglobin, neutrophil count, or platelet count occurred in 13% of patients treated with VALCHLOR and 17% treated with Comparator.

• DRUG INTERACTIONS No drug interaction studies have been performed with VALCHLOR. Systemic exposure has not been observed with topical administration of VALCHLOR; therefore, systemic drug interactions are not likely.

• USE IN SPECIFIC POPULATIONS >> Pregnancy Pregnancy Category D Risk Summary Mechlorethamine can cause fetal harm when administered to a pregnant woman. There are case reports of children born with malformations to pregnant women systemically administered mechlorethamine. Mechlorethamine was teratogenic in animals after a single subcutaneous administration. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal Data Mechlorethamine caused fetal malformations in the rat and ferret when given as single subcutaneous injections of 1 mg/kg. Other findings in animals included embryolethality and growth retardation when administered as a single subcutaneous injection. >> Nursing Mothers It is not known if mechlorethamine is excreted in human milk. Due to the potential for topical or systemic exposure to VALCHLOR through exposure to the mother’s skin, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. >> Pediatric Use Safety and effectiveness in pediatric patients have not been established. >> Geriatric Use A total of 79 patients age 65 and older (31% of the clinical trial population) were treated with either VALCHLOR or the comparator in the clinical trial. Forty-four percent (44%) of patients age 65 or older treated with VALCHLOR achieved a Composite Assessment of Index Lesion Severity (CAILS) response compared to 66% of patients below the age of 65. Seventy percent (70%) of patients age 65 and older experienced cutaneous adverse reactions and 38% discontinued treatment due to adverse reactions, compared to 58% and 14% in patients below the age of 65, respectively. Similar differences in discontinuation rates between age subgroups were observed in the comparator group.

Manufactured for: Actelion Pharmaceuticals US, Inc. South San Francisco, CA 94080, USA © 2014 Actelion Pharmaceuticals US, Inc. All rights reserved.

VAL-00170 0814

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PMO LIVE

Case Report: Intense Maintenance in a Woman with High-Risk Multiple Myeloma The Third Annual PMO Live Conference, a Global Biomarkers Consortium Initiative, took place in San Francisco, CA, on October 31 – November 1, 2014. PMO Live is the only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. The following is a case report from the meeting.

T

remendous progress has been made in the treatment of patients with multiple myeloma (MM) over the past 2 decades. The 5-year relative survival ratio increased from 26.3% in 1975 to 45.1% in 2006, when only 3 drugs were approved for the treatment of MM. The arsenal of drugs approved by the FDA has now expanded to include thalidomide, lenalidomide, bortezomib, doxorubicin, Ajay K. Nooka, MD, MPH carfilzomib, and pomalidomide.

“We have more treatment options, leading to more [treatment] heterogeneity,” said Ajay K. Nooka, MD, MPH, assistant professor of hematology and medical oncology, Winship Cancer Institute of Emory University, Atlanta, GA. “There is no consensus amongst us about what is optimal induction therapy and optimal salvage therapies.”

The arsenal of drugs approved by the FDA has now expanded to include thalidomide, lenalidomide, bortezomib, doxorubicin, carfilzomib, and pomalidomide.

Although several molecular biomarkers are under development, genetic biomarkers are more acceptable for guiding therapy in MM. Chromosomal abnormalities in MM are translocations involving 14q32: t(11;14), t(4;14), and t(14;16); chromosome 13 abnormalities: monosomy, del(13), 13q translocations; del(17p); and hyperdiploidy.

High-risk features include the presence or deletion of p53; deletion of 1p; immunoglobulin heavy chain translocations – t(4;14) or t(14;16) – by fluorescence in situ hybridization (FISH) or by metaphase cytogenetics; or presentation as plasma cell leukemia (≥20% circulating plasma cells in peripheral blood).

A case report in high-risk MM was presented by

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Nooka at the Third Annual PMO Live Conference, a Global Biomarkers Consortium Initiative.

Case: Stage III MM A 57-year-old Caucasian female diagnosed with stage III MM in October 2008 presents with back pain, fatigue, increasing shortness of breath, chest pain, and progressive anemia for 1 year. Her presenting laboratory values are as follows: total protein, 7.4 g/dL; protein, 2.1 g/dL (IgG kappa); β2-microglobulin, 19.9; free kappa, 1407 mg/L; free lambda, 9 mg/L; ratio, 145; IgG, 3195 mg/dL; IgA, <40 mg/dL; IgM, <35 mg/dL; hemoglobin, 5.4; hematocrit, 16; platelet count, 241; creatinine, 1.8 mg/dL; calcium, 9.2 mg/dL. A bone marrow biopsy showed 90% cellularity with 22% plasma cells. FISH revealed del(17p) in 43 of the 50 cells.

An MRI of the spine revealed a compression fracture at L5. The patient underwent kyphoplasty and then initiated induction therapy with lenalidomide, bortezomib, and dexamethasone (RVD).

Treatment Although improvements in progression-free survival (PFS) and overall survival (OS) have been realized across all stratifications of patients with MM, progress has been less impressive among high-risk patients with del(17p), said Nooka. These patients have a PFS of close to 1 year and a median OS of 18 to 24 months.

The case patient is young with a high tumor burden and is transplant eligible, and the consensus is to treat with a combination of immunomodulatory therapy and proteasome inhibitor therapy. Obtaining a response with bortezomib-containing induction regimens is relatively easy, said Nooka, but the challenge is to maintain a response among high-risk patients such as this one.

Intense Maintenance After induction with 4 cycles of RVD, a stringent complete response (sCR) is obtained in nearly 20%.

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After autologous stem cell transplant, the rate of CR plus sCR improves to about 40%. A consolidation/ maintenance approach to treatment to continuously suppress malignant clones has been evaluated in highrisk patients with MM. With initiation of RVD maintenance, 51% of patients achieved sCR, and 96% achieved at least a very good/partial response as best response (Leukemia. 2014;28:690-693). The RVD maintenance regimen translated into a median PFS of 30 months and a 3-year OS of 93% in patients with del(17p). The regimen was well tolerated with no grade 3/4 neuropathy.

“If we’re able to give an initial induction therapy with a combination of a proteasome inhibitor, an immunomodulatory drug, and steroids, give it early after transplant, and maintain the response with a maintenance regimen consisting of those 3 agents, we are able to deliver good response rates, and the safety is acceptable,” he said. “We’ve never had a patient who was not able to tolerate this maintenance regimen.”

He continued, “I would treat this patient with initial induction therapy with RVD for 4 cycles, early transplant, and an intense maintenance approach.”

In the case patient, intense maintenance was continued for 3 years, followed by single-agent lenalidomide maintenance.

The patient continues to do well.

The question then becomes: how long should the intense maintenance approach be continued? In the case patient, intense maintenance was continued for 3 years, followed by single-agent lenalidomide maintenance. The patient continues to do well.

While on RVD maintenance (and single-agent lenalidomide), continuation of bisphosphonates, thromboprophylaxis, and prophylactic acyclovir is advised. u

Interview With the Innovators An exclusive PMO series

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

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

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ASH 2014

Personalizing Myeloma Treatment Can Limit the Use of Expensive Drugs

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“The VRD regimen has not yet been shown to improve overall survival. If we can limit the toxicity and cost by using 2 drugs, there should be no reason to add a third,” Narkhede said.

At ASH 2014, a pilot study testing this model was presented by Mayur Narkhede, MD, of the Department of Internal Medicine, Cleveland Clinic, who remarked that the triplet of bortezomib, lenalidomide, and dexamethasone (VRD) is preferred by many centers because of its higher rates of response, although there has been no survival difference.

“Since no test predicts who may experience harm from insufficient or excessive therapy, we designed a care path that starts with 2 drugs but adapts treatment early to achieve uniform myeloma control,” Narkhede said.

The researchers noted that 3 drugs convey a higher risk for side effects, especially peripheral neuropathy, and treatment with 3 drugs is considerably more expensive than with 2.

Care Path Adds Third Drug Only When Necessary Reu and a colleague developed the care path for patients not participating in clinical trials. It advises initial treatment with lenalidomide/dexamethasone or bortezomib/dexamethasone, with therapy adjusted depending on the initial response. When patients do not achieve at least a partial response to frontline treatment, clinicians add the other novel agent; cyclophosphamide and liposomal doxorubicin may also be given. The choice between lenalidomide/dexamethasone and bortezomib/ dexamethasone is based on insurance coverage and the status of the kidney; patients with evidence of renal disease receive bortezomib/dexamethasone.

In a pilot study of 24 patients, response-adapted therapy allowed disease control with the lenalidomide/dexamethasone or bortezomib/dexamethasone doublet in approximately 60% of patients; subsequent triplets controlled disease in another 30% of patients, and 10% of patients required a fourth drug.

“Response-adapted therapy also avoided progression during induction therapy and, so far, also death during follow-up,” Narkhede reported.

Of the 24 patients, 17 received lenalidomide/dexamethasone initially and 7 received bortezomib/dexamethasone. Of the 17 patients who received lenalidomide/dexamethasone, 12 had a partial response or better.

Of the 7 patients who received bortezomib/dexamethasone, 3 had at least a very good partial response. After a median follow-up of 10 months, none of the 24 patients had progressed. The doublet provided disease control in the majority of patients, and only 1 patient developed grade 3 peripheral neuropathy.

Compared with VRD for all patients, which is an emerging trend, doublets reduced the rate of peripheral neuropathy and the cost of treatment. The researchers estimated that the savings for this small cohort exceeded $4000 per cycle.

“Overall survival will be the ultimate assessment of the utility of this approach, but response assessments to date support the ongoing use of the care path,” Narkhede said. u

or patients with newly diagnosed multiple myeloma, clinicians are moving from doublet to triplet regimens. Cleveland Clinic myeloma specialists, however, have found that most patients can be sufficiently – and less expensively – treated with 2 drugs, reserving the use of the third agent for patients who respond insufficiently to 2.

This is personalized medicine at its best, according to Frederic Reu, MD, senior investigator at the Department of Translational Hematology and Oncology Research, Cleveland Clinic, who codesigned the care path.

“The problem with multiple myeloma research now is that everyone ignores the huge heterogeneity of this disease. No one adjusts the treatment plan according to anything that can be measured,” Reu said in an interview with American Health & Drug Benefits.

“The problem with multiple myeloma research now is that everyone ignores the huge heterogeneity of this disease.

No one adjusts the treatment plan according to anything that can be measured.”

– Frederic Reu, MD

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Genomic Panel Likely to Be Cost-effective in AML

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enomic sequencing methods are likely to be more cost-effective than stepwise addition of single mutational testing in patients with intermediate-risk acute myeloid leukemia (AML), found Sonya Cressman, PhD, a health economist at the Canadian Centre for Applied Research in Cancer Control, Vancouver.

“Genomic sequencing costs have decreased in recent years while the potential list of mutations with prognostic value in AML has increased, hence a genome-wide sequencing approach at diagnosis may offer cost savings when integrated into clinical practice,” she said.

Using a decision analytic model, her group found acceptable incremental cost-effectiveness ratios (ICERs) for genomic sequencing over single mutational testing that would improve further if the cost of sequencing is reduced.

Testing for mutations in genes of prognostic importance in AML can inform treatment decisions once first complete remission (CR1) is achieved. The National Comprehensive Cancer Network currently recommends testing for 3 genes in intermediate-risk AML: FLT3ITD, NPM1, and CEBPA. “Evidence suggests that testing for 6 others will alter CR1 treatment decisions,” said Cressman. These 6 are IDH1, IDH2, TET2, ASXL1, MLL-PTD, and PHF-6.

A decision tree was used to simulate treatment decisions and outcomes during remission induction. These data were fed into 3 postremission Markov models in which 10-year costs and outcomes following CR1 with stem cell transplant versus chemotherapy or induction failure were calculated. The model was based on 10 years of patient data in British Columbia, and costs for each healthcare state (ie, remission, relapse, death) were added.

REPRINTS

AML patients who undergo stem cell transplantation in CR1 incur higher up-front costs than those treated with chemotherapy alone, she said, but survive significantly longer and have longer relapse-free survival. Cost savings may be realized from a reduction of salvage transplants if high-risk patients are treated with a transplant in CR1.

The model assumed a price of $5000 for the gene panel, “which is a very conservative estimate. Apparently, it’s more like $1000,” said Cressman.

Utilizing the genomic sequencing panel increased the rate of stem cell transplants by 13% and yielded an ICER of $55,316 per life-year gained.

The cost of a stem cell transplant had a strong impact on cost-effectiveness, whereas the cost of the genomic test and the addition of other mutational tests were minor contributions to the simulated ICERs. In the model, all genomic testing strategies yielded an ICER <$100,000 (Canadian) per life-year gained, the threshold that normally defines cost-effective. Passive FLT3-ITD, NPM1, and IDH1/2 testing dominated the model. Testing for FLT3-ITD, NPM1, MLL-PTD, ASXL1, TET2, and PHF-6 mutations produced an ICER of $97,880 per life-year gained.

Utilizing the genomic sequencing panel increased the rate of stem cell transplants by 13% and yielded an ICER of $55,316 per life-year gained. “It’s pretty likely that this will be considered a cost-effective way to work up AML in an intermediate-risk group,” she concluded. u

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

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CHEMOTHERAPY FOUNDATION SYMPOSIUM

Scientific Exploration of Obesity and Breast Cancer Link

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nvestigators at Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, Rockefeller University, and the National Cancer Institute are moving forward in their understanding of the adverse association between obesity Clifford Hudis, and breast cancer. Preliminary studMD ies show associations between adipocytes, aromatase, proinflammatory cytokines, low-grade chronic inflammation, and breast tumors. Improved understanding of these associations will hopefully lead to targeted interventions.

Why the focus on obesity and breast cancer? Obesity is projected to affect more than 60% of the population in the United States by the year 2030. This will have widespread consequences for many diseases, said Clifford Hudis, MD, chief of the Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center, New York City, and immediate past president of ASCO.

A small number of obese and overweight patients do not have evidence of low-grade chronic inflammation, and a modest number of overweight and even lean patients demonstrate elevated proinflammatory mediators and CLS of the breast.

“The unprecedented change in rates of obesity has broad public health implications. What does this have to do with cancer? Uterine cancer mortality is higher in obese people, and cancers of the esophagus, pancreas, breast, and liver are associated with obesity,” he explained.

Further, obesity is a risk factor for postmenopausal breast cancer (but not for premenopausal breast cancer).

“Explanations for this association are both facile and complex,” Hudis continued.

“We all know that adipocytes make estrogen, but the answer as to why this happens is complex and involves insulin and insulin-like growth factor. A new discovery

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is that adipocytes produce inflammatory macrophages that alter interleukin (IL)-6, IL-1, and tumor necrosis factor-alpha,” Hudis explained.

“We began to develop the notion that at least part of this was due to increased inflammation. Postmenopausal breast cancer may be a consequence of chronic low-grade inflammation in visceral fat and breast tissue,” he said.

Studies in mice showed the highest aromatase levels in oophorectomized animals in white adipose tissue in the mammary gland and visceral fat. Animals on a eucaloric diet seemed to put on a few pounds during menopause induced by oophorectomy.

“An unexpected finding we stumbled on were crownlike structures [CLS] consisting of dead or dying adipocytes in the animals, surrounded by macrophages that secrete proinflammatory mediators. This is a toxic stew of inflammation in the mammary gland of the mouse.

Higher amounts of fat in oophorectomized animals contribute to the rates of CLS,” he explained.

The investigators went on to look at this in normal tissue in women’s breasts in patients undergoing surgery.

In an initial series of 30 patients, they encountered parallel findings to what they saw in mice, including histological evidence of CLS of the breast white adipose tissue associated with increasing body mass index.

Hudis pointed out that a small number of obese and overweight patients do not have evidence of low-grade chronic inflammation, and that a modest number of overweight and even lean patients demonstrate elevated proinflammatory mediators and CLS of the breast.

“We have confirmed the pattern seen in mice in women’s breasts,” he emphasized. “We think this is a systemic phenomenon, and the white adipose tissue of the breast can be a sentinel for generalized inflammation,” Hudis said.

The current goal of studies is to define biomarkers that identify adipocyte inflammation with the potential to modulate and target it.

“We think this axis of obesity-inflammation-aromatase may be useful for reducing the risk of breast cancer or its progression. It may be a biomarker, and we need to scientifically investigate the effect of lifestyle changes and anti-inflammatory agents on these lesions,” he said. “We think that obesity may replace cigarette smoking as the nation’s number 1 risk factor for cancer.” u

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PARP Inhibitors in Gynecologic Cancer: More Questions Than Answers

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ARP inhibitors are an area of intense interest in gynecologic cancers. At least 8 PARP inhibitors are currently in various stages of development, with olaparib and veliparib the most studied, but to date, there are no FDA approvals of these agents. Ongoing phase 1-3 trials should shed light on best use of these drugs.

Despite the enthusiasm for PARP inhibition in gynecologic cancers, more research is needed to understand the biological mechanisms of action, to identify which patients will be most responsive, to find the best way to administer these drugs, and to identify predictive and prognostic biomarkers, according to a presentation at the recent 2014 Chemotherapy Foundation Symposium.

“We don’t have the answers to these questions yet.

PARP inhibitors are an important group of drugs in ovarian cancers, and we await the results from several studies. So far, finding the answers to these questions is a ping-pong game between basic science and clinical studies,” said Tamar Safra, MD, head of the OncoGynecological Unit at Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv, Israel.

It is not clear which of the suggested mechanisms is most important. Suggested mechanisms include synthetic lethality, the nonhomologous end joining DNA repair pathway, PTEN-deficient cells, the presence of specific genes associated with ovarian cancer, and PARP1 trapping.

Studies suggest that the patients who benefit from PARP inhibitors are those with germline or somatic BRCA1/2 mutations and cancers that display other BRCA-like deficiencies.

“Regarding biomarkers, we are in a bad position [in ovarian cancer]. We know BRCA1/2 are markers, but we don’t know whether any others can be used as selective or predictive biomarkers. We need further study,” Safra said. “We also need further study on mechanisms of resistance to PARP inhibitors, and once we identify those, we need to find ways to overcome resistance.”

In studies of PARP inhibitors, significant responses are observed in BRCA germline mutation carriers, she continued. Accumulated information suggests a wider application of PARP in serous ovarian cancer. “We await results of many studies of these agents,” she said.

Fifteen percent to 18% of ovarian cancers are related to BRCA1/2 mutations, and 50% of serous ovarian can-

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cers show disruption of homologous repair pathways. These groups of patients may have the best response to PARP inhibition, she said.

Safra reviewed some of the key studies to date. An early phase 2 study of olaparib versus pegylated doxorubicin in patients with BRCA mutations Tamar Safra, MD and recurrent ovarian cancer had disappointing results in progression-free survival (PFS) (J Clin Oncol. 2012;30:372-379).

“We thought these drugs would change the life of BRCA carriers,” she said. “An important point here is that olaparib was more effective in BRCA carriers.”

Olaparib as maintenance therapy in platinum-sensitive relapsed serous ovarian cancer (high-risk patients) reduced the risk of disease progression by 65% versus placebo but had no effect on overall survival (OS) (N Engl J Med. 2012;366:1382-1392).

Fifteen percent to 18% of ovarian cancers are related to BRCA1/2 mutations, and 50% of serous ovarian cancers show disruption of homologous repair pathways.

In a subset of patients with BRCA mutations, olaparib maintenance therapy achieved an 82% reduction in risk of progression versus placebo, with a median PFS of 11 months versus 4 months, which was highly sig­ nificant (P≤.00001). (J Clin Oncol. 2013;31[suppl].

Abstract 5505).

“Maintenance therapy with olaparib seems to be a good option in platinum-sensitive disease,” she said.

Several studies have combined olaparib with chemotherapy. In a phase 2 study of platinum-sensitive serous ovarian cancer, olaparib maintenance therapy after pac­ litaxel/carboplatin achieved a median PFS of 12.2 months versus 9.6 months with chemotherapy alone (J Clin Oncol. 2012;30[suppl]. Abstract 5001).

“It is still an open question what would have happened if olaparib was given alone,” Safra said.

Two ongoing studies are looking at biologics combined with PARP inhibitors. Interim results of a phase 2 study presented at ASCO 2014 showed improved PFS with olaparib plus cediranib (an antiangiogenic agent)

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versus olaparib alone: median PFS was 17.7 months with the combination versus 9 months with olaparib alone (P=.005). (J Clin Oncol. 2014;32[suppl]. Abstract LBA5500). BRCA mutation carriers had a small advantage, while noncarriers had a larger benefit in PFS. No OS advantage was observed for olaparib.

A second ongoing phase 1 study is exploring the combination of olaparib plus BKM120, a PI3K inhibitor, she said.

“Thus far, PARP inhibitors have proven efficacy as

maintenance therapy in BRCA mutation carriers and as treatment for active disease. We know there is single-agent activity with a good toxicity profile, and we’ve seen the potential benefit of selected combination therapy with chemotherapy and with cediranib. We await the results of ongoing trials to tell us the best setting for these drugs, whether single or combination therapy is better, and whether PARP inhibitors can be used as prevention in BRCA carriers,” Safra said. u

Basket Trials Based on Genomics Hold Promise

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he concept of “basket trials” is gaining traction as a strategy for studying cancers according to driver mutations rather than by tumor type. These studies are made possible by the dramatically reduced cost of performing David Hyman, MD next-generation sequencing platforms that characterize the landscape of individual cancer genomes across a wide variety of cancer types.

“The organizing principle of basket trials is that patients have a qualifying genomic alteration regardless of tumor site. Any type of tumor can be included. The trials entail an independent analysis by tumor lineage targeted to low-prevalence genomic alterations [ie, <5% in frequency]. Once a genomic alteration has a higher prevalence, it is advisable to perform a study on a single tumor type,” explained David Hyman, MD, Memorial Sloan Kettering Cancer Center (MSKCC), New York City.

“Most of these studies are encouraged to have other cohorts for serendipitous disease discovery,” he added.

Therapy for all cohorts is uniform.

One example of a basket trial being conducted at MSKCC is that of tumors with ERBB2 mutations treated with neratinib. This study has 6 “baskets” – bladder, colon, endometrial, gastric, ovarian, and “other” cancers.

“We use statistical analysis that sets high bars and allows us to enroll small numbers of patients, but we may be missing active agents by setting the bar this high,” Hyman said.

At the National Cancer Institute (NCI), “match” trials are also under way, he continued. Nine new match trials have been announced. Among these are: non-

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BRAF V600 and BRAF fusion; ALK/ROS1 translocation (non-lung); TSC1/2 loss of function mutations; EGFR2 T790M mutations (non-lung); and 4 others.

At the NCI, the approach is as follows: an actionable mutation is detected by genetic sequencing, and the tumor is then treated with the study agent. Patients with stable disease or complete or partial responses continue on the study drug until disease progression. Those with no response stop the drug. All patients who progress are biopsied again and sequenced and put on a new study drug if a new actionable mutation is detected.

Gynecologic cancers require special considerations for basket trials, Hyman continued. An assay is needed to detect copy number alterations. There may be financial barriers to study participation. Also, it is not clear if the primary end point should be RECIST measurable disease or detectable CA125 antigen.

“This would be ideal, but it may not be applicable,” Hyman said.

“You have to consider comorbidities associated with gynecologic cancers, and how these comorbidities might interact with cancer drugs. For example, many endometrial cancer patients have diabetes, and this would affect interaction with PI3KCa inhibitors,” Hyman explained.

MSKCC investigators use an integrated mutation profiling approach to these basket trials. Germline and mutation DNA are collected, followed by genetic profiling done by MSK-IMPACT, a new testing approach that screens for mutations in over 300 genes at once, in a CLIA lab. Results are entered into the electronic medical record regarding eligibility for a basket trial protocol.

“As we work to develop these programs, it is critically important to have informatics so we can identify patients who are eligible for these trials,” he stated. u

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SAVE THE DATE JULY 22-25, 2015 THE WESTIN SEATTLE • SEATTLE, WASHINGTON

The Global Biomarkers Consortium (GBC) and World Cutaneous Malignancies Congress (WCMC) will be holding their fourth annual joint meeting focused on personalized and precision medicine in oncology (PMO) on July 22-25, 2015, in Seattle, Washington.

July 22-24 A Focus on the Application of Molecular Biomarkers in Clinical Practice Across Multiple Tumor Types

SCHEDULE OF EVENTS (subject to change)

July 24-25 Spotlight on Cutaneous Malignancies, Including Melanoma, Cutaneous T-Cell Lymphoma, and Basal Cell Carcinoma

CONFERENCE CO-CHAIRS

Sanjiv S. Agarwala, MD

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

Jorge E. Cortes, MD

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

Hope S. Rugo, MD

Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Hope Comprehensive S. Rugo, M.D. Cancer Center San of Francisco, Professor MedicineCA Director, Breast Oncology and Clinical Trials Education University of California San Francisco Helen Diller Fami Cancer Center San Francisco, CA

www.pmo-live.com

PMOLive2015_112114

Hope S. Rugo, MD, is a Professor of Medicine in the Div

EDITORIAL

FACT SHEET: President Obama’s Precision Medicine Initiative

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uilding on President Obama’s announcement in his State of the Union Address, today the Administration is unveiling details about the Precision Medicine Initiative, a bold new research effort to revolutionize how we improve health and treat disease.

Launched with a $215 million investment in the President’s 2016 Budget, the Precision Medicine Initiative will pioneer a new model of patient-powered research that promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients.

Advances in precision medicine have already led to powerful new discoveries and several new treatments that are tailored to specific characteristics of individuals, such as a person’s genetic makeup, or the genetic profile of an individual’s tumor.

Most medical treatments have been designed for the “average patient.” As a result of this “one-size-fits-allapproach,” treatments can be very successful for some patients but not for others. This is changing with the emergence of precision medicine, an innovative approach to disease prevention and treatment that takes into account individual differences in people’s genes, environments, and lifestyles. Precision medicine gives clinicians tools to better understand the complex mechanisms underlying a patient’s health, disease, or condition, and to better predict which treatments will be most effective.

Advances in precision medicine have already led to powerful new discoveries and several new treatments that are tailored to specific characteristics of individuals, such as a person’s genetic makeup, or the genetic profile of an individual’s tumor. This is leading to a transformation in the way we can treat diseases such as cancer. Patients with breast, lung, and colorectal cancers, as well as melanomas and leukemias, for instance, routinely undergo molecular testing as part of patient White House press release, January 30, 2015.

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care, enabling physicians to select treatments that improve chances of survival and reduce exposure to adverse effects.

The potential for precision medicine to improve care and speed the development of new treatments has only just begun to be tapped. Translating initial successes to a larger scale will require a coordinated and sustained national effort. Through collaborative public and private efforts, the Precision Medicine Initiative will leverage advances in genomics, emerging methods for managing and analyzing large data sets while protecting privacy, and health information technology to accelerate biomedical discoveries. The Initiative will also engage a million or more Americans to volunteer to contribute their health data to improve health outcomes, fuel the development of new treatments, and catalyze a new era of data-based and more precise medical treatment.

Key Investments to Launch the Precision Medicine Initiative Complementing robust investments to broadly support research, development, and innovation, the President’s 2016 Budget will provide a $215 million investment for the National Institutes of Health (NIH), together with the Food and Drug Administration (FDA), and the Office of the National Coordinator for Health Information Technology (ONC) to support this effort, including: • $130 million to NIH for development of a voluntary national research cohort of a million or more volunteers to propel our understanding of health and disease and set the foundation for a new way of doing research through engaged participants and open, responsible data sharing.

• $70 million to the National Cancer Institute (NCI), part of NIH, to scale up efforts to identify genomic drivers in cancer and apply that knowledge in the development of more effective approaches to cancer treatment.

• $10 million to FDA to acquire additional expertise and advance the development of high quality, curated databases to support the regulatory structure needed to advance innovation in precision medicine and protect public health.

• $5 million to ONC to support the development of interoperability standards and requirements that

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EDITORIAL

address privacy and enable secure exchange of data across systems.

Objectives of the Precision Medicine Initiative • More and better treatments for cancer: NCI will accelerate the design and testing of effective, tailored treatments for cancer by expanding genetically based clinical cancer trials, exploring fundamental aspects of cancer biology, and establishing a national “cancer knowledge network” that will generate and share new knowledge to fuel scientific discovery and guide treatment decisions.

• Creation of a voluntary national research cohort: NIH, in collaboration with other agencies and stakeholders, will launch a national, patient-powered research cohort of one million or more Americans who volunteer to participate in research.

Participants will be involved in the design of the Initiative and will have the opportunity to contribute diverse sources of data – including medical records; profiles of the patient’s genes, metabolites (chemical makeup), and microorganisms in and on the body; environmental and lifestyle data; patient-generated information; and personal device and sensor data. Privacy will be rigorously protected. This ambitious project will leverage existing research and clinical networks and build on innovative research models that enable patients to be active participants and partners. The cohort will be broadly accessible to qualified researchers and will have the potential to inspire scientists from multiple disciplines to join the effort and apply their creative thinking to generate new insights. The ONC will develop interoperability standards and requirements to ensure secure data exchange with patients’ consent, to empower patients and clinicians and advance individual, community, and population health.

• Commitment to protecting privacy: To ensure from the start that this Initiative adheres to rigorous privacy protections, the White House will launch a multi-stakeholder process with HHS and other Federal agencies to solicit input from patient groups, bioethicists, privacy, and civil liberties advocates, technologists, and other experts in order to identify and address any legal and technical issues related to the privacy and security of

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data in the context of precision medicine.

• Regulatory modernization: The Initiative will include reviewing the current regulatory landscape to determine whether changes are needed to support the development of this new research and care model, including its critical privacy and participant protection framework. As part of this effort, the FDA will develop a new approach for evaluating Next Generation Sequencing technologies – tests that rapidly sequence large segments of a person’s DNA, or even their entire genome. The new approach will facilitate the generation of knowledge about which genetic changes are important to patient care and foster innovation in genetic sequencing technology, while ensuring that the tests are accurate and reliable.

The Initiative will include reviewing the current regulatory landscape to determine whether changes are needed to support the development of this new research and care model, including its critical privacy and participant protection framework.

• Public-private partnerships: The Obama Administration will forge strong partnerships with existing research cohorts, patient groups, and the private sector to develop the infrastructure that will be needed to expand cancer genomics, and to launch a voluntary million-person cohort. The Administration will call on academic medical centers, researchers, foundations, privacy experts, medical ethicists, and medical product innovators to lay the foundation for this effort, including developing new approaches to patient participation and empowerment. The Administration will carefully consider and develop an approach to precision medicine, including appropriate regulatory frameworks, that ensures consumers have access to their own health data – and to the applications and services that can safely and accurately analyze it – so that in addition to treating disease, we can empower individuals and families to invest in and manage their health. u

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THE LAST WORD EDITORIAL

To Regulate or Not to Regulate LaboratoryDeveloped Tests, That Is the Question Edward Abrahams, PhD President Personalized Medicine Coalition

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o issue in personalized medicine has drawn more attention during the past 10 years than how laboratory-developed tests (LDTs) should be regulated, nor has any other so divided proponents of personalized medicine more than competing opinions on how best to protect the public’s health while encouraging innovation in diagEdward nostics. With the exception of a guidance to Abrahams, PhD regulate companion diagnostics, little progress has been made to provide clarity for the field since the first guidance to regulate in vitro diagnostic multivariate assays, increasingly common molecular tests that produce a diagnostic or predictive index, was issued in 2005 and later withdrawn.

The divisions in the community were on full display at an FDA public workshop on January 8-9, 2015, regarding the agency’s proposed framework, which was issued late last year and is presently under review. Opposing sides made their arguments and outlined their concerns.

The opposing perspectives are summarized neatly in back-to-back opinion pieces JAMA published online on January 5, 2015. Arguing that the FDA should regulate LDTs, Joshua Sharfstein, MD, secretary of the Maryland Department of Health and Mental Hygiene and former health policy advisor to Congressman Henry Waxman, contends that the current state of affairs, in which laboratories are regulated but not the tests they produce, poses a flagrant risk to public health. He writes, “A patient travels by an ambulance that is regulated, to a hospital that is regulated, for care using medicines that are regulated. Yet today, that same patient’s life or death could hinge on whether a single, unregulated diagnostic test result is meaningful.”

Arguing that the proposed LDT guidelines threaten the “emergence of genomic medicine,” James P. Evans, MD, PhD, and Michael S. Watson, PhD, medical geneticists at the University of North Carolina and the American College of Medical Genetics and Genomics, respectively, argue that the FDA’s regulatory framework, despite its good intentions, “could result in the closure of many laboratories, undermine innovation, and potentially limit patient choice,” if for no other reason than the FDA does not have the capacity to carry out its plans to regulate the tests that would come under its purview.

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The Personalized Medicine Coalition (PMC) was also invited to participate in the workshop and will have presented formal views to the FDA at the end of January.

Because PMC does not represent a single interest group or particular business model, and because the coalition listens to all the points of view in the continuing conversation about regulating LDTs and has incorporated them into our recommendations, it has developed a position that we believe can help move the field forward.

As Amy Miller, PMC executive vice president, told the workshop, “While some of our members actively oppose FDA’s regulation of lab tests, stating that device regulation was not designed to fit laboratory medicine, and some of our members actively support it and want the framework implemented as quickly as possible, arguing that many important tests are now unregulated, the coalition is committed to improving this framework so that personalized medicine can advance and improve the quality of patient care, thus reaping system cost saving.”

Based on our extensive work with PMC members last year, PMC, she said, believes that FDA’s proposed new framework is a “good start,” but unfortunately omits 2 critical components: an outline of LDT risk classification and clarification on the harmonization between the current program for laboratory inspections administered by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Amendments (CLIA) and FDA’s manufacturing regulations. In short, the proposed framework does not diminish the uncertainty in the field in a way that would enable it to move forward.

Miller also told the workshop that PMC recommends releasing the 2 guidances in draft before finalizing the framework, giving both the agency and the community time to fill in the blanks regarding the important issues of risk classification and FDA-CLIA harmonization before superimposing a new regulatory system on an emerging field.

Whereas we understand that the FDA is under pressure to finalize the LDT guidances and to assert its regulatory authority on the emergence of molecular medicine, PMC urges the agency “to take the time to get it right. Future investment in the field depends on clear, reasonable guidelines, which are in our power to develop now, not at some future date.” u

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ersonalized edicine in Oncology

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