TAP Vol 3 Issue 14 Supplement - Reports from Best of ASCO Annual Meeting '12 by Harborside Press LLC

VOLUME 3, ISSUE 14

SEPTEMBER 15, 2012

Editor-in-Chief, James O. Armitage, MD

ASCOPost.com

Reports from

Best of ASCO Annual Meeting ’12 ®

Inside this Supplement Coverage of more than 40 key abstracts on: •• Targeted Therapy in Lung Cancer •• Cytotoxic Chemotherapy for Breast Cancer •• Refining Treatment for HER2-positive Breast Cancer •• Optimal Use of Rituximab in Non-Hodgkin Lymphoma

Best of ASCO® Boston

•• ABVD vs BEACOPP in Hodgkin Lymphoma •• Carfilzomib in Relapsed/ Refractory Multiple Myeloma •• Improved Outcomes in Chronic Myeloid Leukemia •• Novel Agents in Lymphocytic Leukemia •• Update on Colorectal Cancer Treatment •• Continuous Androgen Deprivation in Metastatic Prostate Cancer •• Novel Drugs for Castrationresistant Prostate Cancer

Best of ASCO® San Diego

•• New Tyrosine Kinase Inhibitor for Renal Cell Carcinoma •• Expanding Armamentarium in Metastatic Melanoma

Visit ASCOPost.com for additional coverage from Best of ASCO® ‘12 Best of ASCO® Chicago

A Harborside Press® Publication

The ASCO Post | SEPTEMBER 15, 2012 | SUPPLEMENT

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Overview

Editorial Board James O. Armitage, MD Editor-in-Chief

Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

Associate Editors Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Douglas W. Blayney, MD Stanford University Medical Center

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center

Philip D. Bonomi, MD Rush University Medical Center

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

Richard Boxer, MD University of Miami

George W. Sledge, MD Indiana University

Harold J. Burstein, MD Dana-Farber Cancer Institute

Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins John A. Fracchia, MD New York Urological Associates Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University

International Editors Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel

Michael P. Link, MD Stanford University Medical Center

Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Harborside Press® Publishing Staff Conor Lynch, Executive Editor Conor@harborsidepress.com

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Contributing Writers: Caroline Helwick and Susan London Disclosure information available at ASCOPost.com

Best of ASCO® Meetings Offer Data, Commentary, and Interaction with the Experts By Caroline Helwick and Susan London

hree Best of ASCO meetings ports on other abstracts from the 2012 were held over the summer in ASCO Annual Meeting and Best of Chicago, Boston, and San Diego. ASCO ‘12, visit ASCOPost.com. The faculty distilled the most interesting and immediately applicable Keeping Oncologists Current data from the Program Chair 2012 ASCO AnKathy D. Miller, Best of ASCO offers a nual Meeting, MD, of Indiprovided personal ana University summary of the most perspectives, and School of Mediimportant abstracts of interacted with cine, Indianapothe year ... these are the attendees for an lis, described the educational exmeeting’s appeal. abstracts that perience that was “Best of ASCO every oncologist needs both valuable and offers a summary practical. to know to be up to date of the most imThis suppleportant abstracts and provide the best care of the year in a ment to The ASCO Post includes covconcise, smaller to their patients. erage of more than format designed — Kathy D. Miller, MD 40 abstracts preto maximize insented at the Best teraction. Reof ASCO® Annual Meeting ‘12. For recontinued on page 23 The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2012 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $235; Individual International: $290; Institutional Domestic: $290; Institutional International $370. Contact subscriptions@harborsidepress.com. Correspondence: Address general inquiries to Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. 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Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

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Thoracic Oncology New Therapies Capitalize on Lung Cancer’s Molecular Vulnerabilities By Susan London

Leora Horn, MD

esearch reported at this year’s ASCO Annual Meeting attests to the tremendous molecular diversity of non–small cell lung cancer (NSCLC) and the power of appropriately selected treatment, according to Leora Horn, MD, of Vanderbilt University Medical Center, who presented data on molecular findings and targeted therapies in lung cancer at the Best of ASCO San Diego meeting. “We are moving beSee Page 23 yond histology in selecting therapy for advanced NSCLC patients, and molecular testing should be considered in both squamous and nonsquamous NSCLC patients,” she recommended.

Squamous Cell NSCLC: Genetically Complex Investigators with The Cancer Genome Atlas Project undertook comprehensive genomic characterization of squamous cell NSCLC tumors from 178 patients.1 Results showed a high rate of somatic mutations in these tumors compared with other common

cancers, with only melanoma having a higher rate. The most commonly mutated genes included TP53, CDKN2A, and PTEN. Although changes in CDKN2A were associated with a loss of function in 72% of tumors, the mechanism of those changes (deletions, mutations, and methylations) differed across tumors. “This is important to know because although you are getting the same phenotype, it may not all be affected by the same mechanism,” Dr. Horn commented. “An analogous situation would be [for] epidermal growth factor receptor (EGFR)…, where we know patients with EGFR mutations respond to therapies with EGFR tyrosine kinase inhibitors, whereas patients with EGFR amplification may not.” Whole-genome sequencing showed an average of 165 somatic rearrangements per tumor, with marked heterogeneity between and within tumors. In addition, mRNA analysis identified four distinct phenotypes: primitive, classical, secretory, and basal. Potential therapeutic targets were identified for 11 genes showing alterations; in some cases, relevant agents are already in clinical trials. “From these data, we know that squamous cell lung cancer is a complex disease. There are multiple different pathways affected that could lead to rational and hopefully successful drug development,” Dr. Horn commented. “We need to consider not only the phenotype but also the method of gene alteration in selecting patients for clinical trials,” she added.

Should EGFR Tyrosine Kinase Inhibitors Be Continued Beyond Progression?

t is not yet clear if it is beneficial to continue first-line EGFR tyrosine kinase inhibitors in patients with EGFR-mutated lung cancer who experience progression and are started on chemotherapy, according to Dr. Horn. Two trials, one in Asia (looking at gefitinib [Iressa]) and one in North America (looking at erlotinib [Tarceva]), will be evaluating outcomes with this practice. “There has been compelling data published on the flare phenomenon in patients who are on a first-line EGFR [tyrosine kinase inhibitor] who stop therapy,” she noted. “Right now, there are no great data to say you should continue the EGFR [tyrosine kinase inhibitor] and add chemotherapy. What I tend to do is either tell the patients to stop the [tyrosine kinase inhibitor] the day they start chemotherapy, to sort of prevent that flare phenomenon, or I just let them finish out their bottle if they have got another 2 weeks’ supply, just let them continue on the [tyrosine kinase inhibitor] while you initiate chemotherapy.”

■

Molecular Testing Requires Planning at Time of Biopsy

“T

he molecular analysis of lung cancer patients is becoming more and more complex,” and clinicians therefore need to consider any additional tissue requirements upfront, Dr. Horn commented. At Vanderbilt University, testing for EGFR, KRAS, and eight other mutations is done using the Lung SnaPshot platform, she explained. If clinicians wish to also test for the ALK, ROS, and RET fusion genes, they must obtain additional tumor specimens for the fluorescence in situ hybridization (FISH) testing used to identify those molecular alterations. “So we need to make sure that we obtain adequate tissue at the time of biopsy to allow molecular testing to be performed,” Dr. Horn noted. However, new technologies are addressing this logistic challenge. “There are some other platforms, such as Foundation Medicine, where all of these mutations and rearrangements can be performed on a single specimen,” she said.

■

Afatinib in EGFR-mutated NSCLC Adenocarcinoma The randomized phase III LUX-Lung 3 trial compared afatinib—an oral tyrosine kinase inhibitor targeting EGFR, the HER2 receptor, and other ErbB

“First-line afatinib, although we should not be comparing across clinical trials, does not appear to be more effective than other EGFR [tyrosine kinase inhibitors],” Dr. Horn maintained. “What this means right now is

Key Lung Cancer Targeted Therapy Findings Presented at Best of ASCO® ‘12 •• Squamous cell lung cancer is a genetically complex disease with alterations of multiple pathways that could potentially be drug targets.

•• Afatinib is superior to chemotherapy as first-line therapy for EGFR-mutated lung adenocarcinoma, whereas docetaxel is superior to erlotinib as second-line therapy for advanced NSCLC with wild-type EGFR.

•• Crizotinib achieves response in more than half of patients with ROS1 rearrangement–positive NSCLC.

•• A novel anti–PD-1 antibody is active in NSCLC and produces durable responses in both squamous and nonsquamous tumors.

family receptors—with chemotherapy (pemetrexed [Alimta] and cisplatin) as first-line treatment in 345 patients with advanced lung adenocarcinoma harboring EGFR mutations.2 Compared with chemotherapy, afatinib conferred better median progression-free survival in the entire trial population (11.1 vs 6.9 months, HR = 0.58, P = .0004) and also in patients with the Del19 or L858R mutation of EGFR (13.6 vs 6.9 months, HR = 0.47, P < .0001). The objective response rate was also better with afatinib overall (56% vs 23%, P < .001) and in the patients with Del19 or L858R mutations (61% vs 22%, P �� < .0001). Afatinib was associated with higher rates of certain grade 3/4 adverse events, but generally better scores for quality of life.

that afatinib is another potential option … for first-line therapy for EGFR mutation–positive NSCLC,” she said. “The bigger issue in my mind is acquired resistance, as all of these patients have a progression-free survival of approximately 1 year,” she added. “So acquired resistance remains a major issue regardless of the EGFR [tyrosine kinase inhibitor] administered.”

Crizotinib in NSCLC with ROS1 Rearrangement In an expansion cohort of a phase I trial, investigators assessed the clinical activity of crizotinib (Xalkori)—an oral tyrosine kinase inhibitor targeting MET, ALK, and ROS—in 15 patients with advanced NSCLC harboring the continued on page 6

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For chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab

EXPAND YOUR OPTIONS A study population in need of additional treatment options1,2

median prior therapies

59%

of patients received prior rituximab

93%

of patients received prior alkylating agents

100%

of patients received prior fludarabine and alemtuzumab

The following serious adverse events (AEs) are discussed in greater detail below: Infusion reactions, cytopenias, progressive multifocal leukoencephalopathy, hepatitis B infection and reactivation, and intestinal obstruction.

To learn more, please visit www.ARZERRA.com. Indication ARZERRA (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The eﬀectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. Important Safety Information Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions. Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Interrupt infusion for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina, or other signs and symptoms of myocardial ischemia. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion. Infusion reactions occurred in 44% of patients on the day of the first infusion

(300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Cytopenias Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. Discontinue ARZERRA if PML is suspected and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture. Hepatitis B Infection and Reactivation Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can occur in patients following treatment with ARZERRA. Screen patients at high risk of HBV infection before initiation of ARZERRA. Closely monitor carriers

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When treated with ARZERRA monotherapy, 42% of patients with CLL refractory to fludarabine and alemtuzumab achieved a partial response1 Patients had received a median of 5 prior therapies

Overall response rate with ARZERRA 60 50 40

42%

The investigator-determined overall response rate in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) There were no complete responses The eﬀectiveness of ARZERRA is based on the demonstration of durable objective responses

30 20 10

FLUDARABINE AND ALEMTUZUMAB REFRACTORY (n=59)

of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. Insuﬃcient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis. Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected. Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. Most Common Adverse Reactions In the pivotal study (total population, n=154) the most common adverse reactions (≥10%, all grades) were neutropenia, followed by pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%).

No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA 6.5 months—median duration of response (95% CI: 5.8, 8.3)

Most Common Serious Adverse Reactions In the pivotal study (total population, n=154), where ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses, the most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Please see Brief Summary of Prescribing Information on adjacent pages. How Supplied: Available as 2 different single-use glass vials for dilution and intravenous administration. Each vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution. References: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011. 2. Tam CS, O’Brien S, Lerner S, et al. Leuk Lymph. 2007;48(10):1931-1939.

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Thoracic Oncology Lung Cancer continued from page 3

ROS1 gene rearrangement.3 The overall response rate was 57%, with some patients experiencing dramatic regression of their pulmonary infiltrates. “Right now, these data are very impressive but premature, with only 15 patients enrolled on the study,” Dr.

Horn commented. “We need to consider ROS1 testing in select NSCLC cohorts and consider enrolling these patients on the ongoing clinical trial.”

Docetaxel vs Erlotinib in EGFR Wild-type NSCLC The randomized phase III TAILOR trial compared erlotinib (Tarceva)

with docetaxel as second-line therapy in 219 patients with NSCLC having wild-type EGFR.4 Patients in the docetaxel group had a higher response rate (14% vs 2%, P = .004) and disease control rate (42% vs 23%, P = .007). Docetaxel also conferred better median progression-free survival (3.4 vs 2.4 months; HR = 0.69; P = .014), with

B:22.5” T:21” S:19”

similar benefit across patient subgroups. “Interestingly, KRAS did not seem to be a prognostic factor in second-line therapy in this cohort of NSCLC patients,” Dr. Horn observed. “Based on data from TAILOR and the IPASS trial, where patients who were EGFR wild-type did better when treated with chemotherapy, we know

Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients BRIEF SUMMARY BRIEF SUMMARY Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients Study 1 and inInjection, the Fludarabineand Alemtuzumab-Refractory Subset ARZERRA® (ofatumumab) Injection, for intravenous infusion ARZERRA®in(ofatumumab) in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset for intravenous infusion of Study 1 (MedDRA 9.0) of Study 1 (MedDRA 9.0) The following is a brief summary only; see full prescribing information The for following is a brief summary only; see full prescribing information for complete product information. complete product information. Fludarabine- and Fludarabine- and AlemtuzumabAlemtuzumabTotal Population Total Population 1 INDICATIONS AND USAGE 1 INDICATIONS AND USAGE Refractory (n = 154) of patients Refractory (n = 154) ARZERRA® (ofatumumab) is indicated for the treatment of patients ARZERRA® (ofatumumab) is indicated for the treatment (n = 59) with chronic lymphocytic leukemia (CLL) refractory to fludarabine and with chronic lymphocytic leukemia (CLL) refractory to fludarabine and (n = 59) Grade Grade All All Grade Allis basedGrade All alemtuzumab. The effectiveness of ARZERRA is based on the demonstration alemtuzumab. The effectiveness of ARZERRA on the demonstration ≥3Body System/ ≥3 Grades Grades ≥3 Grades Grades Body System/ of durable objective responses [see Clinical Studies (14) of full prescribing of durable objective responses [see Clinical Studies (14)≥3 of full prescribing information]. No data demonstrate an improvement in disease-related information].Adverse No dataEvent demonstrate an improvement in disease-related %Adverse Event % % % % % % % symptoms or increased survival with ARZERRA. symptoms or increased survival with ARZERRA. Infections and infestations Infections and infestations Pneumoniaa 23 14 25 15 Pneumoniaa 23 14 25 15 4 CONTRAINDICATIONS 4 CONTRAINDICATIONS Upper respiratory tract Upper respiratory tract None. None. 11 0 3 0 11 0 3 0 infection infection 5 WARNINGS AND PRECAUTIONS 5 WARNINGS AND PRECAUTIONS Bronchitis 11 <1 19 2 Bronchitis 11 <1 19 2 5.1 Infusion Reactions ARZERRA can cause serious infusion reactions5.1 Infusion Reactions b ARZERRA can cause serious infusion reactions 8 8 pulmonary 10edema, 10 Sepsisb 8 8 10 10 manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, manifesting as Sepsis bronchospasm, dyspnea, laryngeal edema, Nasopharyngitis 8 cardiac ischemia/infarction, 0 8 0 Nasopharyngitis 8 0 8 0 flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, flushing, hypertension, hypotension, syncope, Herpespain, zoster 6 1 7Infusion 2 Herpes zoster 6 1 7 2 back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion back pain, abdominal pyrexia, rash, urticaria, and angioedema. 2 Sinusitis 5 2 3 2 reactions occur more frequently with the first 2 infusions [see Adverse reactions occurSinusitis more frequently with the first52 infusions 2[see Adverse3 BloodPremedicate and lymphatic Blood and lymphatic Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and Reactions a (6.1)]. with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing system disorders system disorders information]. Interrupt infusion for infusion reactions of any severity. Institute information]. Interrupt of any Institute Anemiainfusion for infusion reactions 16 5 severity.17 8 Anemia 16 5 17 8 medical management for severe infusion reactions including angina ormedical other management severe infusion reactions including angina or other Psychiatricfor disorders Psychiatric disorders signs and symptoms of myocardial ischemia [see Dosage and Administration signs and symptoms of myocardial ischemia7[see Dosage Insomnia 0 and Administration 10 0 Insomnia 7 0 10 0 (2.3) of full prescribing information]. In a study of patients with moderate (2.3) of full prescribing information]. In a study of patients with moderate Nervous system disorders Nervous system disorders to severe chronic obstructive pulmonary disease, an indication for which to severe chronic obstructive pulmonary disease, an indication for which 6 0 bronchospasm 7 0 Headache 6 0 7 0 ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm ARZERRA is notHeadache approved, 2 of 5 patients developed Grade 3 Cardiovascular disorders Cardiovascular disorders during infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia during and infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia and Hypertension 0 0 Hypertension 5 0 8 0 thrombocytopenia can occur with ARZERRA. Monitor complete blood counts thrombocytopenia can occur with ARZERRA.5Monitor complete blood 8counts Hypotension 0 and increase 3 0 Hypotension 5 0 3 0 (CBC) and platelet counts at regular intervals during therapy, and increase (CBC) and platelet counts at regular intervals5 during therapy, <1 or 4 cytopenias. 7 2 Tachycardia 5 <1 7 2 the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. the frequency ofTachycardia monitoring in patients who 5develop Grade 3 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal Respiratory, thoracic, and Respiratory, thoracic, and leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. leukoencephalopathy including fatal PML, can occur with ARZERRA. mediastinal(PML), disorders mediastinal disorders Consider PML in any patient with new onset of or changes in pre-existing Consider PML inCough any patient with new onset19of or changes 0 in pre-existing 19 0 Cough 19 0 19 0 neurological signs or symptoms. Discontinue ARZERRA if PML is suspected, neurological signs or symptoms. Discontinue Dyspnea 14ARZERRA if2PML is suspected, 19 5 Dyspnea 14 2 19 5 and initiate evaluation for PML including consultation with a neurologist, and initiate Gastrointestinal evaluation for PML including consultation with a neurologist, disorders Gastrointestinal disorders brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation Diarrhea 18 0 19 0 Diarrhea 18 0 19 0 Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can Nausea 11 0 12 0 Nausea 11 0 12 0 occur in patients following treatment with ARZERRA. Screen patients atoccur high in patients following treatment with ARZERRA. Screen patients at high Skin and before subcutaneous Skin and subcutaneous risk of HBV infection before initiation of ARZERRA. Closely monitor carriers risk of HBV infection initiation of ARZERRA. Closely monitor carriers tissue disorders tissue disorders of hepatitis B for clinical and laboratory signs of active HBV infection during of hepatitis B for clinical and laboratory signs of active HBV infection during c 14 following <1 the last infusion 17 2 Rashc 14 <1 17 2 treatment with ARZERRA and for 6 to 12 months following the last infusion treatment with Rash ARZERRA and for 6 to 12 months Urticaria ARZERRA in patients 8 who develop 0 viral hepatitis 5 0 Urticaria 8 0 5 0 of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis of ARZERRA. or Discontinue or reactivation of viral hepatitis, and institute appropriate treatment. Insufficient reactivation of viral hepatitis, and institute appropriate treatment. Insufficient Hyperhidrosis 5 0 5 0 Hyperhidrosis 5 0 5 0 data exist regarding the safety of administration of ARZERRA in patientsdata withexist regarding the safety Musculoskeletal andof administration of ARZERRA in patients with Musculoskeletal and active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine connective tissue disorders connective tissue disorders can occur in patients receiving ARZERRA. Perform a diagnostic evaluation can occur in patients receiving ARZERRA. Perform a diagnostic evaluation Back pain 8 1 12 2 Back pain 8 1 12 2 if obstruction is suspected. 5.6 Immunizations The safety of immunization if obstruction isMuscle suspected. 5.6 Immunizations spasms 5 The safety 0 of immunization 3 0 Muscle spasms 5 0 3 0 with live viral vaccines during or following administration of ARZERRA has with live viral vaccines during or following administration of ARZERRA has General disorders and General disorders and not been studied. Do not administer live viral vaccines to patients who not havebeen studied. Do not administer live viral vaccines to patients who have administration site administration site recently received ARZERRA. The ability to generate an immune response recently to received ARZERRA. The ability to generate an immune response to conditions any vaccine following administration of ARZERRA has not been studied.any vaccineconditions following administration of ARZERRA has not been studied. Pyrexia 20 3 25 5 Pyrexia 20 3 25 5 6 ADVERSE REACTIONS 6 ADVERSE REACTIONS Fatigue 15 0 15 0 Fatigue 15 0 15 0 The following serious adverse reactions are discussed in greater detailThe in following serious reactions are 9discussed in<1greater detail Edemaadverse peripheral 8 in 2 Edema peripheral 9 <1 8 2 other sections of the labeling: other sections of the labeling: Chills 8 0 10 0 Chills 8 0 10 0 • Infusion Reactions [see Warnings and Precautions (5.1)] • InfusionaReactions [see Warnings and Precautions (5.1)] a Pneumonia includes pneumonia, lung infection, lobar pneumonia, and Pneumonia includes pneumonia, lung infection, lobar pneumonia, and • Cytopenias [see Warnings and Precautions (5.2)] • Cytopenias [see Warnings and Precautions (5.2)] bronchopneumonia. bronchopneumonia. • Progressive Multifocal Leukoencephalopathy [see Warnings and • Progressive Multifocal Leukoencephalopathy [see Warnings and b b Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. Precautions (5.3)] Precautions (5.3)] c c includes rash, macular, rash vesicular. Rash includes rash, rash macular, and rash vesicular. • Hepatitis B Reactivation [see Warnings and Precautions (5.4)] • HepatitisRash B Reactivation [seerash Warnings andand Precautions (5.4)] • Intestinal Obstruction [see Warnings and Precautions (5.5)] • IntestinalInfusion Obstruction [see Warnings and Precautions Reactions: Infusion reactions occurred(5.5)] in 44% of patients on the Infusion Reactions: Infusion reactions occurred in 44% of patients on the The most common adverse reactions (≥10%) in Study 1 were neutropenia, The most common adverse reactions (≥10%)29% in Study 1 day of the first infusion (300 mg), on the were day ofneutropenia, the second infusion day of the first infusion (300 mg), 29% on the day of the second infusion pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, pneumonia,(2,000 mg), pyrexia, cough, diarrhea, anemia, fatigue, dyspnea,infusions. rash, Infections:(2,000 mg), and less frequently during subsequent A and less frequently during subsequent infusions. Infections: A nausea, bronchitis, and upper respiratory tract infections. The most common nausea, bronchitis, and upper respiratory tract infections. Theviral, mostorcommon total of 108 patients (70%) experienced bacterial, fungal infections. total of 108 patients (70%) experienced bacterial, viral, or fungal infections. serious adverse reactions in Study 1 were infections (including pneumonia serious adverse in Study 1 infections≥Grade 3 (includinginfections, pneumonia A totalreactions of 45 patients (29%)were experienced of which A19total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 and sepsis), neutropenia, and pyrexia. Infections were the most common and sepsis),(12%) neutropenia, andThe pyrexia. Infections were the most were fatal. proportion of fatal infections in common the fludarabine- and (12%) were fatal. The proportion of fatal infections in the fludarabine- and adverse reactions leading to drug discontinuation in Study 1. 6.1 Clinical adverse reactions leading to drug discontinuation in Study 1. 6.1 Clinical alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patientsalemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients Trials Experience Because clinical trials are conducted under widely varying Trials Experience Because clinical trials at arebaseline, conducted under developed widely varying with normal neutrophil counts 45 (42%) ≥Grade 3with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 conditions, adverse reaction rates observed in the clinical trials of a drug conditions,neutropenia. adverse reaction rates(18%) observed in the Grade 4 clinical trials of a drug Nineteen developed neutropenia. Some patients neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients cannot be directly compared to rates in the clinical trials of another drug cannot and be directly compared to rates in the neutropenia clinical trials>2 weeks of anotherindrug and experienced new onset Grade 4 duration. experienced new onset Grade 4 neutropenia >2 weeks in duration. may not reflect the rates observed in practice. The safety of monotherapy may not reflect the rates observed in practice. The for safety of monotherapy 6.2 Immunogenicity There is a potential immunogenicity with therapeutic 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic with ARZERRA was evaluated in 181 patients with relapsed or refractorywith ARZERRA was such evaluated in 181 patients with relapsed or refractory proteins as ofatumumab. Serum samples from patients with CLL inproteins such as ofatumumab. Serum samples from patients with CLL in CLL in 2 open-label, non-randomized, single-arm studies. In these studies, CLL in 2 open-label, non-randomized, single-arm immunosorbent studies. In theseassay studies, Study 1 were tested by enzyme-linked (ELISA) forStudy 1 were tested by enzyme-linked immunosorbent assay (ELISA) for ARZERRA was administered at 2,000 mg beginning with the second dose ARZERRA was administered at 2,000 mgduring beginning withthe the24-week second dose anti-ofatumumab antibodies and after treatment period. anti-ofatumumab antibodies during and after the 24-week treatment period. th for 11 doses (Study 1 [n = 154]) or 3 doses (Study 2 [n = 27]). The datafor 11 doses (Study 1 [n = 154]) 3 doses (Study 2 [n = 27]). The and datain 33 patients Results were negative or in 46 patients after the 8 infusion Results were negative in 46 patients after the 8th infusion and in 33 patients th described in Table 1 and other sections below are derived from 154 patients described in Table 1 and other sections below areassay derived fromare 154 patients after the 12 after infusion. Immunogenicity results highly dependent on the 12th infusion. Immunogenicity assay results are highly dependent on in Study 1. All patients received 2,000 mg weekly from the second dose in Study 1. several All patients received 2,000 mg weekly from second assay dose methodology, factors including assay sensitivity and the specificity, several factors including assay sensitivity and specificity, assay methodology, onward. Ninety percent of patients received at least 8 infusions of ARZERRA onward. Ninety percent of patients least 8 infusions of ARZERRA sample handling, timing ofreceived sample at collection, concomitant medications, and sample handling, timing of sample collection, concomitant medications, and and 55% received all 12 infusions. The median age was 63 years (range: and4155% received all disease. 12 infusions. The median was 63 years (range: of 41antibodies underlying underlying For these reasons,age comparison of incidence to disease. For these reasons, comparison of incidence of antibodies to to 86 years), 72% were male, and 97% were White. to 86 years), 72% were and 97%ofwere White. to other products may be misleading. ARZERRA withmale, the incidence antibodies ARZERRA with the incidence of antibodies to other products may be misleading.

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Thoracic Oncology that chemotherapy is preferred over EGFR [tyrosine kinase inhibitors] in patients with NSCLC who are EGFR wild-type,” she concluded.

Anti–PD-1 Antibody in Advanced NSCLC A phase I trial assessed the activity and safety of immune therapy with an

antibody to PD-1 (a protein that suppresses antitumor activity) in 296 patients with various tumor types, 122 of whom had advanced NSCLC.5 The trial did not identify a maximum tolerated dose, and there was no association between drug dose and the rate of adverse events. The rate of grade 3/4 drug-re-

7 DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with ARZERRA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or well-controlled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the recommended human dose of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use Clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA in patients with hepatic impairment have been conducted. 10 OVERDOSAGE No data are available regarding overdosage with ARZERRA.

Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared to the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared to control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared to the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological significance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals. 17 PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)] • Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Warnings and Precautions (5.2)] • Signs of infections including fever and cough [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)] • New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.3)] • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.4)] • New or worsening abdominal pain or nausea [see Warnings and Precautions (5.5)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring for blood counts [see Warnings and Precautions (5.2)] • Avoiding vaccination with live viral vaccines [see Warnings and Precautions (5.6)] Manufactured by: GLAXO GROUP LIMITED Greenford, Middlesex, UB6 0NN, United Kingdom U.S. Lic. 1809 Distributed by:

GlaxoSmithKline Research Triangle Park, NC 27709 ©2011, GlaxoSmithKline. All rights reserved. September 2011 ARZ:6BRS ©2011 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. AZA295R0 September 2011

ease regression. The 24-week rate of progression-free survival was 26%. “This agent is the first immune therapy drug with activity in NSCLC patients. The benefit appears to be durable and was seen in both squamous and nonsquamous NSCLC,” Dr. Horn commented. “The findings of this study support the importance of the PD-1 pathway in NSCLC across different histologies.” She noted that additional published data showed a correlation between expression of the ligand of PD-1 (PD-L1) on tumor cells and the response to the antibody.6 “PDL1 may turn out to be another marker where we can select patients who will benefit from therapy with either an anti–PD-1 antibody or an anti– PD-L1 antibody,” she proposed. “Based on these data, they have gone straight from phase I to phase�� III,” �� with two large randomized trials opening in lung cancer, Dr. Horn noted.

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Disclosure: Dr. Horn is an unpaid advisor for Astellas, Genentech, and OSI.

References 1. Govindan R, Hammerman PS, Hayes DH, et al: Comprehensive genomic characterization of squamous cell carcinoma of the lung. 2012 ASCO Annual Meeting. Abstract 7006. Presented June 4, 2012. 2. Yang JC-H, Schuler MH, Yamamoto N, et al: LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFRactivating mutations. 2012 ASCO Annual Meeting. Abstract LBA7500. Presented June 4, 2012. 3. Shaw AT, Camidge DR, Engelman JA, et al: Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. 2012 ASCO Annual Meeting. Abstract 7508. Presented June 2, 2012. 4. Garassino MC, Martelli O, Bettini A, et al: TAILOR: A phase III trial comparing erlotinib with docetaxel as the second-line treatment of NSCLC patients with wildtype (wt) EGFR. 2012 ASCO Annual Meeting. Abstract LBA7501. Presented June 4, 2012. 5. Brahmer JR, Horn L, Antonia S, et al: Clinical activity and safety of anti-PD1 (BMS-936558, MDX-1106) in patients with advanced non-small-cell lung cancer (NSCLC). 2012 ASCO Annual Meeting. Abstract 7509. Presented June 2, 2012. 6. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-2454, 2012.

B:15.125” T:14” S:12”

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the human dose of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies. 13.3 Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15 to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared to control values).

lated adverse events was 14% in patients overall and 8% in patients with NSCLC. The rate of grade�� 1/2 pneumonitis was 2% in patients overall and 3% in patients with NSCLC; three patients developing pneumonitis died. The overall response rate was 18% in patients with NSCLC, with some patients having dramatic dis-

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Breast Cancer Cytotoxic Chemotherapy for Breast Cancer: Are We Done Tweaking It? By Caroline Helwick

Steven J. Isakoff, MD, PhD

hile novel targeted agents may grab the headlines in the treatment of breast cancer, oncologists still debate the optimal delivery of conventional cytotoxic chemotherapy, still a vital component of treatment. At the Best of ASCO Boston meeting, Steven J. Isakoff, MD, PhD, of Massachusetts General Hospital in Boston, commented upon the new data in this field that can help guide everyday practice.

End of an Era of Cytotoxic Trials? National Surgical Adjuvant Breast and Bowel Project (NSABP) B-38 asked whether adding gemcitabine to a taxane-based adjuvant regimen could improve outcomes in patients with node-positive breast cancer, but the final analysis found no benefit. The addition of gemcitabine (G) to a dose-dense regimen of doxorubicin/cyclophosphamide (AC) followed by paclitaxel (P) was no better than AC→P alone or the standard docetaxel/doxorubicin/cyclophosphamide (TAC) regimen.1 The study enrolled 4,894 women with operable, node-positive breast cancer, randomly assigning them to (1) AC × 4 followed by paclitaxel × 4 every 2 weeks, (2) the same plus

gemcitabine given with the paclitaxel, or (3) TAC every 3 weeks × 6. Disease-free survival at 5 years was 82.2% with dose-dense AC→P, 80.6% with dose-dense AC→PG, and 80.1% with standard TAC. Overall survival was approximately 90% in all arms. However, the toxicity profiles, with more neuropathy and anemia observed on the dose-dense arms and more diarrhea and febrile neutropenia on TAC. “How do we move forward?” Dr. Isakoff asked. “As Dr. Kathy Miller noted during her discussion of this abstract at ASCO, it is unlikely that any third-generation regimen will prove superior, and there is something in these results for everyone. There are regional variations in treatment, and all are reasonable. Personal preferences may prevail, and that’s okay. My own choice is dose-dense AC→P. Patients finish treatment faster, and there is less febrile neutropenia.” Major improvements are unlikely with additional standard cytotoxics, or further modifications of dose and schedule, he added. “The era of large and broad adjuvant trials is over, and our focus should be on biologics and targeted therapy.”

Benefit of Maintenance Chemotherapy in Subsets In patients with metastatic breast cancer who respond to paclitaxel/ gemcitabine (PG), maintenance with the same regimen doubled the time to progression and improved overall survival vs observation in a phase III Korean Cancer Study Group (KCSG)-BR 0702/NCT00561119 study of 324 patients.2 Patients received six cycles of PG, and the re-

Key Findings in Breast Cancer Presented at Best of ASCO® ‘12 •• There is no additional benefit to adding gemcitabine to a taxane-based adjuvant regimen.

•• Subsets of metastatic breast cancer patients who respond to paclitaxel

plus gemcitabine can benefit from maintenance chemotherapy: those with hormone receptor–negative tumors, visceral disease, high tumor burden, young age (< 50 years), and premenopausal status.

•• Weekly paclitaxel plus bevacizumab yields better outcomes than weekly ixabepilone or weekly nab-paclitaxel plus bevacizumab.

•• Postchemotherapy expression of the proliferative Ki-67 marker in

the residual tumor is prognostic for disease-free survival; the highest proliferative expression is associated with worst outcome.

sponders were randomly assigned to observation or to continued treatment with the regimen. Certain subsets of patients were found to benefit from continued treatment. Maintenance PG chemotherapy after six cycles should be considered in patients with metastatic hormone receptor–negative tumors, visceral disease, high tumor burden, young age (<�� 50), and premenopausal status, the investigators concluded. From the time of randomization, median progression-free survival

The era of large and broad adjuvant trials is over, and our focus should be on biologics and targeted therapy. —Steven J. Isakoff, MD, PhD

was 3.8 months in the observation arm and 7.5 months in the maintenance arm, for a 27% reduction in risk (P �� =�� .026). Six-month progression-free survival was 36% vs 59.7% (P = .00023), respectively, and median overall survival was 28 vs 36.8 months, respectively (P = .048). While pointing out several methodologic issues with this study, Dr. Isakoff noted that the overall results are consistent with prior studies showing that longer duration of treatment has superior disease-free and overall survival. “The study provides additional data that maintenance was quite effective, but it came with a cost,” he said. “There was an increase in nearly all toxicities, including nausea, emesis, diarrhea, constipation, neutropenia, anemia, and neuropathy. However, using validated EORTC instruments, the investigators found no detriment on quality of life.”

Weekly Paclitaxel Holds Its Own Weekly paclitaxel proved superior to newer, more expensive microtubule agents in a comparison of weekly regimens plus bevacizumab (Avastin) for the treatment of metastatic breast cancer in the phase III

open-label Cancer and Leukemia Group B (CALGB) 40502/North Central Cancer Treatment Group (NCCTG) N063H trial of 799 chemotherapy-naive patients.3 Weekly ixabepilone (Ixempra) at 16 mg/m2 was significantly less effective than weekly paclitaxel at 90 mg/m2, and weekly nab-paclitaxel (Abraxane) at 150 mg/m2 was no better than weekly paclitaxel. Overall tolerability was also best with paclitaxel. The study closed after the second interim analysis, when ixabepilone and nab-paclitaxel had both crossed the futility boundary for superiority. The study concluded that at these doses and schedules, the newer agents offer no advantage but they do increase toxicity. At a median followup of 12 months, median progression-free survival was 10.6 months with weekly paclitaxel, 9.2 months with nab-paclitaxel, and 7.6 months with ixabepilone (nab-paclitaxel vs paclitaxel, HR = 1.19, P �� =�� .12; ixabepilone vs paclitaxel, HR 1.54, P < .0001). Overall survival was not significantly different among the arms, with approximately 50% of patients alive at 2 years, though it was numerically lowest with ixabepilone. Grade 3 or 4 hematologic and nonhematologic toxicities were lowest with weekly paclitaxel. “CALGB 40502 convincingly showed that not only is there no improvement with novel microtubule agents, but they performed worse. It is hard to know why,” Dr. Isakoff commented. “It is unlikely that this occurred by chance, or that activity for bevacizumab differs when paired with the different agents. Is there less potent microtubule inhibition with the newer agents? Preclinical studies suggest they are actually more potent. Were the drugs given on the wrong dose and schedule? Doses were based on data from previous trials, though ixabepilone given weekly is backed by less strong data,” he said. “The most likely explanation is that toxicity attenuated exposure to the drug,” he suggested. Disconcontinued on page 9

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Breast Cancer Refining Current Treatments and Looking Ahead in HER2-positive Breast Cancer By Caroline Helwick

n a study presented at the ASCO Plenary Session, trastuzumab emtansine (T-DM1), the antibody-drug conjugate linking trastuzumab (Herceptin) to a cytotoxic agent, improved progressionfree survival by 3.2 months, representing a 35% reduction in risk of progression in the phase III EMILIA trial.1

EMILIA Study Details EMILIA randomly assigned 991 HER2-positive patients who had locally advanced or metastatic breast cancer and who had previously received a taxane and trastuzumab. Patients received T-DM1 or capecitabine (Xeloda) plus lapatinib (Tykerb) every 3 weeks until progression. Patients experiencing disease progressoin on standard therapy were allowed to cross over to T-DM1. At the time of this presentation, patients receiving T-DM1 had a disease-free survival of 9.6 months, vs 6.4 months with capecitabine/lapatinib (P < .0001) (Fig. 1). “T-DM1 readily outpaced capecitabine/lapatininb. All subgroups had relatively comparable benefit,” noted Harold J. Burstein, MD, PhD,

Does Lapatinib Prevent CNS Metastases in HER2-positive Breast Cancer? By Susan London

apatinib has shown some efficacy against existing brain metastases in patients with HER2-positive breast cancer but not in preventing them in the first place, according to Hope S. Rugo, MD, Professor of Medicine and Director, Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center. In a trial comparing lapatinib (Tykerb)/capecitabine (Xeloda) vs capecitabine alone, the first site of progression was less frequently the brain in the group receiving the combination, she noted.1 “But over the course of following those patients for progression, there was an identical number of brain metastases in both arms.” And the MA.31 trial comparing trastuzumab (Herceptin) and lapatinib is tracking the incidence of brain metastases as a secondary endpoint.2 “So far, there has been absolutely no

difference,” she commented. “So at the present time, there would be no indication to use lapatinib for prevention of brain metastases, although clearly we have trials that indicate some response once you have existing brain metastases,” Dr. Rugo concluded. “We’ll get more information looking at the ALTTO trial,” which is comparing trastuzumab, sequential lapatinib, and trastuzumab, and the combination of lapatinib and trastuzumab in the adjuvant setting.3

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Disclosure: Dr. Rugo has received research funding from Abraxis BioScience, Bristol-Myers Squibb, and Roche/Genentech.

References 1. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006. 2. Gelmon K, Boyle F, Kaufman B, et al: Open-label phase III randomized controlled trial comparing taxane-

Hope S. Rugo, MD

based chemotherapy with lapatininb or trastuzumab as first-line therapy for women with HER2+ metastatic breast cancer: Interim analysis of NCIC CTG MA.31/ GSK EGF 108919. 2012 ASCO Annual Meeting. Abstract LBA671. Presented June 3, 2012. 3. ClinicalTrials.gov: ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study; BIG 2-06/N063D. Last updated August 23, 2012. Available at http://clinicaltrials. gov/ct2/show/NCT00490139. Accessed September 2, 2012.

continued on page 10

Cytoxic Chemotherapy for Breast Cancer continued from page 8

tinuation rates were higher with the newer regimens (approximately 45% vs 25% with paclitaxel), and 45% of patients receiving nab-paclitaxel had been dose-reduced by the third cycle.

Ki-67 Is Predictive and Prognostic Postchemotherapy expression of the proliferative Ki-67 marker in the residual tumor was prognostic for disease-free survival in a correlative analysis of the GeparTrio trial,4 which evaluated neoadjuvant response-guided TAC (docetaxel, doxorubicin, cyclophosphamide) regimens in 2,072 patients with operable or locally advanced breast cancer. The study found benefit for response-guided therapy primarily in the estrogen receptor–positive subgroup. Ki-67 was measured in 1,165 prechemotherapy core biopsies and

in 676 postchemotherapy surgical samples. Residual tumors with the highest proliferation expression (>�� 35% staining) had very poor outcomes, while those with the lowest (0%–15% staining) had better disease-free survival. The hazard ratios for patients with the highest Ki-67 expression were 1.64 for disease-free survival (P < .0001) and 1.82 for overall survival (P < .0001). Patients who achieved a pathologic complete response had the best outcomes overall, superior even to those with the lowest Ki-67 expression in the residual tumor. The same patterns were observed in hormone receptor–positive and – negative patients, but the curves were shifted downward in hormone receptor–negative patients, reflecting worse outcomes overall. “Centrally assessed post-treatment Ki-67 adds independent and additional prognostic information of the outcome after surgery,” Dr. Isakoff commented, “but in real practice, I think that heterogeneity

causes challenges.” There is no standard for reading Ki-67 in the clinic, many pathologists don’t report Ki67, there can be heterogeneity in the tumor bed, and there is no standard cut-off for Ki-67 expression levels, he explained. “But the study does show that the post-treatment Ki-67 fraction identifies a group at high risk for relapse, for whom we clearly need better treatments,” he added. “Studies are ongoing to determine how to manage patients with residual disease, and these correlative markers may be useful in them.”

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Disclosure: Dr. Isakoff is a consultant or advisor for Abbott Laboratories.

References 1. Swain SM, Tang G, Geyer CE, et al: NSABP B-38: definitive analysis of a randomized adjuvant trial comparing dose-dense AC→ paclitaxel plus gemcitabine with DD AC→P and with docetaxel, doxorubicin, and cyclophosphamide (TAC) in women with operable, node-positive breast cancer. ASCO

2012. Abstract LBA1000. Presented June 5, 2012. 2. Im YH, Park YH, Jung KH, et al: A phase III, multicenter, randomized trial of maintenance versus observation after achieving clinical responses in patients with metastatic breast cancer who received six cycles of gemcitabine plus paclitaxel as first-line chemotherapy. 2012 ASCO Annual Meeting. Abstract 1003. Presented June 5, 2012. 3. Rugo H, Barry WT, Moreno-Aspitia A, et al: CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly paclitaxel compared to weekly nanoparticle albumin bound nab-paclitaxel or ixabepilone +/- bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. 2012 ASCO Annual Meeting. Abstract CRA1002. Presented June 4, 2012. 4. Von Minckwitz G, Mueller B, Blohmer JU, et al: Prognostic and predictive impact of Ki-67 before and after neoadjuvant chemotherapy on pCR and survival: Results of the GeparTrio trial. 2012 ASCO Annual Meeting. Abstract 1023. Presented June 4, 2012.

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Breast Cancer

continued from page 9

of Dana-Farber Cancer Center, Boston, who presented the findings at the Best of ASCO Boston meeting. Median overall survival was not reached with TDM-1, and was 23.3 months with capecitabine/ lapatinib, for a 38% reduction in mortality risk that was not statistically significant. More than 65% of the T-DM1 recipients were alive at the time of analysis, compared to 47.5% of the capecitabine/lapatinib group. An equally striking difference was in tolerability. Dose reductions were required for only 16.3% of the T-DM1 arm, compared to 53.4% with capecitabine and 27.3% with lapatinib. Patient-reported outcomes

in the first-line metastatic setting and found trastuzumab to be superior to lapatinib, each given with a taxane (weekly paclitaxel or docetaxel every 3 weeks) until progression.2 In the study of 652 patients, median progression-free survival was 8.8 months with lapatinib vs 11.4 months with trastuzumab, indicating a 33% increased risk of progression with lapatinib (P = .01). In women with centrally confirmed HER2overexpressing tumors, the difference between the arms approached 5 months (P = .003), though overall survival differences have not been observed. Lapatinib therapy was associated with more adverse events than trastuzumab, most notably diarrhea, and more treatment discontinuations.

Key Findings in HER2-positive Breast Cancer Presented at Best of ASCO® ‘12 •• The novel antibody-drug conjugate T-DM1 delays progression by over 3 months in metastatic breast cancer

•• Trastuzumab is superior to lapatinib in the first-line metastatic setting, but the combination of trastuzumab plus lapatinib yields higher pathologic response rates in the neoadjuvant setting.

•• The widespread use of bisphosphonates to improve non–bone-related outcomes in breast cancer is not currently supported by data.

were also significantly better with T-DM1. “This is a remarkably well tolerated product, and that’s exciting,” Dr. Burstein said. “It lacks the typical side effects of chemotherapy because its small dose is mostly delivered selectively to the tumor site.” Because of its strong efficacy and minimal toxicity, “T-DM1 will become a standard second-line treatment in HER2-positive disease,” he predicted. Editors’ note: New data from the phase III EMILIA study were reported in a press release issued by Genentech on August 26 2012. These updated results showed that T-DM1 significantly improved overall survival in HER2positive metastatic breast cancer compared to the combination of lapatinib and capecitabine. See the September 15, 2012, issue of The ASCO Post (page 32) for more information, or visit ASCOPost.com.

Trastuzumab Superior to Lapatanib Meanwhile, the phase�� III Canadian MA.31/GSK EGF 108919 trial compared current anti-HER2 agents

Combined HER2 Blockade: Best Neoadjuvant Strategy? Five large trials have shown that trastuzumab plus lapatinib yields higher pathologic complete response rates than trastuzumab alone, and the most recent was presented at the ASCO Annual Meeting.3 National Surgical Adjuvant Breast and Bowel Project (NSABP) B-41 involved 529 patients who received four cycles of doxorubicin plus cyclophosphamide (AC) followed by weekly paclitaxel (P) plus either trastuzumab, lapatinib, or trastuzumab plus lapatinib prior to surgery. The pathologic complete response rate was 52.5% in the trastuzumab arm, 53.2% in the lapatinib arm, and 62% with trastuzumab plus lapatinib, for a trend favoring the combination (P = .095). By hormone receptor status, the combination yielded a numeric, though not a statistically significant, benefit over the single agents and was higher among hormone receptor–negative patients (73.0%) than hormone receptor–positive patients (55.6%), continued on page 11

Browsing the Anti-HER2 Options

“W

here do current findings leave us in terms of anti-HER2 therapy options?” asked Harold J. Burstein, MD, PhD, of DanaFarber Cancer Center, Boston, who moderated the Best of ASCO Boston meeting. New drugs are joining trastuzumab (Herceptin) and lapatinib (Tykerb), and there will be some juggling for position, though the FDA-indicated labeling is guiding their use at this point, he said. Harold J. Burstein, MD, PhD

New Options and Current Standards

In the first-line setting for metastatic disease, docetaxel/trastuzumab/ pertuzumab (Perjeta) was recently approved (weekly paclitaxel can be used instead of docetaxel), but Dr. Burstein has economic concerns with this regimen. The estimated wholesale cost of pertuzumab is $5,900 a month; when paired with trastuzumab at $4,500 a month, this means that a typical 18-month course of treatment exceeds $187,000. In the second-line and refractory settings, T-DM1 is expected to receive FDA approval. “Its side-effect profile and possible quality-of-life advantages will make it an appealing first-line option, but this will not be the labeled indication.” In the third and subsequent lines, chemotherapy plus trastuzumab or lapatinib plus capecitabine (Xeloda) remain the standards. Trials are examining whether ongoing pertuzumab treatment might be clinically valuable here. At least one early-phase trial has examined the triplet of T-DM1, pertuzumab, and paclitaxel in heavily pretreated patients, which Dr. Burstein called “the most expensive treatment regimen in all of medical oncology.” While it appears reasonably well tolerated, with a response rate of about 40% it seems no better than single-agent T-DM1, he noted.

Impact of ALLTO In the neoadjuvant setting, dual HER2 inhibition with trastuzumab plus lapatinib yields the highest pathologic complete response rates but has not been adopted in clinical practice. For one thing, lapatinib has not been shown to alter the natural history of the disease, an issue that is being studied in the adjusted Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALLTO) trial. Last fall, ALLTO discontinued the single-agent lapatinib arm due to lack of benefit, and is continuing to study single-agent trastuzumab, trastuzumab followed by lapatininb, and trastuzumab plus lapatinib. The results of ALLTO may change the way lapatinib will be used (or not used) moving forward, including its role in neoadjuvant treatment. Meanwhile, the next generation of neoadjuvant studies is being built around drugs other than lapatinib, he said.

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1.0

Proportion progression-free

HER2-positive Breast Cancer

0.8

IRC

Cap + Lap HR=0.650 (95% CI, 0.55, 0.77) T-DM1 P<0.0001

INV

Cap + Lap HR=0.658 (95% CI, 0.56, 0.77) T-DM1 P<0.0001

0.6

0.4

0.2 0.0

No. at risk by independent review: Cap + Lap 496 404 310 176

129

T-DM1

183

130

495

419

341

236

101

Time (mos)

Unstratified HR by independent review=0.66 (P<0.0001).

0 12

Fig. 1: Progression-free survival by independent review committee (IRC) and investigator review (INV) in EMILIA trial. Cap = capecitabine; Lap = lapatinib. Reprinted with permission from Blackwell et al.1

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Hematologic Oncology Which Rituximab-based Regimen Works Best in Non-Hodgkin Lymphoma? By Caroline Helwick

Michael E. Williams, MD

he treatment of non-Hodgkin lymphoma (NHL) patients has been recently informed by several important studies, which were discussed at the Best of ASCO Boston meeting by Michael E. Williams, MD, of the University of Virginia Cancer Center in Charlottesville.

Bendamustine Outperforms R-CHOP in NHL In a presentation at this year’s ASCO Annual Meeting Plenary Session, German investigators reported that in the phase�� III Study Group Indolent Lymphomas (StiL) NHL1 trial, the combination of bendamustine

HER2-positive Breast Cancer continued from page 10

which Dr. Burstein called an “exciting” result for HER2-positive, estrogen receptor–negative disease. When defined as absence of residual disease in both the breast and nodes, pathologic complete responses were achieved by 60.2% with the combination, 49.4% with trastuzumab, and 47.4% with lapatinib, for a strong trend favoring the combination (P = .056). “In B-41, trastuzumab plus lapatinib was better. Now we have five trials, including two NCI-supported studies, all showing the same result, yet no one is calling the combination an important advantage and no one is moving forward with this regimen,” he said. “Why? That’s a good question with no real answer.”

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Disclosure: Dr. Burstein reported no potential conflicts of interest.

References 1. Blackwell KL, Miles D, Gianni L, et al: Primary results from EMILIA, a phase 3 study of trastuzumab emtansine (TDM1) versus capecitabine and lapatinib in HER2-positive locally advanced or meta-

(Treanda) plus rituximab (Rituxan), or BR, more than doubled the median progression-free survival vs standard treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and proved more tolerable as well in patients with NHL.1 While B-R has been a recommended treatment option by the National Comprehensive Cancer Network since the initial study data were announced in 2009, many U.S. oncologists have not yet utilized the regimen. The updated StiL NHL1 results will likely change that, according to Dr. Williams, who was also the invited discussant of the study at the Annual Meeting. “The U.S. Intergroup trials have now adopted B-R as a backbone of the current clinical trials for indolent and mantle cell lymphomas,” he said. “I think this was among the most practice-changing abstracts at ASCO.”

StiL NHL1 Details The study randomly assigned 549 patients newly diagnosed with

Key Findings in Non-Hodgkin Lymphoma Presented at Best of ASCO® ‘12 •• Bendamustine plus rituximab doubled the time to disease progression,

compared with R-CHOP, and represents an acceptable front-line regimen in non-Hodgkin lymphoma.

•• In a subgroup analysis of the RESORT trial, nonfollicular lymphoma

subtypes benefited from maintenance rituximab, as compared with retreatment upon progression.

•• A comparison of three different rituximab-based regimens for follicular

lymphoma concluded that R-CHOP and R-FM are both superior to R-CVP in delaying treatment failure, and R-CHOP offered the best risk/benefit ratio.

stage III or IV indolent or mantle cell NHL to standard R-CHOP or B-R. After a median follow-up of 45 months, median progression-free survival was 69.5 months with B-R vs 31.2 months with R-CHOP, a 42% reduction in the risk of progression (P = .0000148). Benefit was seen in all subgroups except marginal zone lymphoma, where progression-free survival was comparable between the arms. Overall survival for all patients, however, was similar at 5 years: 80.1% with B-R

and 77.8% with R-CHOP. B-R was associated with significantly less toxicity, with only skin toxicity being more common with this regimen. Dr. Williams pointed out that See Page 23 bendamustine was given at 90 mg/m2 in the study, whereas the FDA-approved dose is 120 mg/m2, a dose he considers too high. He also continued on page 12

A Tough Call: The T1a HER2-positive Tumor By Susan London

he optimal adjuvant management of T1a HER2-positive breast cancers is uncertain and requires an individualized approach, according to Hope S. Rugo, MD, Professor of Medicine and Director, Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center. “There is some controversial data looking at small HER2-positive tumors suggesting that the T1a tumors may have a very good prognosis, but that’s probably very much modified by ER [estrogen receptor] status,” she said. For the ER-negative group, “we don’t have any data on the benefits of static breast cancer previously treated with trastuzumab and a taxane. 2012 ASCO Annual Meeting. Abstract LBA1. Presented June 3, 2012. 2. Gelmon K, Boyle F, Kaufman B, et al: Open-label phase III randomized controlled trial comparing taxane-based

using trastuzumab [Herceptin] alone, and it may be that chemotherapy alone is sufficient, or no therapy,” Dr. Rugo commented. “You have to individualize your treatment choices based on the age of the patient and your level of concern. You have these anecdotes of a young patient with a 0.2-cm ER-negative, HER2-positive tumor who came back 18 months later with massive metastatic disease and was dead in months. So you don’t want to just dismiss it.… In a young patient, I usually do treat with a short course of something, even if they have a very small ER-negative, HER2-positive tumor. I have found that in my cyber-tumor boards that generally, my chemotherapy with lapatininb or trastuzumab as first-line therapy for women with HER2+ metastatic breast cancer: Interim analysis of NCIC CTG MA.31/ GSK EGF 108919. 2012 ASCO Annual Meeting. Abstract LBA671. Presented June 3, 2012.

colleagues do as well.” For the ER-positive group, “we don’t really know how to treat those patients either,” Dr. Rugo commented. “In ER-positive T1a tumors, I tend to use hormone therapy and not use any directed therapy.” Oncologists may occasionally want to consider obtaining an Oncotype DX recurrence score or Mammaprint score, for example, in a patient with relative contraindications to therapy. “There can be unusual situations where it might help direct you a little bit,” she said.

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Disclosure: Dr. Rugo has received research funding from Abraxis BioScience, BristolMyers Squibb, and Roche/Genentech.

3. Robidoux A, Tang G, Rastogi P, et al: Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: NSABP protocol B-41. 2012 ASCO Annual Meeting. Abstract LBA506. Presented June 3, 2012.

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Hematologic Oncology Rituximab in NHL continued from page 11

advocates giving the regimen every 4 weeks for most patients, not every 3, to avoid excessive hematologic toxicity. “StiL NHL1 establishes B-R as a front-line regimen for indolent B-cell NHL and non–transplant-eligible mantle cell lymphoma patients. It shows equivalent or better responses than R-CHOP and with less toxicity,” Dr. Williams noted. He acknowledged, however, that caveats include the following: the median progression-free survival of 31 months with R-CHOP appears somewhat short compared with some comparable trials, there are limited data as yet on the ability to collect stem cells after B-R, the detailed results have not been published in a peer-reviewed journal, and confirmatory data are needed. “B-R is not yet the standard of care,” he concluded, “but we can say that it is an active regimen. The study certainly supports the use of BR as a front-line treatment.”

Value of Maintenance in NHL Subtypes Eastern Cooperative Oncology Group (ECOG) 4402, the phase III RESORT trial, showed no benefit for maintenance rituximab (given every 3 months) vs retreatment upon progression in follicular lymphoma as presented by the study chair Brad Kahl, MD, at the 2011 ASH Annual Meeting,2 but a planned subgroup analysis showed that nonfollicular patients (n = 137) who responded to rituximab weekly times 4 rituximab induction therapy did fare better on maintenance.3 In the subgroup analysis presented at ASCO by Dr. Williams, a higher rate of response to rituximab induction was observed in patients with follicular lymphoma (70%) than in those with nonfollicular disease (39%, P < .001). By nonfollicular subtype, the responses rate was much higher for marginal zone lymphomas (51%) than for small lymphocytic lymphoma (22%). At a median follow-up of 4.3 years, the time to treatment failure was 3.74 years for maintenance rituximab vs 1.07 years for retreatment (P = .0002). At 3 years, 100% of the maintenance arm vs 70% of the retreatment arm remained free of the need for cytotoxic therapy, Dr. Williams reported.

Is Watch and Wait the Best Strategy for Indolent NHL in the Rituximab Era?

ata from the RESORT and its planned subanalysis can guide oncologists in optimizing treatment for indolent non-Hodgkin lymphoma (NHL) with low–tumor burden advanced-stage disease, according to Michael E. Williams, MD, of the University of Virginia Cancer Center in Charlottesville. The phase III RESORT trial showed no benefit for maintenance rituximab (one dose every 3 months indefinitely) in follicular lymphoma patients with indolent disease who responded to rituximab weekly times four vs a “watch and wait” strategy that re-treats upon progression. However, a recent subanalysis suggests that for nonfollicular subtypes, especially marginal zone lymphoma, maintenance may be beneficial. In the subanalysis, time to treatment failure was extended by more than 2 years with maintenance rituximab.

Guiding Treatment These findings are guiding Dr. William’s treatment approach. “For follicular lymphoma, we recommend “We found that maintenance rituximab performed much better for patients in these subgroups who respond to initial rituximab induction, but not in follicular lymphoma where a retreatment strategy is preferred based upon our data,” Dr. Williams said.

Advanced Follicular Lymphoma An Italian study comparing three different rituximab-based regimens concluded that R-CHOP and R-FM (rituximab, fludarabine, mitroxantrone) are both superior to R-CVP (rituximab, cyclophosphamide, vincristine, prednisone) in delaying treatment failure.4 RCHOP and R-FM showed similar antilymphoma activity, and R-CHOP and R-CVP were less toxic than R-FM. Therefore, “R-CHOP was associated with the best risk/benefit ratio,” Dr. Williams noted. Response rates were approximately 90% per arm, but progression-free survival at 3 years was 68% with R-CHOP, 63% with R-FM, and 52% with R-CVP. The efficacy of R-FM was diluted by the much higher rate of grade 3/4 neu-

retreatment upon progression for low–tumor burden disease; and we do not give maintenance therapy after rituximab induction therapy. The study showed that many patients go 3, 4, and even 5 years without progressive disease after four doses of rituximab,” he said. “For nonfollicular indolent dis-

lymphoma, the initial response rate to rituximab weekly times four is discouraging, he added. “There are other, more promising agents that should be evaluated in these patients.” Dr. Williams said the promising results with bendamustine have also affected his practice. “For older patients, we increasingly are using bendamus-

For follicular lymphoma, we recommend retreatment upon progression for low–tumor burden disease; we give rituximab weekly times four and we do not give maintenance therapy after rituximab induction therapy. —Michael E. Williams, MD

ease, responders—mostly those with have marginal zone lymphomas—maintenance rituximab is an acceptable strategy,” he continued, “but the numbers are small and need to be confirmed in additional studies.” Though maintenance was also more beneficial than retreatment in patients with small lymphocytic tropenia, exceeding 30% by the third of six planned cycles, compared with 20% with R-CHOP and 13% with RCVP. Secondary cancers and progressive disease were also more common with R-FM. “The take-home message is that RCHOP is more active than R-CVP, and there is no role for fludarabine-based treatment front-line in this disease. It is stem-cell depleting and may impair the ability to transplant patients, and certainly is more toxic,” Dr. Williams advised. It remains to be answered whether R-CVP might be equivalent to RCHOP if it is followed by rituximab maintenance, he added, “and it could be that bendamustine/rituximab may trump all of these regimens.”

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Disclosure: Dr. Williams has received research funding from Genentech and Cephalon and has served on advisory boards for Genentech.

References 1. Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment in patients with indolent and mantle cell lymphomas: Updated

tine/rituximab front-line. For follicular patients with high-volume disease who need a quick response, or for patients in whom we suspect or confirm transformed lymphoma, we still use R-CHOP and add 2 years of maintenance therapy for responding patients based on the recent PRIMA trial,” he said.

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results from the StiL NHL1 study. 2012 ASCO Annual Meeting. Abstract 3. Presented June 3, 2012. 2. Kahl BS, Hong F, Williams ME, et al: Results of Eastern Cooperative Oncology Group Protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. 2011 American Society of Hematology Annual Meeting. Abstract LBA6. Presented December 13, 2011. 3. Williams ME, Hong F, Kahl BS, et al: A subgroup analysis of small lymphocytic and marginal zone lymphomas in the Eastern Cooperative Oncology Group protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden indolent non-Hodgkin lymphoma. 2012 ASCO Annual Meeting. Abstract 8007. Presented June 2, 2012. 4. Federico M, Luminari S, Dondi A, et al: R-CVP versus R-CHOP versus R-FM as first-line therapy for advanced-stage follicular lymphoma: Final results of FOLL05 trial from the Fondazione Italiana Linfomi. 2012 ASCO Annual Meeting. Abstract 8006. Presented June 2, 2012.

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Hematologic Oncology ABVD and BEACOPP Yield Equivalent Survival in Hodgkin Lymphoma By Caroline Helwick

n the EORTC 20012 randomized phase�� III trial comparing eight cycles of ABVD vs eight cycles of BEACOPP, Hodgkin lymphoma patients achieved equivalent overall survival with either regimen, but BEACOPP was more toxic.1 “Our approach, and that of most U.S. centers, is to use ABVD,” Michael E. Williams, MD, of the University of Virginia Cancer Center in Charlottesville said at the Best of ASCO Boston meeting. “It See Page 23 is best to treat with full doses on schedule. You don’t need cytokine support, which may reduce the risk of bleomycin pulmonary toxicity, and you can treat through the neutropenia by using prophylactic antibiotics.”

Significant Risk Reduction at 4 Years The study compared an escalated BEACOPP 4+4 regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarba-

zine, prednisolone) to eight cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) without radiotherapy in 549 high-risk stage III-IV Hodgkin lymphoma patients. While

and 88%, respectively.2 “In this high-risk group, conventional dose escalation with BEACOPP 4+4 has better progressionfree survival than ABVD, yet it is

Key Findings in Hodgkin Lymphoma Presented at Best of ASCO® ‘12 •• In the EORTC 20012 phase III trial in Hodgkin lymphoma patients, eight

cycles of ABVD and eight cycles of BEACOPP achieved equivalent survival, but BEACOPP was more toxic.

costs, fertility issues, risk of relapse, risk of salvage treatment and immediate and late morbidities. “Both regimens are highly effective and can currently share the claim for the ‘current standard of care,’” Dr. Williams concluded. “In the future, we will utilize risk-adapted therapy based on interim PET results. This will allow us to tailor therapy so we don’t overtreat patients, yet maintain high cure rates by minimizing early and late toxicities.”

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Disclosure: Dr. Williams reported no potential conflicts of interest.

complete responses were observed in 83% of each arm, a highly significant difference in progression-free survival emerged at 4 years: 69.4% with ABVD vs 84.0% with BEACOPP, a 50% reduction in risk (P = .0003). Mortality risk was reduced by 29% with BEACOPP, but this was not statistically significant. Overall survival at 4 years was 86.7% with AVBD and 90.3% with BEACOPP (P = .208). This confirms the findings of a recent Italian study in which overall survival at 7 years was 89%

not good enough to improve overall survival,” he noted. Early treatment discontinuations were recorded for 13.9% of the BEACOPP arm vs 10.5% of the ABVD arm, and progression or relapse was observed in 7.7% vs 12.7%, respectively.

Both Highly Effective Regimens Additional considerations, he said, may guide physician and patient treatment decisions between the regimens: treatment burden and

References 1. Carde PP, Karrasch M, Fortpied C, et al: ABVD (8 cycles) versus BEACOPP (4 escalated cycles ≥ baseline) in stage III-IV high-risk Hodgkin lymphoma: First results of EORTC 20012 Intergroup randomized phase III clinical trial. 2012 ASCO Annual Meeting. Abstract 8002. Presented June 2, 2012. 2. Viviani S, Zinzani PL, Rambaldi A, et al: ABVD versus BEACOPP for Hodgkin’s lymphoma when highdose salvage is planned. N Engl J Med 365:203-212, 2011.

Will Carfilzomib Add Value to Multiple Myeloma Treatment? By Caroline Helwick

arfilzomib (Kyprolis), the nextgeneration proteasome inhibitor recently approved by the FDA for relapsed/refractory multiple myeloma, showed strong activity in the front-line setting when paired with lenalidomide (Revlimid) and low-dose dexamethasone (CRd).1 The study evaluated stringent complete responses in 53 newly diagnosed patients who received induction therapy with CRd and, in some cases, stem cell transplant. Patients continued CRd for cycles 9 to 24, and a few patients initiated maintenance therapy with lenalidomide at the last best tolerated dose.

improve with longer treatment, and M protein steadily decreased. Over 90% of the 22 patients who achieved at least a complete response had no evidence of minimal residual disease. Responses after extended treatment included at least a near-complete response in 67% of patients and a stringent complete response in 45%

Key Findings in Multiple Myeloma Presented at Best of ASCO® ‘12 •• Carfilzomib, the next-generation proteasome inhibitor recently approved

for relapsed/refractory multiple myeloma, showed strong activity in the front-line setting when paired with lenalidomide (Revlamid) and low-dose dexamethasone.

Major Findings At a median of 12 cycles, 98% of patients responded, including 81% with a very good partial response or better, 62% with a complete response, and 42% with a stringent complete response. There were no differences by disease stage or cytogenetics. Responses continued to

tients progressed. After extended treatment, patients continued to tolerate treatment well, with limited dose modifications. Peripheral neuropathy was observed in about 20% of patients after CRd induction, and persisted (grades 1 and 2) in only 11% during maintenance.

after four or more cycles (median of 13), and at least a near-complete response in 78% and stringent complete response in 61% after eight or more cycles (median of 16). Progressionfree survival was 97% at 12 months and 92% at 24 months. At a median follow-up of 13 months, only two pa-

Looking Ahead Michael E. Williams, MD, of the University of Virginia Cancer Center in Charlottesville, commented on the findings and their implications at the Best of ASCO Boston meeting. “The low risk of neuropathy with carfilzomib is encouraging, since this has

been a problematic issue with bortezomib [Velcade].” He predicted that carfilzomib will find a place in the triple-drug regimens that have not been See Page 23 standard front-line therapy and which have led to deep remissions and disease control, especially when coupled with maintenance therapy. “As we become able to control disease with regimens generating these durable remissions, I anticipate that over the next few years, fewer patients will be going to transplant early,” he said.

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Disclosure: Dr. William has received research funding from and been a consultant for Celgene and Onyx.

Reference 1. Jakubowiak AJ, Dytfeld D, Griffith KA, et al: A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 120:1801-1809, 2012.

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Hematologic Oncology New Agents Are Achieving Deeper Responses in CML By Caroline Helwick

Attaya Suvannasankha, MD

s tyrosinse kinase inhibitors become increasingly effective in treating chronic myeloid leukemia (CML), major molecular responses (≥�� 3-log �� reduction in BCR-ABL transcripts) are being achieved for a growing percentage of patients. “In the new era of tyrosinse kinase inhibitors, we are learning how to achieve better, deeper response durations,” said Attaya Suvannasankha, MD, of Indiana University School of Medicine, Indianapolis, who discussed recent data on the three currently availSee Page 23 able tyrosine kinase inhibitors and one on the horizon at the Best of ASCO Boston meeting.

DASISION 3-Year Data The DASISION phase III trial established that in newly diagnosed chronic phase CML patients, dasatinib (Sprycel) at 100 mg daily has superior efficacy over imatinib (Gleevec) at 400 mg daily and achieves faster, deeper responses by 3 months, which are known to improve outcomes. Major molecular responses were achieved by 68% receiving dasatinib and 55% receiving imatinib; the probability of achieving a major molecular response was 64% higher with dasatinib (P < .0001), and there

was less transformation to accelerated or blast phase with dasatinib.1 More importantly, response rates were deeper with dasatinib, as indicated by 4-log (MR4) and 4.5-log (MR4.5) reductions in BCR-ABL. At 3 years, the MR4 was 35% with dasatinib vs 22% with imatinib (P = .00635) and the MR4.5 was 22% vs 12% (P = .00069), respectively. In an exploratory analysis, deeper response at 3 months was associated with a higher probability of progression-free survival and overall survival at 3 years, and decreased transformation to accelerated phase or blast crisis. In the study, however, overall and progression-free survival remained similar, with approximately 92% of patients in each arm alive. Side effects were usually mild but differed between the arms, with dasatinib associated with more pleural effusion and imatinib associated with more superficial edema and gastrointestinal effects. Speaking to the issue of continuing on a drug or switching therapy, Dr. Suvannasankha described the 12-month follow-up of the ENESTcmr trial (Evaluating Nilotinib Efficacy and Safety in Clinical Trials—complete molecular response), which evaluated 207 CML patients achieving a complete cytogenetic response but not a molecular response, on imatinib (ie, remaining BCR-ABL–positive after 2 years). The study found that twice as many patients achieved deep molecular responses after switching to nilotinib (Tasigna) at 400 mg twice daily, vs staying on imatinib, 400 to 600 mg/d.2 Patients who switched also demonstrated improvements in MR4 and MR4.5 and were less likely to progress or transform.

Key Findings in CML Presented at Best of ASCO® ‘12 •• Three-year data from the DASISION trial establishes that in newly

diagnosed chronic phase CML patients, dasatinib at 100 mg daily has superior efficacy over imatinib at 400 mg daily and achieves faster, deeper responses by 3 months, which are known to improve outcomes.

•• The next-generation tyrosine kinase inhibitor ponatinib has robust efficacy in CML patients resistant to or intolerant of other tyrosine kinase inhibitors, and is especially active in patients with the T315I mutation.

•• In patients lacking a molecular response after 2 years of imatinib

treatment, switching to nilotinib doubles the chance of achieving a deep molecular response, vs remaining on imatinib.

Maximizing Tyrosine Kinase Inhibitor Therapy in CML

econd-generation tyrosine kinase inhibitors as initial therapy in chronic myeloid leukemia (CML) continue to prove their worth by demonstrating protection against disease progression and by producing increasingly “higher quality” remissions, said Attaya Suvannasankha, MD, of Indiana University School of Medicine, Indianapolis, at the Best of ASCO Boston meeting. “But the translation of this benefit—survival, ‘curative’ potential—is yet to be determined,” she added. Discussing the clinical implications of recent data, she sees the use of a second-generation tyrosine kinase inhibitor in the front-line setting “worthwhile,” as it is associated with “greater benefit, higher efficacy, and deeper responses” than imatinib and is essentially even more effective in patients with the T315I mutation. At this point, however, Dr. Suvannasankha still typically initiates treatment with imatinib. “We have long-term follow-up with imatinib, and it is well tolerated in most patients,” she explained.

Alternative Strategy Dr. Suvannasankha emphasized that her threshold for switching to a second-generation tyrosine kinase inhibitor is low, and when patients do not achieve a major molecular response by 3 months or, at the most, 6 months, or when they do not tolerate imatinib well, she starts them on nilotinib or dasatinib (selecting the agent according to toxicity profile). She does not advocate increasing the imatinib dose. “Switching to a second-generation tyrosine kinase inhibitor is an effective, alternative way to improve the quality of molecular remissions,” she said. She acknowledged, however, that front-line use of second-generation tyrosine kinase inhibitors is rational, but gains in progression-free and overall survival are not yet apparent, “and progression and deaths still occur.” Nevertheless, comparisons with imatinib consistently show the advantages of these agents in terms of depth of response, likelihood of response, and reduction in transformation rates. “The manifestation of these benefits may take more time,” she said. Looking ahead, Dr. Suvannasankha commented that ponatinib provides a “remarkable ability to salvage resistant disease, especially T315I patients, and its earlier use may prove even better, as was seen in the less treated T315I cohort in the trial.”

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Disclosure: Dr. Suvannasankha reported no potential conflicts of interest.

This means, according to Dr. Suvannasankha, “that after 1 or 2 years, if there is no major molecular response, you can assume the patient is unlikely to become more responsive. If you don’t see this response right away, there may not be an advantage to waiting.”

When Imatinib, Dasatinib, and Nilotinib Fail For patients whose disease progresses after therapy with first- and second-generation tyrosine kinase inhibitors, clinicians can expect to have a new treatment option: the thirdgeneration tyrosinse kinase inhibitor ponatinib. Ponatinib was designed to target not only native BCR-ABL but also its isoforms that carry mutations

conferring resistance to treatment with existing tyrosinse kinase inhibitors, including the T315I mutation for which no effective therapy currently exists. Ariad Pharmaceuticals filed for accelerated approval of the drug in August. Ponatinib showed robust efficacy in the 10-month follow-up of the phase II PACE trial, an open-label study of 499 patients with CML or Philadelphia chromosome–positive acute lymphoblastic leukemia who were resistant to or intolerant of nilotinib or dasatinib, or who had the T315I mutation.3 Major cytogenetic response was achieved by 54% of chronic phase patients, including 70% of patients with continued on page 15

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Hematologic Oncology Encouraging Data Presented for Monoclonal Antibodies and Novel Oral Agent in Lymphocytic Leukemias By Caroline Helwick

ovel agents may transform the outcomes of lymphocytic leukemias. In acute lymphocytic leukemia (ALL), encouraging data were presented for two monoclonal antibodies, and in See Page 23 chronic lymphocytic leukemia (CLL), a completely novel class of agents produced surprisingly robust results, said Attaya Suvannasankha, MD, of Indiana University School of Medicine, Indianapolis, at the Best of ASCO Boston meeting.

BiTE Antibody The anti-CD19 bi-specific T-cell engager (BiTE) antibody blinatumomab produced responses (complete remission or complete remission with partial hematologic recovery) in 72% of patients with relapsed/refractory B-precursor ALL in a phase II study of 36 patients.1 All but two responders achieved a molecular response. Median overall survival in this heavily pretreated population was 9.0 months, and the median duration of hematologic complete remission was 8.9 months. BiTE antibodies are designed to direct the body’s cell-destroying T cells against tumor cells, enabling T cells to recognize and attack tumor cells in much the same manner as naturally occurring T cells. Blinatumomab targets CD19, which is expressed by 100% of leukemia cells. Fully reversible central nervous system events leading to treatment interruptions were observed

Deeper Response in CML continued from page 14

the T315I mutation and 49% of refractory/intolerant patients. In the accelerated phase, the primary endpoint of major hematologic response was achieved by 58%, including 60% refractory/intolerant and 50% with the T315I mutation. In blast phase CML, a major hematologic response was reached by 34%, 35%, and 33%, respectively. Responses improved over time. The best responses were seen in patients who had received no more than

in six patients, including three with seizures and three with encephalopathy; all six patients continued treatment at a lower dose. A global phase II trial has been initiated.

Inotuzumab Ozogamicin Other investigators reported encouraging results with inotuzumab ozogamicin, an anti-CD22 monoclonal antibody conjugated to calecheamicin. In relapsed/refractory ALL, inotuzumab was associated with a 52% overall response rate, including

refractory ALL,” she said, “but the duration of response remains short. It’s possible these drugs could be used as a bridge to allogeneic stem cell transplant. Because of their limited side effects, patients can go on to tolerate transplant quite nicely.”

Novel Oral Agent for CLL In chronic lymphocytic leukemia (CLL), the Bruton’s tyrosine kinase inhibitor ibrutinib holds promise. The oral agent is the first drug designed to target Bruton’s tyrosine kinase, a pro-

Key Findings in Lymphocytic Leukemia Presented at Best of ASCO® ‘12 •• Single-agent activity is promising for two novel drugs in relapsed/ refractory acute lymphocytic leukemia.

•• The anti-CD19 bi-specific T-cell engager (BiTE) antibody blinatumomab

produced responses in 72% of patients and led to a median survival of 9 months.

•• The anti-CD22 monoclonal antibody inotuzumab ozogamycin produced

responses in 52% of patients and led to a median progression-free survival of 5 months.

11% complete responses, “which is very high for single-agent therapy,” Dr. Suvannasankha noted.2 Median progression-free survival is currently 5 months. A pivotal trial of weekly inotuzumab vs standard of care in relapsed/refractory ALL is planned, and the drug is currently being evaluated in combination with low-intensity chemotherapy in patients < 60 years of age. “These agents have impressive single-agent activity in relapsed/

tein that is critical for B-cell receptor signaling in B lymphocytes and essential for CLL cell survival and proliferation. Other such agents are in development. In a phase II study of 31 previously untreated patients, the overall response rate was 75%, including 10% complete and 65% partial responses with daily dosing. The progressionfree survival rate at 15 months was 96%, and all subgroups responded equally well. Response to the single agent included complete remissions

two tyrosine kinase inhibitors. “This was a highly resistant population, and only about 25% had achieved a major cytogenetic response on second-line therapy. We saw significant responses of about 54% across the board, whether in chronic phase or more advanced phases of the disease. In blast phase, whether mutated or not, response rates were about 34%. Also we saw many major molecular repsonses, which we do not see with the earliergeneration tyrosine kinase inhibitors,” she pointed out. “Importantly, the

T315I mutation cohort consistently shows higher response rates than the overall chronic phase population.”

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Disclosure: Dr. Suvannasankha reported no potential conflicts of interest.

References 1. Hochhaus A, Shah NP, Cortes JE, et al: Dasatinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: DASISION 3-year follow-up. 2012 ASCO Annual Meeting. Abstract 6504. Presented June 4, 2012. 2. Lipton JH, Hughes TP, Leber B, et

with no morphologic evidence of CLL. “[Bruton’s tyrosine kinase] is a promising new target for CLL, and so far with the [Bruton’s tyrosine kinase] inhibitors, a lack of resistance has been seen across all subgroups, including patients with the 17p deletion. This means that conventional prognostic factors may not be as relevant with these drugs,” Dr. Suvannasankha said. “Continuing daily dosing is well tolerated, allowing for extended treatment,” she added. “With the caveat that the follow-up is short and the long-term toxicity unknown, it is conceivable that for older or sicker patients this could be a nonchemotherapy treatment that gives long-term disease suppression, and for younger patients, we might be able to combine this with chemotherapy for curative potential.”

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Disclosure: Dr. Suvannasankha reported no potential conflicts of interest.

References 1. Topp M, Goekbuget N, Zugmaier G, et al: Effect of anti-CD19 BiTE blinatumomab on complete remission rate and overall survival in adult patients with relapsed/refractory B-precursor ALL. 2012 ASCO Annual Meeting. Abstract 6500. Presented June 4, 2012. 2. Jabbour E, O’Brien SM, Thomas DA, et al: Inotuzumab ozogamycin, a CD22 monoclonal antibody conjugated to calcecheamicin, given weekly, for refractoryrelapse acute lymphocytic leukemia. 2012 ASCO Annual Meeting. Abstract 6501. Presented June 4, 2012.

al: Switch to nilotinib versus continued imatinib in patients with chronic myeloid leukemia in chronic phase with detectable BCR-ABL after 2 or more years on imatinib: ENESTcmr 12-month follow-up. 2012 ASCO Annual Meeting. Abstract 6505. Presented June 4, 2012. 3. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al: PACE: A pivotal phase II trial of ponatinib in patients with CML and Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. 2012 ASCO Annual Meeting. Abstract 6503. Presented June 4, 2012.

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Gastrointestinal Cancer Evidence Is Changing Colorectal Cancer Treatment Landscape By Susan London

Michael Overman, MD

ey colorectal cancer studies presented at this year’s ASCO Annual Meeting are changing the treatment landscape in this disease, according to Michael Overman, MD, of The University of Texas MD Anderson Cancer Center, who reviewed the data at the Best of ASCO San Diego meeting. The mix included several studies of targeted agents likely to expand options for metastatic disease. It also included promising studies on prognostic markers in stage II/III disease, and a disappointing one on managing colorectal cancer liver metastases.

Bevacizumab Continued Beyond Progression The randomized phase III TML study assessed continuation of bevacizumab (Avastin)—an inhibitor of vascular endothelial growth factor (VEGF)—with new, second-line chemotherapy beyond first progression in 814 patients with metastatic colorectal cancer.1 Patients who continued bevacizumab had better progression-

free survival (5.7 vs 4.1 months, HR = 0.67, P �� <�� .0001) and overall survival (11.2 vs 9.8 months, HR = .83, P = .0211). Adverse events were not increased with continuation. “I do think that the FDA will likely have a label change for bevacizumab based on these data,” Dr. Overman predicted. “At present, the label says that bevacizumab is approved for first- or second-line treatment.… I think this will probably change, and it will be firstand second-line use going forward.”

Novel Targeted Agents Present Mixed Picture The randomized phase III VELOUR trial tested addition of zivaflibercept (Zaltrap)—a fusion protein just approved by the FDA that binds VEGF-A, VEGF-B, and placental growth factor—to FOLFIRI (leucovorin, fluorouracil [5-FU], irinotecan) in 1,226 patients with metastatic colorectal cancer after failure of an oxaliplatin regimen.2 The investigators found improved overall survival with aflibercept vs placebo (13.5 vs 12.1 months, HR = 0.82, P = .003). Only 28% of patients had previously received bevacizumab. “Though similar efficacy was seen in that subgroup, the study was not powered to answer that question within this subgroup,” Dr. Overman commented. Some chemotherapyrelated adverse events were increased with added aflibercept.

Progression-free Survival Curve for Regorafenib Hints at Subgroup Effect

n all likelihood, only a subset of patients given regorafenib derive benefit, as suggested by the progression-free survival curve seen in the CORRECT trial, according to Dr. Overman. “This is a very interesting curve. The medians don’t really capture the difference.… If you look more at the area of separation between the two, that’s captured better with a hazard ratio—big difference,” he noted. “This curve is … reminiscent of another curve that we’ve seen before. That other curve is related to the experience we have had with anti-EGFR antibodies. This is actually a curve pulled from panitumumab [Vectibix] vs best supportive care prior to any knowledge about KRAS. And this shape of the curve is a subset effect,” he explained, whereby patients with wild-type KRAS benefit, but patients with mutant KRAS do not. “This is the same thing we are seeing with regorafenib—likely a population that is getting no benefit and a population that is getting benefit,” Dr. Overman asserted. “One of the problems we have right now is we have no way to determine what that population is. So that’s a very interesting area for us to explore and try to sort out.”

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Key Findings in Colorectal Cancer Presented at Best of ASCO® ‘12 •• Continuing bevacizumab (Avastin) beyond progression on first-line chemotherapy improves outcomes.

•• Ziv-aflibercept added to chemotherapy, and regorafenib as a single agent are both efficacious in metastatic colorectal cancer. Perifosine added to chemotherapy is not.

•• Adding erlotinib to bevacizumab maintenance after first-line therapy prolongs progression-free survival.

•• Perioperative chemotherapy for potentially resectable liver metastases of colorectal cancer does not improve overall survival.

•• Oncotype DX and ColoPrint are valid prognostic indicators in patients with resected stage II disease.

“With the caveats of a cross-trial comparison, my sense is that aflibercept activity is similar to bevacizumab, but I do think the toxicities are more pronounced,” he said. “My question would be, what is the role of aflibercept in clinical practice? With the TML data, I think it’s uncertain. Clearly the TML findings actually apply better to the population that we see here—the majority of the patients in the front line receive bevacizumab in the United States.” The phase III CORRECT trial randomly assigned 760 patients with progressive metastatic colorectal cancer despite standard therapy (including bevacizumab) 1:2 to placebo or regorafenib—an oral tyrosine kinase inhibitor with VEGFR2 and other targets.3 Regorafenib yielded better median progression-free survival (1.9 vs 1.7 months, HR = 0.49, P < .000001) and overall survival (6.4 vs 5.0 months, HR = 0.77, P = .005) (see sidebar, “Progression-free Survival Curve for Regorafenib Hints at Subgroup Effect”). However, the response rate was merely 1%, Dr. Overman noted. “This agent does not give you responses. If you have a patient who has symptomatic pain from a metastatic site, you should palliate that prior to giving regorafenib.” Progression-free survival was similar across subgroups. Certain adverse events were more common with regorafenib, but health-related quality of life did not differ. “I think this will become a new standard of care for chemorefractory metastatic colorectal cancer,” he predicted. “It has not been approved

at present, though it is undergoing FDA review.” The phase III X-PECT trial randomly assigned 468 patients with refractory metastatic disease to placebo or perifosine—which inhibits the PI3K-Akt/PKB pathway and interrupts signal transduction at the cell membrane—each combined with capecitabine (Xeloda).4 The investigators found no significant improvement in progression-free survival or overall survival, which Dr. Overman speculated was related to issues arising in the transition from the earlier phase II trial to the phase III trial. Summing up, he said, “I think we will be having new indications and drugs come into play. The benefits are modest,” at about 1.5 months’ gain in overall survival, “though real. These See Page 23 benefits are probably going to be very expensive.… We desperately need biomarkers to guide optimal use of these agents.”

Adding Erlotinib to Maintenance The randomized phase III DREAM (OPTIMOX3) trial tested bevacizumab with vs without erlotinib (Tarceva)—an epidermal growth factor receptor (EGFR) inhibitor—as maintenance therapy after bevacizumab-containing firstline chemotherapy in 446 patients with metastatic colorectal cancer.5 Addition of erlotinib improved progression-free survival (5.75 vs 4.57 months, HR = 0.73, P = .005).

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Gastrointestinal Cancer However, “for practice, I don’t think [this trial] is applicable,” Dr. Overman commented. “It’s thoughtprovoking and interesting and surprising,” given previous studies. “But there are a lot of unanswered questions here.” For example, there was no KRAS mutation analysis, and some previous studies have found that combined VEGFR and EGFR inhibition, at least with chemotherapy, is harmful. “The maintenance arm was nonstandardized—fluoropyrimidines are the standard maintenance therapy for colorectal cancer,” Dr. Overman added. “I do not believe this study changes that in any regard.”

Perioperative Chemotherapy for Liver Metastases Investigators reported long-term survival results in the European Organisation for Research and Treatment of Cancer (EORTC) 40983 trial, which evaluated perioperative chemotherapy for liver metastases of colorectal cancer.6 A total of 364 patients with up to four potentially resectable liver metastases were randomly assigned to surgery or to FOLFOX4 (leucovorin, 5-FU, oxaliplatin), surgery, and more FOLFOX4. Previously reported results showed better progression-free survival with chemotherapy (35% vs 28%, HR = 0.79, P = .058). But updated results, after a median follow-up of 8.5 years, showed no significant difference in overall survival. “This is kind of a sobering study. What it means for us is that we are going to have to go back and really rethink what we are doing here a little bit,” Dr. Overman commented. “I think the benefit of perioperative chemotherapy in colorectal cancer liver metastases is less than perceived.”

New Tools for Postresection Prognostication In the first of a trio of validation studies, investigators validated the Oncotype DX colon cancer recurrence score in 892 patients from the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial with stage�� II or III disease treated with adjuvant 5FU/leucovorin alone or with additional oxaliplatin.7 The score performed well at predicting 5-year recurrence risk across patients dually stratified by stage and treatment arm (P < .001). “You get a relative benefit that

appears fairly similar across the board, but as your risk [rises], you get more absolute benefit. So could you find some low-risk patients who don’t get much added benefit from oxaliplatin? In some sense that’s possible,” Dr. Overman commented. “I don’t think this is really ready for us to be using.… But it’s kind of an interesting concept.” A second study validated the ColoPrint classifier in 227 patients with stage II colon cancer having T3 disease with microsatellite stability (see sidebar, “Is Microsatellite Instability Status Also Predictive in Stage II Disease?”).8 The 3-year recurrence-free survival was 92% in the low-risk group and 80% in the highrisk group (P = .02). “This is the intermediate group, the one for which we have kind of a challenge as far as what to do,” Dr. Overman observed. “This was statistically significant—more so than any clinical variables—and a fairly nice separation…” But ColoPrint requires frozen tissue, and “it’s kind of challenging right now to have this done.” “Oncotype DX and ColoPrint… have had nice validation done. And I think in context of other risk factors such as [microsatellite instability] and other kinds of classic highrisk factors, they can be used to help guide the discussion,” he said. “But they don’t trump all these other factors.” A third study validated microRNA-21, which is associated with multiple oncogenic processes, in 520 patients with stage II colon cancer.9 Higher microRNA-21 in relation to nuclear density predicted poorer cancer-specific survival (HR = 1.41, P < .001). However, it was not as strong a predictor as T4 stage or perforation. “It appears to be an independent new marker,” Dr. Overman said. “How’s it going to help us? I’m not quite sure it’s ready to be incorporated or used right now … though it is interesting and novel in that it is a micro RNA.”

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Disclosure: Dr. Overman has received research support from Amgen, Roche, and Bristol-Myers Squibb; and is on the advisory board and lectures for SanofiAventis and Roche.

References 1. Arnold D, Andre T, Bennouna J, et al: Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic

Is Microsatellite Instability Status also Predictive in Stage II Disease?

“M

icrosatellite instability status is a validated prognostic marker in stage II colorectal cancer. It is the strongest prognostic marker we have in that group,” Dr. Overman commented. “The fact is that we should be getting this [test] consistently to help us make this discussion [of prognosis] easier.” Recent data further suggest that microsatellite instability status may also predict benefit from therapy or lack thereof. An initial report suggested that patients with microsatellite instability–high status (indicating deficient mismatch repair) and stage II or III disease universally do not derive progressionfree survival benefit from adjuvant fluorouracil (5FU) chemotherapy.1 However, an update of the same data set suggested that the issue is more complex, with variation according to the origin of the microsatellite instability–high status.2 Specifically, patients with germline origin (mainly younger patients with hereditary nonpolyposis colorectal cancer, a family history, and genetically driven microsatellite instability–high status) did appear to benefit. But patients with sporadic origin (mainly older patients with methylation of the MLH1 gene) did not. “So I think this predictive issue [for lack of 5-FU benefit] is a little more complex. It really appears to be limited to sporadic [microsatellite instability]–high status,” Dr. Overman concluded. “It would be nice to actually have some confirmatory data that give us a final answer.”

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Disclosure: Dr. Overman has received research support from Amgen, Roche, and BristolMyers Squibb; and is on the advisory board and lectures for Sanofi-Aventis and Roche.

References 1. Sargent DJ, Marsoni S, Monges G, et al: Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28:3219-3226, 2010. 2. Sinicrope FA, Foster NR, Thibodeau SN, et al: DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst 103:863-875, 2011. colorectal cancer (mCRC) previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study). 2012 ASCO Annual Meeting. Abstract CRA3503. Presented June 3, 2012. 2. Allegra CJ, Lakomy R, Tabernero J, et al: Effects of prior bevacizumab (B) use on outcomes from the VELOUR study: A phase III study of aflibercept (Afl) and FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin regimen. 2012 ASCO Annual Meeting. Abstract 3505. Presented June 3, 2012. 3. Van Cutsem E, Sobrero AF, Siena S, et al: Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC). 2012 ASCO Annual Meeting. Abstract 3502. Presented June 3, 2012. 4. Bendell JC, Ervin TJ, Senzer NN, et al: Results of the X-PECT study: A phase III randomized double-blind, placebo-controlled study of perifosine plus capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC). 2012 ASCO Annual Meeting. Abstract LBA3501. Presented June 3, 2012. 5. Tournigand C, Samson B, Scheithauer W, et al: Bevacizumab (Bev) with or without erlotinib as maintenance

therapy, following induction first-line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy and safety results of the International GERCOR DREAM phase III trial. 2012 ASCO Annual Meeting. Abstract LBA3500. Presented June 3, 2012. 6. Nordlinger B, Sorbye H, Glimelius B, et al: EORTC liver metastases intergroup randomized phase III study 40983: long-term survival results. 2012 ASCO Annual Meeting. Abstract 3508. Presented June 3, 2012. 7. O’Connell M, Lee M, Lopatin M, et al: Validation of the 12-gene colon cancer recurrence score (RS) in NSABP C07 as a predictor of recurrence in stage II and III colon cancer patients treated with 5FU/LV (FU) and 5FU/LV+oxaliplatin (FU+Ox). 2012 ASCO Annual Meeting. Abstract 3512. Presented June 1, 2012. 8. Salazar R, Tabernero J, Moreno V, et al: Validation of a genomic classifier (ColoPrint) for predicting outcome in the T3-MSS subgroup of stage II colon cancer patients. 2012 ASCO Annual Meeting. Abstract 3510. Presented June 1, 2012. 9. Kjaer-Frifeldt S, Hansen T, Nielsen BS, et al: The prognostic importance of miRNA-21 in stage II colon cancer: a population-based study. 2012 ASCO Annual Meeting. Abstract 3513. Presented June 1, 2012.

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Genitourinary Oncology Continuous Androgen Deprivation Remains Standard of Care in Newly Diagnosed Metastatic Prostate Cancer But not without fierce debate By Caroline Helwick

ontinuous androgen deprivation therapy remains the standard of care for newly diagnosed hormone-sensitive metastatic prostate cancer, according to the phase III Southwest Oncology Group (SWOG) 9346 intergroup trial presented at this year’s ASCO Plenary Session.1

Study Rationale The large international trial of 3,040 men failed to show noninferiority of intermittent androgen deprivaSee Page 23 tion vs continuous androgen deprivation. Intermittent treatment has been proposed, and frequently employed, as possibly a more tolerable and equally effective approach in this patient population. The SWOG trial set out to test this

assumption. The subjects had newly diagnosed metastatic disease and prostate-specific antigen (PSA) levels

ping treatment at that point until a rise in PSA was observed or symptoms appeared—or to continuous therapy.

care in metastatic prostate cancer.

survival with intermittent androgen deprivation would be noninferior to continuous therapy if the upper 95% confidence boundary for the hazard ratio did not reach or include 1.2. However, this criterion was not met. The hazard ratio of 1.09 favored continuous therapy (9% more deaths occurred on the intermittent arm), and the upper boundary of the 95% confidence interval was 1.24, so the conclusion was that the two treatments could not be called equivalent.

≥ 5 ng/mL, for which they received hormone therapy (goserelin [Zoladex] and bicalutamide) for 7 months. Patients whose PSA fell to ≤ 4 ng/mL (ie, responders who were therefore particularly hormone-sensitive) were randomly assigned to either intermittent therapy—stop-

Reference 1. Hussain M, Tangen CM, Higano CS, et al: Intermittent versus continuous androgen deprivation in hormone sensitive metastatic prostate cancer patients: Results of S9346 (INT-0162), an international phase III trial. 2012 ASCO Annual Meeting. Abstract 4. Presented June 3, 2012.

Key Findings in Genitourinary Cancer Presented at Best of ASCO® ‘12 •• In newly diagnosed hormone-sensitive, metastatic prostate cancer, SWOG

9345 failed to show noninferiority of intermittent androgen deprivation vs continuous androgen deprivation.

•• Continuous androgen deprivation therapy should remain the standard of

Major Data At a median follow-up of 9.2 years, median overall survival was 5.1 years with intermittent androgen deprivation and 5.8 years with continuous therapy (HR = 1.09; 95% CI = 0.95– 1.24). The study design specified that

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How Should SWOG 9346 Be Interpreted?

he findings of Southwest Oncology Group (SWOG) 9346 sparked controversy at the ASCO Annual Meeting, and the interpretations were debated at an official postpresentation discussion. At the Best of ASCO Boston meeting, William K. Oh, MD, of Mount Sinai School of Medicine, New York—who also served as the invited discussant at ASCO—had a definite opinion. “My conclusion is that intermittent androgen deprivation therapy is inferior to continuous therapy,” he said. “Neither this, nor any randomized trial has ever shown a superior cancer outcome with intermittent therapy. This concept, based on preclinical studies from 20 years ago, must no longer be propagated.”

Why Treat Intermittently? The practice of intermittent androgen deprivation therapy has been widely adopted as a means of reducing adverse events, cost of treatment, and patient inconvenience. The practice is backed by preclinical data from

long ago, and also by nearly two dozen phase II trials and a few phase III trials that found this strategy safe and effective. However, most of the trials have not been designed appropriately, or powered adequately, to show survival effects, and certainly none has shown that intermittent therapy is superior to continuous, Dr. Oh said. Only the National Cancer Institute of Canada (NCIC) PR7 trial in nonmetastatic disease with rising prostate-specific antigen (PSA) after radiation therapy showed equivalent survival between continuous and intermittent therapy.

Questions Remain The findings of SWOG 9346, a “Herculean effort,” still leave questions unanswered, he said. For one thing, the study only randomly assigned the most androgen-sensitive patients, the “optimal” 64% of the initial cohort who responded to 7 months of induction. In addition, patients on the intermittent arm nevertheless spent about two-thirds

of their time on treatment, once the 7-month induction is figured in. That said, “How intermittent was this?” he asked. Prior studies have suggested that testosterone recovery can take at least 4 months, and some older patients never fully recovery. This particular study reported only a minimal impact on side effects with the intermittent approach, he said. But the real question, he continued, is this: “If there is a survival benefit, how much difference in quality of life would you need to see in order to justify a worse survival with intermittent therapy?” The study showed a 9% higher mortality risk with intermittent treatment.

Additional Concerns Dr. Oh further stated that he is bothered by the lack of a biologic rationale for the subgroup differences. “This finding is speculative and not necessarily intuitive, especially according to the definitions used in this study,” he said, adding that subgroup analyses must always be interpreted

with caution. Posing another widely raised question, Dr. Oh asked, “Is ‘not noninferior,’ which is the statistically correct term for what the study showed, equal to ‘inferior’? From a statistical point of view, they are not the same. But clinically, I question whether this makes a difference. To us as clinicians and to our patients, is a 9% difference in survival, which was over 8 months, meaningful to patients? In the castration-resistant setting, drugs are approved based on this. I think it might be meaningful to many patients.” The bottom line from this expert: “Intermittent androgen deprivation therapy is inferior to continuous therapy, but of course we should consider intermittent therapy for patients with a poor quality of life on continuous therapy. It’s not unreasonable to give these patients a break,” he said. “But the standard of care in metastatic prostate cancer should be continuous treatment.”

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Disclosure: Dr. Oh reported no potential conflicts of interest.

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Genitourinary Oncology Novel Drugs Enhance—but Complicate—Prostate Cancer Treatment By Caroline Helwick

William Oh, MD

hree emerging agents for castration-resistant prostate cancer are extending lives and defining their roles in the treatment scenario, according to William Oh, MD, of Mount Sinai School of Medicine, New York, who commented on new data at the Best of ASCO Boston meeting. “We are talking about androgen deprivation approaches and novel ways to treat bone metastases, and they are moving the needle on survival. The hazard ratios are remarkably similar,” he said. “It’s both a good time and a complex time, as we figure out how each drug will be used.”

Abiraterone in Chemonaive Patients Abiraterone acetate (Zytiga) is an androgen biosynthesis inhibitor that has shown a survival improvement when used after docetaxel. At this year’s ASCO Annual Meeting, the global phase III COU-AA-302 study also showed a survival benefit in chemotherapy-naive patients.1

8.3 months with placebo but had not been reached with abiraterone (HR = 0.43; P < .0001). Overall survival was 27.2 months with placebo and was not reached with abiraterone (HR = 0.75; P = .0097). [In this early analysis, the P value was not yet significant, but a strong trend was noted.] Abiraterone was also associated with significantly more objective responses and greater declines in prostate-specific antigen (PSA). “The time to all landmarks favored abiraterone,” Dr. Oh noted. The unblinding of the data at the second interim analysis and the subsequent allowance of crossovers was considered unwise by some, as it could compromise the final survival analysis, but Dr. Oh pointed to the strong trend toward a survival benefit and the clear clinical benefit in delaying disease progression. “I believe a drug like this should be available to patients in the prechemotherapy space, and I am hopeful that this one will be,” he concluded.

Enzalutamide’s Survival Benefit Enzalutamide (Xtandi), formerly MDV3100, is an oral androgen receptor signaling inhibitor that targets multiple steps in the androgen receptor signaling pathway. It inhibits binding of androgens to the androgen receptor, inhibits nuclear translocation of the androgen receptor, and inhibits the association of the androgen receptor with DNA.

Key Findings in Genitourinary Cancer Presented at Best of ASCO® ‘12 •• Several agents with different mechanisms of action are demonstrating

survival benefits in castration-resistant prostate cancer: abiraterone acetate (Zytiga), enzalutamide (Xtandi), and radium-223 chloride.

•• While initially studied in the postchemotherapy setting, promising results suggest these agents may ultimately be used earlier in the disease.

The 1,088 patients with metastatic castration-resistant disease were randomly assigned to abiraterone plus prednisone or placebo. Based on favorable findings for overall survival, radiographic progression-free survival, and secondary endpoints, the study was unblinded early at a median follow-up of 22 months. Progression-free survival was

The AFFIRM trial evaluated enzalutamide in the postchemotherapy setting in 1,199 patients with castration-resistant prostate cancer who had shown disease progression on docetaxel (median of eight cycles).2 In this heavily pretreated population, median overall survival was 18.4 months with enzalutamide vs 13.6 months with placebo

A Closer Look at Radium-223

illiam Oh, MD, of Mount Sinai School of Medicine, New York, posed some questions about the first-in-class alpha emitter radium-223 chlo-

ride. “Is this an anticancer drug or a bone-targeted drug?” he said. “With abiraterone acetate (Zytiga) and enzalutamide (Xtandi), we see declines in PSA—an anticancer biomarker we rely on—that were not shown with radium-223. We have also not seen evidence that this agent is killing cancer in the bone. So there is an important biologic question about how radium-223 is inducing a survival benefit.” Other questions, he continued, are who should receive it and when should it be administered? In the ALSYMPCA trial, all patients had bone metastases but no visceral metastases. In actual clinical practice, many patients have both. Should the drug be given to this group? If the drug is beneficial to patients deemed “unfit for chemotherapy,” as were included in this study, what is the definition of that? In determining the optimal time to give radium-223, there are lessons to be learned from other radiopharmaceuticals, he said. “We don’t routinely use the other radiopharmaceuticals, partly because they are not as good. But did they fail because they were used too late? We have learned that if you use radiopharmaceuticals earlier, they may have more value.”

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Disclosure: Dr. Oh is a consultant for Bayer, Janssen, Medivation, Millennium, Astellas, and Dendreon. He has received research funding from Millennium.

(HR = 0.631, P < .0001). Median progression-free survival was 8.3 vs 3.0 months (HR = 0.248, P < .0001). A > 50% drop in PSA was achieved by 54% of patients, and all secondary endpoints favored the treatment arm. Tumor response was “impressive” in soft tissues, including some complete responses, and side effects and quality of life were also better on treatment. Serious adverse events were comparable (28% with enzalutamide and 34% with placebo), but the occurrence of seizures in 0.6% of the treatment arm “needs to be watched,” he said. “Enzalutamide is associated with a startling survival benefit, even after progression on chemotherapy, and the toxicity is remarkably mild,” Dr. Oh concluded. “This is a stunning survival benefit in these very sick patients. It’s exciting to know that we can really move the needle on survival with well-tolerated drugs targeting the pathway we have known about for years,” he said. “The question now is whether we should use enzalutamide earlier,” he added. “I think we really should be moving these drugs up to the prechemotherapy setting—PREVAIL will evaluate enzalutamide in chemonaive patients—and use them with new

metastatic disease, as adjuvant treatment, and/or upon rising PSA after failure of surgery or radiation.”

First-in-class Alpha Emitter Radium-223 chloride (Alpharadin) is an investigational bone-targeting treatment that uses alpha particles to induce double-strand DNA breaks in adjuvant tumor cells. The short penetration of alpha emitters results in highly localized tumor cell killing and minimal damage to surrounding normal tissues. The phase III ALSYMPCA trial evaluated radium-223 in 921 patients with symptomatic castration-resistant prostate cancer and bone metastases who had received (or were considered unfit for) docetaxel.3 Patients were randomly assigned to six radium-223 injections or placebo, plus best standard of care. In the updated analysis, median overall survival was significantly improved with radium-223, from 11.3 months with placebo to 14.9 months (HR = 0.695, P = .00007). A survival benefit was observed whether or not patients had received docetaxel or bisphosphonates. Time to first skeletal-related event was also significantly delayed with radium-223, from a median of 6.7 months with continued on page 20

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Genitourinary Oncology Another Tyrosine Kinase Inhibitor Joins the Lineup in Renal Cell Carcinoma By Caroline Helwick

he novel tyrosine kinase inhibitor tivozanib was superior to sorafenib (Nexavar) for the treatment of advanced renal cell carcinoma in the phase III TIVO-1 trial.1 Tivozanib is a potent, selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, with a long half-life that is designed to optimize blockade while minimizing off-target toxicities. See Page 23 For first-line treatment, 517 patients were randomly assigned to receive tivozanib at 1.5 mg/d given 3 weeks on/1 week off or sorafenib at 400 mg twice daily given continuously. Median progressionfree survival was 11.9 months with tivozanib vs 9.1 months with sorafenib (HR = 0.797; P �� = .042). In most subgroups, tivozanib was favored, and about one-third of patients had a measurable response on the drug. Side effects mostly associated with tivozanib included hypertension, dys-

phonia, and back pain, while those most likely with sorafenib included diarrhea, hand-foot syndrome, and alopecia.

Many First-line Options William K. Oh, MD, of Mount Sinai School of Medicine, New York, commented on the findings at Best of ASCO Boston. He said tivozanib

NCCN, whereas sunitinib (Sutent) has a category 1 rating, is used more often, and may have been a more reliable comparator, he suggested. “The FDA approved the design, but the investigators picked the wimpiest guy in the room to pick a fight with,” he commented. Secondly, he noted that determining the best initial targeted therapy

Key Findings in Genitourinary Cancer Presented at Best of ASCO® ‘12 •• In advanced renal cell carcinoma, tivozanib is more efficacious than sorafenib and should be considered a first-line treatment option.

joins an already “crowded space” as a first-line option. No fewer than seven drugs are acceptable by the National Comprehensive Cancer Network (NCCN). Dr. Oh presented several concerns about the drug and the TIVO-1 trial, one being the choice of sorafenib as the reference standard. Sorafenib has a category 2A recommendation from the

in metastatic renal cell carcinoma is a challenge for clinicians. Efficacy, toxicity, cost, and patient acceptance are all relevant factors; given equivalent efficacy, many choices will be made based on toxicity, he said. Finally, he questioned whether tivozanib is much different from current first-line therapies. The results of an ongoing noninferiority study com-

continued from page 19

Putting It All Together Drugs with different mechanisms of action now populate the treatment landscape for prostate cancer. They all offer survival benefits in the 20% to 40% range, with P values that

Moving Forward “What we really need in metastatic renal cell carcinoma is an understanding of tyrosine kinase inhibitor resistance,” Dr. Oh concluded. “No question, we are much better off than before we had the tyrosine kinase inhibitors, but the problem is that these agents are very similar to each other. We need better drugs that focus on new targets, as we have seen in tumors such as lung cancer, to move forward in renal cell carcinoma.”

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Disclosure: Dr. Oh disclosed a relationship with Pfizer.

Reference 1. Motzer RJ, Nosov D, Eisen T, et al: Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinomas: Results from a phase III randomized, open-label, multicenter trial. 2012 ASCO Annual Meeting. Abstract 4501. Presented June 2, 2012. Disclosure: Dr. Oh is a consultant for Bayer, Janssen, Medivation, Millennium, Astellas, and Dendreon. He has received research funding from Millennium.

Novel Drugs in Prostate Cancer placebo to 12.2 months (HR = 0.64, P < .0001). “This is not surprising, given the drug’s mechanisms of action. It is honing to the bone and potentially killing cancer cells there,” Dr. Oh said. Adverse event rates were similar; in fact, “the safety of the drug was actually better than placebo.” Further follow-up in all randomized patients continues to show a highly favorable safety profile. “Radium-223, a first-in-class alpha emitter, may provide a new standard of care for the treatment of patients with castration-resistant prostate cancer and bone metastases,” Dr. Oh concluded.

paring pazopanib to sunitinib will be informative, he said.

Fig. 1: Treatment landscape in prostate cancer. Courtesy of William K. Oh, MD.

are progressively getting smaller, said Dr. Oh. The promising results seen with radium-223, enzalutamide, and abiraterone have triggered interest in using these drugs earlier in castrationresistant disease, and they are now being evaluated in both the pre- and

postchemotherapy state (Fig. 1). Should they prove effective in the earlier setting, the role of chemotherapy—which Dr. Oh still considers a good option, especially after progression on androgen pathway drugs— may be shifted far down the road, he predicted.

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References 1. Ryan CJ, Smith MJ, De Bono JS, et al: Interim analysis results of COUAA-302, a randomized, phase III study of abiraterone acetate in chemotherapynaive patients with metastatic castrationresistant prostate cancer. 2012 ASCO Annual Meeting. LBA4518. Presented June 2, 2012. 2. De Bono JS, Fizazi K, Saad F, et al: Primary, secondary, and quality-of-life endpoint results from the phase III AFFIRM study of MDV3100, an androgen receptor signaling inhibitor. 2012 ASCO Annual Meeting. Abstract 4519. Presented June 2, 2012. 3. Parker C, Nilsson S, Heinrich D, et al: Updated analysis of the phase III, doubleblind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer patients with bone metastases (ALSYMPCA). 2012 ASCO Annual Meeting. Abstract LBA4512. Presented June 4, 2012.

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Melanoma Exciting New Agents Offer Further Treatment Options for Metastatic Melanoma saw preliminary data on yet another radically different approach.” Dr. Sabel discussed the expanding treatment armamentarium at the Best of ASCO Boston meeting.

BRAF and MEK Inhibition Packs a Punch Michael Sabel, MD

“T

his is a very exciting time in melanoma,” said Michael Sabel, MD, of the University of Michigan, Ann Arbor. “For years, we chugged along with few options for systemic therapy. Then in 2010 and 2011, we saw melanoma data presented at ASCO plenary sessions. At See Page 23 ASCO 2012, we expanded in these areas and, in addition,

In metastatic melanoma patients with BRAF mutations, two new agents are headliners in this rapidly evolving scenario, and they may prove most powerful in combination. In the global BREAK-3 trial, the BRAF inhibitor dabrafenib led to a median progression-free survival of 5.1 months vs 2.7 months with dacarbazine, a 70% reduction in risk (P < .0001).1 In the related phase II BREAK-MB study of dabrafenib in patients with brain metastases, the intracranial disease control rate exceeded 80% (Fig. 1).2 Importantly, squamous cell carci-

Maximum percent change from baseline intracranial measurement

By Caroline Helwick

100 80 60 40 20 0 -20 -40 -60 -80 -100

Fig. 1: Cohort A in the BREAK-MB study: Maximal intracranial target lesion reduction in BRAF V600E mutation–positive patients with no prior brain treatment. OIRR = overall intracranial response rate; ORR = overall response rate. Reprinted with permission from Kirkwood et al.2

nomas and keratoacanthomas—which have plagued patients on vemurafenib (Zelboraf)—were seen in only 7% of patients, and photosensitivity in just 3%. Another global effort turned in im-

Melanoma Treatment Options Exploding, but Old Standbys Should Remain

ew drugs are rapidly changing the treatment paradigm for stage IV melanoma, but there is still validity to some of the old standbys, according to Michael Sabel, MD, of the University of Michigan, Ann Arbor, who described the shifting landscape of melanoma treatment at the Best of ASCO Boston meeting. He reminded attendees that for otherwise healthy patients, interleukin (IL)-2 produces durable responses in a small percentage of patients. “We are so caught up in talking about BRAF inhibitors for BRAF-mutated tumors and the antiCTLA4 antibody ipilimumab for wild-type BRAF, but we don’t want to forget about this,” he said. For less healthy patients, dacarbazine is often still appropriate. Surgery as well remains a prominent player in metastatic disease, with complete resection of tumors yielding long-term survival in as many as 40% of properly selected patients. “Any patient who is potentially surgically resectable should be evaluated for resection,” said Dr. Sabel, who is an oncologic surgeon. “What

will be interesting is defining the role of surgery as new agents become incorporated.”

Future Combinations “Treatment choices have certainly become more confusing,” he said. Looking ahead, he maintained that IL-2 will still be a consideration, as will surgery, in many patients. When

Any patient who is potentially surgically resectable should be evaluated for resection…What will be interesting is defining the role of surgery as new agents become incorporated. — Michael Sabel, MD

combined with the gp100 vaccine, IL-2 responses improve, he noted. “IL-2 may see resurgence in the

OIRR: 39% ORR: 38% Intracranial disease control rate: 81% Overall disease control rate: 80%

future as more data emerges about combining it with vaccines,” he predicted, adding that the use of a vaccine with anti-PD1 or ipilimumab “to generate a novel immune response, then take the brakes off with the others” is, at least theoretically, another interesting idea. For patients with BRAF-mutated melanoma, dabrafenib joins vemurafenib in the growing arsenal of agents against these tumors and should prove extremely valuable in patients with brain metastases, he said. He added that dabrafenib will probably not be positioned as a drug to use after vemurafenib resistance emerges. “This is not intrinsically logical,” he pointed out. The combination of dabrafenib and the MEK inhibitor trametinib is very exciting, Dr. Sabel noted, largely due to the lower risk for skin toxicity observed with this combination. “Combination therapy is where we are going, not just for higher response rates but for almost eradicating squamous cell carcinomas,” he commented.

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Disclosure: Dr. Sabel reported no potential conflicts of interest.

pressive results for the MEK inhibitor trametinib, validating that targeting the MEK pathway is a viable strategy. In the METRIC study of 322 patients previously treated with chemotherapy (but not vemurafenib), median progression-free survival was 4.8 months with trametinib compared to 1.5 months with chemotherapy—a 55% reduction in risk (P < .0001).3 In spite of crossovers, at 6 months, overall survival was 74% vs 56%—a 46% reduction in risk (P = .0136). Dr. Sabel was impressed not only with the robust responses but with the activity of dabrafenib in intracranial disease and also its lack of skin toxicity. “One could say this is a game-changer,” he said, noting that it could conceivably eliminate the need for whole brain radiotherapy altogether in this subset. Regarding trametinib, he said the drug’s optimal use remains unclear, but it is likely not as sequential therapy, as it does not seem to overcome vemurafenib resistance. Trametinib and other MEK inhibitors will most likely be best used in combination with BRAF inhibitors to block two related molecular pathways (MEK is downstream of BRAF). A study of this combination, also presented at this year’s ASCO Annual Meeting, showed a 100% disease control rate and a median progressionfree survival of almost 11 months among patients who were optimally dosed.4

Anti-PD-1: Next Chapter in Melanoma Immunotherapy Following on the heels of ipilumumab (Yervoy), another form of immune continued on page 22

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Melanoma New Agents for Melanoma continued from page 21

blockade—inhibition of the PD-1 (programmed death-1) checkpoint—seems tailor-made for melanoma. In a study presented at the Annual Meeting, 94 advanced melanoma patients received intravenous the anti-PD-1 antibody BMS-936558 in escalating doses every 2 weeks.5 The overall response rate was 28%, and 6% of patients achieved stable disease ≥�� 24 weeks. Most side effects were immune-related, though three treatment-related deaths occurred on study, including two due to pneumonitis. A subanalysis of the data hinted that the PD-L1 protein might serve as a biomarker of response. More than one-third of patients expressing PD-L1 responded to immunotherapy, whereas responses were not observed among patients lacking PD-L1 expression. “These are early data, but we see rather significant stabilization of disease and, in many cases, objective responses. BMS936558 blockade of the PD-1 pathway may represent a new immune therapy,” Dr. Sabel said. “There is strong evidence that the drug is biologically active and is actually improving the immunologic control of disease, not just stimulating an immune response. What is particularly interesting is the potential for having a marker to predict response to an immunologic treatment, which we have never had in melanoma.”

Biochemotherapy for Adjuvant Treatment Biochemotherapy with cisplatin, vinblastine, dacarbazine plus interleukin (IL)-2 (Proleukin) and interferon, administered for 9 weeks, improved recurrence-free survival by 24% vs high-dose

NOW ! LE AVAILAB

interferon alfa-2b (Intron A)—1 month induction, 11 months maintenance— in patients with high-risk melanoma in the phase III Intergroup SWOG S0008 trial.6 Given its lack of a survival benefit, however, it should not be the standard of care, Dr. Sabel maintained.

the same: 56% at 5 years. The trade-off was an excess of grade 4 toxicity with biochemotherapy. “This regimen is tough to deliver, but it’s shorter,” he noted. “Despite more toxicity acutely, more patients got through this than interferon.”

Key Findings in Melanoma Presented at Best of ASCO® ‘12 •• The BRAF inhibitor dabrafenib reduces disease progression in metastatic melanoma by 70% and achieves a disease control rate of 80% in patients with brain metastases.

•• The MEK inhibitor trametinib reduces disease progression by 55% and is associated with a survival benefit as well.

•• The combination of BRAF and MEK inhibition may produce the greatest

effect, and is associated with less skin toxicity than is historically seen with vemurafenib.

•• Immunotherapy via antibody-mediated blockade of the protein PD-1 and

its ligand PD-L1 induces durable tumor regression in advanced melanoma.

•• Biochemotherapy with cisplatin, vinblastine, dacarbazine plus interleukin-2 and interferon is better than high-dose interferon alfa-2b in delaying recurrence, but does not improve survival and should not be the standard of care in patients with high-risk melanoma.

•• Surgical resection is still a viable treatment for many patients with metastatic disease.

Compared with high-dose interferon, the biochemotherapy regimen was associated with a median recurrence-free survival improvement of more than 2 years (4.3 vs 1.9 years) and an 8% absolute improvement in recurrence-free survival at 5 years (47% vs 39%, P = .034). “Biochemotherapy is the first and only therapy to demonstrate a statistically significant improvement in recurrence-free survival compared to highdose interferon in high-risk stage III melanoma patients,” Dr. Sabel noted. Overall survival, however, was exactly

“We have had many attempts to find a less toxic regimen that matched interferon and have been unable to do so,” he continued. “Here, the regimen at least improves recurrence-free survival, but the lack of an overall survival difference is upsetting. Therefore, we can’t say that it should replace the standard of care.”

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Disclosure: Dr. Sabel reported no potential conflicts of interest.

References 1. Hauschild A, Grob JJ, Demidov LV,

et al: Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma. 2012 ASCO Annual Meeting. Abstract LBA 8500. Presented June 4, 2012. 2. Kirkwood JM, Long GV, Trefzer U, et al: BREAK-MB: A phase II study assessing overall intracranial response rate to dabrafenib (GSK2118436) in patients with BRAF V600E/k mutation-positive melanoma with brain metastases. 2012 ASCO Annual Meeting. Abstract 8501. Presented June 4, 2012. 3. Robert C, Flaherty KT, Hersey P, et al: METRIC phase III study: Efficacy of trametinib, a potent and selective MEK inhibitor, in progression-free survival and overall survival, compared with chemotherapy in patients with BRAFV600E/K mutant advanced or metastatic melanoma. 2012 ASCO Annual Meeting. Abstract LBA8509. Presented June 4, 2012. 4. Weber JS, Flaherty KT, Infante JR, et al: Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. 2012 ASCO Annual Meeting. Abstract 8510. Presented June 4, 2012. 5. Hodi FS, Sznol M, McDermott DF, et al: Clinical activity and safety of antiPD-1 (BMS-936558, MDX-1106) in patients with advanced melanoma. 2012 ASCO Annual Meeting. Abstract 8507. Presented June 4, 2012. 6. Flaherty LE, Moon J, Atkins MB, et al: Phase III trial of high-dose interferon alpha2b versus cisplatin, vinblastine, DTIC plus IL-2 and interferon in patients with highrisk melanoma (SWOG S0008): An Intergroup study of CALGB, COC, ECOG and SWOG. 2012 ASCO Annual Meeting. Abstract 8504. Presented June 4, 2012.

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Overview Best of ASCO® continued from page 2

gardless of your practice setting or focus, these are the abstracts that every oncologist needs to know to be up to date and provide the best care to their patients,” said Dr. Miller, who also moderated the San Diego meeting.

School of Medicine, New York, discussed his take on the pivotal comparison of intermittent vs continuous androgen-deprivation therapy in prostate cancer in the S9346 trial. “Intermittent androgen-deprivation therapy is inferior in metastatic disease and should no longer be propagated,” he concluded (see page 19). The program featured data and expert perspectives on the new BRAF inhibitor dabrafenib in melanoma (BREAK-3 trial) (see page 21) and the novel agent T-DM1 in breast cancer (EMILIA trial) (see page 10), along with many other investigations. In addition, attendees had ample opportunity to query speakers as to

the next 2 to 3 years,” she explained. “Exciting developments with a longer timeline to impacting practice are important, but they aren’t the focus of Best of ASCO.” Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute, who chaired and moderated the Boston meeting, emphasized that Best of ASCO is complementary to the Annual Meeting. “At ASCO there is the excitement of hearing the raw data, the full presentation, the smaller trials that give preliminary and provocative peeks at the data, as well as the many excellent educational talks and debates. But for working clinicians who want the ‘takeaways’ for their practices, the information

Kathy D. Miller, MD

Jonathan S. Berek, MD, MMS, who chaired the San Diego meeting, said the overarching goal is to produce a program that will improve patient care. “You want to get out the most up-to-date information from the Annual Meeting in a way that people on the front lines can translate to how they practice oncology,” said Dr. Berek, of Stanford Cancer Institute in Palo Alto.

Clinical Pearls Are the Focus Specialists in the various tumor types positioned the most recent data for use in the clinic and addressed the nuances of incorporating new agents—such as ziv-aflibercept (Zaltrap) for metastatic colorectal cancer (see page 16). In prostate cancer, for example, William Oh, MD, of Mount Sinai

Best of ASCO allows clinicians to ask direct questions of the speakers and present their own clinical cases. That close engagement with the faculty is a real plus. — Harold J. Burstein, MD, PhD

their own approaches to challenging scenarios, such as the management of isolated liver metastases in colorectal cancer, and to essentially bring their own challenging cases to the faculty for consultation.

Complementing the Annual Meeting Selecting 75 key abstracts from more than 10,500 presented at ASCO was a very difficult task for the 24-member program committee, Dr. Miller said. “We looked for abstracts that will change practice today or in

Using QR Codes The QR (Quick Response) codes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading. These barcodes can be read by any mobile device with a camera, QR code–reading software, and internet access. Some devices come with the software preinstalled; if not, visit your device’s application store (such as the iTunes Store or the Android Market) and download the software of your choice.

they need right away, I think Best of ASCO is great.” He added, “Best of ASCO allows clinicians to ask direct questions of the speakers and present their own clinical cases. That close engagement with the faculty is a real plus.” Dr. Berek pointed out that Best of ASCO also gives those who also attended the Annual Meeting an opportunity to attend sessions they missed at ASCO. “ASCO is one of the world’s greatest meetings, but it’s massive and it’s difficult to get to everything,” he noted. “Plenty of

Jonathan S. Berek, MD, MMS

oncologists go to the Annual Meeting and then come to this meeting to hear the synthesis, and there are probably people who benefit more from this straightforward format. This is a great way to get a summary of the most clinically applicable abstracts—the studies that are most directly relevant to the practice of most oncologists.”

Opportunities for Networking The smaller Best of ASCO meetings also provide opportunities for networking with colleagues and the faculty, added Dr. Miller. “The schedule allows ample time for questions and informal interactions—something that just isn’t possible with a meeting of more than 25,000 oncology professionals. The more intimate setting is a big plus.” “These Best of ASCO meetings play a very important part in sustaining the highest quality of oncologic care,” Dr. Berek concluded. “There is great value in this kind of program.”

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Disclosure: Dr. Berek has received research funding from AstraZeneca and Genentech. Drs. Burstein and Miller reported no potential conflicts of interest.

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Resistance or intolerance to CML therapy may occur. In some cases, repeatedly. Even today, with a number of available options for treating resistant/intolerant chronic phase chronic myeloid leukemia (CP-CML), a gap in therapy exists. One post-imatinib study found 42% of patients discontinued dasatinib as a second-line therapy by 6 years due to disease progression and/or study drug toxicity.1 Another post-imatinib study found 47% of patients discontinued nilotinib by 4 years due to disease progression and/or drug-related adverse events. 2 Itâ&#x20AC;&#x2122;s clear that for these patients, unmet medical needs persist.

Visit CMLResponseProject.com to learn more. References: 1. Rea D, Vellenga E, Junghanss C, et al. Six-year follow-up of patients with imatinib-resistant or imatinib-intolerant chronic-phase chronic myeloid leukemia (CP-CML) receiving dasatinib. Poster presented at: 17th EHA Annual Congress; June 14-17, 2012; Amsterdam, The Netherlands. 2. Le Coutre PD, Giles FJ, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or -intolerant patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 48-month follow-up results of a phase 2 study. Poster presented at: 53rd ASH Annual Meeting and Exposition; December 10-13, 2011; San Diego, CA. ÂŠ2012 ARIAD Pharmaceuticals, Inc. All rights reserved. 5347112