TAP Vol 2 Issue 15 Supplement - Reports from Best of ASCO® Annual Meeting ’11

Lung cancer 3

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Breast cancer 7

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Colorectal cancer 11

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Lymphoma 15

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Myeloma 21

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

SUPPLEMENT

VOLUME 2, ISSUE 15 OCTOBER 15, 2011

ASCOPost.com

REPORTS from

Best of ASCO Annual Meeting ’11 ®

INSIDE THIS SUPPLEMENT Coverage of more than 50 key abstracts on: ■■ Molecular Diversity in Metastatic Lung Cancer ■■ Locoregional Lung Cancer Management ■■ Breast Cancer Prevention and Treatment Strategies ■■ Colorectal Cancer Standards of Care

Best of ASCO® Miami

■■ Noncolorectal Gastrointestinal Cancers ■■ Lymphoma Management ■■ Research in Multiple Myeloma ■■ Genitourinary Cancers: Prognostic Strategies and Novel Therapies ■■ Ovarian Cancer Screening and Outcomes ■■ Novel Therapies for Metastatic Melanoma ■■ High-risk GIST and Soft-tissue Sarcoma ■■ Issues in Head and Neck Cancer

Best of ASCO® Seattle

A Supplement to The ASCO Post™

A Harborside Press® Publication

The ASCO Post | OCTOBER 15, 2011 | SUPPLEMENT

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Introduction

T

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 National Comprehensive Cancer Network

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 Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University

Harold J. Burstein, MD Dana-Farber Cancer Institute

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Robert W. Carlson, MD Stanford University Medical Center

Lynn D. Wilson, MD Yale University School of Medicine

Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center

Stanley H. Winokur, MD Singer Island, Florida

Jay S. Cooper, MD Maimonides Medical Center

William C. Wood, MD Winship Cancer Institute, Emory University

John Cox, DO Texas Oncology

INTERNATIONAL EDITORS

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 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 Michael P. Link, MD Stanford University Medical Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina 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 Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan 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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Melanie Serge, Marketing Project Manager Melanie@harborsidepress.com

Contributing Writers: Caroline Helwick and Susan London

Disclosure information available at ASCOPost.com.

he ASCO Post is pleased to present this special supplement with a focused review of more than 50 key abstracts from the Annual Meeting of the American Society of Clinical Oncology (ASCO), as presented and discussed at the Best of ASCO ’11 meetings ( July 29-30, 2011, Miami, Florida, and August 5-6, 2011, Seattle, Washington).

Each report is accompanied by expert perspective and key points.

The abstracts discussed herein represent those having particular importance and relevance to the clinical management of the patient with cancer.

A full index is provided below.

To view the original presentations and other references, readers may use the Quick Response codes found in this supplement. These bar codes can be read by any mobile device with a camera, QR code—reading software, and internet access.

Look for additional coverage of the Best of ASCO ’11 meetings in the October 15th issue of The ASCO Post or online at ASCOPost.com.

■

Index: Best of ASCO® ’11 Abstracts Reported in this Supplement Thoracic Oncology Metastatic Lung Cancer

■■ Abstract CRA7506: Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s lung cancer mutation consortium. Kris MG, et al.

■■ Abstract 7503: Erlotinib vs chemotherapy in advanced non-small-cell lung cancer patients with EGFR mutations: Interim results of the European Tarceva vs chemotherapy phase III randomized trial.

Rosell R, et al.

■■ Abstract LBA7511: Efficacy, tolerability and biomarker analyses from a phase III, randomized, placebo controlled, parallel group study of gefitinib as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer in China (INFORM). Zhang L, et al.

■■ Abstract 7505: Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. Spigel DR, et al.

■■ Abstract LBA7512: Prospective biomarker analysis from MONET1, a randomized, placebo-controlled, double-blind phase 3 study of motesanib plus carboplatin/paclitaxel in advanced nonsquamous non–small-cell lung cancer. Bass MB, et al.

■■ Abstract CRA7510: PARAMOUNT: Phase III study of maintenance pemetrexed plus best supportive care versus placebo plus best supportive care immedi-

ately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer.

Paz-Ares LG, et al.

Locoregional Lung Cancer

■■ Abstract 7002: Randomized phase 2 trial on refinement of early stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine (CVb) - TREAT. Kreuter M, et al.

■■ Abstract 7003: Proteomic analysis for detection of NSCLC: Results of ACOSOG Z4031. Harpole D, et al.

■■ Abstract 7004: Evaluation of disease-free survival as surrogate endpoint for overall survival using two individual patient data meta-analyses of adjuvant chemotherapy in operable non-small cell lung cancer. Michiels S, et al.

Breast Cancer

■■ Abstract LBA504: NCIC CTG MAP.3: A phase III placebo-controlled Breast Cancer Prevention Trial of exemestane in postmenopausal women at risk for breast cancer. Goss P, et al.

■■ Abstract 505: TBCRC 006: A multicenter phase II study of neoadjuvant lapatinib and trastuzumab in patients with HER2-overexpressing breast cancer.

Chang J, et al.

■■ Abstract 506: Correlation of molecular effects and pathologic complete continued on page 31

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.

ASCOPost.com | OCTOBER 15, 2011 | SUPPLEMENT

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Thoracic Oncology Research Increasingly Points to the Role of Molecular Diversity in Metastatic Lung Cancer

By Susan London

M

olecular diversity—its existence, extent, and implications for therapy—was a central theme of key metastatic lung cancer studies presented at this year’s ASCO meeting, according to D. Ross Camidge, MD, PhD, of the University of Colorado, Denver, who addressed major findings in advanced lung cancer at the Best of ASCO Seattle meeting.

D. Ross Camidge, MD, PhD

Adenocarcinomas Are Highly Molecularly Diverse More than half of lung adenocarcinomas have a mutation driving the cancer that is potentially amenable to drug therapy, but the specific gene mutated differs more often than not, finds a study by the National Cancer Institute’s Lung Cancer Mutation Consortium.1 The investigators assessed 10 molecular markers in 1,000 stage IV adenocarcinomas. Of the first 516 undergoing full molecular analysis, 54% had a so-called actionable mutation—ie, one with a targeting drug available or in development (Fig. 1). Mutations were found in all 10 genes, with the majority in the genes for KRAS (22%

of all tumors studied), EGFR (17%), and EML4-ALK (7%).

Additionally, in 97% of these tumors, there was only a single driving actionable mutation. The rare double mutations were usually related to PI3 kinase.

“Now the question you may be asking yourself is, do these represent the lung adenocarcinomas which I see in my practice?” Dr. Camidge noted. Patient demographics presented subsequently2 suggest they don’t: 59% of the patients were female, the median age was 60, and 31% were never-smokers.

“Although exact proportions [of patients] in your clinic may differ from [data compiled by the Consortium], I still think you will agree that we are starting to clearly understand that lung adenocarcinoma is not a single disease on the molecular level,” he maintained.

Erlotinib vs Chemotherapy in NSCLC with EGFR Mutations The targeted agent erlotinib (Tarceva) is more efficacious than chemotherapy as first-line therapy for advanced NSCLC having activating mutations of the epidermal growth factor receptor (EGFR), according to interim results of the phase III EURTAC trial.3 A total of 174 patients were randomly assigned to platinum-based doublet chemotherapy or erlotinib, an EGFR tyrosine kinase inhibitor. Patients in the erlotinib group had better progressionfree survival (9.7 vs 5.2 months; HR = 0.37; P < .0001) and a better objective response rate (58% vs 15%).

No mutation detected KRAS 22% AKT1 NRAS MEK1 MET AMP HER2 PIK3CA BRAF 2% Double mutations 3%

EGFR 17%

EML4-ALK 7%

Mutation found in 54% (280/516) of tumors; 97% mutually exclusive Fig. 1: Incidence of oncogenic drivers in 516 analyzed cases of lung adenocarcinoma. Courtesy of D. Ross Camidge, MD, PhD. Adapted from Kris MG, et al.1

Key Metastatic Lung Cancer Findings Presented at Best of ASCO® ■■ More than half of stage IV adenocarcinomas have a driving mutation

potentially amenable to drug therapy, but the specific gene mutated differs more often than not.

■■ Erlotinib improves progression-free survival compared with

chemotherapy as first-line therapy for advanced NSCLC having EGFRactivating mutations (9.7 vs 5.2 months).

■■ Maintenance therapy with gefitinib improves progression-free survival in advanced NSCLC having an EGFR mutation (16.6 vs 2.8 months).

■■ Adding MetMAb to erlotinib improves outcomes in NSCLC with higher Met expression, but which patients benefit is still unclear.

■■ Adding motesanib to carboplatin/paclitaxel improves response rate and progression-free survival, but not overall survival in advanced nonsquamous NSCLC.

■■ Continuation maintenance therapy with pemetrexed improves

progression-free survival in nonsquamous NSCLC (3.9 vs 2.6 months), with benefit mainly restricted to patients who had a response to the drug in the first-line setting.

Overall survival did not differ significantly between groups, but the data are not mature. Additionally, most patients given chemotherapy who had disease progression received second-line therapy—usually an EGFR tyrosine kinase inhibitor. “So I would be very surprised if overall survival is likely to be positive in this study,” Dr. Camidge commented.

The take-home message here? “If you are known to have an EGFR mutation in time to make a first-line treatment decision, then it would appear that progression-free survival and objective response rate are far better if you get an EGFR tyrosine kinase inhibitor than chemotherapy,” he said.

Results of this study, conducted in Europe, are consistent with those conducted in Asia, Dr. Camidge added. This suggests “that it’s the tumor’s molecular biology and not the host’s molecular biology which is really the dominant driver of results. That is, an EGFR-mutant Asian patient is very similar to an EGFR-mutant Caucasian patient.”

Switch Maintenance Therapy with Gefitinib The phase III INFORM trial found that switch maintenance therapy (immediate non–cross resistant alternative therapy) with the targeted agent gefitinib (Iressa) is efficacious in patients with locally advanced or meta-

static NSCLC.4 Patients in China were eligible for the trial if they had completed four cycles of first-line platinum-based chemotherapy without progressive disease or unacceptable toxicity. In all, 296 patients were randomly assigned to gefitinib (another EGFR tyrosine kinase inhibitor) or placebo.

The rate of progression-free survival was better with gefitinib in the entire trial population (median, 4.8 vs 2.6; HR = 0.42; P < .0001). Only a quarter of patients had tissue available for EGFR mutation status, of whom 38% had an EGFR mutation. Gefitinib improved progression-free survival in patients with an EGFR mutation (16.6 vs 2.8 months; HR = 0.17) but not in those without one.

“When you start using an EGFR tyrosine kinase inhibitor in trials, you cannot ignore the idea of EGFR mutation anymore,” Dr. Camidge stressed.

Furthermore, “you cannot apply information obtained in a group where you don’t know the mutation-specific status to [a patient] for whom you increasingly do know the status. Unknown status is completely useless.”

A second option for switch maintenance, erlotinib, was tested in the SATURN trial, which also showed greater benefit among patients with EGFR mutations.5 And a third option, pemetrexed (Alimta), appears efficacious continued on page 4

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Thoracic Oncology Metastatic Lung Cancer continued from page 3

for treating nonsquamous tumors that may or may not have an EGFR mutation,6 although more-detailed analyses are still needed.

MetMAb Trial Suggests Benefit Adding the investigational agent MetMAb to erlotinib improves outcomes in patients with advanced NSCLC whose tumors show higher expression of Met, the phase II OAM4558g trial concluded.7 A total of 137 patients needing second- or third-line therapy were randomly assigned to SEE PAGE 2 erlotinib plus either placebo or MetMAb, an antibody that blocks binding of hepatocyte growth factor to Met. Amplification of Met is known to be a key mechanism of resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant tumors.

Adding MetMAb did not improve outcomes in the trial population as a whole. But among patients falling into a so-called Met diagnostic-positive group, identified by immunohistochemistry, adding MetMAb improved both progression-free survival (2.9 vs 1.5 months; HR = 0.53; P = .04) and overall survival (12.6 vs 3.8 months; HR = 0.37; P = .002). Among Met diagnostic-negative patients, adding MetMAb appeared to worsen both outcomes. The findings have prompted a similar phase III trial restricted to Met diagnostic-positive patients.

“We have lots of unanswered questions about who is really benefiting,” Dr. Camidge commented. He expressed concerns about the trial’s methodology, including use of MetMAb in combination therapy without obvious justification, the lack of a biologic rationale for selecting the cutpoint for the Met diagnostic-positive group, and marked imbalance in EGFR mutations within each diagnostic group that could have explained observed differences.

Finally, in stratified analyses of EGFR mutation status, overall survival in the Met diagnostic-positive group was shown only for nonmutant tumors. “We don’t know that [those with mutant tumors] benefit from this combination, so I don’t see data justifying keeping them in the phase III study beyond preserving trial size and potential market size,” Dr. Camidge said.

Motesanib in Advanced Nonsquamous NSCLC The phase III MONET1 trial showed that adding the investigational drug motesanib to carboplatin/paclitaxel therapy improves response rate and progression-free survival but not overall survival in patients with advanced nonsquamous NSCLC.8 A total of 1,090 patients were randomly assigned to chemotherapy plus either placebo or motesanib, an oral inhibitor of the vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, platelet-derived growth factor (PDGF) receptor, and Kit. Compared with their counterparts in the placebo group, patients in the motesanib group had a higher response rate (40% vs 26%) and progression-free survival (HR = 0.79; P = .0006), but not overall survival.

“This is another antiangiogenic [tyrosine kinase inhibitor] disappointment,” Dr. Camidge commented, and one that is as yet without explanation.

“Clearly, there is desperate need to find the group of people who may or may not benefit from these [agents], and maybe we are looking in the wrong place,” he proposed. “Maybe we need to start to look in the host because it is the host vasculature which is actually climbing into the tumor.”

Maintenance with Pemetrexed in Responsive Tumors The phase III PARAMOUNT trial finds that patients with advanced nonsquamous NSCLC who have completed pemetrexed-containing first-line therapy with at least stable disease fare better if they continue to receive pemetrexed for maintenance.9 But benefit is greatest for those who had a response to the drug in the first-line setting.

The 539 patients in PARAMOUNT were assigned 2:1 to receive best supportive care plus either continued pemetrexed or placebo. Progressionfree survival was superior with pemetrexed (3.9 vs 2.6 months; HR = 0.64; P = .0002). But patients in that group had higher rates of grade 3/4 fatigue (4.2% vs 0.6%), anemia (4.5% vs 0.6%), and neutropenia (3.6% vs 0%). Overall survival data are still immature.

Dr. Camidge questioned the clinical significance of the 1.3-month gain in progression-free survival and noted subgroup analyses showed that benefit was mainly restricted to patients who had a partial or complete response to the drug in first-line therapy. “So the bottom line of whom to give pemetrexed to in the maintenance setting is

Molecular Heterogeneity Complicates Management of Resistance

T

he molecular heterogeneity of lung cancers will make it a challenge to manage resistance in this era of targeted therapy, according to D. Ross Camidge, MD, PhD, of the University of Colorado, Denver. A case in point: the anaplastic lymphoma kinase (ALK) story.

SEE PAGE 2 Recently updated data for crizotinib (Xalkori), an ALK inhibitor, show that it is active in ALK-positive NSCLC, with an overall response rate of 61% and a median progression-free survival of 10 months.1 The 6- and 12-month rates of overall survival were 90% and 81%. “This is still really impressive data when you are giving the right drug to a very molecularly defined group of people,” he commented. Yet some patients clearly develop resistance.

Use of Hsp90 Inhibitors Meanwhile, research has suggested that heat shock protein 90 (Hsp90) inhibitors may be most active in NSCLC with an ALK gene rearrangement. In a trial testing the Hsp90 inhibitor ganetespib in advanced NSCLC after failure of prior treatments, the patients having the greatest response indeed had ALK-positive tumors.2 But in a first-ever observation, two patients with disease progression on the drug had ALK-positive tumors and had experienced treatment failure with crizotinib.

“The initial assumption was [that] Hsp90 inhibitors may be the next best thing for ALK-positive patients after failure of crizotinib,” Dr. Camidge commented. “Yet both of these people are not responding to the Hsp90 inhibitor.”

This observation attests to tumors’ molecular heterogeneity and underscores its importance in therapy. When you use a very specific inhibitor, and then after many months, “the cancer squirms out [by] finding acquired resistance, then it’s back to the beginning again. Heterogeneity will reemerge in terms of mechanisms of resistance,” he explained. “Therefore, the assumption that you should be able to go straight from one drug to the next without recharacterizing the tumor almost certainly will not be true.”

■

References 1. Camidge DR, Bang Y, Kwak EL, et al: Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC). ASCO Meeting 2011. Abstract 2501. Presented June 3, 2011.

2. Wong K, Koczywas M, Goldman JW, et al: An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC). ASCO Meeting 2011. Abstract 7500. Presented June 4, 2011.

the people who were already benefiting from pemetrexed,” he said.

“Now, stable disease is a very broad category,” Dr. Camidge added.

“I would be very interested in seeing a waterfall plot [by which we might distinguish] the people who were minor responders and may be deriving benefit, from those who were actually slowly progressing.”

Recent data suggest that certain biomarkers, such as ALK positivity, may also help identify the patients most likely to benefit from pemetrexed.10 “I don’t know the reason for that,” he said, “but it gets back to the idea that when you molecularly fragment your group of patients with lung cancer, you can start to see patterns that you never knew existed before.”

■

Disclosure: Dr. Camidge has received honoraria from Pfizer, OSI, and AstraZeneca for ad hoc advisory boards and research funding from Lilly.

References 1. Kris MG, Johnson BE, Kwiatkowski DJ, et al: Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s Lung Cancer Mutation Consortium (LCMC). 2011 ASCO Annual Meeting.

Abstract CRA7506. Presented June 5, 2011.

2. Johnson BE, Kris MG, Kwiatkowski D, et al: Clinical characteristics of planned 1000 patients with adenocarcinoma of lung (ACL) undergoing genomic characterization in the US Lung Cancer Mutation Consortium (LCMC). 14th World Conference on Lung Cancer. Abstract 16.01. Presented July 5, 2011.

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Thoracic Oncology 3. Rosell R, Gervais R, Vergnenegre A, et al: Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. 2011 ASCO Annual Meeting. Abstract 7503. Presented June 5, 2011.

4. Zhang L, Shenglin M, Song X, et al: Efficacy, tolerability, and biomarker analyses from a phase III, randomized, placebocontrolled, parallel group study of gefitinib as maintenance therapy in patients with locally advanced or metastatic non-small

cell lung cancer (NSCLC; INFORM; CTONG 0804). 2011 ASCO Annual Meeting. Abstract LBA7511. Presented June 5, 2011.

5. Cappuzzo F, Ciuleanu T, Stelmakh L, et al: Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multicentre, randomised, placebocontrolled phase 3 study. Lancet Oncol 11:521-529, 2010.

6. Ciuleanu T, Brodowicz T, Zielinski C, et al: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: A randomised, double-blind, phase 3 study. Lancet 374:1432-1440, 2009.

7. Spigel DR, Ervin TJ, Ramlau R, et al: Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. 2011 ASCO Annual Meeting. Abstract 7505. Presented June 5, 2011.

8. Scagliotti G, Vynnychenko I, Ichinose Y, et al: An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). 2011 ASCO Annual Meeting. Abstract LBA7512. Presented June 6, 2011.

9. Paz-Ares LG, De Marinis F, Dediu M, et al: PARAMOUNT: Phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo plus BSC immediately following induction treatment with pem plus cisplatin for advanced nonsquamous non-small cell lung cancer (NSCLC). 2011 ASCO Annual Meeting. Abstract CRA7510. Presented June 5, 2011.

10. Camidge DR, Kono SA, Lu X, et al: Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progressionfree survival on pemetrexed. J Thorac Oncol 6:774-780, 2011.

Incremental Advances Demonstrated in Management of Locoregional Lung Cancer

By Susan London

D

ata presented at the ASCO Annual Meeting this year on the management of locoregional lung cancer present a mixed picture, with some advances and some disappointments, according to H. Jack West, MD, of the Swedish Cancer Institute in Seattle, who reviewed studies in this area at the Best of ASCO Seattle meeting.

H. Jack West, MD

The randomized phase II TREAT trial demonstrated that when it comes to adjuvant therapy for non–small cell lung cancer (NSCLC), the doublet of cisplatin and pemetrexed (Alimta) is more feasible to administer than the doublet of cisplatin and vinorelbine.1

Among the 132 patients studied, the rate of clinical feasibility (defined as no deaths due to cancer, toxicity, or comorbidities; no patient early withdrawals; and no dose-limiting toxicities) was higher with cisplatin/pemetrexed (95.5% vs 75.4%, P = .001; Table 1). The mean duration of therapy was similar (11.2 vs 9.9 weeks).

Dose delays and interruptions were about twice as common in the cisplatin/vinorelbine arm, solely due to adjustments in vinorelbine.

Generalizability of the trial is limited, according to Dr. West. “This is a younger, cherry-picked, fitter population than at least the people who walk into my office on average,” he noted.

Also, the majority were male, and 38% had stage IB disease (a group for whom chemotherapy has debatable benefit).

“Adjuvant cisplatin-based chemotherapy is still standard of care, at least for stage II and IIIA resected NSCLC, and arguably for selected stage IB patients,” Dr. West said. “The [existing] evidence is strongest for cisplatin and vinorelbine,… but the reality is that it is truly challeng-

Key Locoregional Lung Cancer Findings Presented at Best of ASCO® ■■ For adjuvant therapy in NSCLC, cisplatin/pemetrexed has a higher

feasibility rate than cisplatin/vinorelbine (95.5% vs 75.4%), indicating greater ability to administer the drug as planned.

■■ A novel serum proteomic profile fails to discriminate between early-stage

NSCLC and benign lesions in patients with clinically suspicious lung nodules.

■■ Disease-free survival is a valid surrogate for overall survival in patients who receive adjuvant therapy for operable NSCLC.

■■ Among patients who undergo surgery and adjuvant chemotherapy, with or without radiation therapy, about 80% of all recurrences occur within the first 3 postoperative years.

Table 1: Adjuvant Cisplatin/Pemetrexed vs Cisplatin/Vinorelbine in NSCLC Cisplatin/ Pemetrexed Feasibility rate

Death

Cisplatin/ Vinorelbine

95.5% 75.4% (CI = 87.5, 99.1) (CI = 63.1, 85.2) P = .001 1.5% 3.1%

Withdrawal of consent

0%

6.2%

Dose-limiting toxicity

3.0%

15.4%

Patients (n = 2)

Patients (n = 10)

Grade 4 neutropenia > 7 days

0

4

Grade 4 thrombocytopenia > 7 days

0

0

Grade 3/4 febrile neutropenia

1

5

Thrombocytopenia with bleeding

0

0

Grade 3/4 nonhematologic toxicity

2

1

Reasons for dose-limiting toxicity (events)a

Multiple reasons possible.

NSCLC = non–small cell lung cancer. Courtesy of Michael Kreuter, MD, and H. Jack West, MD. Adapted from Kreuter M, et al.1 a

ing to administer. So despite the lack of randomized data in the adjuvant setting, cisplatin/pemetrexed is clearly more feasible per the TREAT trial.”

That said, there are several other reasonable options, such as cisplatin/ gemcitabine. “And in truth, it needs to be an individualized decision with your judgment, working with the patient in front of you,” he maintained.

Proteomic Profile in Cancer Detection In patients with lung nodules that are clinically suspicious for stage I cancer, a new serum proteomic profile is not helpful for determining which are indeed cancer and which are simply benign lesions, finds the phase II

American College of Surgeons Oncology Group (ACOSOG) Z4031 trial.2 Serum was collected before and 60 and 90 days after surgery for resection of the nodules in 913 patients and analyzed by mass spectrometry. Pathology showed that 79% of the patients had NSCLC. Mass spectrometry failed to identify a sufficient number of high-signal proteins, resulting in low sensitivity of the profile. In the validation set, the profile failed to discriminate significantly any-histology NSCLC vs benign lesions; squamous NSCLC vs benign lesions; adenocarcinoma NSCLC vs benign lesions; or squamous vs adenocarcinoma NSCLC. continued on page 6

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Thoracic Oncology Locoregional Lung Cancer continued from page 5

“The implications today: No need to go back and start sending off [serum] for this. It’s not yet ready for use,” Dr. West commented. “But it’s still an admirable goal, and I hope and expect we’ll see more efforts along these lines, hopefully more successfully as our technology improves.”

Results have been more encouraging in another recent study that also used mass spectrometry proteomics, but this time working with a predefined biomarker profile generated using prospectively collected data from SEE PAGE 2 tumor tissue and cell lines.3 Results suggested that this profile does discriminate NSCLC from controls. Moreover, it works similarly well in patients who had never smoked.

“This is still early, it’s not yet available, and it needs more validation,” Dr. West cautioned. “But it at least should give a glimpse that this is not pie-in-thesky work and that we may still succeed.”

Disease-free Survival as Surrogate for Overall Survival In a development that may help expedite clinical trials, new data show that disease-free survival can serve as

an earlier surrogate endpoint for overall survival in patients who undergo lung cancer resection and receive adjuvant chemotherapy.4 Investigators conducted a pair of meta-analyses using individual patient data. One analysis used data from 5,379 patients in 17 trials testing surgery with vs without adjuvant chemotherapy (median follow-up, 5.7 years). The other analysis used data from 2,247 patients in 7 trials testing surgery plus radiation therapy, with vs

overall survival at the patient level (r = 0.93) and the trial level (R = 0.99).

Additionally, in the analysis looking at surgery plus chemotherapy, with vs without radiation therapy, about 80% of all recurrences occurred within the first 3 postoperative years.

“So [the investigators] propose that disease-free survival can be used as a surrogate for overall survival in adjuvant chemotherapy for lung cancer, potentially as the primary endpoint,” Dr. West noted. But he also concurred with

Today’s postrecurrence treatments work better, and patients are living longer, which may weaken the correlation between disease-free and overall survival. ­—H. Jack West, MD

without adjuvant chemotherapy (median follow-up, 6.4 years).

In the first meta-analysis, investigators found a strong correlation between disease-free survival and overall survival at the patient level (r = 0.91) and the trial level (R = 0.96). Similarly, in the second meta-analysis, there was a strong correlation between disease-free survival and

them that new analyses will be needed to see if the same holds true with targeted therapies. “It would be a mistake to generalize these results,” he said.

“My own caveat on this is that I am not sure that the results will hold as true in an era today of effective therapies,” he commented. “Today’s postrecurrence treatments work better, and

patients are living longer, which may weaken the correlation between disease-free and overall survival and necessitate longer follow-up.”

■

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

References 1. Kreuter M, Vansteenkiste JF, Fischer JR, et al: Randomized phase II trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed (CPx) versus cisplatin and vinorelbine (CVb): TREAT. 2011 ASCO Annual Meeting. Abstract 7002. Presented June 7, 2011.

2. Harpole D, Ballman KV, Oberg AL, et al: Proteomic analysis for detection of NSCLC: Results of ACOSOG Z4031.

2011 ASCO Annual Meeting. Abstract 7003. Presented June 7, 2011.

3. Birse C, Laiger R, Bruce R, et al: Serum biomarker panel detects lung cancer in never smokers. American Association for Cancer Research 102nd Annual Meeting. Abstract 2813. Presented April 4, 2011.

4. Michiels S, Mauguen A, Fisher D, et al: Evaluation of disease-free survival as surrogate endpoint for overall survival using two individual patient data meta-analyses of adjuvant chemotherapy in operable non-small cell lung cancer. 2011 ASCO Annual Meeting. Abstract 7004. Presented June 7, 2011.

Searching for More Efficacious, Less Toxic Adjuvant Chemotherapy for NSCLC

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ccumulating data are helping to better define the risk-benefit profile of various adjuvant chemotherapy regimens for non–small cell lung cancer (NSCLC) and the impact of adding biologic agents to the mix, according to H. Jack West, MD, of the Swedish Cancer Institute in Seattle.

In the randomized E1505 trial, investigators are testing the combination of bevacizumab (Avastin) with adjuvant chemotherapy in stage IB to IIIA NSCLC. Patients are given chemotherapy (any of four cisplatin doublets, at the treating physician’s discretion) with or without bevacizumab.

In an analysis reported after accrual of 636 of 1,500 planned patients, the chemotherapy regimen chosen was cisplatin/vinorelbine in 27% of patients, cisplatin/docetaxel in 33%, cisplatin/gemcitabine in 25%, and cisplatin/pemetrexed (an option added belatedly) in 16%.1 “Any of those regimens that are

included in the trial are really considered to be appropriate choices,” Dr. West commented. “But speaking to the challenge of administering some of these, I will say that the reasoning behind the inclusion of these other alternatives is really an extrapolation from the metastatic setting, where we have volumes of work showing the comparability of one platinum-based doublet or another.”

Challenging Options For example, although as efficacious as the rest, cisplatin/docetaxel is challenging to administer, as suggested by data from a phase II trial conducted at Memorial Sloan-Kettering Cancer Center.2 Between 31% and 55% of patients could not complete even the targeted three cycles of chemotherapy.

“And these are Memorial patients,” Dr. West said, noting that the regimen could be even more challenging at facilities with less fit patients and less expertise giving cisplatin regularly. “I think it’s just

worth factoring into the equation of what treatment to select.”

He noted that the National Comprehensive Cancer Network (NCCN) lists eight cisplatin-containing regimens as options for adjuvant chemotherapy after resection of NSCLC, as well as an alternative carboplatincontaining regimen for patients who cannot receive cisplatin.3 As for adding bevacizumab, the E1505 trial has found a higher overall rate of grade 3/4 toxicity. But perhaps more worrisome, the rate of grade 5 toxicity was 3.8% with bevacizumab compared with 2.5% without it, though this preliminary analysis did not separate treatmentrelated deaths from deaths due to disease recurrence.

“That is something we should continue to follow as the trial continues and data mature,” Dr. West commented. “We want to ensure that our treatments are as safe as possible, but especially when you’re treating them and they may have already

been cured by the surgery they have completed.”

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References SEE PAGE 2 1. Wakelee HA, Dahlberg SE, Keller SM, et al: Interim report of on-study demographics and toxicity from E1505, a phase III randomized trial of adjuvant (adj) chemotherapy (chemo) with or without bevacizumab (B) for completely resected early-stage non-small cell lung cancer (NSCLC). 2011 ASCO Annual Meeting. Abstract 7013. Presented June 7, 2011.

2. Azzoli CG, Krug LM, Miller VA, et al: A phase II tolerability study of cisplatin plus docetaxel as adjuvant chemotherapy for resected non-small cell lung cancer. J Thorac Oncol 2:638-644, 2007.

3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Non-Small Cell Lung Cancer.

Version 3.2011. Available at http:// www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed September 14, 2011.

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Breast Cancer Breast Cancer Studies Explore Wide Variety of Prevention and Treatment Strategies, Offering New Insights

By Caroline Helwick

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t the Best of ASCO® meeting in Miami, Harold Burstein, MD, PhD, Dana-Farber Cancer Institute, Boston, and Carey K. Anders, MD, University of North Carolina at Chapel Hill, presented high-impact breast cancer abstracts that will enable clinicians to optimize their use of radiotherapy and biologics. Best of ASCO conference moderator Daniel F. Hayes, MD, of the University of Michigan, contributed to the discussion.

Exemestane Prevents Invasive and Preinvasive Breast Cancers in MAP.3 Trial The aromatase inhibitor exemestane, taken for 5 years, significantly reduced invasive and preinvasive breast cancers in postmenopausal women at increased risk, in the large National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MAP.3 randomized trial.1 The study enrolled 4,560 postmenopausal women with at least one risk factor: age ≥ 60; 5-year Gail risk score > 1.66%; prior atypical ductal hyperplasia, lobular hyperplasia, or lobular carcinoma in situ; or prior ductal carcinoma in situ. Subjects were randomly assigned to exemestane at

25 mg/d or placebo, for 5 years.

At a median follow-up of 3 years, 11 breast cancers occurred in the exemestane arm vs 32 in the placebo arm, for annual incidence rates of 0.19% and 0.55%, respectively, and resulting in a 65% reduction in cancer with exemestane (P = .002). The protective effect was striking among the estrogenreceptor (ER)-positive subset, 7 of whom developed cancer on exemestane compared with 27 on placebo—a 73% risk reduction (P = .0008). Preinvasive and precursor lesions were also reduced with exemestane.

Serious toxicities were lacking, but the exemestane group reported more adverse events (P = .003), including more bodily pain (P < .001), and somewhat worse quality of life. The number needed to treat to prevent one breast cancer over 5 years, however, was just 26 with exemestane, compared with 95 for tamoxifen.

The MAP.3 trial joins two other important trials—the National Surgical Adjuvant Breast and Bowel Project (NSABP) P1 study and the Study of Tamoxifen and Raloxifene (STAR) P2 trial—showing “qualitatively similar” results to the NCIC study, Dr. Burstein noted.

Key Breast Cancer Findings Presented at Best of ASCO® ■■ Exemestane, taken for 5 years, led to a 65% reduction in invasive breast cancers among postmenopausal women at risk for the tumor and also protected against preinvasive cancers and precursor lesions.

■■ A regimen of lapatanib plus capecitabine reduced lesion volume and

delayed the need for whole-brain radiotherapy in two-thirds of HER2positive patients with brain metastases.

■■ Anti-HER2 blockade with trastuzumab plus lapatinib can produce high

pathologic CR rates in HER2-positive/ER-negative patients; pathologic CR is predictive of outcome in this subset, but not in ER-positive patients.

■■ Regional nodal irradiation, added to whole-breast irradiation, improved disease-free survival, with a trend toward improved overall survival.

■■ In metastatic triple-negative breast cancer, iniparib combined with

gemcitabine/carboplatin numerically improved progression-free and overall survival in a phase III trial, but the differences were not statistically significant.

■■ Metronomic chemotherapy was not superior to dose-dense chemotherapy.

■■ Bevacizumab added to standard neoadjuvant regimens improved clinical and pathologic response rates.

■■ SNPs in two genes were associated with increased risk for paclitaxelinduced neuropathy; the presence of two variants conveyed a 60% increased risk.

“What this says about breast cancer prevention is that there are multiple options for women who want them,” he concluded (see sidebar, “Studies

Studies Sparked Questions to Breast Cancer Specialists

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ased on the MAP.3 findings, should we be using exemestane to prevent breast cancer in high-risk patients?

Dr. Harold Burstein: The risk of developing breast cancer was 2.5% in the placebo arm, vs 1% to 1.5% risk with exemestane. Also, the cancers that were avoided were probably ones with good prognosis. You have to ask, therefore, “How important is this therapy?”

While exemestane was reasonably well tolerated in the study, there are real side effects. Osteoporosis was not increased, but with only 3 years of followup the late effects may not be obvious.

Many cancer drugs have side effects that all but the most motivated patients will balk at, so will women who don’t even have cancer take them?

We have proven the concept of prevention of breast cancer. The question is, “Have we shown it in a way that is compelling to real people in the real

world?” I am not sure we have, but for patients who are interested, we clearly have well-documented options.

Dr. Daniel F. Hayes: I agree. Exemestane does not look any more protective than the other aromatase inhibitors, and recent data suggest there may be a slight excess of cardiovascular events with these agents, vs tamoxifen, over 10 years or so. In terms of using these drugs in the prevention setting, where the benefit is very small and no reduction in mortality has been seen so far, we must be thoughtful about their widespread adoption.

Based on the MAP.3 data, can I use an aromatase inhibitor instead of tamoxifen in the postmenopausal ductal carcinoma in situ (DCIS) patient after surgery, especially if she has cardiovascular risk factors and I am worried about thromboembolism?

Carey K. Anders, MD

Dr. Carey K. Anders: In the absence of data, I would not recommend an aromatase inhibitor. Your rationale makes sense, but I would not leap from a preventive strategy to treatment of preinvasive disease.

Dr. Burstein: In every setting, from prevention to in situ cancer to early-stage cancer to metastatic disease, tamoxifen and the aromatase inhibitors have had almost continued on page 8

Sparked Questions to Breast Cancer Specialists”).

Neoadjuvant Therapy for HER2-positive Disease Two important studies evaluated the benefit of combining trastuzumab (Herceptin) and lapatinib (Tykerb) for more complete HER2 blockade in the neoadjuvant setting.

In the Translational Breast Cancer Research Consortium (TBCRC) 006 phase II study, lapatinib and trastuzumab, given together for 12 weeks without chemotherapy, produced high pathologic complete response (CR) rates in 66 patients with tumors > 3 cm or > 2 cm with palpable lymph nodes.

The pathologic CR rate overall was 28%, including 21% in ER-positive patients and 40% in the ER-negative subset.2 “The study examined the question of whether we can move away from chemotherapy and just give biologics, and the data suggest it may be possible in select patients,” Dr. Burstein said.

The findings have been consistent in a number of studies (Fig. 1, page 8).

Dr. Burstein also described the US Oncology study in which patients who continued on page 8

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Breast Cancer Prevention and Treatment Strategies continued from page 7

received trastuzumab plus lapatinib for 2 weeks, then FEC 75 (fluorouracil, epirubicin, cyclophosphamide) for four cycles followed by paclitaxel, achieved a 74% pathologic CR rate, compared with 54% with trastuzumab alone and 45% with lapatinib.3 Data are also converging to form another trend among HER2-positive patients: that pathologic CRs after neoadjuvant therapy are more likely in ER-positive than in ER-negative tumors. But, he added, pathologic CR is not universally prognostic for outcome, contrary to conventional belief. In German neoadjuvant trials, HER2-positive, ER-positive patients had similar outcomes regardless of whether pathologic CR was achieved, while in ER-negative patients pathologic CR was highly predictive of improved outcomes (P < .0001), as Gunter Von Minckwitz, MD, PhD, and colleagues reported at the 2011 ASCO Annual Meeting.4 “The idea that pathologic CR is the endpoint that matters with neoadjuvant therapy probably pertains only to certain subsets: triple-negative, HER2positive/ER-negative, and perhaps luminal B patients, who are not particu-

Studies Sparked Questions continued from page 7

identical activity. The one gap is DCIS. If I thought my patient needed one of these drugs and could not take tamoxifen, I would not quibble about using an aromatase inhibitor, but because of the data void, I would generally prefer tamoxifen.

Dr. Hayes: I would argue that tamoxifen is probably safer in the average patient. I am concerned about the long-term risk of osteoporosis and heart disease. The patient with DCIS has less than a 5% chance of distant recurrence or death. I would not use an aromatase inhibitor unless she cannot take tamoxifen and is at very high risk of breast cancer.

What study from this year’s ASCO Annual Meeting do you consider most practice-changing?

Dr. Anders: I would say the Whelan study of regional nodal irradiation was the most practicechanging.1 Our radiation oncologists have actually been doing re-

80% 70% 60% 50% 40% 30% 20% 10% 0%

T

L

Trial

neoALTTO

Regimen

Paclitaxel

T+L

T

L

T+L

T

CHER-LOB

Paclitaxel FEC

L

T+L

T

L

T+L

USON

GeparQuinto

TBCRC 006

FEC Paclitaxel

EC Docetaxel

No Chemo

Fig. 1: Pathologic complete response rates with neoadjuvant anti-HER2 therapies. CHER-LOB = Preoperative Chemotherapy plus Lapatinib or Trastuzumab or Both in HER2-positive Operable Breast Cancer; EC = epirubicin, cyclophosphamide; FEC = fluorouracil, epirubicin, cyclophosphamide; L = lapatinib; neoALLTO = Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation; TBCRC = Translational Breast Cancer Research Consortium; T = trastuzumab; USON = US Oncology. Courtesy of Harold Burstein, MD, PhD.

larly endocrine-sensitive,” Dr. Burstein explained. “If a tumor is luminal A or very sensitive to endocrine therapy, or HER2-positive/ER-positive, it is unclear that pathologic CR is prognostic.”

Lapatinib/Capecitabine Controls Brain Metastases The French phase II LANDSCAPE trial found lapatinib plus capecitabine gional nodal irradiation, based on postmastectomy findings, but these data reinforce that practice. For patients with one to three positive nodes or tumors > 3 cm, you should consider regional nodal irradiation.

Dr. Burstein: We have undersold the value of regional radiotherapy for a long time, although data from postmastectomy patients have shown its value. I find the Whelan data very compelling.

Dr. Hayes: I agree. Clinicians should discuss this paper with their radiation oncologists.

Studies are now showing improved outcomes with combined HER2 blockade. How do you give trastuzumab and lapatinib together in clinical practice?

Dr. Burstein: Three trials have shown that combining trastuzumab and lapatinib improves pathologic complete response (CR) rates, and a fourth study is ongoing. Personally, I think the question has been answered. But does any of this matter in terms of improving long-term outcome? For this, we await the re-

to be highly active against brain metastases in patients with HER2-positive metastatic breast cancer.5 The regimen produced a 67% central nervous system volumetric response rate and delayed the need for whole-brain radiotherapy among 43 patients who were followed for a median of 14 months.

A reduction ≥ 80% in central nervous system lesion volume was obsults of ALLTO, which is evaluating the combination in the adjuvant setting with SEE PAGE 2 adequate numbers of patients followed long-term.

If ALLTO shows a win for the combination, lapatinib will be incorporated into standard adjuvant treatment and therefore will be part of neoadjuvant regimens as well.

Secondly, it will validate, at least in HER2-positive patients, that achieving pathologic CRs will lead to long-term improvements in outcomes. At this point, outside of a clinical trial, however, trastuzumabbased treatment remains the standard, and I am not giving combination anti-HER2 therapy.

■

Reference 1. Whelan TJ, Olivotto I, Ackerman I, et al: NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer. 2011 ASCO Annual Meeting. Abstract LBA1003. Presented June 6, 2011.

served in 20.9% of patients, while 46.5% had a reduction of 50% to 80%.

Only 14% had central nervous system progression.

“These findings open the door to the idea that soon we will be looking at drug therapy for central nervous system metastases,” Dr. Burstein predicted. “For the moment, however, the standard of care remains local therapy—surgical resection, stereotactic radiotherapy, or whole-brain radiotherapy—while we wait for more on this therapeutic drug approach.”

Regional Irradiation Improves Outcomes in Early Breast Cancer In a study considered “practicechanging” by many specialists, Canadian investigators showed that the addition of regional nodal irradiation to whole-breast irradiation significantly improved disease-free survival, preventing both locoregional and distant recurrences, with a trend toward improved overall survival.6 The MA.20 trial included 1,832 women with node-positive or highrisk node-negative breast cancer who, after surgery, were randomly assigned to whole-breast irradiation (50 Gy in 25 fractions, with boost irradiation of 10 Gy in 5 fractions permitted) or whole-breast plus regional nodal irradiation (45 Gy in 25 fractions) to the internal mammary, supraclavicular, and high axillary lymph nodes.

Five-year disease-free survival was 84.0% in the whole-breast irradiation arm and 89.7% in the whole-breast/ regional nodal irradiation arm, for a

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Breast Cancer 33% reduction in events (P = .003).

Locoregional disease-free survival was 94.5% with whole-breast irradiation and 96.8% with the combined irradiation strategy—a 42% reduction in risk (P = .02). More unexpectedly, distant disease-free survival was 87.0% with whole-breast irradiation and 92.4% with the combination—a 36% reduction in risk (P = .002). Five-year overall survival rates were 90.7% and 92.3%, respectively, which represented a 23% nonsignificant reduction in mortality (P = .07).

The trade-off for this disease-free survival improvement was more radiation dermatitis with the additional regional nodal irradiation (50% vs 40%, P < .001), pneumonitis (1.3% vs 0.2%, P = .01), and lymphedema (7% vs 4%, P = .004).

Dr. Anders commented that the results are in keeping with what is being observed in the postmastectomy setting, where “irradiation to the regional nodes has translated into improved overall survival, both in patients with one to three positive nodes and in those with four or more.” The implication of MA.20 is that “all women receiving breast-conserving surgery for nodepositive or high-risk node-negative disease may be considered for regional irradiation, individualizing treatment for the anticipated toxicities.”

Iniparib Surprises and Disappoints in Phase III Trial Contrary to phase II results, iniparib failed to improve outcomes in an openlabel phase III trial of 519 women with stage IV triple-negative breast cancer randomly assigned to gemcitabine/carboplatin or to the same plus iniparib.7 Median progression-free survival was 5.1 months in the iniparib arm vs 4.1 months with chemotherapy alone (P = .027), which was a 21% reduction in risk that did not meet the prespecified alpha (P = .01). Median overall survival in the two arms was 11.8 and 11.1 months, respectively (P = .28). In an exploratory analysis of subgroups, patients who received iniparib in second- or third-line therapy had a 35% reduction in mortality risk and a longer progression-free survival.

The findings contradicted the encouraging results of the phase II trial, Dr. Anders noted, but she questioned whether the results were “truly inconsistent.”

“The hazard ratios are not very different, so whether the phase III results are qualitatively or quantitatively different we do not know,” she offered.

Other Breast Cancer Studies of Note

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t this year’s Best of ASCO® Miami meeting, Harold Burstein, MD, PhD, discussed several studies he found interesting and relevant to clinical practice.

Genomic Assays One study examined two genomic assays for ER-positive breast cancer, Oncotype DX and PAM50, and found considerable overlap among the genes considered relevant to the tumor.1 Gene profiles in essentially all the available assays have about a 50% overlap, “so the concordance among the assays is not surprising,” he said. “We are converging on a fairly similar set of messages in distinguishing favorable from less favorable prognoses.”

Role of Treatment Costs Other investigators examined the Surveillance, Epidemiology, and End Results (SEER)Medicare database and found little relationship between cost of care, SEE PAGE 2 outcomes, and quality.2 They identified 27 quality measures and determined the cost of treatment within 1 year of a breast cancer diagnosis. Costs varied from approximately $17,000 to nearly $27,000, and these expenditures were not related to survival; across five expenditure quintiles, 86% to 89% of patients were alive at 5 years, indicating quality of care was good, “regardless of the cost,” he noted.

“Whether this was a perfect use of health-care resources, or whether you could accomplish the same with less is unknown, but the provocative data suggest there is marked variation.”

Lifestyle Intervention Addressing the issue of treatment-associated weight gain among Future studies with biologic correlates are planned.

Neoadjuvant Bevacizumab Increases Complete Responses In NSABP B-40, which enrolled 1,206 high-risk patients, bevacizumab added to neoajuvant regimens (docetaxel [alone or with capecitabine

patients with breast cancer, Canadian investigators showed that “vigorous intervention works.”3 Over a 12-month period, patients receiving only educational information by mail lost no weight but women who participated in a telephone-based intervention (19 calls, mailings, and a participant manual) significantly increased their physical activity, reduced caloric intake, and lost an average of 10% of their weight. “These are compelling data showing we can invest resources and help patients lose weight, though whether this translates to an impact on cancer recurrence is an important question yet unanswered,” he commented.

Treatment-related Weight Gain and Survival In fact, another study validated that body mass index significantly increased in premenopausal patients during endocrine therapy (ovarian suppression), especially in those treated with tamoxifen in the ABCSG-12 trial.4 However, no differences in disease-free survival were observed between patients who gained > 0.5 kg after 1 year vs those with no weight gain. “Weight gain did not impact the natural history of the disease,” he noted. “Together with the previous study, we can say that lifestyle intervention programs can improve dietary habits and weight. However, weight gain in the adjuvant setting may be of minimal prognostic significance anyway.”

Switching Endocrine Therapies and Bone Loss Finally, discouraging findings came from a subanalysis of the Breast International Group (BIG) 1-98 trial, which examined tamoxifen, letrozole, and a “switch” strategy of endocrine therapy.5 The question was whether a patient can “bank bone” by initiating treatment with tamoxifen, before “spending bone” by switching to an aromatase inhibitor.

(Xeloda) or gemcitabine] followed by doxorubicin/cyclophosphamide) significantly increased clinical and pathologic CR rates, especially in the hormone receptor (HR)-positive subset.8 Neither capecitabine nor gemcitabine conferred additional benefit to neoadjuvant docetaxel, but these agents did contribute to toxicity.

Clinical CRs were observed in 64.3%

Harold Burstein, MD, PhD

“It doesn’t look as if this is very protective,” he said. “Switching to the aromatase inhibitor, you see bone loss.

Aromatase inhibitor–induced osteoporosis is still an issue.”

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References 1. Bastien RR, Ebbert MT, Boucher KM, et al: Using the PAM50 breast cancer intrinsic classifier to assess risk in ER+ breast cancers: A direct comparison to Oncotype DX. 2011 ASCO Annual Meeting. Abstract 503. Presented June 5, 2011.

2. Hassett MJ, Neville BA, Weeks JC: The relationship between cost, quality, and outcomes among women with breast cancer in SEER-Medicare. 2011 ASCO Annual Meeting. Abstract 6001.

Presented June 7, 2011.

3. Segal R, Pond GR, Vallis M, et al: Randomized trial of a lifestyle intervention for women with early-stage breast cancer receiving adjuvant hormone therapy: Initial results. 2011 ASCO Annual Meeting. Abstract 512. Presented June 7, 2011.

4. Pfeiler G, Königsberg R, Mlineritsch B, et al: Effect of change of body mass index during therapy on the efficacy of endocrine therapy in premenopausal patients with breast cancer: An analysis of the ABCSG-12 trial. 2011 ASCO Annual Meeting. Abstract 514.

Presented June 7, 2011.

5. De Censi A, Sun Z, Thurlimann BJK, et al: Bone mineral density (BMD) in participants (pts) of trial BIG 1-98 comparing adjuvant letrozole (L) versus tamoxifen (T) or their sequence. Abstract 516. Presented June 7, 2011.

of patients receiving bevacizumab vs 55.8% of those who did not get bevacizumab (P = .006), and pathologic CRs were achieved in 34.5% and 28.4%, respectively (P = .027). The additional benefit of bevacizumab was most striking among HR-positive women (a 70% increase), whereas it was lacking in the triple-negative subset. continued on page 10

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Breast Cancer Prevention and Treatment Strategies continued from page 9

Dr. Anders put the findings in context with similar studies, including the GeparQuinto study, in which bevacizumab did not provide additional benefit overall but did improve outcomes in triple-negative breast cancer.9 “This is somewhat in contrast to B-40,” she noted, “and fuels interest in the results of the ongoing Cancer and Leukemia Group B (CALGB) 40603 study of neoadjuvant chemotherapy.” The four-arm study has a 2×2 factorial design, with a paclitaxel backbone and random assignment to carboplatin and bevacizumab.

Metronomic Chemotherapy Not Superior to Every-2-week Schedule Adjuvant chemotherapy delivered according to a metronomic dosing schedule was not superior to chemotherapy given every 2 weeks in the Southwest OncolSEE PAGE 2 ogy Group (SWOG) S0221 trial.10 The still-accruing phase III study of 3,250 patients with node-positive or high-risk node-negative disease

is comparing a metronomic schedule of AC (weekly doxorubicin, daily oral cyclophosphamide) and filgrastim (Neupogen) for 15 weeks to dose-dense doxorubicin and IV cyclophosphamide plus pegfilgrastim (Neulasta) given every 2 weeks for six cycles. The arms were further randomly assigned to paclitaxel given weekly or every 2 weeks with pegfilgrastim. (The paclitaxel component has not yet been analyzed.)

The interim analysis of 2,662 patients showed 5-year disease-free survival to be 79% in the metronomic arm and 82% in the dose-dense arm (P = .16); overall survival was also similar at approximately 86%. Toxicity profiles did differ, however, as more cases of grade 3/4 mucositis and hand-foot syndrome were observed with metronomic AC and more hematologic toxicity was seen with dose-dense AC. The design was modified so that all new patients receive AC every 2 weeks for four, not six, cycles, before randomization to the paclitaxel arms.

“These results were surprising,” Dr. Anders commented, but she added, “There was no difference in the schedules, though there was difference in toxicity, which means a patient who develops toxicity on one schedule can be

Stay Tuned for More Information on Neuropathy-related Genes

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ccording to Daniel F. Hayes, MD, of the University of Michigan, Ann Arbor, who moderated the Best of ASCO® Miami conference, taxane-induced neuropathy is a more complicated story than the study by Schneider and colleagues may suggest.

“There are now three observations regarding inherited germline single-nucleotide polymorphisms (SNPs) and the risk of taxane-induced neuropathy, each using samples from North American breast cancer group trials and each completely I foresee a day when different,” he told The ASCO Post. In we will be able to addition to Schneider’s trial based on E5103, tissue samples from SWOG predict who will S0221 and CALGB 40101 also demonget toxicity. strate significant—though disparate— ­—Daniel F. Hayes, MD genetic associations. The investigators from these three studies are now collaborating in an effort to validate one or more of these variants. “Each investigator has made observations in one dataset, and they will now take that data and apply it to the other datasets,” Dr. Hayes said.

“Right now, I would not use any of the data to withhold taxanes, but I foresee a day when we will be able to predict who will get toxicity,” he said. “We will then be able to determine who should perhaps not receive a taxane in spite of its benefit, or should get one taxane vs the other.”

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switched to the other without compromising efficacy.”

Gene Variants Predict for Taxane-induced Neuropathy The presence of two single-nucleotide polymorphisms (SNPs), or common genetic variations, residing in two genes—RWDD3 and TECTA—was associated with an increased risk of developing taxane-induced peripheral neuropathy in a cohort of patients with breast cancer from the Eastern Cooperative Oncology Group (ECOG) E5103 trial.11 Neuropathy was reported by 60% of persons with two copies of the RWDD3 variant allele, compared to 27% among persons lacking the variant. The homozygous variant in TECTA was associated with a 55% incidence of peripheral neuropathy.

Both clinical and genetic predictors of taxane-induced neuropathy appear to exist. ­—Carey K. Anders, MD

The findings were derived from a genome-wide association study of 2,204 patients with breast cancer receiving adjuvant chemotherapy. More than 1.2 million SNPs were identified per subject. Among the 613 patients who developed grade 2–4 peripheral neuropathy, 6 missense SNPs were associated with risk, along with (but independent of) advancing age and African-American race.

“Both clinical and genetic predictors of taxane-induced neuropathy appear to exist,” Dr. Anders noted. If future studies are confirmatory, the information will help clinicians “discuss risk with patients and make informed choices about taxane schedules.”

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Disclosure: Dr. Burstein reported no relevant conflicts of interest. Dr. Anders reported receiving research funding from Novartis, BiPar Sciences, and sanofi-aventis.

Dr. Hayes holds stock in Oncimmune, LLC; has served as a consultant for Chugai Pharmaceuticals and Biomarker Strategies; and has received research funding from Pfizer, Novartis, and Veridex ( Johnson & Johnson).

References 1. Goss P, Ingle JN, Ales-Martinez J, et al: Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—A randomized, placebo-controlled clinical trial. 2011 ASCO Annual Meeting. Abstract LBA504. Pre-

sented June 5, 2001.

2. Chang JCN, Mayer IA, Forero-Torres A, et al: TBCRC006: A multicenter phase II study of neoadjuvant lapatinib and trastuzumab in patients with HER2-overexpressing breast cancer. 2011 ASCO Annual Meeting. Abstract 506. Presented June 5, 2011.

3. Holmes FA, Nagarwala YM, Espina VA, et al: Correlation of molecular effects and pathologic complete response to preoperative lapatinib and trastuzumab, separately and combined prior to neoadjuvant breast cancer chemotherapy. 2011 ASCO Annual Meeting. Abstract 506. Presented June 5, 2011.

4. Von Minckwitz G, Kaufmann M, Kuemmel S, et al: Correlation of various pathological complete response definitions with long-term outcome and the prognostic value of pCR in various breast cancer subtypes: Results from the German neoadjuvant meta-analysis. 2011 ASCO Annual Meeting. Abstract 1028. Presented June 4, 2011.

5. Bachelot TD, Romieu G, Campone M, et al: LANDSCAPE: An FNCLCC phase II study with lapatinib and capecitabine in patients with brain metastases from HER2-positive metastatic breast cancer before whole brain radiotherapy. 2011 ASCO Annual Meeting. Abstract 509. Presented June 5, 2011.

6. Whelan TJ, Olivotto I, Ackerman I, et al: NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer. 2011 ASCO Annual Meeting. Abstract LBA1003. Presented June 6, 2011.

7. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al: A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer. 2011 ASCO Annual Meeting. Abstract 1007.

Presented June 6, 2011.

8. Bear HD, Tang G, Rastogi R, et al: The effect on pCR of bevacizumab and/ or antimetabolites added to standard neoadjuvant chemotherapy: NSABP protocol B-40. 2011 ASCO Annual Meeting. Abstract LBA1005. Presented June 6, 2011.

9. Gerber B, Eidtmann H, Rezai M, et al: Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 686 triple-negative primary breast cancers: Secondary endpoint analysis of the GEPARQUINTO study. 2011 ASCO Annual Meeting. Abstract 1006. Presented June 6, 2011.

10. Budd GT, Barlow WE, Moore HCF, et al: First analysis of SWOG S0221: A phase III trial comparing chemotherapy schedules in high-risk early breast cancer.

2011 ASCO Annual Meeting. Abstract 1004. Presented June 6, 2011.

11. Schneider BP, Li L, Miller K, et al: Genetic associations with taxane-induced neuropathy by genome wide association study in E5103. 2011 ASCO Annual Meeting. Abstract 1000. Presented June 4, 2011.

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Gastrointestinal Cancer Standards of Care Confirmed in Latest Group of Colorectal Cancer Trials

By Susan London

C

olorectal cancer studies reported at this year’s ASCO meeting offered little in the way of practicechanging information, according to Axel Grothey, MD, of the Mayo Clinic in Rochester, Minnesota. But they did confirm existing standards of care, he noted at the Best of ASCO® meeting in Seattle.

Both agents were well tolerated, but a higher rate of hand-foot syndrome was seen with capecitabine, and a higher rate of leukopenia with 5-FU. Capecitabine is clearly not inferior to 5-FU in this setting, Dr. Grothey pointed out. “Overall, I think that based on these data, capecitabine can replace 5-FU in the perioperative treatment of locally advanced rectal cancer, and a lot of us have already been doing that,” he commented.

Neoadjuvant Therapy for Rectal Cancer

Axel Grothey, MD

Perioperative Therapy for Rectal Cancer Capecitabine (Xeloda) is at least as efficacious as fluorouracil (5-FU) when used in perioperative chemoradiotherapy for locally advanced rectal cancer, a phase III noninferiority trial found.1 A total of 392 patients were split into strata (adjuvant or neoadjuvant radiochemotherapy) and randomized to receive capecitabine or 5-FU (given intermittently in the neoadjuvant stratum) during radiation therapy. In the neoadjuvant stratum, the investigators found trends toward more tumor downstaging and more pathologic complete responses with capecitabine than with 5-FU. After a median of 52 months, capecitabine-treated patients had better 5-year disease-free survival (67.8% vs 54.1%, P = .035) and overall survival (75.7% vs 66.6%, P = .052). An exploratory test for superiority of overall survival bordered on significant (P = .053).

Adding oxaliplatin to neoadjuvant radiochemotherapy for locally advanced rectal cancer does not improve outcomes and increases gastrointestinal toxicity, finds the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial.2 The 1,253 patients with clinical stage II or III disease underwent 2-by2 randomization for base chemotherapy (5-FU, here given continuously vs capecitabine) and for added oxaliplatin (with vs without)—each with the same radiation therapy.

The rate of surgical downstaging did not differ between the groups receiving 5-FU and capecitabine, or between those given oxaliplatin vs no oxaliplatin. The same was true for the rate of pathologic complete response. But the incidence of diarrhea of any grade with added oxaliplatin was more than doubled (15.4% vs 6.6%, P = .0001).

The findings provide yet more evidence that capecitabine is “an adequate substitute” for 5-FU in this setting, according to Dr. Grothey. “The addition of oxaliplatin did not improve outcome and added significant toxicities,” he said. “But we need longer follow-up

Key Colorectal Cancer Findings Presented at Best of ASCO® ■■ Capecitabine works at least as well as 5-FU in perioperative

chemoradiotherapy for locally advanced rectal cancer; adding oxaliplatin to either in the neoadjuvant setting increases toxicity but not benefit.

■■ Patients with high-risk stage II colon cancer may benefit from addition of oxaliplatin to 5-FU adjuvant therapy.

■■ Metastatic colorectal cancers having the G13D KRAS mutation behave much like wild-type KRAS disease; thus, patients with these cancers may still derive some benefit when an anti-EGFR antibody is added to chemotherapy.

■■ There is high concordance between colorectal primaries and metastases

on specific clinically used mutations, such as RAS/BRAF and p53. But when more than 1,000 cancer- and treatment-relevant genes are studied, concordance is poor.

Is G13D KRAS Mutational Status Ready for Prime Time?

I

ndividual oncologists will have to decide for themselves whether the results from the pooled analysis of cetuximab trials regarding G13D KRAS mutational status are ready for clinical application, according to Axel Grothey, MD, of the Mayo Clinic in Rochester, Minnesota.

“We still need confirmatory data,” Dr. Grothey commented. In fact, a similar analysis of trials using the anti-EGFR antibody panitumumab (Vectibix) could soon be presented at an international meeting. In the meantime, “do I utilize [anti-EGFR therapy] in my clinical practice when I have a patient with G13D mutation? Yes, I do…if I see I am running out of options,” he said.

“I’m not going to use EGFR antibodies as first-line therapies in these patients, but… [I might use them] in the last-line setting,” Dr. Grothey said.

Other Health-care Systems Meeting Chair Charles D. Blanke, MD, of the University of British Columbia in Canada, pointed out that the calculus might differ in other health-care systems.

“Using anti-EGFR antibodies in G13D mutant disease seems like a reasonable thing to do if patients are paying for it or even if it is diffused among insurance companies and payers,” he elaborated. “In our case, we have to decide whether to fund it or not for the province of British Columbia. [Our protocols are] evidence-based, and we have a limited pie…. So the question is, should we fund it now? Is the evidence Charles D. Blanke, MD strong enough?”

“No, not yet,” Dr. Grothey replied, noting the some of the reported study’s analyses were based on small numbers of patients. “I’d like to see the data from the panitumumab trials.” (Editor’s note: Watch future issues of The ASCO Post for coverage of the panitumumab trials from the European Multidisciplinary Cancer Congress in Stockholm.)

Should that second anticipated analysis have the same results, the case would be sealed. “What I say right now is, I utilize [anti-EGFR therapy] as a salvage therapy option in select patients with G13D,” Dr. Grot concluded. “It’s not that common—about 8% of all patients who you might see and 18% of the KRAS mutant tumors.”

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to see whether this might translate into more time-related endpoints and longterm endpoints, such as overall survival and disease-free survival.”

Adjuvant Oxaliplatin for Highrisk Stage II Colon Cancer A pooled analysis of four NSABP trials found that adding oxaliplatin to adjuvant 5-FU chemotherapy may improve outcomes of high-risk stage II colon cancer.3 Of the four trials (C-05 through C-08), with a total of 3,000 patients, only one trial randomly assigned patients to oxaliplatin, Dr. Grothey cautioned.

Outcomes among all patients with stage II disease did not differ between oxaliplatin and no oxaliplatin. But in the high-risk subgroup, there were trends showing small absolute incre-

ments in 5-year adjusted estimates of disease-free survival (4.4%), time to recurrence (5.2%), and overall survival (3.5%) with addition of the drug.

“Now we are diving more and more into subgroups and pooled, unplanned analysis,” Dr. Grothey commented.

“But I think there is still, from my personal perspective, some room for oxaliplatin in terms of using it in very select patients in high-risk stage II tumors.”

Cetuximab in Metastatic Colorectal Cancer with G13D KRAS Mutation Patients with mutant KRAS metastatic colorectal cancer who have the G13D mutation may still derive benefit from cetuximab (Erbitux), based on continued on page 12

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Gastrointestinal Cancer Colorectal Cancer continued from page 11

a pooled exploratory analysis of data from first-line trials.4 Five of six colorectal studies assessing chemotherapy with vs without addition of antibodies to epidermal growth factor receptor (EGFR), such as cetuximab, have shown a benefit in patients with wild-type KRAS tumors, but no benefit and even potential detriment in patients with mutant KRAS, Dr. Grothey noted. In the new analysis, which pooled data from the CRYSTAL and OPUS trials, 6% of the 689 patients had the G13D KRAS mutation.

With chemotherapy alone, compared with their counterparts having other KRAS mutations, patients with the G13D mutation had poorer progressionfree survival (HR = 1.54; P = .0847) and overall survival (HR = 1.39; P = .0988).

But within the KRAS G13D mutation group, addition of cetuximab showed trends toward improved progressionfree survival (HR = 0.60; P = .1037; Fig. 1) and overall survival (HR = 0.80; P = .37). The relative benefits mirrored those in patients with KRAS wild-type disease.

“It seems to be that patients with G13D KRAS mutations behaved similarly and they benefited in a similar way from cetuximab as patients with KRAS wild type,” Dr. Grothey commented.

Study

Population

Median (months) chemotherapy + cetuximab vs chemotherapy

HR [95% CI]

Pooled Analysis

KRAS wt (n=845)

9.6 vs 7.6

0.66 [0.55-0.80]

KRAS mt-G13D (n=83)

7.4 vs. 6.0

0.60 [0.32-1.12]

KRAS mt-G12V (n=125)

5.6 vs. 8.8

1.55 [0.94-2.56]

KRAS mt-other (n=325)

6.7 vs. 8.1

1.37 [1.02-1.84]

KRAS wt (n=666)

9.9 vs. 8.4

0.69 [0.56-0.86]

KRAS mt-G13D (n=60)

7.5 vs. 7.4

0.72 [0.33-1.57]

KRAS mt-G12V (n=91)

6.7 vs. 8.2

1.43 [0.79-2.59]

KRAS mt-other (n=246)

7.1 vs. 7.7

1.19 [0.84-1.68]

KRAS wt (n=179)

8.3 vs. 7.2

0.57 [0.37-0.88]

KRAS mt-G13D (n=23)

5.7 vs. 5.6

0.40 [0.13-1.21]

KRAS mt-G12V (n=34)

4.4 vs. 9.4

1.89 [0.73-4.86]

KRAS mt-other (n=79)

5.5 vs. 8.6

2.06 [1.12-3.76]

CRYSTAL

OPUS

0.1 0.5 Benefit under chemotherapy + cetuximab

P

VELOUR Results The 1,226 patients enrolled had all experienced failure of oxaliplatinbased therapy. The rate of adverse events leading to treatment discontinuation was about twice as high with aflibercept as with placebo (26.6% vs 12.1%). In addition to the usual anti-VEGF therapy adverse effects such as hypertension, patients had more diarrhea and neutropenia.

With a median follow-up of 22.3

2.0 Benefit under chemotherapy alone

Fig. 1: KRAS mutation status and treatment effect on progression-free survival. mt = mutant; wt = wild type. Courtesy of Axel Grothey, MD. Adapted from Tejpar X, et al.4

Concordant Mutations Found in Primary, Metastatic Colorectal Cancers An analysis finds primary colorectal cancers and their metastases show a high degree of concordance when it comes to mutations that are used for clinical decision-making and prognostication.5 In the sequencing analysis of 84 pairs

of matched primaries and metastases, the primaries were more likely to have to have a BRAF mutation (P = .01) and less likely to have a p53 mutation (P < .001). Still, using formalin-fixed, paraffin-embedded samples, the investigators found a high concordance between the primaries and metastases for mutational status of RAS/ BRAF (97.6%), PI3 kinase (98.8%), and

Will Aflibercept Break Dry Spell in New Agents for Colorectal Cancer? romising results were recently presented from VELOUR, a second-line phase III trial comparing FOLFIRI (leucovorin, fluorouracil, irinotecan) with vs without aflibercept, a fusion protein that binds placental growth factor, VEGFA, and VEGFB.1 “This is an important trial because it might lead to the approval of a novel agent for colorectal cancer,” said Dr. Grothey.

1.0

months, the aflibercept group had better progression-free survival (6.9 vs 4.67 months; HR = 0.758; P = .00007) and overall survival (13.5 vs 12.06 months; HR = 0.817; P = .0032).

“The survival curves…split early, they stay separate, and there is clearly survival benefit, although it’s perhaps not as strong as we would like it to be,” Dr. Grothey commented.

In subgroup analyses, benefit appeared greater in patients who were bevacizumab (Avastin)-naive than in those who had received bevacizumab.

Similar Trial In the similar E3200 Intergroup trial, which tested second-line FOLFOX4 with vs without bevacizumab, all of the patients were bevacizumab-naive, compared with 70% in the VELOUR trial.

“When you compare outcome parameters—overall survival, progres-

sion-free survival, and response rates—side by side, they seem to be very similar,” SEE PAGE 2 he said, while acknowledging the pitfalls of cross-trial comparisons. Aflibercept is “probably not as new as we would like it to be, particularly since 70% of these patients did not have bevacizumab first line. But it will be interesting to see how this plays out.”

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Reference 1. Van Cutsem E, Tabernero J, Lakomy R, et al. Intravenous (IV) aflibercept versus placebo in combination with irinotecan/5-FU (FOLFIRI) for secondline treatment of metastatic colorectal cancer (MCRC): Results of a multinational phase 3 trial (EFC10262-VELOUR). 13th ESMO World Congress on Gastrointestinal Cancer. Abstract 0-0024.

Presented June 25, 2011.

p53 (95.2%). The value was 90.5% when all three were considered.

“This means, if we just focus on these mutations—which we do right now in our clinical practice—you do not need to biopsy metastases,” Dr. Grothey commented. “You can make do with the primary tumor.”

Colorectal Tumors and Liver Metastases Genetically Dissimilar A study of a cancer mini‑ genome—1,264 genes relevant to the biology and treatment of cancer— shows that colorectal cancer primaries differ genetically from their liver metastases if one looks closely enough.6 Investigators analyzed formalinfixed, paraffin-embedded tissue from 21 patients who developed liver metastases, finding 8,405 genetic variations in the genes studied.

Analyses showed marked losses and gains of genetic variations going from the primary to the metastasis, regardless of receipt of adjuvant chemotherapy; on average, tumors lost 70 variations and gained 83 variations.

“There was not a single tumor where primary tumor and metastasis were completely identical. All tumors had variations in the genetic makeup between primary tumor and metastasis, either as loss mutations or gain mutations,” Dr. Grothey commented.

“So we can now say, if we focus on KRAS and BRAF, that they are ge-

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Gastrointestinal Cancer netically similar,” he said. “But if you look at the whole genome in this analysis, primary tumors SEE PAGE 2 and metastases are different in their genetic makeup, and we know that because tumors respond heterogeneically to treatment.”

In this case, the investigators concluded that genetic analysis of metastases at the start of treatment may be better than relying on archival primary tumor.

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Disclosure: Disclosure: Dr. Grothey has received research support from Genentech, Imclone/Eli Lilly, Daiichi, and Bayer.

References 1. Hofheinz R, Wenz FK, Post S, et al: Capecitabine (Cape) versus 5-fluorouracil (5-FU)–based (neo)adjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): Long-term results of a randomized, phase III trial. 2011 ASCO Annual Meeting. Abstract 3504.

Presented June 4, 2011.

2. Roh MS, Yothers GA, O’Connell MJ, et al: The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma

Risk-based Approach Needed for Stage II Colorectal Cancer

M

anagement of stage II colorectal cancer remains a considerable gray area where an individualized risk-based approach and more molecular research are needed, according to Axel Grothey, MD, of the Mayo Clinic in Rochester, Minnesota.

“Stage II is a little bit more complicated than stage III,” he commented. The initial step in his personal decision algorithm for managing stage II disease is to discern the patient’s risk for poor outcomes, first using clinical information.

Dr. Grothey’s viewpoint is that

patients are at high risk if they have T4 tumors and/or had fewer than 12 lymph nodes examined at resection.

“Those patients can be candidates for a stage III–like approach,” with adjuvant FOLFOX [leucovorin, fluorouracil, oxaliplatin] or XELOX [capecitabine (Xeloda), oxaliplatin], or an alternative regimen if they cannot receive oxaliplatin.

In the remaining stage II patients, oncologists can use a biologic marker, deficient mismatch repair phenotype (or microsatellite instability, MSI), to

further risk-stratify.

“MSI-high tumors have excellent outcomes, with a very low rate of recurrence. These tumors are low risk, and they should not be treated,” Dr. Grothey maintained.

“For the intermediate-risk patients, this is exactly where we need molecular signatures—something like Oncotype DX, ColoPrint, or GCC [guanylyl cyclase C],” he concluded. “This is an area of active research right now to identify patients who might be candidates for chemotherapy or no treatment.”

of the rectum: NSABP R-04. 2011 ASCO Annual Meeting. Abstract 3503. Presented June 4, 2011.

3. Yothers GA, Allegra CJ, O’Connell MJ, et al: The efficacy of oxaliplatin (Ox) when added to 5-fluorouracil/leucovorin (FU/L) in stage II colon cancer. 2011 ASCO Annual Meeting. Abstract 3507.

Presented June 4, 2011.

4. Tejpar S, Bokemeyer C, Celik I, et al: Influence of KRAS G13D mutations on outcome in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy with or without cetuximab. 2011 ASCO Annual Meeting.

Abstract 3511. Presented June 4, 2011.

5. Vakiani E, Janakiraman M, Shen R, et al: Comparative genomic analysis of

primary versus metastasis in colorectal carcinomas. 2011 ASCO Annual Meeting.

Abstract 10500. Presented June 6, 2011.

6. Vermaat JSP, Nijman IJ, Koudijs MJ, et al: Primary colorectal tumors and their metastasis are genetically not the same: Implications for choice of targeted treatment? 2011 ASCO Annual Meeting. Abstract 3535. Presented June 6, 2011.

Further Risk Stratification

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Practice-changing Evidence in Treatment of Noncolorectal GI Cancers

By Susan London

S

tudies presented at the ASCO Annual Meeting in the field of noncolorectal gastrointestinal cancer both reaffirmed certain standards of care and introduced some practice-changing data, according to A. Craig Lockhart, MD, of Washington University in St. Louis.

Perioperative Therapy for Gastric Cancer After curative resection of gastric or gastroesophageal junction cancer, the combination of ECF (epirubicin, cisplatin, and infusional 5-FU) is not more efficacious or safer than the standard of bolus fluorouracil (5-FU) and

leucovorin when incorporated into a chemoradiation scheme, according to findings of the Cancer and Leukemia Group B (CALGB) 80101 trial.1 Among 546 patients with resected tumors, each regimen was given before and after chemoradiation. The postchemoradiation doses of epirubicin and cisplatin in ECF were reduced because of toxicity concerns. Trial results showed that the two groups did not differ significantly regarding disease-free and overall survival, and had similar rates of toxicities.

“A question that came up is, did the downgrading of the epirubicin and cisplatin doses potentially impact the efficacy

Key Noncolorectal GI Cancer Findings Presented at Best of ASCO® ■■ Epirubicin, cisplatin, and infusional 5-FU does not have better efficacy or

safety than standard 5-FU/leucovorin as part of perioperative therapy for gastric or gastroesophageal junction cancer.

■■ Giving adjuvant XELOX (capecitabine/oxaliplatin) after D2 resection

improves 3‑year disease-free survival in gastric cancer (74% vs 60%).

■■ Relative to best supportive care for advanced gastric cancer, second-line chemotherapy prolongs overall survival by 1.3 months.

■■ Sorafenib can be given at full dose and may provide some benefit in

patients with advanced hepatocellular carcinoma and Child-Pugh B status.

■■ Cisplatin is not superior to mitomycin when used with 5-FU as a component of chemoradiation for anal cancer.

[of the ECF]. I don’t think we have the answer at this time,” Dr. Lockhart said.

“It does not appear that ECF is any better than the standard Intergroup 0116 approach” of 5-FU/leucovorin, he commented. “Incorporating ECF, making the 0116 regimen more complicated by adding other drugs to it, does not appear to improve survival, so the 0116 approach is still a standard.”

Adjuvant XELOX in Gastric Cancer The phase III CLASSIC trial showed that giving XELOX (capecitabine [Xeloda] plus oxaliplatin) in the adjuvant setting improves disease-free survival in gastric cancer even after the more extensive D2 resection.2 In all, 1,035 patients in South Korea, China, and Taiwan underwent a D2 resection and were randomly assigned to XELOX or observation. Median dose intensity was 85% for capecitabine and 98% for oxaliplatin, and there were no unexpected toxicities.

The 3-year rate of disease-free survival was better with XELOX (74% vs 60%; HR = 0.56; P < .0001; Fig. 1). Rates of recurrence were reduced at all sites: locoregional, peritoneal, and distant. Overall survival did not differ. “But this study had

A. Craig Lockhart, MD

not been going on long enough to look at that definitively,” Dr. Lockhart noted.

“Adjuvant XELOX is a standard option following a D2 resection,” he concluded.

“In my opinion, this is practice-changing.”

Second-line Chemotherapy for Advanced Gastric Cancer Second-line chemotherapy has a 1.3-month survival benefit in fit patients with advanced gastric cancer, a phase III trial revealed.3 The 193 patients were randomly assigned 2:1 to second-line chemotherapy (docetaxel or irinotecan) or best supportive care. Relative dose intensity was 95% for docetaxel and 93% for irinotecan.

With a median follow-up of 17 months, overall survival was better with second-line chemotherapy than with continued on page 14

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Gastrointestinal Cancer continued from page 13

best supportive care (5.1 vs 3.8 months, P = .009). Benefit did not differ between docetaxel and irinotecan recipients.

“Interestingly, no quality-of-life data were presented,” Dr. Lockhart noted. However, there was a trend toward a lower rate of grade 3/4 fatigue with chemotherapy vs best supportive care (18% vs 27%). And a similar study of second-line irinotecan found an improvement in symptoms.4 “Second-line chemotherapy can be considered a standard approach for patients with good performance status…who want to receive second-line therapy,” he maintained.

Sorafenib for Child-Pugh B Patients with Hepatocellular Carcinoma Patients with advanced hepatocellular carcinoma having Child-Pugh B class liver function may derive some benefit from sorafenib (Nexavar) and can start on the full dose, according to new data.5 In a second interim analysis of the GIDEON study, which is assessing sorafenib therapy in routine clinical practice, investigators analyzed data from 1,612 patients. The Child-Pugh class was A, B, and C in 70%, 27%, and 3% of patients, respectively.

The majority of patients received the full 800-mg dose of sorafenib, regardless of Child-Pugh class. However, the

median treatment duration fell off with 1.0 class—it was 14, 9, 74% and 4 weeks with A, 0.8 B, and C class. The XELOX, n=520 0.6 corresponding rate 60% Observation, n=515 of adverse events 0.4 leading to treatment discontinuation was HR=0.56 (95% CI 0.44–0.72) 0.2 24%, 38%, and 51%.

P < .0001 Median overall 0.0 survival was 10.3, 6 12 18 24 30 36 42 48 0 4.8, and 2.0 months.

Time (months) The 10.3 months in No. left XELOX 520 443 410 333 246 166 74 30 10 patients with class A Observation 515 414 352 286 209 147 58 22 6 liver function is “re* Primary endpoint met at 1st interim analysis assuring” because it mirrors that in clini- Fig. 1: Three-year disease-free survival in the CLASSIC trial. Courtesy of A. Craig Lockhart, MD. Adapted from Bang Y, et al.2 cal trials, according according to long-term results of the prising as we thought cisplatin was goto Dr. Lockhart. The results suggest Radiation Therapy Oncology Group ing to potentially change the way that we the same dosing strategy can be used (RTOG) 98-11 trial.6 practice. It did not,” for patients with Child-Pugh A and B A total of 650 patients were randomly Dr. Lockhart assertclass, he said. assigned to cisplatin (induction with ed. “5-FU/mitomy“Right now, there is no indication 5-FU and cisplatin before chemoradiacin along with radiato treat Child-Pugh C patients with tion with 5-FU and cisplatin) or mitomytion therapy remains sorafenib,” Dr. Lockhart maintained.

SEE PAGE 2 cin (only chemoradiation with 5-FU and the standard for pa“I would argue that Child-Pugh B pamitomycin). Compared with cisplatin, tients with anal canal carcinomas.” tients probably don’t benefit much Disclosure: Dr. Lockhart has received mitomycin yielded higher 5-year rates from sorafenib either, but if you don’t research funding from Allos, Amgen, Bayer, of disease-free survival (67.7% vs 57.6%, have other options, such as a clinical Imclone/Lilly, Novartis, Merck, Millennium, P = .004) and overall survival (78.2% vs trial, I don’t think it’s wrong to [offer Pfizer, Sanofi-Aventis, and Zenyaku.

70.5%, P = .02), and a trend toward a it].”

References lower rate of colostomy failure (11.9% vs 1. Fuchs CS, Tepper JE, Niedzwiecki D, Cisplatin in Chemoradiation 17.3%, P = .075). Male sex, a primary tuet al: Intergroup trial CALGB 80101. 2011 for Anal Cancer mor larger than 5 cm, and clinically posiASCO Annual Meeting. Abstract 4003.

Cisplatin is not superior to the stantive lymph nodes were all independent Presented June 7, 2011. dard mitomycin when used with 5-FU adverse prognostic factors.

2. Bang Y, Kim YW, Yang H, et al: Adjuin chemoradiation for rectal cancer, “The results remain somewhat sur3-year disease-free survival*

Noncolorectal Gastrointestinal Cancer

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Will East-West Differences Limit Transferability of Clinical Trial Results?

D

ifferences in patients’ tumor characteristics and in surgical practices between eastern and western countries may limit the transferability of clinical trial results in early gastric cancer, according to Dr. Lockhart.

One major difference is tumor location. For example, in the Asian CLASSIC trial, distal tumors largely predominated, whereas in trials conducted in western populations, 20% to 30% of patients have had proximal tumors.

Extent of Surgery A second major difference is the extent of surgery. All patients in the CLASSIC trial underwent a D2 resection (resection of the regional lymphatics, the perigastric lymph nodes, and the lymph nodes along the named vessels of the celiac axis), with a median of 42 to 43 lymph nodes

examined. But just 10% and 30% of patients in the western Intergroup 0116 and MAGIC studies, respectively, had a D2 resection, and the median numbers of lymph nodes examined in western trials is more typically in the teens.

“Definitely, the type of surgery that’s being performed in Asia is substantially different than what we are doing in our current clinical trials,” he said. “And I think that’s impactful in that now there are new recommendations that D2 resections need to be standard or at least routinely attempted.” Those new recommendations also call for examination of more than 15 lymph nodes.1 Oncologists may worry about increased morbidity of a D2 vs D1 resection, Dr. Lockhart said. Reassuringly, a long-term follow-up comparison found that at least in terms of postoperative sur-

vival, patients given a D2 resection, in fact, fared better.2 “But I do think their recovery time SEE PAGE 2 is somewhat longer than in the patients who are undergoing the D1 resections,” he added.

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References 1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Gastric Cancer (including cancer in the proximal 5 cm of the stomach). Version 2.2011. Available at http://www.nccn.org/professionals/ physician_gls/pdf/gastric.pdf.

Accessed September 1, 2011.

2. Songun I, Putter H, Kranenbarg EM, et al: Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 11:439-449, 2010.

vant capecitabine and oxaliplatin for gastric cancer: Results of the phase III CLASSIC trial. 2011 ASCO Annual Meeting. Abstract LBA4002. Presented June 7, 2011.

3. Park SH, Lim DH, Park K, et al: A multicenter, randomized phase III trial comparing second-line chemotherapy plus best supportive care with BSC alone for pretreated advanced gastric cancer. 2011 ASCO Annual Meeting. Abstract 4004. Presented June 7, 2011.

4. Thuss-Patience PC, Kretzschmar A, Bichev D, et al: Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer: A randomised phase III study of the AIO. Eur J Cancer July 8, 2011 (early release online).

5. Marrero JA, Lencioni R, Kudo M, et al: Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib (GIDEON) second interim analysis in more than 1,500 patients. 2011 ASCO Annual Meeting. Abstract 4001. Presented June 7, 2011.

6. Gunderson LL, Winter KA, Ajani JA, et al: Long-term update of U.S. GI intergroup RTOG 98-11 phase III trial for anal carcinoma. 2011 ASCO Annual Meeting.

Abstract 4005. Presented June 7, 2011.

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Hematology Similar Outcomes Confirmed in Variety of Lymphoma Treatment Comparisons

By Susan London

T

hree abstracts reported at the Best of ASCO® meeting in Seattle provide guidance to hematologists when it comes to long-standing gray areas in lymphoma management, according to Oliver Press, MD, PhD, of the Fred Hutchinson Cancer Research Center and the University of Washington, Seattle.

factor support, or to receive eight cycles of R-CHOP-21 plus eight cycles of rituximab alone. Patients given the standard regimen (R-CHOP-21) were more likely to stop treatment early (19.8% vs 10.7%) and had higher rates of toxicities.

After a median of 39 months, overall survival did not differ between R-CHOP-21 and R-CHOP-14 overall or in subgroup analyses (Fig. 1). Failure-free survival was identical.

The investigators “did admit afterwards that they wished they had just done six cycles of each [regimen], because there’s a lingering question there.

But I think most people felt that six cycles is adequate,” Dr. Press noted.

“I think you can use either regimen,” he concluded. “Most people find R-CHOP-21 more user friendly and patients generally find it easier to tolerate. If you are in a hurry to get done, R-CHOP-14 is okay if you give it with growth factors. But there’s not a compelling reason in terms of outcome to use it.”

Oliver Press, MD, PhD

Compressed R-CHOP in Diffuse Large B-cell Lymphoma A phase III UK trial in patients with newly diagnosed, CD20-positive diffuse large B-cell lymphoma found that giving R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone) every 14 days instead of the standard every 21 days allows patients to finish chemotherapy sooner but does not improve outcomes.1 More than half of patients in the trial were 60 or older, and none were younger than 19 years.

In all, 1,080 patients were randomly assigned to receive six cycles of R-CHOP-14 plus eight cycles of rituximab with growth

No Gain Seen in Survival with Upfront Transplant for NHL Upfront autologous transplantation after successful induction does not improve survival in patients with high-intermediate or high International Prognostic Index (IPI) non-Hodgkin lymphoma, according to results of a phase III trial.2 More than three-fourths of the 370

Research Is Taking the Guesswork Out of Lymphoma Management

T

he selected studies answer some critical questions in lymphoma that hematologists face daily and that have been the source of intense debate in the field, according to Oliver Press, MD, PhD, of the Fred Hutchinson Cancer Research Center and the University of Washington, Seattle.

“I think the studies give reassurance and guidance to the practicing oncologist, who can feel comfortable giving R-CHOP on a 3-week cycle, which is user friendly for the doctor and the patient,” he commented in an interview. “Second, it is very reasonable to defer transplant and only give it to patients who have disease recurrence—not to do it expectantly, but to wait until the patient demonstrates it’s necessary. And third, you don’t need to give maintenance rituximab to patients with large-cell lymphomas after transplant; it’s expensive treatment, and the expense isn’t warranted after transplant in that situation.”

Lingering Questions At the same time, there are lingering questions. For example, is there a better rituximab-containing regimen for diffuse large B-cell lymphoma that gets away from CHOP? To that end, a phase III trial (Cancer and Leukemia Group B [CALGB] 50303) is pitting R-CHOP-21 against dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab). The investigation has several embedded molecular studies, too.

“I think it’s a very important study and it could transform our treatment and improve the cure rate if EPOCH-R is superior—it may change entirely the way we treat large-cell–lymphoma patients,” Dr. Press contended. “So I would strongly encourage everyone to participate in that trial.”

■

enrolled patients had diffuse large B-cell lymphoma. One-third had a high ageadjusted IPI. The 253 patients having a partial response or better to induction therapy were randomly assigned to con-

1.0 0.9 0.8

Probability

0.7 0.6

Events, n (%)

0.5

2-yr OS

0.4 0.3 0.2

R-CHOP-14

123 (23%)

117 (22%)

81%

83%

Log-rank test

P = .70

HR (95% CI)

0.95 (0.74–1.23)

R-CHOP-21 R-CHOP-14

0.1 0.0 0

1

2

3

4

5

6

120 117

28 30

1

Years from randomization

Patients at risk R-CHOP-21 R-CHOP-14

R-CHOP-21

540 540

474 476

392 393

234 242

1

Fig. 1: Overall survival in study of R-CHOP every 14 vs 21 days for diffuse large B-cell lymphoma. OS = overall survival; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. Courtesy of Oliver Press, MD. Adapted from Cunningham D, et al.1

solidation with upfront transplantation or no upfront transplantation (simply more cycles of therapy).

Although rates of grade 3/4 toxicities were higher in the group receiving upfront transplantation, the 2-year rate of progression-free survival was better in this group (69% vs 56%; P = .005).

The 2-year rate of overall survival was not, mainly because of a high rate of salvage transplantation after relapse in the other group. However, exploratory subgroup analyses suggested both progression-free and overall survival benefits of upfront transplantation for patients with a high IPI. Eleven other studies have looked at upfront transplantation, Dr. Press noted. “The current trial was organized to try to ask this question for a 12th time and to try to come up with a definitive answer. I’ll leave it up to you to decide whether that happened or not,” he said.

The findings have led some to endorse upfront transplant for high-IPI patients. “But you have to remember it was an unplanned retrospective subset analysis,” he cautioned. “And whether that’s good enough for you, I think the debate will go on.” continued on page 21

Her struggle is fresh, but she can

move on with new confidence.

with the administration of systemic steroids, circulatory support measures, and temporarily withholding GLEEVEC • Bullous dermatologic reactions (eg, erythema multiforme and StevensJohnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of GLEEVEC at a lower dose with or Important Safety Information without concomitant corticosteroids or antihistamines following resolution • GLEEVEC is often associated with edema and occasionally serious fluid or improvement of the bullous reaction retention. Patients should be weighed and monitored regularly for signs and • Clinical cases of hypothyroidism have been reported in thyroidectomy symptoms of fluid retention, which can be serious or life-threatening, and patients undergoing levothyroxine replacement during treatment with be advised to report any rapid, unexpected weight gain. The probability of GLEEVEC. TSH levels should be closely monitored in such patients edema tended to be increased among older patients (>65 years) or those • Consider potential toxicities—specifically liver, kidney, and cardiac toxicity— taking higher doses of GLEEVEC. If severe fluid retention occurs, manage and immunosuppression from long-term use with diuretic therapy and withhold GLEEVEC until the event has resolved and then resume depending on the initial severity of the event • Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant • Cytopenias have been reported. Complete blood counts should be while taking GLEEVEC tablets and to avoid breast-feeding while taking performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). GLEEVEC tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use Dose reduction or treatment interruption may be required for severe adequate contraception. If the patient does become pregnant while taking neutropenia or thrombocytopenia (see full Prescribing Information for dose GLEEVEC, the patient should be advised of the potential hazard to the fetus adjustment recommendations) • Growth retardation has been reported in children and pre-adolescents • Severe congestive heart failure and left ventricular dysfunction have receiving GLEEVEC. The long-term effects of prolonged treatment with occasionally been reported. Most of the patients with reported cardiac GLEEVEC on growth in children are unknown; therefore, monitoring of events have had other comorbidities and risk factors, including advanced growth in children taking GLEEVEC is recommended age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, • Cases of tumor lysis syndrome (TLS), including fatal cases, have been and any patient with signs or symptoms consistent with cardiac failure reported. The patients at risk of TLS are those with tumors having a high should be evaluated and treated proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken • Hepatotoxicity, occasionally severe, may occur. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with • In the Phase 2 unresectable or metastatic GIST trial (400 mg/day; both short-term and long-term use of GLEEVEC. Assess liver function before 600 mg/day), severe (NCI Grades 3/4) lab abnormalities—including initiation of treatment and monthly thereafter or as clinically indicated. anemia (3%; 9%) and neutropenia (10%; 11%)—were reported among Monitor liver function when combined with chemotherapy known to be patients receiving GLEEVEC. In Phase 3 unresectable or metastatic associated with liver dysfunction. A 25% decrease in the recommended GIST trials (400 mg/day; 800 mg/day), severe adverse reactions (NCI dose should be used for patients with severe hepatic impairment. If severe Grades 3/4/5), including abdominal pain (14%; 12%), edema (9%; 13%), hepatotoxicity occurs, GLEEVEC should be withheld until the event has fatigue (12%; 12%), nausea (9%; 8%), vomiting (9%; 8%), diarrhea resolved and then resumed depending on the initial severity of the event (8%; 9%), rash (8%; 9%), and myalgia (6%; 4%), were reported among patients receiving GLEEVEC • In the Phase 3 unresectable or metastatic GIST studies, 13% of patients reported (NCI Grades 3/4) hemorrhage at any site. In the Phase 2 • In the adjuvant treatment of GIST trials (GLEEVEC; placebo), severe unresectable or metastatic GIST study, 5% of patients were reported (NCI Grades 3 and above) lab abnormalities—increase in liver enzymes to have severe gastrointestinal (GI) bleeds and/or intratumoral bleeds.

(ALT) (3%; 0%), (AST) (2%; 0%), decreased neutrophil count (3%; 1%), GI tumor sites may have been the source of GI bleeds and decrease in hemoglobin (1%; 0%)—and severe adverse reactions (NCI Grades 3 and above), including abdominal pain (3%; 1%), diarrhea • In patients with hypereosinophilic syndrome and cardiac involvement, (3%; 1%), rash (3%; 0%), fatigue (2%; 1%), nausea (2%; 1%), vomiting cardiogenic shock and left ventricular dysfunction have been associated (2%; 1%), white blood cell count decreased (1%; 0%), and periorbital with initiation of GLEEVEC. The condition was reported to be reversible

GLEEVEC® (imatinib mesylate) tablets are indicated for adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. Approval is based on recurrence-free survival with a median follow-up of 14 months. Clinical benefit has not been demonstrated by a long term effect on recurrence-free survival or survival.

GLEEVEC for adjuvant therapy in KIT+ GIST

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With a median follow-up of 14 months, more than double the number of patients in the placebo arm experienced disease recurrence compared with those in the GLEEVEC arm (HR=0.398 [95% CI: 0.259, 0.610], P<0.0001): GLEEVEC 30/359=8.4%, placebo 70/354=19.8%1 Some serious adverse reactions may occur, including severe congestive heart failure, left ventricular dysfunction, hepatotoxicity, edema, hemorrhage, GI perforation, and hypothyroidism1 The most frequently reported adverse reactions at the time of discontinuation were edema, GI disturbances, fatigue, decreased hemoglobin, and rash1

GLEEVEC Significantly Improves RFS vs Placebo1 100

80

Patients with RFS (%)

■

60

ACTIVE TREATMENT PERIOD

40

NONTREATMENT FOLLOW-UP GLEEVEC (n=359)

20

Placebo (n=354)

0 0

6

12

18

24

30

36

42

48

54

Time to recurrence (months) Patients at risk: GLEEVEC

359

258

207

166

105

60

33

23

5

Placebo

354

243

186

138

89

57

34

19

8

1

A Phase 3, randomized, double-blind study of adjuvant GLEEVEC vs placebo was conducted in 713 patients following resection of primary KIT+ GIST. The efficacy end point of the study was recurrence-free survival (RFS), defined as the time from date of randomization to the date of recurrence or death from any cause.

edema (1%; 0%), were reported among patients receiving adjuvant treatment with GLEEVEC • There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and GI perforation • GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Significant reductions in imatinib concentrations may occur when GLEEVEC is administered concomitantly with agents that are strong CYP3A4 inducers such as rifampin, St. John’s wort, and enzyme-inducing anti-epileptic drugs, eg, phenytoin. The use of concomitant strong CYP3A4 inducers should be avoided. If patients must be administered a strong CYP3A4 inducer, the dosage of GLEEVEC should be increased by at least 50% and clinical response should be carefully monitored. Caution is recommended when GLEEVEC is administered with CYP3A4 inhibitors such as ketoconazole, with CYP2D6 substrates that have a narrow therapeutic window, or with CYP3A4 substrates that have a narrow therapeutic window. Other examples of commonly used drugs that may significantly interact with GLEEVEC include acetaminophen, warfarin, erythromycin, and metoprolol. Grapefruit juice should also be avoided in patients taking GLEEVEC. (Please see full Prescribing Information for other potential drug interactions) • Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg are not recommended. GLEEVEC should be used with caution in patients with severe renal impairment

Common Side Effects of GLEEVEC Tablets • Almost all patients who received GLEEVEC in the Phase 3 unresectable or metastatic GIST studies experienced adverse reactions at some time.

Overall, the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema and rash/related terms, which were reported more frequently in the 800-mg group. The most frequently reported adverse reactions (400 mg/day; 800 mg/day) (all Grades) were edema (77%; 86%), fatigue (69%; 75%), nausea (58%; 65%),

abdominal pain (57%; 55%), diarrhea (56%; 58%), rash and related terms (56%; 70%), vomiting (37%; 41%), myalgia (32%; 30%), anemia (32%; 35%), anorexia (31%; 36%), and arthralgia (14%; 12%). Therapy with GLEEVEC was discontinued for adverse reactions in 5% of patients at both dose levels studied* • In the adjuvant treatment of GIST trials, almost all GLEEVEC- and placebo-treated patients experienced adverse reactions at some time.

The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include (GLEEVEC; placebo) (all Grades) diarrhea (59%; 29%), fatigue (57%; 41%), nausea (53%; 28%), periorbital edema (47%; 15%), decreased hemoglobin (47%; 27%), peripheral edema (27%; 15%), rash (26%; 13%), vomiting (26%; 14%), abdominal pain (21%; 22%), anorexia (17%; 9%), arthralgia (15%; 15%), and myalgia (12%; 12%)* • In the adjuvant GIST trial, drug was discontinued for adverse events in 17% of GLEEVEC- and 3% of placebo-treated patients. Edema, GI disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation* • Supportive care may help reduce the severity of some mild-to-moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary • For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron • GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation • Patients should be informed to take GLEEVEC exactly as prescribed, and not to change their dose or stop taking GLEEVEC unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose *For more detailed study information, please see full Prescribing Information.

Please see brief summary of Prescribing Information on the following pages.

Reference: 1. GLEEVEC (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2011. ®

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2011 Novartis

Printed in USA

9/11

GLI-1030100

GLEEVEC (imatinib mesylate) tablets for oral use Initial U.S. Approval: 2001 BRIEF SUMMARY: The following information refers to adult patients with Kit-positive GIST. Experience with other indications may differ. Please see package insert for full prescribing information.

1 INDICATIONS AND USAGE 1.8 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

1.9 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. Approval is based on recurrence-free survival with a median follow-up of 14 months. Clinical benefit has not been demonstrated by a long term effect on recurrence-free survival or survival.

4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Fluid Retention and Edema Gleevec is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1) in the full prescribing information]. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Gleevec dose and age >65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. Severe fluid retention was reported in 9% to 13.1% of patients taking Gleevec for GIST [see Adverse Reactions (6.11)].

5.2 Hematologic Toxicity Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia.

These generally occur within the first several months of therapy [see Dosage and Administration (2.11) in the full prescribing information].

5.3 Severe Congestive Heart Failure and Left Ventricular Dysfunction Severe congestive heart failure and left ventricular dysfunction have occasionally been reported in patients taking Gleevec. Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study in 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.

5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with Gleevec [see Adverse Reactions (6.3)]. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of Gleevec. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with Gleevec interruption and/or dose reduction [see Dosage and Administration (2.10) in the full prescribing information].

When Gleevec is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.

5.5 Hemorrhage In the newly diagnosed CML trial, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages.

5.6 Gastrointestinal Disorders Gleevec is sometimes associated with GI irritation. Gleevec should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation.

5.7 Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of Gleevec therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec should be considered at the initiation of therapy.

5.8 Dermatologic Toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Gleevec. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon re-challenge. Several foreign post-marketing reports have described cases in which patients tolerated the reintroduction of Gleevec therapy after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.

5.9 Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients.

5.10 Toxicities from Long-Term Use It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals.

An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in worsening of normally

suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans).

Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Nonneoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.

5.11 Use in Pregnancy Pregnancy Category D Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec.

Sexually active female patients taking Gleevec should use adequate contraception. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area. [see Use in Specific Populations (8.1)] 5.12 Children and Adolescents Growth retardation has been reported in children and pre-adolescents receiving Gleevec. The long term effects of prolonged treatment with Gleevec on growth in children are unknown. Therefore, close monitoring of growth in children under Gleevec treatment is recommended. [see Postmarketing Experience (6.13)] 5.13 Tumor Lysis Syndrome Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL and eosinophilic leukemia receiving Gleevec. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.

6.2 Hematologic Toxicity Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses ≥750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease.

In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 4 and 5 in the full prescribing information). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5 in the full prescribing information). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively.

These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with Gleevec, but in rare cases require permanent discontinuation of treatment.

6.3 Hepatotoxicity Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5 in the full prescribing information) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.

6.5 Adverse Reactions in Other Subpopulations In older patients (≥65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation.

6.11 Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST In the Phase 3 trials the majority of Gleevec-treated patients experienced adverse reactions at some time.

The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec [see Dosage and Administration (2.10) in the full prescribing information]. Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%).

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec are shown in Table 9.

Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group.

Table 9 Number (%) of Patients with Adverse Reactions where Frequency is ≥10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Imatinib 400 mg Imatinib 800 mg N=818 N=822 All Grades All Grades Grades 3/4/5 Grades 3/4/5 Reported or Specified Term % % % % Edema 76.7 9.0 86.1 13.1 Fatigue/lethargy, malaise, asthenia 69.3 11.7 74.9 12.2 Nausea 58.1 9.0 64.5 7.8 Abdominal pain/cramping 57.2 13.8 55.2 11.8 Diarrhea 56.2 8.1 58.2 8.6 Rash/desquamation 38.1 7.6 49.8 8.9 Vomiting 37.4 9.2 40.6 7.5 Myalgia 32.2 5.6 30.2 3.8 Anemia 32.0 4.9 34.8 6.4 Anorexia 31.1 6.6 35.8 4.7 Other GI toxicity 25.2 8.1 28.1 6.6 Headache 22.0 5.7 19.7 3.6 Other pain (excluding tumor related pain) 20.4 5.9 20.8 5.0 Other dermatology/skin toxicity 17.6 5.9 20.1 5.7 Leukopenia 17.0 0.7 19.6 1.6 Other constitutional symptoms 16.7 6.4 15.2 4.4 Cough 16.1 4.5 14.5 3.2 (continued)

Table 9 Number (%) of Patients with Adverse Reactions where Frequency is ≥10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Imatinib 400 mg Imatinib 800 mg N=818 N=822 All Grades All Grades Grades 3/4/5 Grades 3/4/5 Reported or Specified Term % % % % Infection (without neutropenia) 15.5 6.6 16.5 5.6 Pruritus 15.4 5.4 18.9 4.3 Other neurological toxicity 15.0 6.4 15.2 4.9 Constipation 14.8 5.1 14.4 4.1 Other renal/genitourinary toxicity 14.2 6.5 13.6 5.2 Arthralgia (joint pain) 13.6 4.8 12.3 3.0 Dyspnea (shortness of breath) 13.6 6.8 14.2 5.6 Fever in absence of neutropenia 13.2 4.9 12.9 3.4 (ANC <1.0 x 109/L) Sweating 12.7 4.6 8.5 2.8 Other hemorrhage 12.3 6.7 13.3 6.1 Weight gain 12.0 1.0 10.6 0.6 Alopecia 11.9 4.3 14.8 3.2 Dyspepsia/heartburn 11.5 0.6 10.9 0.5 Neutropenia/granulocytopenia 11.5 3.1 16.1 4.1 Rigors/chills 11.0 4.6 10.2 3.0 Dizziness/lightheadedness 11.0 4.8 10.0 2.8 Creatinine increase 10.8 0.4 10.1 0.6 Flatulence 10.0 0.2 10.1 0.1 Stomatitis/pharyngitis (oral/pharyngeal mucositis) 9.2 5.4 10.0 4.3 Lymphopenia 6.0 0.7 10.1 1.9 Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 10.

Table 10 Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial 400 mg 600 mg (n=73) (n=74) % % CTC Grades1 Grade 3 Grade 4 Grade 3 Grade 4 Hematology Parameters – Anemia 3 0 8 1 – Thrombocytopenia 0 0 1 0 – Neutropenia 7 3 8 3 Biochemistry Parameters – Elevated Creatinine 0 0 3 0 – Reduced Albumin 3 0 4 0 – Elevated Bilirubin 1 0 1 3 – Elevated Alkaline Phosphatase 0 0 3 0 – Elevated SGOT (AST) 4 0 3 3 – Elevated SGPT (ALT) 6 0 7 1 1CTC Grades: neutropenia (Grade 3 ≥0.5-1.0 x 109/L, Grade 4 <0.5 x 109/L), thrombocytopenia (Grade 3 ≥10-50 x 109/L, Grade 4 <10 x 109/L), anemia (Grade 3 ≥65-80 g/L, Grade 4 <65 g/L), elevated creatinine (Grade 3 >3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), albumin (Grade 3 <20 g/L) Adjuvant Treatment of GIST The majority of both Gleevec and placebo treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously reported in other patient populations including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Gleevec and placebo treated patients respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention and diarrhea), fatigue, low hemoglobin and rash were the most frequently reported adverse reactions at the time of discontinuation.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Gleevec are shown in Table 11.

Table 11 Adverse Reactions Reported in the Adjuvant GIST Trial (≥5% of Gleevec Treated Patients)(1) All CTC Grades CTC Grade 3 and above Gleevec Placebo Gleevec Placebo (n=337) (n=345) (n=337) (n=345) Preferred Term % % % % Diarrhea 59.3 29.3 3.0 1.4 Fatigue 57.0 40.9 2.1 1.2 Nausea 53.1 27.8 2.4 1.2 Periorbital Edema 47.2 14.5 1.2 0 Hemoglobin Decreased 46.9 27.0 0.6 0 Peripheral Edema 26.7 14.8 0.3 0 Rash (Exfoliative) 26.1 12.8 2.7 0 Vomiting 25.5 13.9 2.4 0.6 Abdominal Pain 21.1 22.3 3.0 1.4 Headache 19.3 20.3 0.6 0 Dyspepsia 17.2 13.0 0.9 0 Anorexia 16.9 8.7 0.3 0 Weight Increased 16.9 11.6 0.3 0 Liver enzymes (ALT) Increased 16.6 13.0 2.7 0 Muscle spasms 16.3 3.3 0 0 Neutrophil Count Decreased 16.0 6.1 3.3 0.9 Arthralgia 15.1 14.5 0 0.3 White Blood Cell Count Decreased 14.5 4.3 0.6 0.3 Constipation 12.8 17.7 0 0.3 Dizziness 12.5 10.7 0 0.3 (continued)

Table 11 Adverse Reactions Reported in the Adjuvant GIST Trial (≥5% of Gleevec Treated Patients)(1) All CTC Grades CTC Grade 3 and above Gleevec Placebo Gleevec Placebo (n=337) (n=345) (n=337) (n=345) Preferred Term % % % % Liver Enzymes (AST) Increased 12.2 7.5 2.1 0 Myalgia 12.2 11.6 0 0.3 Blood Creatinine Increased 11.6 5.8 0 0.3 Cough 11.0 11.3 0 0 Pruritus 11.0 7.8 0.9 0 Weight Decreased 10.1 5.2 0 0 Hyperglycemia 9.8 11.3 0.6 1.7 Insomnia 9.8 7.2 0.9 0 Lacrimation Increased 9.8 3.8 0 0 Alopecia 9.5 6.7 0 0 Flatulence 8.9 9.6 0 0 Rash 8.9 5.2 0.9 0 Abdominal Distension 7.4 6.4 0.3 0.3 Back Pain 7.4 8.1 0.6 0 Pain in Extremity 7.4 7.2 0.3 0 Hypokalemia 7.1 2.0 0.9 0.6 Depression 6.8 6.4 0.9 0.6 Facial Edema 6.8 1.2 0.3 0 Blood Alkaline Phosphatase Increased 6.5 7.5 0 0 Dry skin 6.5 5.2 0 0 Dysgeusia 6.5 2.9 0 0 Abdominal Pain Upper 6.2 6.4 0.3 0 Neuropathy Peripheral 5.9 6.4 0 0 Hypocalcemia 5.6 1.7 0.3 0 Leukopenia 5.0 2.6 0.3 0 Platelet Count Decreased 5.0 3.5 0 0 Stomatitis 5.0 1.7 0.6 0 Upper Respiratory Tract Infection 5.0 3.5 0 0 Vision Blurred 5.0 2.3 0 0 (1)All adverse reactions occurring in ≥5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.

6.12 Additional Data from Multiple Clinical Trials The following adverse reactions have been reported during clinical trials of Gleevec.

Cardiac Disorders: Estimated 0.1%-1%: congestive cardiac failure, tachycardia, palpitations, pulmonary edema, Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion Vascular Disorders: Estimated 1%-10%: flushing, hemorrhage Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynauds phenomenon, hematoma, Clinical Laboratory Tests: Estimated 0.1%-1%: blood CPK increased, blood LDH increased, Estimated 0.01%-0.1%: blood amylase increased Dermatologic: Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, nail disorder, purpura, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae Estimated 0.01%-0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, erythema multiforme, leucocytoclastic vasculitis Digestive: Estimated 1%-10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis Estimated 0.1%-1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis, Estimated 0.01%-0.1%: colitis, ileus, inflammatory bowel disease, General Disorders and Administration Site Conditions: Estimated 1%-10%: weakness, anasarca, chills Estimated 0.1%-1%: malaise Hematologic: Estimated 1%-10%: pancytopenia, febrile neutropenia Estimated 0.1%-1%: thrombocythemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia Hepatobiliary: Estimated 0.1%-1%: hepatitis, jaundice Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis1 Hypersensitivity: Estimated 0.01%-0.1%: angioedema Infections: Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Estimated 0.01%-0.1%: fungal infection Metabolic and Nutritional: Estimated 1%-10%: weight decreased Estimated 0.1%-1%: hypophosphatemia, dehydration, gout, increased appetite, decreased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia Estimated 0.01%-0.1%: hyperkalemia, hypomagnesemia Musculoskeletal: Estimated 1%-10%: joint swelling Estimated 0.1%-1%: joint and muscle stiffness Estimated 0.01%-0.1%: muscular weakness, arthritis Nervous System/Psychiatric: Estimated 1%-10%: paresthesia, hypesthesia Estimated 0.1%-1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor Estimated 0.01%-0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis

Renal: Estimated 0.1%-1%: renal failure acute, urinary frequency increased, hematuria, renal pain Reproductive: Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema Respiratory: Estimated 1%-10%: epistaxis Estimated 0.1%-1%: pleural effusion Estimated 0.01%-0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage Special Senses: Estimated 1%-10%: conjunctivitis, vision blurred, eyelid edema, conjunctival hemorrhage, dry eye Estimated 0.1%-1%: vertigo, tinnitus, eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss Estimated 0.01%-0.1%: papilledema1, glaucoma, cataract 1Including some fatalities 6.13 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of Gleevec.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous system disorders: cerebral edema1 Eye disorders: vitreous hemorrhage Cardiac disorders: pericarditis, cardiac tamponade1 Vascular disorders: thrombosis/embolism, anaphylactic shock Respiratory, thoracic and mediastinal disorders: acute respiratory failure1, interstitial lung disease Gastrointestinal disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation1 [see Warnings and Precautions (5.6)], diverticulitis Skin and subcutaneous tissue disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome Musculoskeletal and connective tissue disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/ myopathy, growth retardation in children Reproduction disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst 1Including some fatalities 777DRUG INTERACTIONS 7.1 Agents Inducing CYP3A Metabolism Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of Gleevec, increased Gleevec oral-dose clearance by 3.8-fold, which significantly (p<0.05) decreased mean Cmax and AUC. Similar findings were observed in patients receiving 400-1200 mg/day Gleevec concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAED’s decreased by 73% compared to patients not receiving EIAED. Concomitant administration of Gleevec and St. John’s Wort led to a 30% reduction in the AUC of imatinib.

Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated. Gleevec doses up to 1200 mg/day (600 mg BID) have been given to patients receiving concomitant strong CYP3A4 inducers. [see Dosage and Administration (2.9) in the full prescribing information].

7.2 Agents Inhibiting CYP3A Metabolism There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when Gleevec was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering Gleevec with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided. Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concentrations.

7.3 Interactions with Drugs Metabolized by CYP3A4 Gleevec increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by Gleevec. Particular caution is recommended when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window (e.g., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus or tacrolimus).

Gleevec will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolobenzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).

Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin.

7.4 Interactions with Drugs Metabolized by CYP2D6 Gleevec increased the mean Cmax and AUC of metoprolol by approximately 23% suggesting that Gleevec has a weak inhibitory effect on CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution is recommended when administering Gleevec with CYP2D6 substrates that have a narrow therapeutic window.

7.5 Interaction with Acetaminophen In vitro, Gleevec inhibits the acetaminophen O-glucuronidate pathway (Ki 58.5 μM). Co-administration of Gleevec (400 mg/day for eight days) with acetaminophen (1000 mg single dose on day eight) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen. Gleevec pharmacokinetics were not altered in the presence of single-dose acetaminophen. There is no pharmacokinetic or safety data on the concomitant use of Gleevec at doses >400 mg/day or the chronic use of concomitant acetaminophen and Gleevec.

888USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.11)].

Gleevec can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses ≥100 mg/kg (approximately equal to the maximum human dose of 800 mg/day based on body surface area). Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered doses ≥45 mg/kg (approximately one-half the maximum human dose of 800 mg/day based on body surface area) also experienced significant post-implantation loss as evidenced by either early fetal resorption or stillbirths, nonviable pups and early pup mortality between postpartum Days 0 and 4. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. Fetal loss was not seen at doses ≤30 mg/kg (one-third the maximum human dose of 800 mg).

There are no adequate and well-controlled studies with Gleevec in pregnant women. Women should be advised not to become pregnant when taking Gleevec. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

8.3 Nursing Mothers Imatinib and its active metabolite are excreted into human milk. Based on data from three breastfeeding women taking Gleevec, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed infant could receive up to 10% of the maternal therapeutic dose based on body weight. Because of the potential for serious adverse reactions in nursing infants from Gleevec, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.5 Geriatric Use In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema [see Warnings and Precautions (5.1)]. The efficacy of Gleevec was similar in older and younger patients.

In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis.

In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of Gleevec was similar in patients older than 65 years and younger patients.

8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 cancer patients with varying degrees of hepatic impairment (Table 12) at imatinib doses ranging from 100-800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepatically-impaired groups and the normal group. Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function. At steady state, the mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function [see Dosage and Administration (2.10) in the full prescribing information].

Table 12 Liver Function Classification Liver Function Test Normal Mild Moderate Severe (n=14) (n=30) (n=20) (n=20) Total Bilirubin ≤ULN >1.0-1.5x ULN >1.5-3x ULN >3-10x ULN SGOT ≤ULN >ULN (can be Any Any normal if Total Bilirubin is >ULN) ULN=upper limit of normal for the institution 8.7 Renal Impairment The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment (Table 13) at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2-fold compared to patients with normal renal function.

The AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment. The AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment. Two patients with severe renal impairment were dosed with 100 mg/day and their exposures were similar to those seen in patients with normal renal function receiving 400 mg/day. Dose reductions are necessary for patients with moderate and severe renal impairment [See Dosage and Administration (2.9) in the full prescribing information].

Table 13 Renal Function Classification Renal Dysfunction Renal Function Tests Mild CrCL = 40-59 mL/min Moderate CrCL = 20-39 mL/min Severe CrCL = <20 mL/min CrCL = Creatinine Clearance 108OVERDOSAGE Experience with doses greater than 800 mg is limited. Isolated cases of Gleevec overdose have been reported. In the event of overdosage, the patient should be observed and appropriate supportive treatment given.

Adult Overdose 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain.

6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases.

8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of Gleevec daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of Gleevec daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of Gleevec on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy.

Pediatric Overdose One 3 year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhea and anorexia and another 3 year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhea.

16 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture.

Dispense in a tight container, USP. T2011-40 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

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Hematology Lymphoma continued from page 15

Maintenance Rituximab for Relapsed Diffuse Large B-cell Lymphoma The Collaborative trial in Relapsed Aggressive Lymphoma (CORAL study) found that giving rituximab as maintenance therapy after transplantation for relapsed, CD20-positive diffuse large B-cell lymphoma fails to improve event-free survival.3 Patients were randomly assigned to R-ICE (rituximab, ifosfamide, carboplatin, etoposide) or R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin) as salvage therapy. Those who experienced a partial or complete response underwent autologous transplantation and were randomly assigned again to either maintenance rituximab for 1 year or observation SEE PAGE 2 only.

Previously published results showed that overall survival did not differ by salvage regimen.4 But R-ICE had a lower rate of adverse events.

Among the 245 patients randomly assigned to maintenance therapy or observation only, those in the former group had a higher rate of serious adverse events (21% vs 13%). Event-free survival did not differ.

“There’s no apparent benefit to rituximab maintenance…at least for diffuse large B-cell lymphoma after transplant,” Dr. Press concluded. The findings were much the same in subgroup analyses. Within the rituximab group, women had better progressionfree survival than men.

■

Disclosure: Dr. Press has served as a consultant for and accepted honoraria from Roche/Genentech.

References 1. Cunningham D, Smith P, Mouncey P, et al: R-CHOP14 versus R-CHOP21: Result of a randomized phase III trial for

Key Lymphoma Findings Presented at Best of ASCO® ■■ Overall survival in diffuse large B-cell lymphoma with R-CHOP-14 for six cycles is not superior to that with R-CHOP-21 for eight cycles.

■■ Upfront transplantation for high-intermediate or high International

Prognostic Index non-Hodgkin lymphoma does not improve overall survival.

■■ Maintenance rituximab after autologous stem cell transplant does not

improve outcomes in relapsed diffuse large B-cell lymphoma and adds toxicity and cost.

the treatment of patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma. 2011 ASCO Annual Meeting. Abstract 8000. Presented June 4, 2011.

2. Stiff PJ, Unger JM, Cook J, et al: Randomized phase III U.S./Canadian intergroup trial (SWOG S9704) comparing CHOP ± R for eight cycles to CHOP ± R for six cycles followed by autotransplant for patients with high-intermediate (HInt) or high IPI grade diffuse aggressive non-Hodgkin lymphoma (NHL). 2011 ASCO Annual Meeting. Abstract 8001.

Presented June 4, 2011.

3. Gisselbrecht C, Glass B, Laurent G, et al: Maintenance with rituximab after autologous stem cell transplantation in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL): CORAL final analysis. 2011 ASCO Annual Meeting. Abstract 8004. Presented June 4, 2011.

4. Gisselbrecht C, Glass B, Mounier N, et al: Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28:4184-4190, 2010.

Multiple Myeloma Research Spotlights Treatment Concerns and Advances

By Susan London

M

yeloma data reported at this year’s ASCO meeting raise concern about the safety of a mainstay class of drugs in this disease, while also hinting at good efficacy of some novel drugs and approaches, according to William I. Bensinger, MD, of the Fred Hutchinson Cancer Research Center, Seattle.

William I. Bensinger, MD

Lenalidomide/Melphalan Linked to Second Malignancies Patients aged 65 years or older with newly diagnosed multiple myeloma have at least twice the rate of second primary malignancies if they receive lenalidomide (Revlimid) concurrently and/or sequentially with melphalan, according to findings of the randomized MM-015 trial.1 With a median follow-up of 30 months, the rate of second invasive cancers was generally low among the 459 patients studied. But it was higher among patients who had initial therapy

with melphalan, prednisone, and lenalidomide (5.9%) and more so in those who received melphalan, prednisone, and lenalidomide initial therapy followed by lenalidomide maintenance therapy (8.0%) than those who had melphalan/ prednisone initial therapy alone (2.6%).

When lenalidomide was used in both initial and maintenance therapy, the rate of second cancers rose over time, especially after year 3, but this treatment strategy also showed the lowest rate of progressive disease or death. Use of lenalidomide and dexamethasone alone— without melphalan—has not been associated with an elevated risk of second cancers, Dr. Bensinger noted. “So there appears to be some synergy between exposure to melphalan and lenalidomide that may increase these second primary cancers,” he speculated.

“At present, the benefit of maintenance on delaying disease progression outweighs the risks,” Dr. Bensinger commented. “But without any differences in overall survival, I think you have to be cautious about recommending this as standard of care.”

Carfilzomib in Relapsed/ Refractory Myeloma The investigational agent carfilzomib, an intravenously administered second-generation proteasome inhibitor,

A Cautious Approach to Maintenance Therapy

H

ematologists should weigh the risks and benefits carefully when considering lenalidomide (Revlimid) or other maintenance therapy for their patients with myeloma, according to William I. Bensinger, MD, of the Fred Hutchinson Cancer Research Center, Seattle.

Lenalidomide is associated with considerable adverse effects that require closer monitoring, and the drug is expensive, costing about $80,000 per year.

“While improved progression-free survival is [desirable], if the overall survival is no different and you can use this drug at relapse for a shorter period of time, what’s the benefit [of maintenance]?” he asked.

Longer Follow-up Needed It will require longer follow-up to determine whether second primaries will become even more common with time. Tangentially, the lenalidomide data have raised concerns about use of thalidomide (Thalomid) concurrently or sequentially with melphalan as well.

“I’m much more cautious about recommending maintenance to my patients,” Dr. Bensinger concluded. “If there’s a clinical trial that looks useful, then it’s worth enrolling them. But off of a clinical trial, I tend to be much more conservative about maintenance therapy.”

■

is active and well tolerated in relapsed and/or refractory myeloma, according to a phase II trial among 52 patients.2 Adding carfilzomib to lenalidomide/dexamethasone achieved a response rate of 78%, with the largest share of patients having a partial response (Table 1). With treatment extending to more than 23 months, no dose-limiting toxicities were observed.

The most common grade 3/4 adverse events were neutropenia (17%), anemia (13%), and hypophosphatemia (13%).

“Prolonged treatment with this drug is possible because it doesn’t appear to have much of a neurotoxicity signal at all,” Dr. Bensinger said, noting that some patients have been on it for nearly continued on page 22

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Hematology Multiple Myeloma continued from page 21

4 years. “It can actually be used as maintenance therapy, although IV therapy is a bit inconvenient for patients if we are using it [in that setting].”

An accruing phase III randomized trial is testing the addition of carfilzomib to lenalidomide/ dexamethasone. “It is possible that this drug SEE PAGE 2 could be available in advance of that trial,” he commented, as a New Drug Application is being submitted for treatment of bortezomib (Velcade)refractory patients. “So if ODAC recommends approval and the FDA agrees, it’s possible that this drug might be available on the market some time next year.”

Upfront Transplantation Upfront tandem transplantation im-

proves progression-free survival compared with the combination of melphalan, prednisone, and lenalidomide in newly diagnosed myeloma, according to data from a phase III trial reported at ASCO by Mario Boccadoro, MD, of the University of Torino, Italy, and colleagues.3 Moreover, compared with low-dose aspirin, low–molecular weight heparin appeared more efficacious at averting thromboembolic events during induction with lenalidomide and dexamethasone. The rates were low in both groups, at less than 3%, but 4 patients experienced pulmonary embolism with aspirin, compared with none with heparin.

“This indicates to me that low-dose aspirin is probably insufficient if you are using a lenalidomide/dexamethasone combination,” Dr. Bensinger said.

With a median follow-up of 20 months, the 2-year rate of progressionfree survival was better with transplan-

Key Myeloma Findings Presented at Best of ASCO® ■■ In older adults with newly diagnosed myeloma, using lenalidomide

concurrently and/or sequentially with melphalan roughly doubles the rate of second primary malignancies, although it is still low.

■■ In relapsed myeloma, adding carfilzomib to lenalidomide/ dexamethasone achieves a response in 78% of patients.

■■ Aspirin appears less efficacious than heparin for averting serious

thromboembolic events during lenalidomide-containing induction therapy.

■■ Upfront tandem transplantation improves progression-free but not overall survival, with higher toxicity.

CONQUERING

Table 1: Best Response to Carfilzomib, Lenalidomide, and Dexamethasone Therapy at the Maximum Protocol Dose in a Phase II Study Response (n = 50)

n (%)

Complete response/near-complete response

11 (22%)

Very good partial response

9 (18%)

Partial response

19 (38%)

Minimal response

1 (2%)

Stable disease

3 (6%) 39 (78%)

Overall response rate Courtesy of William I. Bensinger, MD. Adapted from Wang M, et al.2

tation than with drug therapy (75% vs 59%; P = .005). Transplantation was associated with significantly higher rates of grade 3/4 adverse events, especially neutropenia and thrombocytopenia.

Overall survival was high and did not differ between groups. But “keep in mind that these trials often take 3 to 5 years before they mature enough that you can see significant differences,” Dr. Bensinger cautioned.

“It might have been a better trial if they stuck to a single autologous transplant, because I don’t think tandem transplants at the present time are considered a standard of care,” he commented.

■

Disclosure: Dr. Bensinger has served on the speakers bureau for Celgene, as a consultant for Onyx and Celgene, and has received clinical trials funding from Onyx and Celgene.

References 1. Palumbo AP, Delforge M, Catalano J, et

al: Incidence of second primary malignancy (SPM) in melphalan-prednisone-lenalidomide combination followed by lenalidomide maintenance (MPR-R) in newly diagnosed multiple myeloma patients (pts) age 65 or older. 2011 ASCO Annual Meeting. Abstract 8007. Presented June 5, 2011.

2. Wang M, Bensinger W, Martin T, et al: Interim results from PX-171-006, a phase (Ph) II multicenter dose-expansion study of carfilzomib (CFZ), lenalidomide (LEN), and low-dose dexamethasone (loDex) in relapsed and/or refractory multiple myeloma (R/R MM). 2011 ASCO Annual Meeting. Abstract 8025. Presented June 4, 2011.

3. Boccadoro M, Cavallo F, Nagler A, et al: Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) in newly diagnosed multiple myeloma (MM) patients: A phase III trial. 2011 ASCO Annual Meeting. Abstract 8020. Presented June 4, 2011.

Cancer.

Together, anything is possible.

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ASCOPost.com | OCTOBER 15, 2011 | SUPPLEMENT

PAGE 23

Genitourinary Oncology Novel Management Strategies Assessed in Renal Cell and Prostate Cancers

By Caroline Helwick

A

t the Best of ASCO Miami meeting, William Oh, MD, of the Tisch Cancer Institute, Mount Sinai School of Medicine, New York, described new trends and remaining questions in the management of renal cell and prostate cancers.

William Oh, MD

Axitinib vs Sorafenib in Second-line RCC Axitinib, a potent and selective investigational vascular endothelial growth factor (VEGF) receptor inhibitor proved superior to sorafenib (Nexavar) in the second-line treatment of renal cell carcinoma.1 Among the 723 patients in the phase III AXIS trial, median progression-free survival was 6.7 months with axitinib and 4.7 with sorafenib—a 34% reduction in risk (P < .0001).

“The investigators noted that more potent biochemical targeting of the VEGF receptor seems to be associated with superior SEE PAGE 2 clinical activity in renal cell carcinoma, and I agree. Their more controversial conclusion was that axitinib should be considered the reference standard in second-line advanced renal cell carcinoma. My com-

ment on this is, ‘maybe,’” Dr. Oh said (see sidebar).

Using Axitinib in Advanced Renal Cell Carcinoma

Intermittent vs Continuous Androgen Suppression for Rising PSA

W

Based on results from a phase III intergroup trial, intermittent androgen suppression is an effective approach for addressing rising prostate-specific antigen (PSA) after radical therapy.2 Intermittent androgen suppression was noninferior to continuous androgen deprivation among 1,386 men with PSA recurrence ≥ 3.0 ng/mL after radiotherapy. All patients received 8 months of initial androgen-deprivation therapy, with duration of off-treatment intervals and switch from intermittent to continuous androgen suppression based on PSA and clinical progression.

After almost 7 years of follow-up, average time spent on androgen-deprivation therapy was 15.4 months in the intermittent androgen suppression group and 43.9 months in the continuous androgen deprivation arm. Overall survival was 9.1 years with continuous and 8.8 years with intermittent androgen suppression (P = .009 for noninferiority). Intermittent androgen suppression therapy was associated with better global quality of life and significant improvements in multiple domains.

“The findings suggest that intermittent androgen suppression is a reasonable option for patients with PSA recurrence, and arguably the standard of care,” Dr. Oh maintained. “My recommendation is to use these cut-points and follow the study’s algorithm (Fig. 1), but a few questions remain. Are some men at greater risk of dying of prostate cancer

Key Genitourinary Cancer Findings Presented at Best of ASCO® ■■ Axitinib was superior to sorafenib in the second-line treatment of renal cell carcinoma, prolonging remission by 2 months.

■■ Intermittent androgen suppression was equivalent to continuous

androgen deprivation in men with rising PSA after definitive therapy.

■■ For metastatic castration-resistant prostate cancer, cabozantinib more than tripled progression-free survival and led to an improvement of metastatic bone lesions on bone scan in 74% of patients.

■■ The presence of circulating tumor cells heralded a worse prognosis

among metastatic castration-resistant prostate cancer patients receiving abiraterone acetate (Zytiga), but there are insufficient data to suggest that CTCs may serve as a surrogate for survival in clinical trials.

■■ A single PSA level early in life discriminated low risk from elevated risk of

prostate cancer death but not well enough to justify an approach for men undergoing screening.

ith a new tyrosine kinase inhibitor joining the armamentarium, the question is how to optimize targeted agents for advanced renal cell carcinoma.

The AXIS trial demonstrated strong clinical activity for axitinib, which was superior to second-line sorafenib (Nexavar) and generally appears most similar to sunitinib (Sutent), according to William Oh, MD, of the Tisch Cancer Institute, Mount Sinai School of Medicine, New York.

Relative Treatment Options “One of the impressive findings in the AXIS trial was that axitinib was clearly well tolerated,” he noted. Median relative dose intensity was higher and treatmentrelated discontinuations were fewer than with sorafenib. “I think of sorafenib as an ‘easier’ tyrosine kinase inhibitor than sunitinib, but axitinib was even better tolerated,” he observed. While more hypertension and hypothyroidism occurred with axitinib, sorafenib produced more hand-foot syndrome, rash, and alopecia.

The question now is how to position axitinib among the treatment options. In AXIS, the most “dramatic” responses were in patients previously treated with cytokines (35% of the cohort), whose progression-free survival was 12.1 months, vs 6.5 months with sorafenib (P < .0001). “But patients typically no longer receive cytokines; therefore, the more relevant issue is how patients previously treated with sunitinib (54% of the cohort) will respond,” he said. In this subset, median progression-free survival was 4.8 months vs 3.4 months, respectively (P = .011). Those previously treated with bevacizumab (Avastin) or temsirolimus (Torisel) were too few in number for analysis.

New Standard of Care?

Should axitinib become the new second-line standard of care? “Maybe,” he said. Only everolimus is backed by level 1 evidence, after primary tyrosine kinase inhibitor therapy. Should axitinib become FDA-approved, it would also have level 1 evidence support. While both drugs produced strong hazard ratios and progression-free survival rates in clinical trials, the RECORD-1 everolimus (Afinitor) study lacked an active control, and therefore, the drugs’ efficacy cannot be compared. The optimal sequence of tyrosine kinase inhibitor and mTOR inhibitor, therefore, remains unknown.

“So far, the phase III studies have not told us what to do with the typical patient in the second-line setting…. The strongest argument for using axitinib may be its relatively favorable toxicity profile. The progression-free survival benefit was statistically significant. Whether it is clinically significant for your patients remains to be seen,” Dr. Oh concluded.

■

with intermittent androgen-deprivation therapy? Prostate cancer deaths were 41% with intermittent androgen suppression, vs 34% with continuous androgen deprivation. And do men need androgen-deprivation therapy at all for rising PSA? It’s the standard of care, but only because we all use it.”

Cabozantinib in Metastatic Castration-resistant Prostate Cancer Add to the growing list of agents for metastatic castration-resistant prostate cancer the drug cabozantinib—a novel inhibitor of MET and VEGFR2—which was granted orphan drug status by the FDA earlier this year. In a phase II trial of 151 patients, median

progression-free survival was 21 weeks with cabozantinib vs 6 weeks with placebo (P = .0007).3 Three-quarters of patients demonstrated evidence of tumor regression, including complete resolution of bone lesions in 19% and partial resolution in 56%. Bone scan resolution correlated highly with clinical effects, such as pain and markers of bone resorption.

“The study was very suggestive that carbozantinib delayed progression. The hazard ratio (HR = 0.13) was impressive for such a small study, and bone scans looked almost too good to be true. In my 20 years in prostate cancer I have never seen anything like this,” Dr. Oh commented. continued on page 24

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PAGE 24

Genitourinary Oncology Genitourinary Cancer continued from page 23

“Before we know for sure if cabozantinib is the real deal, two things need further assessment—toxicity and quality of life,” he added. “When drugs are going to delay but not eradicate disease, we need to know patients can tolerate them long-term.”

A

Evidence of clinical disease progression?

NO

How Prognostic Are Circulating Tumor Cells?

The presence of ≥ 5 circulating tumor cells (CTCs) heralded a worse prognosis among the 1,195 patients enrolled in the phase III study of abiraterone acetate (Zytiga) plus prednisone postdocetaxel.4 Circulating tumor cells were counted at baseline and periodically posttreatment. Conversion from < 5 CTCs per 7.5 mL to ≥ 5 was predictive of overall survival, and elevated CTCs correlated with an attenuation of treatment effect. Conversion was significantly more likely in the abiraterone arm: 48% by week 12 vs 17% with placebo (P < .0001); median overall survival was 22 vs 10 months, respectively.

“This was a large study with ambitious goals, but it was basically negative. It was unable to show that circulating tumor cells could substitute for overall survival in clinical trials,” Dr. Oh noted. “In the multivariate analysis, baseline lactate dehydrogenase remained as powerful a prognostic factor as CTCs (P < .0001), and it is a 60-year-old biomarker that costs $40.

PSA level was not prognostic, but PSA declines were not compared to CTCs as surrogates. So circulating tumor cells may have their greatest promise as a ‘liquid biopsy’ to target cancers in a personalized approach.”

Importance of Age-specific PSA Ranges A case control study among 12,090 Swedish men found PSA to be strongly associated with risk of prostate cancer death or metastasis up to 30 years later.5 For men screened at ages 45 to 49, PSA > 1.6 ng/mL predicted 44% of deaths; for men screened at ages 51 to 55, PSA > 2.4 ng/mL predicted 48% of deaths.

“This study reiterates the importance of age-specific ranges and long natural history. Early PSA discriminated men at low risk from men at elevated risk of death from prostate cancer many years later, but at this time we cannot use a single PSA to rule out future cancer. More study is needed, especially in other populations,” he said.

■

Completes 8-mo treatment cycle

NO, PSA < 4

YES, while on hormone therapy: hormone resistance declared YES, PSA > 4

Is PSA > 4 ng/mL (4 μg/L)?

Is PSA rising? eg, 1 ng/mL (1 μg/L) above last PSA

YES

NO

B

Switch to CAD until hormone resistance declared

Remain on IAS arm and commence nontreatment interval

Off-treatment interval: PSA monitoring every 2 mo Is PSA > 10 ng/mL (10 μg/L)?

YES, PSA > 10

NO, PSA < 10

< 2-mo interval after completing 8-mo treatment cycle?

NO

YES

Remain on IAS arm Resume protocol therapy

Clinical evidence of disease progression?

YES

Switch to CAD until hormone resistance

NO

Remain on nontreatment interval (reassess PSA in 2 mo)

Fig 1: (A) Algorithm for patient on intermittent androgen suppression starting a nontreatment interval. (B) Algorithm for patient on intermittent androgen suppression restarting therapy. CAD = continuous androgen deprivation; IAS = intermittent androgen suppression; PSA = prostate-specific antigen. Courtesy of William Oh, MD. Adapted from Crook JM, et al.3

Disclosure: Dr. Oh has a consultant or advisory relationship with Medivation, Dendreon, Amgen, Bellicum, and Pfizer.

References 1. Rini BI, Escudier B, Tomczak P, et al: Axitinib versus sorafenib as second-line therapy for metastatic renal cell carcinoma: Results of phase III AXIS trial. 2011 ASCO Annual Meeting. Abstract 4503.

Presented June 6, 2011.

2. Hussain M, Smith MR, Sweeney C, et al: Cabozantinib (XL184) in metastatic castration-resistant prostate cancer: Results from a phase II randomized discon-

tinuation trial. 2011 ASCO Annual Meeting. Abstract 4516. Presented June 6, 2011.

3. Crook JM, O’Callaghan CJ, Ding K, et al: A phase III randomized trial of intermittent versus continuous androgen suppression for PSA progression after radical therapy (NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/UK Intercontinental Trial CRUKE/01/013). 2011 ASCO Annual Meeting. Abstract 4514. Presented June 6, 2011.

4. Scher HI, Heller G, Molina A, et al: Evaluation of circulating tumor cell enumeration as an efficacy response biomarker of overall survival in metastatic castra-

tion-resistant prostate cancer: Planned final analysis of COU-AA-301, a randomized, double-blind, placebo-controlled, phase III study of abiraterone acetate plus low-dose prednisone post docetaxel.

2011 ASCO Annual Meeting. Abstract LBA4517. Presented June 6, 2011.

5. Lilja H, Savage C, Gerdtsson A, et al: Toward a rational strategy for prostate cancer screening based on long-term risk of prostate cancer metastases and death: Data from a large, unscreened, populationbased cohort followed for up to 30 years.

2011 ASCO Annual Meeting. Abstract 4512. Presented June 6, 2011.

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PAGE 25

Gynecologic Oncology Screening for Ovarian Cancer May Do More Harm Than Good, but New Therapies for the Disease Are Improving Outcomes

By Caroline Helwick

A

t the Best of ASCO Miami meeting, Daniela Matei, MD, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, described how new approaches are significantly prolonging remission in ovarian cancer.

tion), and the lack of a standardized approach to positive screens. But the trial is consistent with other large studies, she said, which have also found no mortality benefit with screening. Results from the UKCTOCS study in the United Kingdom, expected in 2015, should help determine definitively the value of screening for ovarian cancer.

Maintenance PARP Inhibitor Extends Remission

Daniela Matei, MD

Ovarian Screening Provides No Benefit The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which employed annual simultaneous CA-125 and transvaginal ultrasound over 4 to 6 years, did not reduce ovarian cancer mortality, and there was, in fact, evidence of harm from diagnostic evaluations and surgery following false-positive screens.1 The randomized study involved 78,216 women aged 55 to 74, enrolled between 1993 and 2001 and followed until February 2010.

At a median follow-up of 12.4 years, cancer was identified in 212 women in the intervention arm and 176 under usual care, while ovarian cancer deaths were recorded in 118 and 100, respectively. Stage I/II tumors were found in 47 and 38 women, and stage III/IV in 163 and 137, respectively. At 10 years, overall survival was approximately 25% in both arms (P = .18). There were 3,285 false-positive screens, leading to 1,080 surgeries and 222 major complications in 163 patients, including infections in 40% and direct surgical complications in 28%. The oophorectomy rate was 33% higher with the intervention: 7.7% vs 5.8%.

“Screening did not impact the detection of early tumors that could improve survival,” she said, calling the PLCO trial “an important study but with limitations.”

Dr. Matei’s concerns included the variable duration of follow-up from the time of enrollment, the use of fixed CA125 cutoffs (ignoring individual varia-

Disease remission was significantly prolonged by maintenance treatment with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in the phase II trial of 265 patients with a prior response to platinum regimens.2 Maintenance with olaparib reduced progressive disease by 65%, with median progression-free survival being 8.4 months with olaparib vs 4.8 months with placebo (P < .00001). Disease progressed in 44% (olaparib) and 72% (placebo). Overall survival data are not yet mature.

Olaparib was well tolerated, though it was associated with increases in nausea (68% vs 35%), fatigue (49% vs 38%), and vomiting (32% vs 14%).

“This is a very timely and important trial,” Dr. Matei commented. An integrated analysis of 500 serous ovarian adenocarcinomas from The Cancer Genome Atlas project found homologous recombination to be defective in 53% of tumors, suggesting that ovarian cancer is a good target not only for platinum agents but also for PARP inhibitors.

Phase III trials of PARP inhibitors in recurrent disease are planned, including an upfront combination of a PARP inhibitor, chemotherapy, and bevacizumab (Avastin) by the Gynecologic Oncology Group. Research efforts should also aim to determine the optimal timing and sequence of such agents, identify predictive biomarkers for homologous repair deficiency, and understand mechanisms of resistance to PARP inhibitors, she said.

Addition of Bevacizumab Extends Remission by 4 Months Maintenance therapy with bevacizumab also prolonged remission by 4 months in 480 platinum-sensitive patients with recurrent cancer (of the ovaries, peritoneum, or fallopian tubes) in the OCEANS trial.3 Bevacizumab added to carboplatin and

Can Society Afford Bevacizumab in Ovarian Cancer?

F

or bevacizumab (Avastin), as for all targeted agents, there is a critical need to identify likely responders as well as patients at risk for serious toxicities, agreed Daniela Matei, MD, of the Indiana University Melvin and Bren Simon Cancer Center, and session moderator Daniel F. Hayes, MD, of the University of Michigan.

A recent cost-effectiveness analysis of Gynecologic Oncology Group (GOG) 218 drove this point home.1 Investigators determined that for the 600-patient trial in advanced disease, the cost of chemotherapy alone (carboplatin/paclitaxel) was $2.5 million, rising to $21.4 million with the addition of bevacizumab, and further to $78.3 million when bevacizumab was continued as maintenance. While progression-free survival also SEE PAGE 2 improved exponentially, from a median of 10, to 21, to 31 months, respectively, the addition of bevacizumab was not cost-effective, the authors maintained.

In the adjuvant setting, the data are not convincing, Dr. Matei noted. “I have been underwhelmed, and I personally don’t prescribe it upfront outside of a clinical trial. For recurrence, perhaps the magnitude of benefit is greater. Certainly the trend for overall survival is there, but we have to take into account the potential toxicities when determining how to use the drug. I do think bevacizumab is active in ovarian cancer,” she acknowledged. “But when and how to give it, and to whom, for the best outcomes—those issues are still up in the air.”

Duration of Therapy Dr. Hayes said he is also troubled by not knowing how best to give bevacizumab, largely because the target is vague. But the even bigger issue, he said, is duration. “All the trials—in colon, lung, breast, and ovarian cancers—have suggested that as long as you give bevacizumab you continue to see benefit. You quit, and the curves collapse. Universally, the curves come together, suggesting we need to keep giving it forever,” he remarked.

“But we cannot afford to give bevacizumab to Daniel F. Hayes, MD every patient, and it’s a disgrace that we have not yet learned who the drug works in and who will have life-threatening toxicity,” he commented. “Unfortunately for our patients, we may be on the verge of throwing the baby out with the bathwater.”

■

Disclosure: Dr. Hayes holds stock in Oncimmune, LLC, has served as a consultant for Chugai Pharmaceuticals and Biomarker Strategies, and has received research funding from Pfizer, Novartis, and Veridex (Johnson & Johnson). Dr Matei has received consulting fees from Genentech.

Reference 1. Cohn DE, Kim KH, Resnick KE, et al: At what cost does a potential survival advantage of bevacizumab make sense for the primary treatment of ovarian cancer: A cost-effectiveness analysis. J Clin Oncol 29:1247-1251, 2011.

gemcitabine, followed by bevacizumab until progression, improved progression-free survival to 12.4 months, from 8.4 with chemotherapy alone—a 52% reduction in risk (P < .0001). Interim overall survival analysis showed a trend toward benefit, with median overall survivals of 35.5 months and

29.9 months, respectively (P = .094).

“Bevacizumab’s activity in ovarian cancer is much higher than in colon, lung, and breast cancers, and comparable to activity in renal cell carcinoma,” Dr. Matei commented. “Three randomized trials have been positive continued on page 26

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PAGE 26

Gynecologic Oncology Gynecologic Cancer continued from page 25

in the adjuvant and recurrent settings.

The most benefit has been seen in higher-risk groups—those with recurrent disease and those suboptimally debulked in the adjuvant setting.”

Future studies in ovarian cancer will be needed to answer questions about dose, duration, and patient selection.

‘Angiogenic Signature’ May Select Patients for Bevacizumab The ideal of establishing molecular profiles to help guide treatment is a step closer, as investigators have identified molecular subgroups using DNA microarray expression data.4 Analysis of formalin-fixed paraffin embedded (FFPE) specimens was linked to prospectively collected clinical data, SEE PAGE 2 and six molecularly

distinct subgroups were significantly related to histology and to differing overall survival rates (P < .0001). Within the serous cohort, the dominant discriminatory biology was associated with angiogenic processes.

“Expression profiling on macrodissected FFPE specimens is feasible with this novel platform, and the molecular profiling correlates tightly with histologic subtype,” Dr. Matei noted. Pending validation, the 25-gene signature with functional angiogenic significance, ie, “angiogenic signature,” may someday help select patients for bevacizumab.

While “we are not there yet” with regard to the molecular classification of ovarian cancer, progress is steady.

Disclosure: Dr. Matei has consulting fees from Genentech.

■

received

References 1. Buys SS, Partridge E, Black A, et al: Effect of screening on ovarian cancer mortality in the Prostate, Lung, Colorectal and

Key Gynecologic Cancer Findings Presented at Best of ASCO® ■■ Screening for ovarian cancer, vs usual care, identified more cancers but did not reduce mortality.

■■ Olaparib as maintenance prolonged remission to almost 9 months, a near-doubling over placebo.

■■ Bevacizumab added to carboplatin and gemcitabine, followed by

maintenance bevacizumab, improved progression-free survival by 4 months.

■■ Genetic subgroups of ovarian cancer can be identified and are associated with different survival rates; an “angiogenic signature” is observed within the serous ovarian cancer cohort.

Ovarian cancer randomized screening trial. 2011 ASCO Annual Meeting. Abstract 5001. Presented June 4, 2011.

2. Ledermann JA, Harter P, Gourley C, et al: Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer. 2011 ASCO Annual Meeting.

Abstract 5003. Presented June 4, 2011.

3. Aghajanian C, Finkler NJ, Rutherford T, et al: OCEANS: A randomized, double-blinded, placebo-controlled phase

Adjuvant Treatment Still Standard in Melanoma, but New Drugs Prolong Life in Metastatic Setting

III trial of chemotherapy with or without bevacizumab in patients with platinumsensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer.

2011 ASCO Annual Meeting. Abstract LBA5007. Presented June 4, 2011.

4. Gourley C, Michie CO, Keating KE, et al: Establishing a molecular taxonomy for epithelial ovarian cancer from 363 formalin-fixed paraffin embedded specimens.

2011 ASCO Annual Meeting. Abstract 5000. Presented June 4, 2011.

Melanoma

By Caroline Helwick

A

t the Best of ASCO® Miami meeting, Omid Hamid, MD, The Angeles Clinic and Research Institute (www.theangelesclinic.org), Los Angeles, California, reviewed abstracts that received a great deal of attention at this year’s Annual Meeting—the new treatments for metastatic melanoma.

He also described key data that had been presented for adjuvant therapy of the disease.

Can Interferon Treatment Time Be Shortened?

The Intergroup E1697 trial evaluated 4 weeks of high-dose interferon alfa-2b (Intron A) induction among 1,150 patients with T3 disease or tu-

mors of any thickness with microscopically positive nodes.1 Patients were randomized to postoperative adjuvant interferon for 5 days per week for 4 weeks, or observation.

“Duration and intensity of therapy may be an important variable for benefit from interferon,” Dr. Hamid noted.

“The study asked whether the induction phase of high-dose interferon is the major contributor of benefit. If effective, the 4-week regimen would be a major improvement in terms of toxicity, convenience, and cost.”

E1697 was terminated early when an interim analysis found no benefit for the experimental approach. Median recurrence-free survival was 7.3

Key Melanoma Findings Presented at Best of ASCO® ■■ In the adjuvant setting, E1697 found no evidence of benefit from an

interferon induction approach, vs a conventional schedule that includes maintenance interferon.

■■ As a first-line agent in metastatic disease, ipilimumab (Yervoy) led

to a 2-month significant improvement in overall survival, for a 28% reduction in risk.

■■ First-line treatment with the BRAF inhibitor vemurafenib (Zelboraf ) reduced the risk of death by 63% and risk of progression by 74%.

■■ Ipilimumab and vemurafenib have different toxicity profiles that require careful monitoring.

months with high-dose interferon and 7.8 months with observation (P = .69), and 5-year overall survival rates were 85% and 82%, respectively (P = .38).

The results are in keeping with those of the largest adjuvant trial ever conducted in stage III melanoma— European Organisation for Research and Treatment of Cancer (EORTC) 18991—which showed that 8 weeks of pegylated interferon alfa-2b (Pegintron, Sylatron) followed by maintenance for up to 5 years improved recurrence-free survival but not distant metastasis-free survival or overall survival, with best results seen in patients who had sentinel node–positive, ulcerated melanoma.

A slightly different approach was reported at the 2011 ASCO by Italian investigators, who found comparable (though not superior) recurrence-free survival with a shorter but more intensive high-dose interferon regimen (4 courses of interferon 5 days per week for 4 weeks every other month).3 The negative results of E1697, along with other studies from the EORTC, support the importance of longer highdose interferon treatment duration (ie, 1 year of maintenance) to optimize outcomes, Dr. Hamid said. “In the adjuvant setting we have learned that to

Omid Hamid, MD

show activity we need trials of about 1,000 patients and 500 events. And future studies must include the two new drugs with efficacy in the metastatic setting,” he added.

Ipilumumab Gives 2-Month Survival Advantage Metastatic melanoma carries an overall survival rate of only 25% at 1 year and 10% at 2 years. This will change with the introduction of ipilimumab (Yervoy) and vemurafenib (Zelboraf), the first drugs shown to improve overall survival in this disease.

In the phase III Study 024 trial, firstline treatment with ipilimumab plus dacarbazine improved overall survival by 2 months, vs dacarbazine alone.4 The fully human monoclonal antibody, a CTLA-4 blocker that augments T-cell activation, was approved by the FDA in March.

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PAGE 27

Melanoma The study randomized 502 untreated patients to dacarbazine plus ipilimumab or dacarbazine alone. Median overall survival was 11.2 months with ipilimumab/dacarbazine vs 9.1 months with dacarbazine, a highly significant 28% reduction in mortality risk (P = .0009).

Survival rates were 47.3% vs 36.3%, respectively, at 1 year; 28.5% vs 17.9% at 2 years; and 20.8% vs 12.2%, respectively, at 3 years. Median duration of response was 19.3 months with ipilumumab/dacarbazine compared to 8.1 months with dacarbazine.

“We see the traditional partial and complete responses, but we also see tumors progress and then respond past the time of initial evaluation,” Dr. Ha-

BRAF Targeting Reduces Mortality by 63%

mid said. “There is a doubling in survival over what we typically see, and a plateau of the tail of the survival curve even many years out from treatment initiation,” he noted.

“In future trials, I think we can evaluate the dose-response effect we see by comparing 10 mg vs 3 mg, followed by maintenance.”

Ipilimumab was also shown, in a study reported at the Annual Meeting, to extend overall survival to 2 years in 26% of patients with brain metastases.5 In addition to further study in this subset, Dr. Hamid suggested ipilimumab be evaluated in combination with cytotoxics, vemurafenib and other targeted agents, novel immunomodulators, and anti-VEGF agents.

Vemurafenib, which targets the BRAF V600E mutation that is present in approximately 50% of patients, was approved August 17 based on the results of the phase III BRIM3 trial.6 BRIM3 compared vemurafenib to dacarbazine in 675 untreated patients with the BRAF V600E mutation.

In the first interim analysis, progression-free survival was 5.3 months with vemurafenib vs 1.6 months with dacarbazine—a 74% reduced risk (P < .0001). Overall survival rates at 6 months were 84% vs 64%, respectively—a 63% reduction (P < .0001).

Confirmed response rates were 48.4% vs only 5.5%, respectively. The ben-

A Proportion not progressed

1.0 0.9 0.8 0.7 0.6 0.5

Ipilimumab+dacarbazine Placebo+dacarbazine

0.4 0.3 0.2 0.1 0.0 1

0

B

2

Years

BRAF-mutated patients

100% Progression-free survival

90% 80% 70% 60%

Vemurafenib

50% 40% 30% 20%

Dacarbazine

10% 0%

0

1

2

3

4

5

6

7

8

9

10

11

12

Months Fig. 1: Progression-free survival curves for ipilimumab in all patients (A) and vemurafenib in BRAF-mutated patients (B) reflect different mechanisms and kinetics. Courtesy of Omid Hamid, MD. Adapted from (A) Wolchok JD, et al,4 and (B) Chapman PB, et al.6

efits in response and survival were seen across all subgroups examined.

“With vemuSEE PAGE 2 rafanib we see an initial separation between the arms that continues. There are durable and ongoing responses. The data in both the first line [BRIM3] and second line [BRIM2]7 seem extremely promising.”

He added that the overall survival curve is markedly different from that of ipilimumab (Fig. 1), “which reflects different mechanisms and kinetics of the drugs.”

■

Disclosure: Dr. Hamid reported receiving consulting and speaking fees for Bristol-Myers Squibb and Roche, research funding from BristolMyers Squibb, GlaxoSmithKline and Roche

References 1. Agarwala SS, Lee SJ, Flaherty LE, et al: Randomized phase III trial of high-dose interferon alfa-2b for 4 weeks induction only in patients with intermediate- and high-risk melanoma (Intergroup trial E 1697). 2011 ASCO Annual Meeting. Abstract 8505. Presented June 4, 2011.

2. Eggermont AM, Suciu S, Santinami M, et al: Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: Final results of EORTC 18991, a randomised phase III trial. Lancet 372:117–126, 2008.

3. Chiarion-Sileni V, Guida M, Romanini A, et al: Intensified high-dose intravenous interferon alpha 2b for adjuvant treatment of stage III melanoma: A randomized phase III Italian Melanoma Intergroup trial. 2011 ASCO Annual Meeting.

Abstract 8506. Presented June 4, 2011.

4. Wolchok JD, Thomas L, Bondarenko IN, et al: Phase III randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma. 2011 ASCO Annual Meeting.

Abstract LBA5. Presented June 5, 2011.

5. Heller KN, Pavlick AC, Hodi FS, et al: Safety and survival analysis of ipilimumab therapy in patients with stable asymptomatic brain metastases. 2011 ASCO Annual Meeting. Abstract 8581. Presented June 5, 2011.

6. Chapman PB, Hauschild A, Robert C, et al: Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine in patients with V600E BRAF-mutated melanoma. 2011 ASCO Annual Meeting.

Abstract LBA4. Presented June 5, 2011.

7. Ribas A, Kim KB, Schuchter LM, et al: BRIM-2: An open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma.

2011 ASCO Annual Meeting. Abstract 8509. Presented June 4, 2011.

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Sarcoma Novel Approaches and Agents Making Headway against Sarcoma

By Susan London

N

ovel approaches and agents reported at the ASCO 2011 Annual Meeting are improving outcomes in sarcoma, a heterogeneous disease with historically poor outcomes, according to William D. Tap, MD, Section Chief of Sarcoma Oncology at Memorial Sloan-Kettering Cancer Center in New York. Dr. Tap presented the sarcoma abstracts at this year’s Best of ASCO Seattle meeting.

Adjuvant Imatinib in High-risk GIST: 1 vs 3 Years In a phase III trial conducted by the Scandinavian Sarcoma Group and Sarcoma Group of the AIO, German (SSG XVIII) among patients with high-risk gastrointestinal stromal tumor (GIST), out-

comes were better with longer adjuvant imatinib therapy.1 A total of 397 patients with resected tumors were randomly assigned to 1 year vs 3 years of imatinib. Results showed that after a median follow-up of 54 months, patients in the 3-year group had better 5-year recurrence-free survival (65.6% vs 47.9%; HR = 0.46; P < .0001) and overall survival (92.0% vs 81.7%; HR = 0.45; P = .019). Those in the 3-year arm were more than twice as likely to discontinue treatment (31.8% vs 14.5%).

“This was a very nicely designed trial,” Dr. Tap commented, and it met its endpoints. “But…I think we will need more time (and events) to see what will happen to the overall survival data.”

The data are telling when it comes

Questions and Answers about Adjuvant Imatinib in GIST

“A

s clinicians, we really need to ask who should receive adjuvant [imatinib], and we have several ways to risk-stratify patients, including tumor characteristics (size, location, mitotic index), mutational analyses, and a recently published nomogram for patient-specific survival,” said William D. Tap, MD, Section Chief of Sarcoma Oncology at Memorial Sloan-Kettering Cancer Center in New York.1 Then, “the question really becomes, what defines risk?… I already see that some physicians are William D. Tap, MD beginning to say if [patients] have a 20%, 30%, 40% increase in [risk of] recurrence or death during a certain time period, they would start [imatinib].” But all of the above factors should be considered.

Cytostatic vs Cytotoxic “The other question is, once you start it, how long should you treat?” Dr. Tap continued. In the trial, whether imatinib was taken for 1 year or 3 years, there was a similar uptick in recurrences after drug discontinuation.

“What this suggests is that we are not curing patients with longer use of [imatinib]; rather, we are just prolonging recurrence-free survival,” he commented. “So the question with a cytostatic drug becomes, once you start [it], are you able to stop it?”

A phase II trial, PERSIST-5, is looking at 5 years of adjuvant imatinib, but results are not out until 2018. “So this is a question that we are going to be faced with for some time,” he said.

“Based on all this data, in my patient population when we start [imatinib], we are going to continue it for the near future, and that often means we talk to the patients about doing it for life,” Dr. Tap concluded. “Until there is other data to suggest that they could come off it, or we find combinations that can turn this from a cytostatic drug into a cytotoxic drug, they SEE PAGE 2 will remain on [imatinib].”

■

Reference 1. Gold JS, Gönen M, Gutiérrez A, et al: Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: A retrospective analysis. Lancet Oncol 10:1045-1052, 2009.

Key Sarcoma Findings Presented at Best of ASCO® ■■ Compared with 1 year of adjuvant imatinib for high-risk gastrointestinal

stromal tumor, 3 years of therapy reduces the 5-year risk of recurrence by 54% and risk of death by 55%, despite a higher rate of discontinuation.

■■ Ridaforolimus prolongs progression-free survival by 3 weeks in patients with advanced sarcoma who have had benefit from chemotherapy.

■■ Pazopanib prolongs progression-free survival by 3 months in patients with progressive soft-tissue sarcoma.

■■ Busulfan/melphalan is superior to carboplatin, etoposide, and melphalan as myeloablative therapy for high-risk neuroblastoma, achieving better event-free survival (49% vs 33%) and overall survival (60% vs 48%).

to tolerability, he noted. “We tend to think of [imatinib] as somewhat of a benign treatment, but it’s clear that if you ask patients to take this drug with no evidence of tumor, a significant proportion of them will stop taking it because of side effects. It is therefore critical to educate patients and physicians about the importance of remaining on treatment. To ensure this, physicians must remain vigilant about assessing and treating potential side effects.”

Ridaforolimus The mTOR inhibitor ridaforolimus improves progression-free survival in patients with advanced sarcoma who have had benefit from chemotherapy, according to results of the phase III SUCCEED trial.2 In this largest of trials to date in soft-tissue and bone sarcoma, 711 patients who achieved at least stable disease with chemotherapy were randomly assigned to ridaforolimus or placebo as maintenance therapy. Progression-free survival was superior with ridaforolimus (median = 17.7 vs 14.6 weeks; HR = 0.72; P = .0001). The rate of clinical benefit (complete response, partial response, or stable disease) was also better (40.6% vs 28.6%; P = .0009).

Dr. Tap noted that the gain in progression-free survival was 3 weeks with independent radiographic review.

“So this was statistically significant… but we have to question ridaforolimus’ true clinical value in sarcoma.”

Indeed, sarcoma is now recognized to be a group of 60 to 80 molecularly distinct diseases, and the trial’s molecular analyses were limited. “When we look at a trial of over 700 patients with sarcoma, we need to assess them according to histology-specific and molecular-specific subsets to really understand who to give this drug to and who not to give this drug to,” he maintained.

“Whether I will use this [drug] clinically is very difficult to answer,” Dr. Tap added. “I imagine there are some patients I may [give ridaforolimus], but for the majority of patients, it’s not something that I am ready to add into my general clinical practice.”

Pazopanib in Soft-tissue Sarcoma The tyrosine kinase inhibitor pazopanib (Votrient) improves progressionfree survival in patients with soft-tissue sarcoma that has progressed despite chemotherapy, concluded investigators who conducted the EORTC phase III PALETTE trial.3 In all, 369 patients were randomly assigned 2:1 to the drug (which targets VEGFR, PDGFR, and c-Kit) or placebo. Progression-free survival was longer with pazopanib than with placebo (median = 4.6 vs 1.5 months; HR = 0.31; P < .0001; Fig. 1). Overall survival was similar between the two groups.

Demographics differed slightly between groups: The pazopanib group had more leiomyosarcomas, a responsive subset based on the phase II data, and lowgrade sarcomas, which in general have a better prognosis. “Whether or not [the differences] contributed to the outcomes is hard to know,” Dr. Tap commented.

Again, a key question to address is which patients will respond to the drug.

“At Memorial Sloan-Kettering, for a few of the more sensitive subtypes, we are looking at pazopanib in combination with gemcitabine and docetaxel in the neoadjuvant setting, and the trial is very heavy with molecular correlates to try to predict which patients should respond and why,” he said.

Myeloablative Therapy for Neuroblastoma A randomized trial found that BuMel (busulfan [Busulfex, Myleran] plus melphalan) is more efficacious than CEM

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Sarcoma (carboplatin, etoposide, and melphalan) as myeloablative therapy for high-risk neuroblastoma in patients responding to rapid COJEC induction therapy (cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide).4 Of 1,577 patients who received the induction therapy, 43% had at least a partial response and were randomly assigned to myeloablative therapy with busulfan/melphalan or carboplatin, etoposide, and melphalan, followed by stem cell transplant, radiation therapy, and postconsolidation therapy. With a median follow-up of 3.5 years, compared with their counterparts given CEM, patients given BuMel had better event-free survival (49% vs 33%; P < .001) and overall survival (60% vs 48%; P = .003). The benefit of BuMel was SEE PAGE 2 greatest in patients with residual disease postinduction. BuMel had a better toxicity profile and was associated with lower rates of ICU admission and death.

According to Dr. Tap, response to CEM in the trial was lower than that seen historically in Children’s Oncology Group studies, possibly due to their use of a different induction regimen—the modified Memorial Sloan-Kettering N6 regimen. “Really the way to study this would be to compare the two regimens

in a head-to-head trial, but I am not 100% Placebo Pazopanib sure they will be 90% able to do that, Median (months) 1.5 4.6 given the signifi80% Hazard ratio 0.31 cant amount of 1 70% 95% CI (0.24,0.40) resources that 60% went into this P-value <.0001 trial,” he com50% mented.

40% More than half of the patients 30% didn’t make it to 20% randomization because they had 10% an inadequate 0% response.

“It’s 0 6 12 18 24 those [initially unresponsive] Months patients that we need to affect,” 3 Dr. Tap said. “As Fig. 1: Progression-free survival in the PALETTE trial. Courtesy of William D. Tap, MD. Adapted from Van Der Graaf WT, et al. we move forward, AIO). 2011 ASCO Annual Meeting. Abphase III trial of pazopanib versus placebo in it would be very nice to see if [emerging stract LBA1. Presented June 5, 2011. patients (pts) with soft-tissue sarcoma (STS) therapies] could be added up front to imwhose disease has progressed during or fol2. Chawla SP, Blay J, Ray-Coquard IL, lowing prior chemotherapy—An EORTC et al: Results of the phase III, placeboprove survival of these patients.”

■

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

References 1. Joensuu H, Eriksson M, Hatrmann J, et al: Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/

controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus (R) as maintenance therapy in advanced sarcoma patients (pts) following clinical benefit from prior standard cytotoxic chemotherapy (CT). 2011 ASCO Annual Meeting.

Abstract 10005 . Presented June 6, 2011.

3. Van Der Graaf WT, Blay J, Chawla SP, et al: PALETTE: A randomized, double-blind,

New Therapies and Prognostic Techniques Highlighted in Head and Neck Cancer

STBSG Global Network Study (EORTC 62072). 2011 ASCO Annual Meeting. Abstract LBA10002. Presented June 6, 2011.

4. Ladenstein RL, Poetschger U, Luksch R, et al: Busulphan-melphalan as a myeloablative therapy (MAT) for high-risk neuroblastoma: Results from the HR-NBL1/ SIOPEN trial. 2011 ASCO Annual Meeting. Abstract 2. Presented June 5, 2011.

Head and Neck Cancer

By Caroline Helwick

D

. Neil Hayes, MD, MPH, of the University of North Carolina at Chapel Hill, described efforts to position the epidermal growth factor receptor (EGFR) inhibitor cetuximab

(Erbitux) in head and neck cancer treatment.

Surprisingly negative results came from the phase III Radiation Therapy Oncology Group (RTOG) 0522 trial

Table 1: After the RTOG 0522 Trial: Where Do We Go from Here?

Address p16-positive and –negative head and neck squamous cell carcinoma separately Goal for patients with p16-positive head and neck squamous cell carcinoma is toxicity reduction (eg, RTOG 1016: RT + cisplatin vs RT + cetuximab) Strategies for patients with p16-negative head and neck squamous cell carcinoma include:

■■ Combining cetuximab with agents having different mechanisms of

action (eg, taxanes; RTOG 0234 suggests RT + cetuximab + docetaxel is potentially better than RT + cetuximab + cisplatin)

■■ Adding cetuximab to multiagent neoadjuvant chemotherapy regimens ■■ Cotargeting multiple deregulated signaling pathways (need well planned preclinical studies)

RT = radiotherapy; RTOG = Radiation Therapy Oncology Group. Courtesy of D. Neil Hayes, MD, MPH.

(N = 940), which showed no benefit to adding cetuximab to the radiation/cisplatin platform for front-line therapy of advanced head and neck squamous cell carcinoma.1 At 2 years, progression-free survival was approximately 64% in both arms; overall survival was 79.7% with chemoradiation (P = .68) and 82.6% with the addition of cetuximab (P = .17). Rates of locoregional relapse and distant metastases were also similar.

Cetuximab increased grade 3/4 mucositis (43% vs 33%; P < .004), in-field skin toxicity (25% vs 15%; P < .001), and out-of-field skin reactions (19% vs 1%; P < .001), but toxicity beyond 90 days was similar between the arms.

“RTOG 0522 was the study of the year in head and neck cancer. Unfortunately, it was flat-out negative,” Dr. Hayes noted.

No differential effect emerged by

D. Neil Hayes, MD, MPH

p16 (HPV status). “While 70% of patients had oropharynx tumors (suggesting HPV positivity), tissue collection was lacking in half the patients.

Our ability to make inferences with this amount of missing data is very limited,” Dr. Hayes said.

Even as a negative study, RTOG 0522 is practice-changing. “Many physicians have been treating with this regimen, assuming this study would be continued on page 30

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Head and Neck Cancer Head and Neck Cancer continued from page 30

positive,” he said. “But we now have no data to support this.”

Cetuximab Equivalent to Cisplatin after Induction The phase II TREMPLIN study (N = 153) evaluated sequential chemoradio-

therapy in previously untreated, operable squamous cell carcinoma of the larynx/ hypopharynx.2 Patients received induction chemotherapy with docetaxel, cisplatin, and fluorouracil; nonresponders underwent laryngectomy, whereas those with more than a 50% response were randomly assigned to radiotherapy plus either cisplatin or cetuximab.

Expert Q and A D. Neil Hayes, MD, MPH, of the University of North Carolina, Chapel Hill, discusses the role of HPV status in head and neck cancer.

A

re you convinced human papillomavirus (HPV) positivity is associated with better prognosis?

Dr. D. Neil Hayes: The HPV story influences almost everything we do in head and neck cancer, though we don’t know quite what to do with it.

Five-year survival approaches 80% in HPV-positive patients vs 50% in HPVnegative patients. All our data on outcomes, however, are in association with treatment, so it is hard to be certain about the natural history. I can expect to cure a 50-year-old nonsmoking patient with T2N2b HPV-positive cancer. But I am also wondering whether I might be overtreating him.

How do you use HPV status to guide treatment decisions?

Dr. Hayes: HPV status can be helpful in individual patients, especially those with poor performance status, for whom we have little data upon which to base treatment decisions. If I am worried about radiation side effects, for example, HPV positivity helps me feel better about choosing less aggressive treatment. I tailor therapy along these lines.

However, unlike many physicians, I do not routinely reduce therapy based on HPV positivity. Studies that have attempted to tease out the outcomes by HPVpositive vs -negative status have not provided clear guidance. In RTOG 0129, patients receiving radiation and cisplatin had better outcomes if they were HPVpositive.1 These data influenced much of our current thinking. And in 2006, Bonner et al showed that cetuximab plus radiotherapy was superior to radiotherapy alone, with most benefit assumed to be in the oropharyngeal and therefore HPV-positive patients.2 But then in 2008, the Vermorken/Hitt study of cetuximab plus chemotherapy had us scratching our heads, because most benefit was seen in the oral cavity, which is the least likely area to be HPV-positive.3 Now RTOG 0522 has shown no significant differential benefit for cetuximab by HPV status.4 There was also a retrospective study from Memorial Sloan-Kettering in which patients treated with cetuximab did worse than those on cisplatin, even after controlling for HPV status.5 Therefore, HPV positivity, and its importance in therapy, may depend on the tumor site and situation. We should be careful about using HPV to make treatment determinations at this point, and not alter treatment outside of a clinical trial.

■

References 1. Gillison JL, Harris J, Westra W, et al: Survival outcomes by tumor human papillomavirus status in stage III-IV oropharyngeal cancer in RTOG 0129. J Clin Oncol 27(15S):Abstract 6003, 2009.

2. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006.

3. Vermorken JB, Mesia R, Rivera F, et al: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:116-127, 2008.

4. Ang KK, Zhang QE, Rosenthal DI, et al: A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas. 2011 ASCO Annual Meeting. Abstract 5500. Presented June 6, 2011.

5. Koutcher L, Sherman E, Fury M, et al: Concurrent cisplatin and radiation versus cetuximab and radiation for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys October 12, 2010 (early release online).

All endpoints were similar between the arms. Larynx preservation rates at 3 months were 95% with cisplatin and 93% with cetuximab (P = .63). Preservation of larynx function at 18 months (or at death) was seen in 87% and 82%, respectively (P = .68). Overall survival was 92% and 89%, respectively (P = .44), and laryngoesophageal dysfunction-free survival was 79% vs 71% (P = .30). Acute toxicities compromising treatment and late toxicities were more common with cisplatin.

Dr. Hayes concluded, “The takehome message is that these two regimens are equivalent, and that cetuximab plus radiotherapy may be reasonable after induction.”

Laser Treatment Effective for Mucositis In a phase III randomized trial of 94 patients, upfront use of low-level laser therapy helped prevent oral mucositis associated with chemoradiation.3 Grade 3/4 mucositis was observed in < 7% of the laser therapy group, compared with almost 50% of controls (who received “placebo” laser applications from the same machine but without light), for an 84% reduction (P < .001). Patients receiving active laser therapy also had less pain, narcotic use, and gastrostomia and better quality of life.

“Mucositis, especially grade 3 and 4, may limit treatment and compromise outcomes. While we need confirmatory data, the study shows we can intervene to improve mucositis.”

Future Directions An international group developed a 30-gene expression profile that predicted clinical outcomes in primary laryngeal carcinoma.4 Median disease-free survival was 34 months in high-risk patients vs 80 months in low-risk patients (P = .01). Recurrences were four times greater among those in the high-risk group (P = .017).

“This elegant study suggests subgroups of patients can be distinguished

according to who will do well and who will do worse. For clinical usefulness, the issue is whether the differSEE PAGE 2 ence between highand low-risk groups will be sufficient to change therapy,” Dr. Hayes commented.

Finally, the novel vascular disrupting agent fosbretabulin (CA4P), combined with carboplatin and paclitaxel, tripled survival in the randomized phase II/ III FACT trial (N = 80), from 9% at 1 year with chemotherapy alone to 26% (P = .065).5 “There is enthusiasm and excitement over this novel therapy for anaplastic thyroid cancer,” Dr. Hayes commented, urging oncologists to have patients enroll in the upcoming phase III trial.

■

Disclosure: Dr. Hayes reported receiving research funding from Lilly and honoraria from Bristol-Myers Squibb, Lilly, and sanofi-aventis.

References 1. Ang KK, Zhang QE, Rosenthal DI, et al: A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas. 2011 ASCO Annual Meeting.

Abstract 5500. Presented June 6, 2011.

2. Lefebvre J, Pointreau Y, Rolland F, et al: Results of the randomized phase II TREMPLIN study. 2011 ASCO Annual Meeting.

Abstract 5501. Presented June 6, 2011.

3. Antunes HS, Herchenhorn D, Araujo CM, et al: Phase III trial of low-level laser therapy to prevent induced oral mucositis in head and neck cancer patients submitted to concurrent chemoradiation.

2011 ASCO Annual Meeting. Abstract LBA5524. Presented June 3, 2011.

4. Fountzilas E, Angouridakis N, Karasmanis I, et al: Prediction of clinical outcome in patients with primary laryngeal carcinoma using gene expression profiling.

2011 ASCO Annual Meeting. Abstract 5505. Presented June 6, 2011.

5. Sosa JA, Elisei R, Jarzab B, et al: Final survival analysis for the FACT trial. 2011 ASCO Annual Meeting. Abstract 5502.

Presented June 6, 2011.

Key Head and Neck Cancer Findings Presented at Best of ASCO® ■■ The addition of cetuximab to a radiation/cisplatin backbone as front-line treatment did not improve progression-free or overall survival.

■■ Outcomes were equivalent in a comparison of postinduction cetuximab and cisplatin plus radiotherapy in cancer of the larynx/hypopharynx.

■■ Upfront use of low-level laser therapy reduced grade 3/4 oral mucositis by 84% in chemoradiation patients.

■■ A 30-gene model stratified risk and predicted clinical outcomes in primary laryngeal carcinoma.

■■ The addition of fosbretabulin to carboplatin/paclitaxel tripled 1-year survival in patients with anaplastic thyroid cancer.

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Index: Best of ASCO® ’11 Abstracts Reported in this Supplement continued from page 2

response to preoperative lapatinib and trastuzumab, separately and combined prior to neoadjuvant breast cancer chemotherapy. Holmes F, et al.

■■ Abstract 509: LANDSCAPE: A French phase II study with lapatinib and capecitabine in patients with brain metastases from HER2-positive metastatic breast cancer before whole brain radiotherapy. Bachelot T, et al.

■■ Abstract LBA1003: NCICCTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer. Whelan TJ, et al.

■■ Abstract 1007: A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer. O’Shaughnessy J, et al.

■■ Abstract LBA1005: The effect on pCR of bevacizumab and/or antimetabolites added to standard neoadjuvant chemotherapy: NSABP protocol B-40.

Bear H, et al.

■■ Abstract 1004: First analysis of SWOG S0221: A phase III trial comparing chemotherapy schedules in high risk early breast cancer. Budd GT, et al.

■■ Abstract 1000: Genetic associations with taxane-induced neuropathy by genome-wide association study in E5103.

Schneider BP, et al.

Gastrointestinal Cancer Colorectal Cancer

■■ Abstract 3504: Capecitabine versus 5-FU–based (neo-)adjuvant chemoradiotherapy for locally advanced rectal cancer. Hofheinz R, et al.

■■ Abstract 3503: The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum.

Roh MS, et al.

■■ Abstract 3507: The efficacy of oxaliplatin when added to 5-FU/leucovorin in stage II colon cancer. Yothers G, et al.

■■ Abstract 3511: Influence of KRAS G13D mutations on outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. Tejpar S, et al.

■■ Abstract #10500: Comparative genomic analysis of primary versus metastasis in colorectal carcinomas. Vakiani E, et al.

■■ Abstract 3535: Primary colorectal tumors and their metastasis are genetically not the same. Vermaat JSP, et al.

Noncolorectal Cancer

■■ Abstract 4003: Postoperative adju-

vant chemoradiation for gastric or gastroesophageal junction adenocarcinoma using epirubicin, cisplatin, and infusional 5-FU before and after CI 5-FU and radiotherapy (CRT) compared to bolus 5-FU/LV before and after CRT. Fuchs CS, et al.

■■ Abstract LBA4002: Adjuvant capecitabine and oxaliplatin for gastric cancer: Results of the phase III CLASSIC trial. Bang YJ, et al.

■■ Abstract 4004: A multicenter, randomized phase III trial comparing secondline chemotherapy plus best supportive care (BSC) with BSC alone for pretreated advanced gastric cancer. Park SH, et al.

■■ Abstract 4001: Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib (GIDEON) second interim analysis in more than 1,500 patients. Marrero JA, et al.

■■ Abstract 4005: Long-term update of U.S. GI intergroup RTOG 98-11 phase III trial for anal carcinoma. Gunderson LL, et al.

Hematologic Cancer Lymphoma

■■ Abstract 8000: R-CHOP14 vs rCHOP21: Result of a randomised phase III trial for the treatment of patients with newly diagnosed diffuse large b-cell non-Hodgkin’s lymphoma. Cunningham D, et al.

■■ Abstract 8001: Randomized phase III US/Canadian intergroup trial (SWOG S9704) comparing CHOP±R x 8 to CHOP±R x 6 followed by autotransplant for patients with high-intermediate (H-Int) or high IPI grade diffuse aggressive nonhodgkin’s lymphoma (NHL). Stiff PJ, et al.

■■ Abstract #8004: Maintenance with rituximab after autologous stem cell transplantation in relapsed patients with CD20 diffuse large b-cell lymphoma (DLBCL).

Gisselbrecht C, et al.

Myeloma

■■ Abstract 8007: Incidence of second primary malignancy (SPM) in melphalanprednisone-lenalidomide combination followed by lenalidomide maintenance (MPR-R) in newly diagnosed multiple myeloma patients (pts) age 65 or older.

Palumbo AP, et al.

■■ Abstract 8025: Interim results from PX-171-006, a phase (Ph) II multicenter dose-expansion study of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed and/or refractory multiple myeloma . Wang M, et al.

■■ Abstract 8020: Melphalan/prednisone/lenalidomide (MPR) versus highdose melphalan and autologous trans-

plantation (MEL200) in newly diagnosed multiple myeloma (MM) patients : A phase III trial. Boccadoro M, et al.

Genitourinary Cancers

■■ Abstract 4503: Axitinib vs sorafenib as second-line therapy for metastatic renal cell carcinoma. Rini BI, et al.

■■ Abstract 4516: Cabozantinib (XL184) in metastatic castration resistant prostate cancer. Hussain M, et al.

■■ Abstract 4514: A phase III randomized trial of intermittent vs. continuous androgen suppression for PSA progression after radical therapy (NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/ UK Intercontinental Trial CRUKE/01/013).

Crook JM, et al.

■■ Abstract LBA4517: Evaluation of circulating tumor cell enumeration as an efficacy response biomarker of overall survival in metastatic castration resistant prostate cancer. Scher HI, et al.

■■ Abstract 4512: Towards a rational strategy for prostate cancer screening based on long-term risk of prostate cancer metastases and death. Lilja H, et al.

Gynecologic Cancer

■■ Abstract 5001: Effect of screening on ovarian cancer mortality in the prostate, lung, colorectal and ovarian (PLCO) cancer randomized screening trial. Buys, SS, et al.

■■ Abstract 5003: Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC). Ledermann JA, et al.

■■ Abstract LBA5007: OCEANS: A randomized, double-blinded, placebocontrolled, phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian primary peritoneal, or fallopian tube cancer. Aghajanian C, et al.

■■ Abstract 5000: Establishing a molecular taxonomy for epithelial ovarian cancer (EOC) from 363 formalin fixed paraffin embedded specimens. Gourley C, et al.

Melanoma

■■ Abstract 8505: Randomized phase III trial of high dose interferon alfa-2b (HDI) for four weeks induction only in patients with intermediate and high-risk melanoma (Intergroup trial E 1697). Agarwala SS, et al.

■■ Abstract LBA5: A phase III randomized study of ipilimumab plus dacarbazine versus dacarbazine alone as first-line treatment in patients with unresectable stage III or IV melanoma. Wolchok JD, et al.

■■ Abstract LBA4: Phase III randomized,

open-label, multicenter trial (BRIM3) comparing BRAF inhibitor RG7204 with dacarbazine in patients with V600E BRAF mutated melanomas. Chapman PB, et al.

■■ Abstract 8509: BRIM-2: An open-label, multicenter phase II study of RG7204 (PLX4032) in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. Ribas A, et al.

Sarcoma

■■ Abstract LBA1: Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence. Joensuu H, et al.

■■ Abstract 10005: Results of the phase III, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus as maintenance therapy in advanced sarcoma patients (pts) following clinical benefit from prior standard cytotoxic chemotherapy.

Chawla SP, et al.

■■ Abstract LBA10002: PALETTE: A randomized double blind phase III trial of pazopanib versus placebo in patients with soft tissue sarcoma (STS) whose disease has progressed during or following prior chemotherapy. An EORTC STBSG global network study (EORTC 62072). Van Der Graaf W, et al.

■■ Abstract 2: Busulphan-melphalan is the superior myeloablative therapy for high risk neuroblastoma. Ladenstein RL, et al.

Head and Neck Cancer

■■ Abstract 5500: A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC). Ang KK, et al.

■■ Abstract 5501: Sequential chemoradiotherapy for larynx preservation: Results of the randomized phase II TREMPLIN study. Lefebvre J, et al.

■■ Abstract LBA5524: Phase ΙΙΙ trial of low-level laser therapy to prevent induced oral mucositis in head and neck cancer patients submitted to concurrent chemoradiation. Antunes H, et al.

■■ Abstract 5505: Prediction of clinical outcome in patients with primary laryngeal carcinoma using gene expression profiling. Fountzilas E, et al.

■■ Abstract 5502: A randomized phase II/III trial of a tumor vascular disrupting agent fosbretabulin tromethamine with carboplatin and paclitaxel in anaplastic thyroid cancer. Sosa JA, et al.

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We engage and execute with a vision, collaborating with the oncology community to deliver personalized and measurable outcomes that improve and extend lives.

We strive to advance the fight against cancer, continuously applying research to clinical practice and targeting the individual needs of people living with cancer.

This is our pledge. This is GSK Oncology.

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06/11