TAP Vol 2 Issue 17

Treating pNET 22

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Biosimilars in cancer treatment 37

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VOLUME 2, ISSUE 17

Younger women with breast cancer 56

NOVEMBER 15, 2011

ASCOPost.com

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

2011 European Multidisciplinary Cancer Congress

Aflibercept Improves Overall Survival in Patients with Metastatic Colorectal Cancer

By Caroline Helwick

T

he novel fusion Aflibercept/FOLFIRI in Colorectal Cancer protein aflibercept added to standard chemo■■ Aflibercept is a new fusion protein of key domains of the human vascular therapy led to an overall endothelial growth factor (VEGF) receptors 1 and 2. It blocks all VEGF-A survival benefit in a global isoforms, VEGF-B, and placental growth factor. phase III trial of second■■ The global phase III VELOUR trial evaluated adding aflibercept to FOLFIRI line metastatic colorectal in the second-line treatment of patients with metastatic colorectal cancer. cancer, reported at the ■■ The primary endpoint, overall survival, was improved with aflibercept 2011 European Multidisover FOLFIRI alone; median overall survival was 13.5 and 12.1 months, ciplinary Cancer Congress respectively, and median progression-free survival was 6.9 and 4.7 1 in Stockholm. months.

“Adding aflibercept to FOLFIRI [leucovorin, fluorouracil (5-FU), irinotecan] in patients with D’Hebron University Hospital in Barcelona, Spain, metastatic colorectal cancer previously treated with who presented the findings at a Presidential Session. oxaliplatin-based regimens reAflibercept is a new fusion protein of key dosulted in overall survival and promains of the human vascular endothelial growth facgression-free survival benefits that tor (VEGF) receptors 1 and 2. It blocks all VEGF-A are both statistically significant isoforms, as well as VEGF-B and placental growth and clinically meaningful,” said factor, and binds with high affinity.

SEE PAGE 60 continued on page 15 Josep Tabernero, MD, of Vall Expert’s Corner

Important Lessons for Oncology from the Front Lines of the AIDS Pandemic

Chemotherapy Drug Shortages: A Preventable Human Disaster

By Hagop M. Kantarjian, MD

T

he issue of chemotherapy drug shortages continues with no end in sight. Many heartfelt human interest stories have been told on television, in newspapers, and even to Congress, but the bottom line is that little, if any, action has been taken.

Uniquely American Problem News of the generic chemotherapy drug crisis hit the airwaves in April, when the shortage of cytarabine, an irreplaceable chemotherapy drug essential to the cure of acute myeloid leukemia (AML), was used to highlight the issue of inadequate supplies of mostly generic drugs. The problem is unique to the United States.

Cytarabine-containing chemotherapy regimens cure 40% of patients with AML; without continued on page 63

Hagop M. Kantarjian, MD, is Professor and Chairman, Department of Leukemia, and Associate Vice President for Global Academic Programs, The University of Texas MD Anderson Cancer Center, Houston.

By Ronald Piana

O

n June 5, 1981, the CDC issued a warning about a rare type of pneumonia discovered among a small group of young gay men in Los Angeles, later determined to be AIDS-related, ushering in the HIV/ AIDS epidemic. Early on, AIDS-related malignancies brought the oncology community into this formidable socio-clinical puzzle. One of the first oncologists on the front lines of the nascent AIDS phenomenon,

internationally regarded AIDS/lymphoma expert, Alexandra Levine, MD, MACP, shared her experiences with The ASCO Post.

Early AIDS Era

What prompted your introduction into HIV/AIDS research and treatment?

In 1982, a young man came to my University of Southern California county hospital office with enlarged lymph nodes. I A small piece of thought he had Hodgkin disease, so I arinformation or a major ranged a lymph node biopsy. I remember breakthrough in one scientific looking at the tissue under a microscope with Dr. Robert Lukes, Head of Hematodiscipline can translate logic Pathology at USC. Dr. Lukes had a magnificent eye, seeing things that othvaluable information into ers could not. To my surprise, he said another scientific area. this pathology was something he’d never seen before.

—Alexandra Levine, MD, MACP

November Is Lung Cancer Awareness Month

MORE IN THIS ISSUE Oncology Meetings Coverage 2011 European Multidisciplinary Cancer Congress ����������������15, 24, 41, 49 53rd ASTRO Annual Meeting ����������������������������� 8–11, 14, 30 AACR Basic Cancer Research Meeting ������������������������������������� 39 AACR Conference on Cancer Health Disparities ������������������������������������� 52 Direct from ASCO ��������������������������������������� 27

continued on page 20

A Harborside Press® Publication

The ASCO Post | NOVEMBER 15, 2011

PAGE 2

News

Novel HDAC Inhibitor May Restore Estrogen Sensitivity in Breast Cancer 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 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

INTERNATIONAL EDITORS 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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Contributing Writers: Charlotte Bath, Barbara Boughton, Jo Cavallo, Margot J. Fromer, Alice Goodman, Caroline Helwick, Eileen O’Gara-Kurtis, Ronald Piana, Susan Reckling, Matthew Stenger, Marian Wiseman Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations Disclosure information available at ASCOPost.com.

Entinostat plus exemestane doubled progression-free survival, with substantial efficacy seen in one subgroup.

By Caroline Helwick

T

he addition of the investigational histone deacetylase (HDAC) inhibitor entinostat significantly delayed breast cancer progression and showed a trend for a survival benefit in the phase II ENCORE 301 study.

The study was conducted in women with advanced estrogen receptor– positive breast cancer failing an aromatase inhibitor. It was reported at the 2011 Breast Cancer Symposium

by Denise A. Yardley, MD, of Sarah Cannon Research Institute and Tennessee Oncology in Nashville, Tennessee.1 “This exciting combination may allow patients to remain on hormonal therapy longer, delaying the development of resistance and the subsequent need for chemotherapy,” Dr. Yardley suggested.

The results were particularly striking among a subset of 49 patients participating in an evaluation of protein acetylaSEE PAGE 60 tion in peripheral

Entinostat in Advanced ER-positive Breast Cancer ■■ In the phase II ENCORE 301

trial of advanced estrogen receptor–positive breast cancer, the novel HDAC inhibitor entinostat, given with exemestane, showed a trend to delayed progression and survival benefit.

■■ HDAC inhibitors induce

hyperacetylation of lysines; substantial benefit was observed among “hyperacetylators,” whose median progression-free survival was 8.5 months.

blood mononuclear cells, revealing that in 13 of these patients (26.5%), HDAC-induced hyper-acetylation correlated with improved median progression-free survival that exceeded 8 months.

Entinostat is a novel oral HDAC inhibitor that has been shown in continued on page 18

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices.

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Copyright ©2011 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com.

Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology.

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ASCOPost.com | NOVEMBER 15, 2011

PAGE 3

News Clinical Guidelines

NCCN Meeting Addresses Issues in Hematologic Malignancies

By Alice Goodman

T

he National Comprehensive Cancer Network (NCCN) 6th Annual Congress on Hematologic Malignancies, held recently in New York, included reviews of the management of hematologic diseases as well as discussions of outstanding issues in the field. The following is a synopsis of some of the important highlights from the meeting.

■■

Follicular Lymphoma

■■ Delays in initiating upfront therapy and maintenance therapy are advised in asymptomatic patients with follicular lymphoma, said Andrew D. Zelenetz, MD, of Memorial Sloan-Kettering Cancer Center, New York, and Chair of the meeting.

■■ Asymptomatic patients with low disease burden have a similar quality of life to that of patients in remission.

■■ Routine treatment of every newly diagnosed patient is ill-advised.

Patients with signs and symptoms, including those with a tumor burden greater than 3 cm and compromised end-organ function, should be treated.

■■ The decision to initiate therapy in an asymptomatic patient should be guided by patient preference.

Some patients want treatment for a disease they know they have, whereas others prefer to wait until they become symptomatic before starting treatment.

■■ Disease proliferation, assessed by image analysis of MIB-1/Li-67 staining, holds promise as a marker for deciding when to initiate therapy.

Chronic Lymphocytic Leukemia

■■ Fluorescence in situ hybridization (FISH) testing for 13q, 11q, and 17p deletions can guide therapy selection for patients with chronic lymphocytic leukemia, said Susan M. O’Brien, MD, of The University of Texas MD Anderson Cancer Center, Houston.

■■ Deletion of the long arm of chromosome 13 (del 13q) is a marker of good prognosis, and standard

■■

■■

■■

NCCN guidelines should be followed for these patients.

The 11q deletion is associated with extensive lymph node involvement, disease progression, and shortened survival. Most patients will experience disease progression within 2 years. Treatment with an alkylating agent is recommended, and FCR (fludarabine, cyclophosphamide, rituximab) is the preferred regimen. FCR is the only regimen to show an improvement in overall survival.

The 17p deletion signals the worst prognosis of these three cytogenetic abnormalities. Currently available therapies are much less effective in this group. Alemtuzumab (Campath) is an option for nonbulky disease. Patients with 17p deletions should be enrolled in a clinical trial.

Older patients with good performance status can be treated with reduced-dose FCR or enrolled in a clinical trial. Those with poor performance status should receive palliative care.

Two novel inhibitors of B-cell signaling (PCI-32765 and CAL-101) are in early stages of development and, thus far, have shown promising results. Both agents appear to be effective in patients with poor-prognosis cytogenetics. Dr. O’Brien estimated that if studies continue to be positive, these drugs will be on the market within 5 years.

■■

■■

■■

Acute Myeloid Leukemia

■■ In addition to conventional prognostic markers such as age, performance status, and cytogenetics for acute myeloid leukemia, testing for three mutations is being used to predict prognosis and risk of relapse, said Jerald Radich, MD, of Fred Hutchinson Cancer Research Center, Seattle.

■■ Mutations in FLT3 and NPM1 have been shown in several studies to be associated with survival and relapse risk. Internal tandem mutations in FLT3 (FLT3-ITD) are associated with a poorer outcome compared

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

■■

Andrew D. Zelenetz, MD

Susan M. O’Brien, MD

Kenneth Anderson, MD

Jerald Radich, MD

Steven Devine, MD

Asher Chanan-Khan, MD

to patients with wild-type FLT3. In addition, measuring the proportion of mutant gene to wild type (the allelic ratio) strengthens the prognostic power.

Conversely, mutations of the NPM1 gene have an improved survival compared to wild-type NPM1. Thus, the best prognosis is in the group with NPM1 mutation and FLT3 wild type; the worst in NPM1 wild type with an FLT3-ITD mutation.

Likewise, there is increasing evidence that mutations in the CEPBA gene are associated with an improved outcome.

The detection of minimal residual disease, usually by flow cytometry, is highly associated with subsequent relapse.

The field is moving toward developing better markers to guide therapy selection in patients with disease progression and to select therapy at diagnosis.

Multiple Myeloma Treatment

■■ “Novel agents have revolutionized the treatment of multiple myeloma and improved survival,” said Kenneth Anderson, MD, of DanaFarber Cancer Institute, Boston.

■■ Combinations of lenalidomide (Revlimid), bortezomib (Velcade),

and dexamethasone, as well as other novel agents, are being studied to improve outcomes further.

■■ “We are learning how to give bortezomib,” Dr. Anderson said. Bortezomib should be given once weekly (not twice weekly), and subcutaneous administration is superior to intravenous delivery in reducing the incidence of peripheral neuropathy.

■■ Newer promising drugs in phase III testing for multiple myeloma include elotuzumab, pomalidomide, and carfilzomib.

■■ Oncogenomic studies are being used to identify novel mutations and potential therapeutic targets at diagnosis and again when mutations change during relapse.

Multiple Myeloma and Maintenance Therapy

■■ Maintenance therapy with thalidomide (Thalomid), lenalidomide, and bortezomib is of value in multiple myeloma, including those who are elderly and those who have undergone autologous stem cell transplant, said Steven Devine, MD, of Ohio State University Comprehensive Cancer Center in Columbus.

■■ Thalidomide improves progressionfree survival and overall survival as continued on page 6

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.

In Advanced Renal Cell Carcinoma...

Indication VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Important Safety Information WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information.

Hepatic Effects: Patients with pre-existing hepatic impairment should use VOTRIENT with caution. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have been observed with VOTRIENT. Use with caution in patients at higher risk of developing QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval,

and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

Hemorrhagic Events: Fatal hemorrhagic events have been reported (all grades [16%] and Grades 3 to 5 [2%]). VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients.

Arterial Thrombotic Events: Arterial thrombotic events have been observed and can be fatal. In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack (all grades [3%] and Grades 3 to 5 [2%]) were observed. Use with caution in patients who are at increased risk for these events.

Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or fistula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula.

Hypertension: Hypertension has been observed. Hypertension was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (88% occurred in the first 18 weeks). Blood pressure should be well-controlled prior to initiating VOTRIENT. Monitor for hypertension and treat as needed. If hypertension persists despite antihypertensive therapy, the dose of VOTRIENT may be reduced or discontinued as appropriate.

Move Forward With VOTRIENT In a phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided significant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 2,3

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 2,3

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 2,3

9.2 months (95% CI, 7.4-12.9)

NCCN Guidelines Category 1 recommendation4 • First-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology

Proven safety profile1,2 • Most common adverse events observed with VOTRIENT (>20%) were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting — Grade 3/4 fatigue occurred in 2% of patients; all grades, 19% — Grade 3/4 asthenia occurred in 3% of patients; all grades, 14%

Most common laboratory abnormalities were ALT and AST increases1 • Grade 3 ALT increases occurred in 10% of patients; grade 4, 2% • In clinical trials, 92.5% of all transaminase elevations of any grade occurred in the first 18 weeks of treatment with VOTRIENT • Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period

Once-daily oral dosing1 • The recommended dosage of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal) • Dose modifications, interruptions, and discontinuations may be required in patients with hepatic impairment, drug interactions, and following adverse events • Forty-two percent of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose-reduced VOTRIENT is a multitargeted tyrosine kinase inhibitor that is indicated for the treatment of patients with advanced RCC.

Wound Healing: VOTRIENT may impair wound healing. Temporary interruption of therapy with VOTRIENT is recommended in patients undergoing surgical procedures. VOTRIENT should be discontinued in patients with wound dehiscence.

Hypothyroidism: Hypothyroidism was reported as an adverse reaction in 26/586 (4%). Monitoring of thyroid function tests is recommended.

Proteinuria: Monitor urine protein. Proteinuria was reported in 44/586 (8%) (Grade 3, 5/586 [<1%] and Grade 4, 1/586 [<1%]). Baseline and periodic urinalysis during treatment is recommended. Discontinue for Grade 4 proteinuria.

Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. Drug Interactions: CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin): Avoid use of strong inhibitors. Consider dose reduction of VOTRIENT when administered with strong CYP3A4 inhibitors.

CYP3A4 Inducers (such as rifampin): Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Adverse Reactions: The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs. 9%), hypertension (40% vs. 10%), hair color changes (depigmentation) (38% vs. 3%), nausea (26% vs. 9%), anorexia (22% vs. 10%), and vomiting (21% vs. 8%).

Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in the VOTRIENT arm versus placebo included increases in ALT (53% vs. 22%), AST (53% vs. 19%), glucose (41% vs. 33%), and total bilirubin (36% vs. 10%); decreases in phosphorus (34% vs.

11%), sodium (31% vs. 24%), magnesium (26% vs. 14%), and glucose (17% vs. 3%); leukopenia (37% vs. 6%), neutropenia (34% vs. 6%), thrombocytopenia (32% vs. 5%), and lymphocytopenia (31% vs. 24%).

VOTRIENT has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (<1%).

Please see Brief Summary of Prescribing Information on adjacent pages.

References: 1. VOTRIENT Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2010. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061–1068. 3. Data on file, GlaxoSmithKline. 4. Referenced with permission from ©National Comprehensive Cancer Network, Inc 2010. All Rights Reserved. NCCN Guidelines™: Kidney Cancer, V.1.2011. NCCN. org Accessed January 12, 2011. NCCN® and NCCN GUIDELINES™ are trademarks owned by the National Comprehensive Cancer Network, Inc.

www.VOTRIENT.com

The ASCO Post | NOVEMBER 15, 2011

PAGE 6

News

NCCN Hematologic Malignancies continued from page 3

maintenance therapy after autologous stem cell transplant, but can be associated with unacceptable toxicity, whereas lenalidomide is also effective and has less toxicity. Data are less ma-

ture for bortezomib as maintenance therapy, but thus far, the drug appears to achieve good responses in patients with poor-risk cytogenetics.

■■ The possibility that the risk of secondary malignancies are increased with lenalidomide maintenance has been raised, but this issue is unresolved. Pa-

tients on lenalidomide maintenance should be monitored closely.

Multiple Myeloma and Bone Disease

■■ Bone disease, which occurs in 84% of multiple myeloma patients, should not be taken lightly, stated

BRIEF SUMMARY VOTRIENT™ (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information.

WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies.

Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).]

1 INDICATIONS AND USAGE VOTRIENT™ is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information].

The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure. [See Clinical Pharmacology (12.3) of full prescribing information.]

If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. The dose of VOTRIENT should not exceed 800 mg. Hepatic Impairment: The dosage of VOTRIENT in patients with moderate hepatic impairment should be reduced to 200 mg per day. There are no data in patients with severe hepatic impairment; therefore, use of VOTRIENT is not recommended in these patients. [See Use in Specific Populations (8.6).] Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. [See Drug Interactions (7.1).] Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided.

VOTRIENT should not be used in patients who can not avoid chronic use of strong CYP3A4 inducers. [See Drug Interactions (7.1).]

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Effects: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed [see Adverse Reactions (6.1)]. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Across all monotherapy studies with VOTRIENT, ALT >3 X upper limit of normal (ULN) was reported in 138/977 (14%) and ALT >8 X ULN was reported in 40/977 (4%) of patients who received VOTRIENT. Concurrent elevations in ALT >3 X ULN and bilirubin >2 X ULN regardless of alkaline phosphatase levels were detected in 13/977 (1%) of patients.

Four of the 13 patients had no other explanation for these elevations. Two of 977 (0.2%) patients died with disease progression and hepatic failure.

Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information].

Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. The safety of VOTRIENT in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT, is unknown. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment.

[See Dosage and Administration (2.2) and Use in Specific Populations (8.6).]

Asher Chanan-Khan, MD, who recently moved to the Mayo Clinic in Jacksonville, Florida.

■■ Dr. Chanan-Khan prefers kyphoplasty to vertebroplasty as surgical intervention for vertebral fractures.

Kyphoplasty is able to restore up to 54% of vertebral height and im-

5.2 QT Prolongation and Torsades de Pointes: In clinical RCC studies of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 11/558 (<2%) of patients. Torsades de pointes occurred in 2/977 (<1%) of patients who received VOTRIENT in the monotherapy studies. In the randomized clinical trial, 3 of the 290 patients receiving VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Hemorrhagic Events: In clinical RCC studies of VOTRIENT, hemorrhagic events have been reported [all Grades (16%) and Grades 3 to 5 (2%)]. Fatal hemorrhage has occurred in 5/586 (0.9%) [see Adverse Reactions (6.1)]. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients.

5.4 Arterial Thrombotic Events: In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack [all Grades (3%) and Grades 3 to 5 (2%)] were observed. Fatal events have been observed in 2/586 (0.3%). In the randomized study, these events were observed more frequently with VOTRIENT compared to placebo [see Adverse Reactions (6.1)]. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an event within the previous 6 months and should not be used in those patients. 5.5 Gastrointestinal Perforation and Fistula: In clinical RCC studies of VOTRIENT, gastrointestinal perforation or fistula has been reported in 5 patients (0.9%). Fatal perforation events have occurred in 2/586 (0.3%). Monitor for symptoms of gastrointestinal perforation or fistula. 5.6 Hypertension: Blood pressure should be well-controlled prior to initiating VOTRIENT. Patients should be monitored for hypertension and treated as needed with anti-hypertensive therapy. Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (88% occurred in the first 18 weeks). [See Adverse Reactions (6.1).] In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced [see Dosage and Administration (2.2)]. VOTRIENT should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. 5.7 Wound Healing: No formal studies on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing.

VOTRIENT should be discontinued in patients with wound dehiscence.

5.8 Hypothyroidism: In clinical RCC studies of VOTRIENT, hypothyroidism reported as an adverse reaction in 26/586 (4%) [see Adverse Reactions (6.1)]. Proactive monitoring of thyroid function tests is recommended.

5.9 Proteinuria: In clinical RCC studies with VOTRIENT, proteinuria has been reported in 44/586 (8%) [Grade 3, 5/586 (<1%) and Grade 4, 1/586 (<1%)] [see Adverse Reactions (6.1)]. Baseline and periodic urinalysis during treatment is recommended. VOTRIENT should be discontinued if the patient develops Grade 4 proteinuria. 5.10 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects.

In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and wellcontrolled studies of VOTRIENT in pregnant women. 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. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. [See Use in Specific Populations (8.1).]

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy studies which included 586 patients with RCC. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled study [see Clinical Studies (14) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced.

ASCOPost.com | NOVEMBER 15, 2011

PAGE 7

News

proves quality of life compared with vertebroplasty, he said. Also, kyphoplasty can be performed on two or three vertebrae grouped together.

■■ The optimal duration of bisphosphonate therapy remains to be defined.

Board/Speakers Bureau, or as a Consultant/ Expert Witness, for Bristol-Myers Squibb Company; Celgene Corporation, Merck & Co., Inc; Millennium Pharmaceuticals, Inc; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals, Inc; and Acetylon Pharmaceuticals, Inc. Dr. Anderson also reported Patent, Equity, or Royalty, from Acetylon Pharmaceuticals, Inc.

■

Disclosure: Dr. Anderson has received research support and/or served on an Advisory

Table 1. Adverse Reactions Occurring in ≥10% of Patients who Received VOTRIENT

Adverse Reactions Diarrhea Hypertension Hair color changes Nausea Anorexia Vomiting Fatigue Asthenia Abdominal pain Headache a

VOTRIENT

Placebo

(N = 290)

(N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 52 3 <1 9 <1 0 40 4 0 10 <1 0 38 <1 0 3 0 0 26 <1 0 9 0 0 22 2 0 10 <1 0 21 2 <1 8 2 0 19 2 0 8 1 1 14 3 0 8 0 0 11 2 0 1 0 0 10 0 0 5 0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N = 290) Parameters Hematologic Leukopenia Neutropenia Thrombocytopenia Lymphocytopenia Chemistry ALT increased AST increased Glucose increased Total bilirubin increased Phosphorus decreased Sodium decreased Magnesium decreased Glucose decreased a

Placebo (N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 37 34 32 31

0 1 <1 4

0 <1 <1 <1

6 6 5 24

0 0 0 1

0 0 <1 0

53 53

10 7

2 <1

22 19

1 <1

0 0

41

<1

0

33

1

0

36

3

<1

10

1

<1

34

4

0

11

0

0

31

4

1

24

4

0

26

<1

1

14

0

0

17

0

<1

3

0

0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Hepatic Toxicity: In a controlled clinical study with VOTRIENT for the treatment of RCC, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 5/290 (2%) of patients on VOTRIENT and 2/145 (1%) on placebo. [See Dosage and Administration (2.2) and Warnings and Precautions (5.1).]

Hypertension: In a controlled clinical study with VOTRIENT for the treatment of RCC, 115/290 patients (40%) receiving VOTRIENT compared with 15/145 patients (10%) on placebo experienced hypertension. Grade 3 hypertension was reported in 13/290 patients (4%) receiving VOTRIENT compared with 1/145 patients (<1%) on placebo. The majority of cases of hypertension

Dr. Chanan-Khan has received research support and served on an Advisory Board/ Speakers Bureau, or as a Consultant/Expert Witness, for Celgene Corporation and Millennium Pharmacuticals, Inc. Dr. Devine has received research support from Genzyme and honoraria from Genzyme and Millennium.

Dr. O’Brien has received research support

were manageable with anti-hypertensive agents or dose reductions with 2/290 patients (<1%) permanently discontinuing treatment with VOTRIENT because of hypertension. In the overall safety population for RCC (N = 586), one patient had hypertensive crisis on VOTRIENT. [See Warnings and Precautions (5.2).] QT Prolongation and Torsades de Pointes: In a controlled clinical study with VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 3/290 (1%) of patients treated with VOTRIENT compared with no patients on placebo. Torsades de pointes was reported in 2/586 (<1%) patients treated with VOTRIENT in the RCC studies. [See Warnings and Precautions (5.3).] Arterial Thrombotic Events: In a controlled clinical study with VOTRIENT, the incidences of arterial thrombotic events such as myocardial infarction/ischemia [5/290 (2%)], cerebral vascular accident [1/290 (<1%)], and transient ischemic attack [4/290 (1%)] were higher in patients treated with VOTRIENT compared to the placebo arm (0/145 for each event). [See Warnings and Precautions (5.4).]

Hemorrhagic Events: In a controlled clinical study with VOTRIENT, 37/290 patients (13%) treated with VOTRIENT and 7/145 patients (5%) on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine (9/37) patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage.

Four (4/290) (1%) patients treated with VOTRIENT died from hemorrhage compared with no (0/145) (0%) patients on placebo. [See Warnings and Precautions (5.5).] In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in 2/586 (<1%) patients treated with VOTRIENT. Hypothyroidism: In a controlled clinical study with VOTRIENT, more patients had a shift from thyroid stimulating hormone (TSH) within the normal range at baseline to above the normal range at any postbaseline visit in VOTRIENT compared with the placebo arm (27% compared with 5%, respectively). Hypothyroidism was reported as an adverse reaction in 19 patients (7%) treated with VOTRIENT and no patients (0%) in the placebo arm. [See Warnings and Precautions (5.7).] Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity.

Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Proteinuria: In the controlled clinical study with VOTRIENT, proteinuria has been reported as an adverse reaction in 27 patients (9%) treated with VOTRIENT. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Lipase Elevations: In a single-arm clinical study, increases in lipase values were observed for 48/181 patients (27%). Elevations in lipase as an adverse reaction were reported for 10 patients (4%) and were Grade 3 for 6 patients and Grade 4 for 1 patient. In clinical RCC studies of VOTRIENT, clinical pancreatitis was observed in 4/586 patients (<1%). Cardiac Dysfunction: Pazopanib has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 4/586 patients (<1%).

7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations. A dose reduction for VOTRIENT should be considered when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers can not be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information].

Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. [See Clinical Pharmacology (12.3) of full prescribing information.]

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.10)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/ kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was

from Gilead and Pharmacyclics.

Dr. Zelenetz is an investigator for and receives research support from Amgen Inc., GlaxoSmithKline, and Genentech, Inc./Roche. Dr. Zelenetz is on an advisory board for Genentech, Inc./Roche, and GlaxoSmithKline.

Dr. Radich reported no potential conflicts of interest.

The ASCO Post | NOVEMBER 15, 2011

PAGE 8

54th ASTRO Annual Meeting Genitourinary Oncology

Fewer Rectal Side Effects with IMRT than with 3D-CRT for Prostate Cancer

By Susan Reckling

T

he use of intensity-modulated radiation therapy (IMRT) is associated with fewer acute and late toxic effects than is three-dimensional conformal radiation therapy (3D-CRT) in men with localized

prostate cancer, according to preliminary analysis of the Radiation Therapy Oncology Group (RTOG) 0126 prostate cancer trial, presented at the Plenary Session of the 53rd American Society for Radia-

reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, 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. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks.

8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 196 subjects (33%) were aged ≥65 years, and 34 subjects (6%) were aged >75 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these subjects and younger subjects. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: The safety and pharmacokinetics of pazopanib in patients with hepatic impairment have not been fully established. In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An interim analysis of data from 12 patients with normal hepatic function and 9 with moderate hepatic impairment showed that the maximum tolerated dose in patients with moderate hepatic impairment was 200 mg per day [see Clinical Pharmacology (12.3) of full prescribing information]. There are no data on patients with severe hepatic impairment [see Dosage and Administration (2.2)]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical studies for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials.

Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted.

However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/ day (approximately 0.8 times the human clinical exposure based on AUC).

Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for

tion Oncology Annual Meeting, in Miami Beach.1 “This study supports the continued use of IMRT in the management of prostate cancer,” said Jeff Michalski, MD, a radiation oncologist at Washington Uni-

26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/ day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the first 4 months of treatment or as clinically indicated. Inform patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away.

• yellowing of the skin or the whites of the eyes (jaundice), • unusual darkening of the urine, • unusual tiredness, • right upper stomach area pain.

• Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs.

• Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

• Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements.

• Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a trademark of GlaxoSmithKline.

©2010, GlaxoSmithKline. All rights reserved.

VTR:3BRS ©2011 The GlaxoSmithKline Group of Companies.

All rights reserved. Printed in USA. VOT233R0 January 2011

versity Medical Center in St. Louis and lead investigator of RTOG 0126.

In this phase III dose-escalation trial, a

Jeff Michalski, MD

total of 748 men were randomly assigned to the high-dose arm. Of this group, 491 received 3D-CRT and 257 received IMRT. The median follow-up was slightly longer for 3D-CRT than for IMRT (4.6 years vs 3.5 years), as IMRT was permitted about a year after the study had begun.

The prescribed dose on the high-dose arm was 79.2 Gy, compared with a standard dose of 70.2 Gy with 3D‑CRT. “Because IMRT requires a more intense level of quality assurance, the study began initially only with 3D-CRT. Once we had established SEE PAGE 60 both the quality assurance and appropriate target volumes for IMRT, we amended the protocol to allow institutions that passed the necessary credentialing guidelines to enroll patients with that modality,” stated Dr. Michalski. Based on the dosimetric

Toxicity Report on IMRT vs 3D-CRT for Prostate Cancer ■■ RTOG 0126 is the first

contemporary cohort study to show a convincing advantage to intensity-modulated radiotherapy (IMRT).

■■ There was a statistically significant difference in favor of IMRT in terms of acute grade 2+ rectal/ bowel and gastrointestinal/ genitourinary toxicity.

■■ A significant reduction was

noted in late grade 2+ GI toxicity with IMRT compared with three-dimensional conformal radiation therapy.

■■ White men experienced more

rectal side effects than did men of other races, regardless of the type of radiation treatment used.

ASCOPost.com | NOVEMBER 15, 2011

PAGE 9

54th ASTRO Annual Meeting comparisons to the bladder and rectum, there was a significant reduction in all dose parameters among patients receiving IMRT, he added.

Reduction in Grades 2+ and 3+ Toxicity In terms of acute grade 2+ rectal/bowel and gastrointestinal/genitourinary toxicity, the investigators found a statistically significant difference in favor of IMRT. “We saw a reduction of these toxicities in 15.1% with 3D-CRT vs 9.7% with IMRT,” revealed Dr. Michalski. Multivariate analysis indicated a significant 28% reduction in grade 2+ GI toxicity with IMRT. Regarding late side effects, there was a significant reduction in grade 2+ GI toxicity with IMRT compared with 3DCRT (15% vs 22%). Moreover, there was a trend for a 27% reduction in late grade 2+ rectal and bowel side effects.

Although there was a similar reduction in grade 3+ GI toxicity with IMRT compared with 3D-CRT (2.6% vs 5%), it was not statistically significant, according to Dr. Michalski. “Although the rates of late effects are very low, we did see that

patients who had experienced grade 2+ GI toxicity had a significantly higher rate of late grade 3 GI toxicity,” he stated.

IMRT significantly lowers the high dose volume of radiation delivered to the bladder and rectum, with less grade 2+ GI toxicity, concluded Dr. Michalski.

“This is the first contemporary cohort to show a convincing advantage to IMRT,” he said.

Surprising Racial Differences The preliminary findings of RTOG 0126 demonstrated a significant increase (15%) in rectal side effects among white men compared with men of other races, regardless of the type of radiation treatment administered. Although nonwhite patients had a lower incidence of acute grade 2+ GI toxicity, there was no difference in late grade 2+ GU toxicity.

“The racial differences were definitely surprising, and we are still unsure as to why this exists,” admitted Dr. Michalski. “Although it could be a real difference in the tolerance to treatment, it could also represent cultural differences in reporting side effects and physician

EXPERT POINT OF VIEW

A

lthough the early toxicity findings of RTOG 0126 seem to favor IMRT over 3D-CRT, formal discussant of this trial, Juanita Crook, MD, FRCPC, of the British Columbia Cancer Agency, Kelowna, British Columbia, Canada, put the study’s findings in perspective.

“Whether or not this is a significant finding depends on the importance of dose escalation,” she stated.

Dr. Crook added that although dose escalation is clearly desirable, IMRT may not be the most effecJuanita Crook, MD, FRCPC tive means of achieving this. Current trials are comparing the efficacy of IMRT to other means of dose escalation, such as brachytherapy boost using either LDR or HDR implants.

In addition, Dr. Crook addressed two other caveats about these preliminary toxicity findings. First, RTOG 0126 is not a randomized comparison, but rather, a planned stratification. “We often seem to embrace technology without level 1 evidence and then have to pursue the evidence after widespread adoption,” she declared. Second, the study was conducted largely in the era before image-guided radiation therapy.

■

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

interpretation of patient descriptions.”

This interesting finding is worthy of further investigation, he concluded.

■

Disclosure: Dr. Michalski has served on advisory boards for Elekta, Inc, Viewray, Inc, and Augmenix, Inc.

Reference 1. Michalski JM, Yan Y, et al: �������� Preliminary analysis of 3D-CRT vs IMRT on the high dose arm of the RTOG 0126 prostate cancer trial. 53rd ASTRO Annual Meeting.

Abstract 2. Presented October 3, 2011.

Preoperative Chemoradiotherapy May Extend Survival for Patients with Esophagogastric Junction Adenocarcinoma

Trimodality Therapy

By Susan Reckling

S

everal American and European clinical trials have yielded mixed results on the survival advantage of preoperative chemoradiotherapy for patients with locally advanced esophagogastric junction adenonocarcinoma.

However, a distinguished panel at the 2011 ASTRO Annual Meeting did agree that surgery alone is not adequate and that trimodality therapy improves

Joel E. Tepper, MD, FASTRO

locoregional control and perhaps survival.1-3 Among the members of the panel were Stephen G. Swisher, MD, The University of Texas MD Anderson Cancer Center, Houston; Joel E. Tepper, MD, FASTRO, University of North Carolina at Chapel Hill School of Medicine; and David H. Ilson,

MD, PhD, Memorial Sloan-Kettering Cancer Center, New York.

Surgery Alone Is Not Enough An assortment of clinical trials in gastric and esophageal cancers has shown that results with surgery alone are disappointing, with poor 3-year survival, admitted Dr. Swisher. “All of us would agree that something more than surgery alone should be done for T2-3 node-positive gastroesophageal junction cancer,” agreed Dr. Ilson.

Dr. Tepper reviewed the gastric data, focusing on the MAGIC trial.4 In this study of more than 500 patients with resectable gastroesophageal cancer (25% with gastroesophageal junction tumors), a statistically significant difference in favor of preoperative chemotherapy over surgery alone was noted in both progression-free and overall survival. However, local failure was still a problem.

In a recent meta-analysis,5 strong evidence of a survival benefit was shown for neoadjuvant chemotherapy or chemoradiotherapy over surgery alone in resectable esophageal carcinoma. “The data were very consistent in continued on page 10

EXPERT POINT OF VIEW

“T

here is a clear message from the clinical trials that the optimal approach [in locally advanced esophagogastric adenonocarcinoma] is a combination of chemotherapy and radiation therapy, given the high rates of local failure with chemotherapy-based treatments alone,” declared David H. Ilson, MD, PhD, Memorial Sloan-Kettering Cancer Center, New York, at the 2011 ASTRO Annual Meeting. All of these studies showed a trend toward improved survival [with preoperative chemoradiotherapy], and local recurrence is reduced with chemoradiotherapy vs chemotherapy alone, he added.

“Chemoradiotherapy is clearly more active [than chemotherapy alone], with pathologic complete response rates of up to 40% and 5-year survival rates of up to 35%,” Dr. Ilson emphasized. “If we get patients into that category of pathologic complete response, they have the best survival—up to 70% at 5 years.” To improve outcomes with preoperative treatment, a clear benchmark is the attainment of pathologic complete response; “this is rare with chemotherapy alone and more common with chemoradiation,” he stated.

New Standard of Care?

“The strongest data support the use of combined chemoradiotherapy, and a paclitaxel-plus-carboplatin regimen may represent a new standard of care,” suggested Dr. Ilson. In the Dutch trimodality study, treatment consisted of weekly paclitaxel and carboplatin, concurrent radiation therapy, and surgery. The R0 resection rate was improved significantly with trimodal treatment over surgery alone (92% vs 67%), and the pathologic complete response rate was 27%.

“This is a strikingly positive study, with a median survival difference of 2 years, one of the biggest differences ever demonstrated in a combined-modality study,” concluded Dr. Ilson.

■

The ASCO Post | NOVEMBER 15, 2011

PAGE 10

54th ASTRO Annual Meeting Esophagogastric Junction Adenocarcinoma continued from page 9

favor of trimodality therapy in esophageal cancer, both squamous and adenocarcinoma,” concurred Dr. Tepper.

However, most of the clinical trials have focused on either gastric or esophageal cancer, Dr. Tepper warned, “and so

Preoperative Chemotherapy vs Chemoradiotherapy

their applicability to GE junction cancer is not always clear.” Furthermore, “the data can be interpreted in different ways in terms of the value of adding surgery to chemoradiation alone,” Dr. Tepper added. “Local recurrence after chemoradiation alone is clearly a problem, justifying the use of trimodality therapy rather than a nonsurgical approach.”

The panel discussed pertinent data comparing preoperative chemotherapy and preoperative chemoradiotherapy for locally advanced esophagogastric cancers. “There has been a shift in the way we approach these diseases,” suggested Dr. Swisher. “In the United

States, we tend to move toward a platform of preoperative chemoradiotherapy; in Europe, many still favor preoperative chemotherapy,” he noted.

“This is a systemic disease, and the role of chemotherapy is important,” stressed Dr. Ilson. According to Dr.

The Role of Clinical Pathways in Supporting Community Oncology A discussion with Bruce Feinberg, M.D., Vice President & Chief Medical Officer, Cardinal Health Specialty Solutions Through its flagship service offering, P4 Pathways, Cardinal Health Specialty Solutions works with hundreds of community oncologists across the nation to establish clinically proven, evidence-based treatment protocols that promote the delivery of high quality, cost-efficient patient care. Since launching the nation’s first cancer care pathways program in 2008, more

Q: A:

Why should oncologists care about cancer care pathways?

Oncologists are increasingly being called upon to do more with less. They’re charged with caring for an increasing number of patients and improving the quality of the care they provide those patients. At the same time, they’re facing the continuing erosion of reimbursement. These challenges are creating uncertain times for community oncology, the backbone of our nation’s cancer care delivery system.

When implemented correctly, cancer care pathways can ultimately play an important role in protecting the longterm financial viability and autonomy of community oncologists. They can help physicians play a meaningful role in improving patient outcomes – and costs – through the consistent use of evidence-based best practices. When coupled with the right compliance measurement tools, pathways can also reduce administrative and other burdens to free up physician time for patient care. Cardinal Health Specialty Solutions is also leveraging pathways to develop new paradigms for compensating physicians for the quality of the care they provide.

Q:

In your view, what factors make pathways programs ‘work’ for physicians?

A:

Most importantly, pathways must improve outcomes. That has to be the number-one priority. Second, physicians need to lead the development of the pathways they’ll be expected to follow. Third, technology and other tools need to make it as efficient as possible for physicians to implement and track pathways compliance.

Cardinal Health Specialty Solutions also believes that pathways should be leveraged to remove administrative burdens – like prior authorization.

than 10 percent of U.S. oncologists have become engaged in P4 Pathways programs, which touch more than 20 million insured patients. Here, Dr. Bruce Feinberg shares his viewpoints on how physician-led pathways programs are creating new paradigms for improving patient care.

We advocate for payors to appropriately incentivize physicians to participate.

The most successful pathways programs provide fair reimbursement for generic medications, lock in reimbursement rates for branded drugs and allow physicians to share in cost savings that are created through reduced hospitalization and drug spend.

Cardinal Health Specialty Solutions understands that cancer care pathways represent a shift in the mindset of oncologists.

They’re helping us leverage pathways to improve the quality and consistency of care. And they’re developing new models that ensure doctors get fairly compensated for delivering that care to patients.

Ram Trehan, MD Greater Washington Oncology Assoc., Silver Spring, MD

Q:

Can pathways be used to help physicians deal with drug shortages?

A:

We are piloting an innovative new system that alerts regional Pathways Steering Committees – comprised of practicing oncologists – of current and potential shortages, and mobilizes them to review evidence to recommend next-best alternative therapies. This approach helps providers mitigate the impact shortages have on patient care, ensures consistency in approach and saves physicians a great deal of time.

Dr. Feinberg can be reached at bruce.feinberg@cardinalhealth.com.

Q:

Should physicians who do not comply with pathways be penalized?

A:

Cardinal Health Specialty Solutions always leads with a clear mandate that physicians have ultimate control of treatment decisions at the point of care. It’s impossible for 100% of patients to be cared for using a limited set of treatment protocols. That’s why our model allows room for individualized medicine and physician discretion.

We set compliance goals, but the physician has ultimate control of treatment decisions at the point of care. For example, we generally expect physicians to be pathways compliant 70+% of the time in year one and 80+% in year two.

To date, physician compliance in each of our pathways programs has exceeded these goals.

Q: A:

Is your approach to cancer care pathways working?

Yes. For example, physicians who participate in our more mature pathways programs spend an average of 40% less time than non-participating physicians on the management of the same disease, while their patients experience 15% fewer emergency room (ER) visits and hospitalizations. Reduced ER visits, alone, are a great example of how pathways programs can improve healthcare quality and costs. One of our more mature pathways programs reduced its ER-related expenses by $5 million in one year. These are great examples of physicians using pathways to free up their own time to focus on other areas of patient care while they’re removing unnecessary costs from the system.

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Cardinal Health Specialty Solutions

Stephen G. Swisher, MD

Swisher, “adding the radiation [to chemotherapy] helps to improve localregional control, perhaps by helping to eradicate the microscopic disease within the lymphatics.”

Mixed Results Mixed results have been reported with preoperative chemotherapy alone, with three European studies showing a survival advantage and one U.S. study showing no survival advantage. Both Drs. Tepper and Ilson called attention to a head-to-head comparison of preoperative chemotherapy and chemoradiotherapy in patients with locally advanced adenocarcinoma of the GE junction. In this phase III randomized

Preoperative Chemoradiotherapy for Esophagogastric Adenocarcinoma ■■ Clinical trials have yielded

mixed results on the survival advantage of preoperative chemoradiotherapy for locally advanced esophagogastric adenonocarcinoma.

■■ Surgery alone is not adequate treatment of T2-3 nodepositive GE junction cancer.

■■ In a phase III randomized

trial, the locoregional failure rate favored preoperative chemoradiotherapy over chemotherapy.

■■ Oncologists in the United

States tend to move toward a platform of preoperative chemoradiotherapy; in Europe, many still favor preoperative chemotherapy without radiation.

ASCOPost.com | NOVEMBER 15, 2011

PAGE 11

54th ASTRO Annual Meeting European study,6 results suggested a survival advantage for preoperative chemoradiotherapy, alSEE PAGE 60 though statistical significance was not achieved. The 3-year survival rates were 40% with the trimodality strategy vs 28% with preoperative chemotherapy. The locoregional failure rate also favored preoperative chemoradiotherapy over chemotherapy (23% vs 41%), added Dr. Swisher.

A similar approach under investigation has been evaluated in the phase II Radiation Therapy Oncology Group (RTOG) 0246 trial. In this study,7

nearly 40 patients with nonmetastatic resectable esophageal cancer received induction chemotherapy followed by concurrent chemoradiation. Many patients with residual disease subsequently underwent selective surgery.

Preliminary results reported by Dr. Swisher, the lead investigator of RTOG 0246, showed a 1-year survival rate of 71% at 22 months’ follow-up.

Although these are early findings, said Dr. Swisher, they are “as good as any survival seen with trimodality in randomized studies.”

■

Disclosure: Drs. Tepper, Ilson, and Swisher reported no potential conflicts of interest.

References 1. Swisher SG: Surgical management of esophageal cancer. ASTRO 53rd Annual Meeting. Presidential Symposium Session I. Presented October 2, 2011.

2. Tepper JE: Radiation therapy in gastro-esophageal cancers. ASTRO 53rd Annual Meeting. Presidential Symposium Session I. Presented October 2, 2011.

3. Ilson DH: Esophageal and GE junction adenocarcinoma: The role of chemotherapy. ASTRO 53rd Annual Meeting.

Presidential Symposium Session I. Presented October 2, 2011.

4. Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11-20, 2006.

Despite Challenges, Combined-modality Therapy Warranted for Locally Recurrent Colorectal Cancer

5. Sjoquist KM, Burmeister BH, Smithers BM, et al: Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma. Lancet Oncol 12:681-692, 2011.

6. Stahl M, Walz MK, Stuschke M, et al: Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 27:851-856, 2009.

7. Swisher SG, Winter KA, Komaki RU, et al: A phase II study of a paclitaxel-based chemoradiation regimen with selective surgical salvage for resectable locoregionally advanced esophageal cancer: Initial reporting of RTOG 0246. Int J Radiat Oncol Biol Phys. April 18, 2011 (early release online).

Gastrointestinal Oncology

By Susan Reckling

E

ncouraging outcomes have been achieved with a combined-modality treatment approach for patients with locally recurrent colorectal cancer in both curative and palliative settings, although room for improvement remains. During a session presented at the American Society for Radiation Oncology (ASTRO) 53rd Annual Meeting, held October 2–6 in Miami Beach, the benefits of intraoperative radiation therapy were explored by Heidi Nelson, MD, of the Mayo Clinic, Rochester, Minnesota,1 and the roles of neoadjuvant and adjuvant chemoradiotherapies were discussed

by Michael J. O’Connell, MD, of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation, Pittsburgh.2

The Surgical Perspective The surgical treatment of locally recurrent, unresectable colorectal cancer is challenging, often requiring a multidisciplinary team of urologists, orthopedic surgeons, plastic surgeons, and pathologists. “Good results are based

on tremendous motivation by patients and the fact that they come in healthy and can withstand a complex treatment,” Dr. Nelson added.

She briefly discussed preoperative assessment, common surgical problems, and outcomes. Preoperative assessment includes the determination of metastatic disease, the extent of local disease, and the use of previous treatments. In addition, patients who have extrapelvic disease or circumferential or extensive pelvic sidewall involvement are not candidates for surgery.

Among the problems encountered during surgery are pelvic/sidewall bleeding, determining the extent of pelvic healing vs tumor, and infections.

“Bleeding is what keeps most surgeons out of these cases,” commented Dr. Nelson. There can be extensive blood loss, as a result of bifurcated and trifurcated vessels that branch deep into the pelvis.

Distinguishing between fibrosis and tumor can be difficult. “Even our pathologist colleagues have trouble differentiating treatment effects, viable tumors, and fibrosis with viable cancer

Surgical and Systemic Treatments for Colorectal Cancer ■■ The surgical treatment of locally recurrent, unresectable colorectal cancer requires a multidisciplinary team.

■■ The strategy of external-beam radiotherapy followed by surgery with

intraoperative radiotherapy and chemotherapy can salvage patients with locally recurrent colorectal cancer.

■■ Long-term survival and disease control in locally recurrent colorectal

cancer may be achievable with combined-modality therapy including intraoperative radiotherapy.

Heidi Nelson, MD

cells,” she revealed. Finally, infections used to be the critical long-term and short-term complication of greatest concern to surgeons. However, with more surgeons performing reconstruction during surgery, the rates of infection have dropped.

Radiotherapy Considerations The use of intraoperative radiation therapy offers several advantages. In addition to localized tumor-directed therapy, intraoperative radiotherapy limits the exposure of normal tissue to radiation and improves local control for patients with high-risk rectal cancer. “The strategy of external-beam radiation therapy followed by surgery with intraoperative radiotherapy and chemotherapy has salvaged a lot of these patients,” stated Dr. Nelson. However, not all patients can tolerate a full regimen of intraoperative radiotherapy. “There is curative intent going in,” she mentioned, “but often patients can’t get a full cure of R1 or R0. We try to keep the radiation dose at 1,250 cGy or below, as toxicities are substantially higher at ≥ 1,500 cGy.”

For patients with colorectal cancer who received combined-modality treatment, the overall survival rate was 90% at 1 year, 70% at 2 years, and 30% at 5 years, according to the series quoted by Dr. Nelson. “It is a little discouraging that it continues to flatten out over time,” she acknowledged. “Best results will come if we can get a clear margin.”

Systemic Therapeutic Options The first goal of systemic therapy in combination with radiation therapy and surgery is cure. According to the findings of a recent study of more than 600 patients,3 long-term survival and disease control were achievable with combined-modality therapy including intraoperative radiotherapy for SEE PAGE 60 patients with locally recurrent colorectal cancer.

The 3-year cumulative incidence of local and distant relapse was 23% and 49%, respectively. Although Dr. O’Connell concedes these are not randomized data, he calls these results “very impressive.”

The evolution of chemotherapy for colorectal cancer into current regimens such as FOLFOX (leucovorin, fluorouracil [5-FU], and oxaliplatin) has helped patients with metastatic disease live longer. “The median survival of patients with distant metastases has improved from approximately 6 months to approximately 2 years,” stated Dr. continued on page 14

Indication HalavenTM is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Important Safety Information Neutropenia • Monitor complete blood counts prior to each dose, and

•

•

increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received Halaven. Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

Pregnancy Category D • Halaven is expected to cause fetal harm when administered to a pregnant woman and patients should be advised of these risks

QT Prolongation • In an uncontrolled ECG study in 26 patients, QT prolongation

Peripheral Neuropathy • Patients should be monitored closely for signs of peripheral • •

motor and sensory neuropathy Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days)

•

was observed on Day 8, independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias; concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities Correct hypokalemia or hypomagnesemia prior to initiating Halaven and monitor electrolytes periodically during therapy.

Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment • For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic and/or moderate (CrCl 30-50 mL/min) renal impairment, a reduction in starting dose is recommended

Please see accompanying brief summary of Halaven full Prescribing Information.

References: 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Breast Cancer. Version 2.2011. http:NCCN.org. Published January 5, 2011. Accessed February 2, 2011. 2. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2010. 3. Saad ED, Katz A, Buyse M. Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials. J Clin Oncol. 2010;28(11):1958-1962. 4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792. 5. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer.

N Engl J Med. 2006;355(26):2733-2743. 6. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2–positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol. 2009;27(12):1999-2006. 7. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666-2676. 8. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2009;27(suppl; abstr 1005). 9. Sparano JA, Vrdoljak E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010;28(20):3256-3263. 10. Jones SE, Erban J, Overmoyer B, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005;23(24):5542-5551. 11. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914-923.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Breast Cancer V.2.2011. © 2011 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed February 2, 2011. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

HALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2011 Eisai Inc. All rights reserved. Printed in USA/June 2011 ERI 81R1

Scan this code to visit www.halaven.com

A preferred single agent in the NCCN Guidelines™1

DISCOVER

OVERALL SURVIVAL

Halaven™: The FIRST and ONLY third-line, single-agent therapy proven to significantly extend overall survival in patients with metastatic breast cancer (MBC) 2-10 The Phase III EMBRACE* trial met its primary endpoint of overall survival (OS) 2,11 • In the primary analysis, conducted when ~50% of events (deaths) had been observed, median OS with Halaven vs Control Arm (Treatment of Physician’s Choice [TPC]) was 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR=0.81 (95% CI: 0.66, 0.99) (P=0.041)† 2,11 UPDATED OVERALL SURVIVAL ANALYSIS (UNPLANNED)†2 Halaven (n=508)

TPC Arm (n=254)

Median OS (months [95% Cl])

13.2 (12.1, 14.4)

10.6 (9.2, 12.0)

Deaths

386

203

1.0 0.9

PROPORTION OF PATIENTS ALIVE

0.8 0.7 0.6

RESULTS CONSISTENT WITH PRIMARY ANALYSIS2

Halaven

0.5

Control Arm

0.4 0.3 0.2 0.1 0.0

0

6

12

18

24

30

36

54 26

11 5

0 0

TIME (MONTHS) Number of patients at risk

508 254

406 178

274 106

142 61

Halaven TPC Arm

Results from an updated, unplanned survival analysis of the Phase III, open-label, multicenter, multinational EMBRACE trial of Halaven vs TPC in patients with MBC (N=762). The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen.

All patients received prior anthracycline- and taxanebased chemotherapy, unless contraindicated. Therapies in the TPC Arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxanes [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracyclines, 10% other chemotherapy) and 3% hormonal therapy.2, 11

CI=confidence interval; HR=hazard ratio.

*EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs E7389 (Eribulin). †Conducted in the intent-to-treat (ITT) population.

Halaven: Quick administration • 2- to 5-minute intravenous infusion on Days 1 and 8 of a 21-day cycle2 Halaven: Safety profile • Studied in the Phase III EMBRACE trial2 Most Common Adverse Reactions • Most common adverse reactions (≥25%) reported in patients receiving Halaven were neutropenia (82%), anemia (58%), asthenia/ fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%)

• The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%)

• Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

ADVANCING SURVIVAL

The ASCO Post | NOVEMBER 15, 2011

PAGE 14

54th ASTRO Annual Meeting Combined-modality Therapy continued from page 11

O’Connell. Long-term follow-up data have confirmed “a persistent, significant benefit for the addition of oxaliplatin to 5-FU and leucovorin, and therefore the FOLFOX regimen has

been considered the standard of care as postoperative adjuvant therapy for high-risk colon cancer.”

The major limitation of FOLFOX for rectal cancer is that many patients cannot tolerate it after radiation therapy and surgery, said Dr. O’Connell.

Therefore, several randomized trials have studied the use of preoperative chemotherapy. Among the advantages of neoadjuvant chemotherapy for rectal cancer are that it spares the rectal sphincter, avoiding colostomy; causes fewer acute long-term toxicities; and Michael J. O’Connell, MD

HALAVENTM (eribulin mesylate) Injection BRIEF SUMMARY – See package insert for full prescribing information.

2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.

Recommended dose delays • Do not administer HALAVEN on Day 1 or Day 8 for any of the following: – ANC <1,000/mm3 – Platelets <75,000/mm3 – Grade 3 or 4 non-hematological toxicities • The Day 8 dose may be delayed for a maximum of 1 week.

– If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose.

– If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later.

Recommended dose reductions • If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 1.

• Do not re-escalate HALAVEN dose after it has been reduced.

Table 1 Recommended Dose Reductions Recommended Event Description HALAVEN Dose Permanently reduce the 1.4 mg/m2 HALAVEN dose for any of the following: ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infection Platelets <25,000/mm3 1.1 mg/m2 Platelets <50,000/mm3 requiring transfusion Non-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2 Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN ANC = absolute neutrophil count.

Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia Severe neutropenia (ANC <500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase >3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin >1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.

Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3.

5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1.

Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503).

Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

5.3 Embryo-Fetal Toxicity There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.

5.4 QT Prolongation In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome.

6 ADVERSE REACTIONS The following adverse reactions are discussed in detail in other sections of the labeling: • Neutropenia • Peripheral neuropathy • QT interval prolongation The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/ fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%).

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

In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).

The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.

Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 HALAVEN (n=503) Control Group (n=247) MedDRA ver 10.0 All Grades ≥ Grade 3 All Grades ≥ Grade 3 Blood and Lymphatic System Disordersa Neutropenia 82% 57% 53% 23% Anemia 58% 2% 55% 4% Nervous system disorders Peripheral neuropathyb 35% 8% 16% 2% Headache 19% <1% 12% <1% General disorders and administrative site conditions Asthenia/Fatigue 54% 10% 40% 11% Mucosal inflammation 9% 1% 10% 2% Pyrexia 21% <1% 13% <1% Gastrointestinal disorders Constipation 25% 1% 21% 1% Diarrhea 18% 0 18% 0 Nausea 35% 1% 28% 3% Vomiting 18% 1% 18% 1% Musculoskeletal and connective tissue disorders Arthralgia/Myalgia 22% <1% 12% 1% Back pain 16% 1% 7% 2% Bone pain 12% 2% 9% 2% Pain in extremity 11% 1% 10% 1% Investigations Weight decreased 21% 1% 14% <1% Metabolism and nutrition disorders Anorexia 20% 1% 13% 1%

Table 2 (cont’d) MedDRA ver 10.0

HALAVEN (n=503) All Grades ≥ Grade 3

Control Group (n=247) All Grades ≥ Grade 3

Respiratory, thoracic, and mediastinal disorders Cough 14% 0 9% 0 Dyspnea 16% 4% 13% 4% Skin and subcutaneous tissue disorders c Alopecia 45% NA 10% NAc Infections and Infestations Urinary Tract Infection 10% 1% 5% 0 a Based upon laboratory data. b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. c Not applicable; (grading system does not specify > Grade 2 for alopecia).

Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colonystimulating factor) was used in 19% of patients who received HALAVEN. Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.

Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the HALAVEN-treated group: • Eye Disorders: increased lacrimation • Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth • General Disorders and Administration Site Conditions: peripheral edema • Infections and Infestations: upper respiratory tract infection • Metabolism and Nutrition Disorders: hypokalemia • Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness • Nervous System Disorders: dysgeusia, dizziness • Psychiatric Disorders: insomnia, depression • Skin and Subcutaneous Tissue Disorders: rash 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D There are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. 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.

In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose.

Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.

8.3 Nursing Mothers It is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established.

8.6 Hepatic Impairment A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. A lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C).

8.7 Renal Impairment No formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that no dose adjustment is necessary for patients with mild renal impairment (CrCl 50-80 mL/min). However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl <30 mL/min).

10 OVERDOSAGE Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day.

There is no known antidote for HALAVEN overdose.

12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies have not been conducted with eribulin mesylate.

Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay.

The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling • Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection such as chills, cough, or burning or pain on urination.

• Advise women of childbearing potential to avoid pregnancy and to use effective contraception during treatment with HALAVEN. –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– HALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2011 Eisai Inc. All rights reserved. Printed in USA / May 2011 ERI 161

increases the chance of an R0 resection with a full dose of chemotherapy.

Local Control The second goal of systemic therapy in combination with radiation therapy and surgery is improvement in local tumor control. “There have been a series of incremental improvements in the use of chemotherapy in the rectal adjuvant setting as part of a combined-modality approach,” Dr. O’Connell reported.

In NSABP R-04,4 which included more than 1,600 patients undergoing preoperative radiation therapy, there appeared to be no significant difference between capecitabine (Xeloda) and continuous intravenous infusion of 5-FU in terms of pathologic complete response, sphincter-saving surgery, and surgical downstaging. The addition of oxaliplatin to either regimen offered no benefit, while significantly increasing toxicity. Although the data analysis on local tumor control, disease-free survival, and overall survival will not be available until the fall of 2013, “capecitabine plus radiation therapy appears to be a very reasonable treatment option,” concluded Dr. O’Connell.

■

Disclosure: Drs. Nelson and O’Connell reported no potential conflicts of interest.

References 1. Nelson H: Locally recurrent colorectal cancer: A surgeon’s perspective. ASTRO 53rd Annual Meeting, Presidential Symposium Session IV. Presented October 2, 2011.

2. O’Connell MJ: Systemic therapy of unresectable rectal cancer. ASTRO 53rd Annual Meeting, Presidential Symposium Session IV. Presented October 2, 2011.

3. Haddock MG, Miller RC, Nelson H, et al: Combined modality therapy including intraoperative electron irradiation for locally recurrent colorectal cancer. Int J Radiat Oncol Biol Phys 79:143-150, 2011.

4. Roh MS, Yothers GA, O’Connell MJ, et al: The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. 2011 ASCO Annual Meeting. Abstract 3503. Presented June 4, 2011.

ASCOPost.com | NOVEMBER 15, 2011

PAGE 15

2011 European Multidisciplinary Cancer Congress Predictive Biomarker for Bevacizumab: Are We Getting Closer?

Plasma VEGF-A correlates with outcomes in several tumor types.

By Caroline Helwick

T

he need to identify a biomarker to guide treatment with bevacizumab (Avastin) is abundantly clear, and studies presented at the 2011 European Multidisciplinary Cancer Congress suggest this goal may be in sight.

“Finding predictive biomarkers is a challenge, but there are candidates,” said Eric Van Cutsem, MD, PhD, of the University Hospitals Leuven in Belgium.

“Despite a global effort, there have

been no tests to tell us which patients will benefit,” Gordon C. Jayson, MD, PhD, of the University of Manchester in the United Kingdom, agreed, but the availability of a more sensitive assay may change that, he said.

In close collaboration with Sanne de Haas, PhD, and Stefan Scherer, MD, PhD, from the Roche/Genentech Biomarker team, investigators analyzed blood samples from six randomized trials in various tumor types using a

Plasma VEGF-A as a Biomarker for Bevacizumab ■■ In six pivotal trials of bevacizumab, baseline plasma VEGF-A was

correlated with prognosis, with high levels heralding a worse prognosis.

■■ In trials in metastatic breast, pancreatic, and gastric cancer, high pVEGF-A

was predictive of better outcomes with bevacizumab, but in studies of metastatic colorectal, non–small cell, and renal cancers, pVEGF-A had no predictive value, although sample processing may have influenced results.

■■ A novel ELISA assay that favors shorter isoforms of pVEGF-A is facilitating these analyses.

Aflibercept/FOLFIRI Improves Survival continued from page 1

Consistency of Benefit

The VELOUR trial randomly assigned 1,226 patients with previously treated metastatic disease to aflibercept (4 mg/kg IV) or placebo, plus FOLFIRI, every 2 weeks until progression.

The trial reached its primary endpoint of overall survival, with a hazard ratio of 0.82 (P = .0032). Median overall

Prespecified subgroup analyses confirmed the consistency of the benefit of aflibercept on both endpoints. The analyses considered the impact of stratification factors (performance status, prior bevacizumab [Avastin] treatment) and patient characteristics (age, gender, geographic region, prior hypertension, number of metastatic sites, disease confined to the liver, location of primary tumor) and observed “the consistency and robustness of the efficacy results across all domains, including prior treatment with bevacizumab,” Dr. Tabernero reported.

The greatest treatment effect was seen among patients who had metastases confined to the liver, as compared to metastases elsewhere or no liver metastases.

Among patients with liver-only metastases, risk of death was reduced by 35%, compared with an 11% risk reduction among the other groups. The results for progression-free survival were similar, he said.

Patients who received bevacizumab previously fared as well on aflibercept as patients who had not received bevacizumab. Median progression-free survival was 6.7 months for patients with prior bevacizumab and overall survival was 12.5

survival was 12.1 months with FOLFIRI alone and 13.5 months with FOLFIRI plus aflibercept, Dr. Tabernero reported.

Positive results were observed as well for progression-free survival, with a hazard ratio of 0.76 (P = .00007). Median progression-free survival was 4.7 months with chemotherapy alone vs 6.9 months with the addition of aflibercept. The investigators noted that response rates were

Pan-tumor Biomarker?

“Of several putative predictive biomarkers for bevacizumab, pVEGF-A is a lead candidate,” said Dr. Jayson.

Plasma VEGF-A is potentially predictive (ie, correlated with outcome after bevacizumab therapy) and prognostic (correlated with outcome regardless of therapy) in metastatic breast, gastric, and pancreatic cancers, although it is prognostic only (not predictive) in metastatic colorectal cancer, non–small cell lung cancer, and

also higher with aflibercept on board, 11.1% vs 19.8%, respectively (P = .0001).

VELOUR Trial

Josep Tabernero, MD

novel enzyme-linked immunosorbent assay (ELISA) that favors shorter vascular endothelial growth factor (VEGF)-A isoforms (VEGF121 and VEGF110), and they correlated plasma VEGF-A (pVEGF-A) with clinical outcomes. Median baseline levels of potential biomarkers were prespecified as a cutpoint to categorize patients as having low or high levels.

Gordon C. Jayson, PhD

renal cell carcinoma.

In his presentation, Dr. Jayson drew from analyses of the AVADO, AVAGAST, and AVITA trials, all demonstrating a predictive benefit for pVEGFA in these tumor types.1 Overall survival in AVAGAST was greatest for patients with metastatic gastric cancer and high pVEGF-A receiving bevacizumab (HR = 0.72; P = .07). In AVADO, progression-free survival was greatest for metastatic breast cancer patients with high continued on page 16

EXPERT POINT OF VIEW

D

avid Kerr, MD, of the University of Oxford, United Kingdom, who is also President of the European Society of Medical Oncology, formally discussed the study, which he called “well designed and well conducted.” He applauded the investigators for performing a preplanned subgroup analysis with a priori biologic rationale rather than “sifting through the data post hoc” to look for associations, but he noted that subgroup analyses, even preplanned, David Kerr, MD should always be considered hypothesis-generating.

Nevertheless, he maintained that the key findings from VELOUR do “change the landscape” of the second-line treatment of advanced disease, which currently contains several effective options. “We have a new agent to consider,” he said, “for those patients who progress following front-line treatment with FOLFOX (leucovorin, fluorouracil, oxaliplatin) with or without bevacizumab (Avastin).”

■

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

months, similar to the overall study results.

The benefit of aflibercept was not dependent upon number of metastatic sites, location of the primary tumor, performance status, occurrence of hypertension, geographic region, or patient age.

The drug was well tolerated, with the frequency of grade 3/4 adverse events in keeping with the anti-VEGF class of agents. Toxicity was not worse for patients with prior exposure to bevacizumab.

■

Disclosure: Dr. Tabernero has served on advisory boards for sanofi-aventis, Roche, and Genentech.

Reference 1. Tabernero J, Van Cutsem E, Lakomy R, et al: Results from VELOUR, a phase 3 study of aflibercept versus placebo in combination with FOLFIRI for the treatment of patients with previously treated metastatic colorectal cancer. 2011 European Multidisciplinary Congress. Abstract 6LBA. Presented September 25, 2011.

The ASCO Post | NOVEMBER 15, 2011

PAGE 16

2011 European Multidisciplinary Cancer Congress Predictive Biomarker for Bevacizumab continued from page 15

pVEGF-A receiving bevacizumab (HR = 0.49; P = .08); the marker was prognostic for overall survival in AVADO.

Predictive Value in Metastatic Pancreatic Cancer Dr. Van Cutsem, provided details from the AVITA trial in metastatic pancreatic cancer, in which pVEGF-A and also pVEGFR2 were both independently correlated with overall and progression-free survival.2 Other assessed angiogenic markers did not correlate with outcomes, he said.

While high baseline pVEGF-A correlated with worse overall survival in the placebo arm, treatment with bevacizumab improved outcomes to put these patients on par with those with low baseline pVEGF-A (P = .03), Dr. Van Cutsem reported.

Eric Van Cutsem, MD, PhD

The hazard ratio for patients with high pVEGF-A levels was 0.56 while the hazard ratio was 1.02 for patients with low VEGF-A levels. A similar pattern was shown for progression-free survival with pVEGF-A, as well as with pVEGFR2 for progression-free and overall survival in pancreatic cancer.

Other Tumor Types “Results with the novel assay showed the potential predictive value for pVEGFA in breast, pancreatic, and gastric cancer. However, these findings were not replicated in metastatic colorectal cancer, non–small cell lung cancer, and renal cell carcinoma,” Dr. Jayson said.

Data from the AVF2107g trial, AVAIL, and AVOREN, respectively, showed that pVEGF-A was prognostic but not predictive. Heavy crossover might have confounded the lack of correlation between the biomarker and overall survival in some tumor types (also in breast, in AVADO), he said.

The value of the biomarker in NSCLC was also discussed at the meeting by Tony Mok, MD, of The Chinese University of Hong Kong.

Dr. Mok presented a biomarker analysis of the ABIGAIL study, a global trial of first-line bevacizumab plus chemotherapy in advanced or recurrent nonsquamous non–small cell lung cancer.3 An exploratory analysis showed that there was a correlation between high baseline pVEGF-A levels and shorter progression-free survival (P = .002), but none of seven candidate biomarkers significantly correlated with overall response to the drug, he reported.

New Assay Aids in the Search It is unclear why biomarker results seem different across tumor types.

The difference in its predictive potential may be a reflection of variations in sample handling, Dr. Jayson suggested.

Citrate was used in colorectal cancer, non–small cell lung cancer, and renal cell carcinoma studies, while EDTA was used in breast, gastric, and

pancreatic cancer studies. Samples in colorectal cancer and renal cell carcinoma were stored long-term, and samples from colorectal cancer, non–

Tony Mok, MD

small cell lung cancer, and renal cell carcinoma were for a subset of samples subjected to at least two freeze-thaw cycles.

“Of course, we cannot exclude a true negative in colorectal cancer, non–small cell lung cancer, and renal cell carcinoma,” he added.

“Sample and assay characteristics may be critical in biomarker read-out,” he said, adding that correct storage duration and minimum freeze-thaw cycles could be important in quality control.

But the value of the novel assay in measuring pVEGF-A is evident, the speakers agreed. “The shorter VEGFA isoform preference of the assay may play a critical role in these findings,” Dr. Van Cutsem said.

Problems with Analyses According to Benjamin Besse, MD, PhD, of the Institut Gustave Roussy in Villejuif, France, circulating pVEGF-A is a prognostic factor, but the data are still insufficient to assess its predictive value. These

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were retrospective studies and small cohorts; in three of six trials, less than 50% of the serum was analyzed, he pointed out.

He added, “Bevacizumab was approved in 2004, and in 2011 there is still no predictive factor. These presentations are good news. But the findings need to be validated prospectively in clinical trials.”

As part of the bevacizumab biomarker program, prospective clinical trials are underway to explore pVEGFA as a predictive marker, speakers responded. In the meantime, Dr. Jayson cautioned, “Don’t start measuring VEGF-A in your patients—yet!”

■

Disclosure: Dr. Van Cutsem has received research funding from Roche. Dr. Jayson has received research funding from Roche and has served on advisory boards for Roche.

References 1. Jayson GC, de Haas S, Delmar P, et al: Evaluation of plasma VEGFA as a potential predictive pan-tumour biomarker for bevacizumab. 2011 European Multidisciplinary Cancer Congress. Abstract 804.

Presented September 24, 2011.

2. Van Cutsem E, Jayson G, Dive C, et al: Analysis of blood plasma factors in the AVITA phase III randomized study of bevacizumab with gemcitabine-erlotinib in patients with metastatic pancreatic cancer.

2011 European Multidisciplinary Cancer Congress. Abstract 803. Presented September 24, 2011.

3. Mok T, Gorbunova V, Juhasz E, et al: Biomarker analysis in BO21015, a phase II randomized study of first-line bevacizumab combined with carboplatingemcitabine or carboplatin-paclitaxel in paitents with advanced or recurrent nonsquamous non-small cell lung cancer.

2011 European Multidisciplinary Cancer Congress. Abstract 9003. Presented September 24, 2011.

ASCOPost.com

ASCOPost.com | NOVEMBER 15, 2011

PAGE 17

News Thoracic Oncology

NCCN Guidelines® for Lung Cancer Screening Now Available

T

he new NCCN Guidelines for Lung Cancer Screening primarily refer to non–small cell lung cancer, the most common type of lung cancer, and recommend helical low-dose computed tomography (LDCT) screening for select patients at high risk for the disease.

In addition to outlining the appropriate use of LDCT screening, the NCCN Guidelines describe risk factors for lung cancer, recommend criteria for selecting high-risk individuals for screening, provide recommendations for evaluation SEE PAGE 60 and follow-up of

nodules found during screening, detail the accuracy of LDCT screening protocols and imaging modalities, and discuss the benefits and risks of screening.

The NCCN Guidelines for Lung Cancer Screening can be found under NCCN Guidelines for Detection,

Prevention, & Risk Reduction on the NCCN.org website or at http://www. nccn.org/professionals/physician_ gls/pdf/lung_screening.pdf.

For the complete updated versions of the NCCN Guidelines and the NCCN Drugs & Biologics

Compendium (NCCN Compendium®), visit NCCN.org. To view the NCCN Guidelines for Patients™, visit NCCN.com. Finally, free NCCN Guidelines mobile apps for iPhone and Android are now available at NCCN.org/mobile.

■

CONTACT

The ASCO Post EDITOR IAL CORR ESPONDENCE James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

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The ASCO Post | NOVEMBER 15, 2011

PAGE 18

News

Novel HDAC Inhibitor continued from page 2

preclinical trials to inhibit growth factor signaling pathways that mediate aromatase inhibitor resistance.

In in vivo studies, entinostat successfully restored estrogen receptor sensitivity after aromatase inhibitor treatment and produced impressive tumor regression. The drug also has demonstrated an excellent safety profile in the treatment of more than 650 patients with breast, lung, colon, and hematologic malignancies.

Denise A. Yardley, MD

Phase II Trial ENCORE 301 (ENtinostat Combinations Overcoming Resistance) was a phase II, randomized, placebocontrolled trial of exemestane with and without entinostat in 130 postmenopausal patients with estrogen receptor–positive advanced breast cancer that had progressed on therapy with a nonsteroidal aromatase inhibitor. ENCORE 301 was designed to test whether the addition of enti-

nostat to exemestane could improve the progression-free survival. After experiencing disease progression on a nonsteroidal aromatase inhibitor, patients were randomized to exemestane daily plus weekly entinostat or placebo.

As shown in Fig. 1, median progression-free survival, the primary endpoint, was 4.28 months with entinostat/exemestane vs 2.27 months with exemestane alone, a 27% statistically significant reduction in risk (P = .06). Rates of overall response and clinical benefit (stable disease at 6 months)were similar between the two arms: approximately 5% and approximately 26%, respectively.

At a median follow-up of 18 months, median overall survival was 26.9 months with the combination vs 20.3 months with exemestane alone, a 54% reduction in mortality risk (P = .055 by 2-sided test), Dr. Yardley reported.

“We saw a trend for an overall survival benefit. This is an exploratory endpoint with data that are still maturing and a subsequent update to be presented at the upcoming CTRCAACR San Antonio Breast Cancer Symposium,” she said.

EXPERT POINT OF VIEW

J

oyce O’Shaughnessy, MD, of Baylor Sammons Cancer Center in Dallas, who moderated the symposium where the results were presented, called the use of entinostat in advanced estrogen receptor–positive breast cancer “very, very promising.” She added, “I agree that it’s time for a phase III trial of this agent.”

The identification of an optimal treatment group is of key interest, Dr. O’Shaughnessy said. A subJoyce O’Shaughnessy, MD analysis of ENCORE 301 will compare patients deemed resistant to endocrine therapy, vs those who are sensitive, to assess relative benefits.

Acetylation Status The results according to acetylation status are intriguing, Dr. O’Shaughnessy observed. “In the overall population, increasing progression-free survival from about 2 months to 4 months is pretty good, but I am even more impressed with the trend for an overall survival benefit. I’m also especially impressed with the pharmacodynamic marker the study may have identified, which was associated with more than an 8-month progression-free survival,” she noted.

“This suggests we might try to increase the percentage of patients who develop acetylation of white blood cells,” she explained. The half-life of the drug is long enough to allow for weekly dosing, and more frequent dosing would not be desirable, she said. “But if we don’t see more toxicity, we may be able to give higher doses in some patients to achieve greater acetylation.

We may also be able to use this finding to optimize patients in the phase III trial.”

■

Disclosure: Dr. O’Shaughnessy reported no potential conflicts of interest.

Pharmacodynamic Analysis As their proposed mechanism of action, HDAC inhibitors induce hyperacetylation of lysines on histones and a number of other proteins. In

Progression probability

a biomarker analysis of 49 patients, protein lysine acetylation measured in blood samples revealed a substantial impact of the combination in 13 of 49 subjects who hy peracetylated (based on a greater 1.00 Exemestane + Entinostat: median PFS = 4.28 mo than median perExemestane + Placebo: median PFS = 2.27 mo cent change in B-cell protein acetylation).

HR = 0.73 (95% CI = 0.49, 1.09) 0.75 Risk of disease proP = .06 by stratified log-rank test (1-sided) gression was reduced by 77% in this group, who had a median 0.50 progression-free survival of 8.54 months on the combination 0.25 vs 1.92 months with exemestane plus placebo.

“This suggests that 0.00 entinostat-induced 0 2 4 6 8 10 12 14 16 18 hy p e r a c e t y l a t i o n Months tracked with improved outcomes and Placebo 31/66 13/33 4/20 4/15 1/7 3/6 0/2 0/1 1/1 may be an exciting potential biomarker Entinostat 15/64 14/45 11/29 3/16 3/10 0/3 0/1 0/1 1/1 of benefit that merits Fig. 1: Progression-free survival (PFS, intent-to-treat analysis) by treatment group, in the ENCORE 301 trial. Courtesy of further exploration,” Denise A. Yardley, MD. she said.

The regimen was well tolerated, and there were no new safety signals.

The combination was associated with more grade 3/4 fatigue (13% vs 2%), gastrointestinal toxicity (10% vs 0%), and neutropenia (13% vs 2%), but these were “uncomplicated without evidence of fever or infections,” she noted. Discontinuations due to adverse events were observed in 11% of the combination arm and 1% of the exemestane-only arm.

“These results support plans for the global, pivotal phase III study due to begin enrollment in early 2012,” Dr. Yardley concluded.

■

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

Reference 1. Yardley DAQ, Ismail-Khan R, Klein P. Results of ENCORE 301, a randomized, phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on a nonsteroidal aromatase inhibitor. 2011 Breast Cancer Symposium.

Abstract 268. Presented September 10, 2011.

ASCOPost.com | NOVEMBER 15, 2011

PAGE 19

Expert’s Corner

The case for Vectibix® QQ2W dosing schedule1

– The recommended dose of Vectibix® is 6 mg/kg every 14 days

660-minute infusion1

– Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes

PPremedication not standardized1

– The use of premedication was not standardized in the clinical trials – The utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown

NNo loading dose1

– No loading dose is required

11% severe infusion reactions reported1

– Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3-4) – Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion – Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions

INDICATION:

Vectibix® is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.

Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal cancer with these mutations.

Important Safety Information, including Boxed WARNINGS: WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. [See Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)].

In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported. Withhold or discontinue Vectibix® for severe or life-threatening dermatologic toxicity and monitor for inflammatory or infectious sequelae.

Terminate the infusion for severe infusion reactions.

occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Cases of fatal and non-fatal interstitial lung disease (ILD) have been observed in patients treated with Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, Vectibix® therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, Vectibix® should be permanently discontinued and the patient should be treated appropriately. In patients with a history or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® must be carefully considered. In clinical studies, patients with a history of, or evidence of, interstitial pneumonitis or pulmonary fibrosis were excluded.

In a randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment (eg, oral or intravenous electrolyte repletion) as needed.

Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months after the last dose.

Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis.

Interrupt or discontinue Vectibix® for acute or worsening keratitis.

Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus and has the potential to cause fetal harm when administered to pregnant women.

Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

The most serious adverse events of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized clinical trial, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in patients treated with Vectibix® included rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); dehydration (16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia (10% vs 4%); Please see brief summary of stomatitis/mucositis (4% vs < 1%); and hypomagnesemia (4% vs 0%). NCI-CTC Reference: 1. Vectibix® (panitumumab) grade 3-5 pulmonary embolism occurred at a higher rate in patients treated with Vectibix® prescribing information, Amgen.

(7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix®.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea

©2011 Amgen Inc. All rights reserved.

61007-R1-V1

Prescribing Information on next page.

08-11 G61228-R1-V1

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Expert’s Corner

Alexander Levine, MD, MACP continued from page 1

I went back to the patient and got a detailed background and history. He was a young gay man, and from our conversation it was obvious that he’d had a multitude of potential pathogenic exposures. I asked if he would let me follow-up with him on a routine basis.

I didn’t know what the diagnosis was, just that it was a lymphoid reaction to something, and not a malignancy. The next day he returned to my office with one of his prior sexual partners who also had enlarged lymph nodes. I biopsied him and it was the exact same Trim: 7.875” “unidentified” clinical issue.

Live: 6.75” Within a month there would be a

Vectibix® (panitumumab) Injection for intravenous Infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix monotherapy. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients With a Between-Group Difference of ≥ 5% (Study 1) Patients Treated With Vectibix Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Grade* All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Fatigue 26 4 15 3 General Deterioration 11 8 4 3 Digestive Abdominal Pain 25 7 17 5 Nausea 23 1 16 <1 Diarrhea 21 2 11 0 Constipation 21 3 9 1 Vomiting 19 2 12 1 Stomatitis 7 0 1 0 Mucosal Inflammation 6 <1 1 0 Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 Peripheral Edema 12 1 6 <1 Respiratory Cough 14 <1 7 0 Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Skin 90 14 6 0 Erythema 65 5 1 0 Dermatitis Acneiform 57 7 1 0 Pruritus 57 2 2 0 Nail 29 2 0 0 Paronychia 25 2 0 0 Skin Exfoliation 25 2 0 0 Rash 22 1 1 0 Skin Fissures 20 1 <1 0 Eye 15 <1 2 0 Acne 13 1 0 0 Dry Skin 10 0 0 0 Other Nail Disorder 9 0 0 0 Hair 9 0 1 0 Growth of Eyelashes 6 0 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0.

Body System Body as a Whole

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or ocular toxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibixtreated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported.

Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration].

Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%). For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10/613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies. No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading.

Postmarketing Experience: The following adverse reactions has been identified during post-approval. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or established a causal relationship to drug exposure: • Skin and subcutaneous tissue disorders: Angioedema [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Skin and subcutaneous tissue disorders: Skin necrosis • Immune system disorders: Anaphylactoid reaction [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.7)] DRUG INTERACTIONS: No formal drug-drug interaction studies have been conducted with Vectibix.

USE IN SPECIFIC POPULATIONS Pregnancy – Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. [see Reproductive and Developmental Toxicology]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.

Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, 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. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix has not been studied in pediatric patients.

Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients.

OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning, Dosage and Administration, Warnings and Precautions and Adverse Reactions], • Diarrhea and dehydration [see Warnings and Precautions], • Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], • Pregnancy or nursing [see Use in Specific Populations].

Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy [see Use in Specific Populations].

This brief summary is based on the Vectibix® prescribing information v12, 06/2011 Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, and 7,807,798 as well as other patents or patents pending. ©2006-2011 Amgen Inc. All rights reserved.

MC46026-F

man with extremely aggressive disease, disseminated in multiple organs throughout his body. It turned out to be B-cell lymphoma. AIDS was not yet described at the time, and was instead called GRID (gay-related immune deficiency).

All these men were described not as having B-cell hyperplasia, but rather, T-cell immune deficiency, which resulted in the widespread infections. I had difficulty figuring out the relationship between the B-cell hyperplasia and the T-cell immune deficiency. But as time went on, perhaps a year, the connection began to materialize: They were all gay men with B-cell hyperplasia that was perhaps a reaction to some common exposure, and I hypothesized that given time, the very abnormal hyperplasia could eventually lead to the development of monoclonal B-cell lymphoma.

The AIDS saga certainly reinforced my belief about how important it is to keep an open mind, as a scientist and clinician, but most importantly as a human being.

I sent out a grant to the NIH to study these patients. The hypothesis again was that this reaction, which later became known as persistent, generalized lymphadenopathy—one of the initial AIDS-related complex type of illnesses—was a prodrome to the development of B-cell lymphoma, and that by following the patients carefully with repeat biopsies I might be able to find (and understand) the moment of transformation to malignant lymphoma. And that’s how I entered the AIDS era.

Trim: 10.75” Live: 9.75”

INDICATIONS AND USAGE Vectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14) in Full Prescribing Information].

The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progressionfree survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations. [see Clinical Studies (14) in Full Prescribing Information].

DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions.

Dose Modifications for Infusion Reactions [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.

Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix.

Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix.

• If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix, treatment may be resumed at 50% of the original dose.

– If toxicities recur, permanently discontinue Vectibix.

– If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached.

Do not administer Vectibix as an intravenous push or bolus.

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS Dermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported.

Withhold Vectibix for severe or life-threatening dermatologic toxicity. [see Boxed Warning, Adverse Reactions, and Dosage and Administration].

Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCICTC grade 3–4).

Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix administration [see Boxed Warning, and Adverse Reactions]. In clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. [see Dosage and Administration].

Increased Toxicity With Combination Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCICTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 4%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. In a single-arm study of 19 patients receiving Vectibix in combination with IFL, the incidence of NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Severe diarrhea and dehydration which may lead to acute renal failure and other complications have been observed in patients treated with Vectibix in combination with chemotherapy.

Pulmonary Fibrosis: Cases of fatal and non-fatal interstitial lung disease (ILD) have been observed in patients treated with Vectibix. In the event of acute onset or worsening of pulmonary symptoms, Vectibix therapy should be interrupted and a prompt investigation of these symptoms should occur. If ILD is confirmed, Vectibix should be permanently discontinued and the patient should be treated appropriately. In patients with a history or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix must be carefully considered. In clinical studies, patients with a history of, or evidence of, interstitial pneumonitis or pulmonary fibrosis were excluded.

Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed.

Photosensitivity: Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.

Ocular Toxicities: Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix therapy for acute or worsening keratitis.

EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit. Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix and for full instructions on assay performance.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Infusion Reactions [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis.

Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Safety data are available from 15 clinical trials in which 1467 patients received Vectibix; of these, 1293 received Vectibix monotherapy and 174 received Vectibix in combination with chemotherapy [see Warnings and Precautions].

The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial.

The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

group of about 20 young men waiting at my office in the morning, all with grossly enlarged lymph nodes. At that point, I was faced with an unbelievably difficult and interesting clinical puzzle.

I began to follow all of these men.

About that time, I also saw my first case of what turned out to be AIDSrelated lymphoma in a young gay

Learning from the AIDS Experience What can the cancer community learn from the AIDS clinical and research experience?

There are so many lessons. From a nonscientific perspective, I learned about the importance of activism. If not for the early AIDS activists, the cancer community would have been much slower in gearing up its own advocacy efforts, which drive research funding and force the scientific community to gear up its efforts. After all,

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Expert’s Corner

we are all in this together.

Also, a small piece of information or a major breakthrough in one scientific discipline can translate valuable information into another scientific area. In the AIDS experience, aside from mechanisms of oncogenesis, the knowledge I gained treating HIV-infected patients was invaluable to my current treatment of immunosuppressed patients with lymphoma and other malignancies.

Many cancer therapies cause severe Tcell depletion, and patients receiving such treatment are at risk for many of the infections we saw during the AIDS epidemic.

I was able to take from that experience knowledge about the use of prophylactic antibiotics, incorporating them into the treatment of patients with various hematologic malignancies whose treatment caused T-cell deficiency and therefore had increased risk of infections. The use of various anti-infectives in HIV-infected patients was a big take-home lesson that has carried over into the practice of oncology, especially in immunosuppressed patients.

The antiretroviral drugs seemed miraculous when they were first developed, and some of those drugs have been used with success in lymphoproliferative malignancies. Learning how to apply combination drugs in a targeted way, such as highly active antiretroviral therapy (HAART), is an example of therapy taken from the oncology community and applied in the AIDS population with great success. So, passion, cutting-edge science, and the expanded knowledge from one condition to another all worked together in a way that has helped us care for many different conditions.

Man of Thousands of Ideas You had the privilege of working in the laboratory with the distinguished virologist Jonas Salk. Please give us a sense of that experience.

That period was one of the blessings of my life. Jonas was a man of thousands of ideas, and he’d call me at all hours of the night to share them. Some of his ideas bordered on crazy, but others were sublime in their crystalline vision. He was alive in a way that most humans only dream of.

Sadly, he didn’t get the respect he deserved from the scientific community. He was working on an AIDS vaccine, which wasn’t given proper testing by the FDA. Supposedly the agency’s concern was the possibility that a live virus might somehow become a biohazard, although studies disproved that premise.

We presented the data at various

likely to be smokers than their noninfected counterparts, contributing to their rise in lung cancer. Work related to HIV in women is another area of my current and prior research interests.

in an appropriate way. During a PBS interview, Bill Moyers asked Jonas if he thought we would ever find the cure for AIDS. And Jonas said with casual aplomb, “Yes, we have the answer.” Moyers sat bolt upright and said, “You have the answer?” Jonas said, “Yes, it’s right here in nature; we’re just not asking the right questions, but when we do, we’ll find the cure.” That was Jonas.

The Human Connection As a humanitarian, any last thoughts?

The AIDS saga certainly reinforced my belief about how important it is to keep an open mind, as a scientist and clinician, but most importantly as a human being. We’re all so sure that we know all the answers about the inner workings of another person’s mind related to the way they behave, but we don’t. If you approach life with that kind of mindset, you’ll walk out being smaller.

Working with so many people who were desperately sick, many of whom died, gave me a greater ability to find something beautiful in just about any person. You can learn almost everything you want to know about human behavior by sitting at a patient’s bedside and listening. My life has become bigger and richer by sharing these intimate times with people from all walks of life I otherwise would never have known.

Throughout the millennia of human history, we’ve only had effective medicines for about 100 years. Yet we have always had healers, and they had to have been effective in one way or another or the profession would not have survived. So, if they didn’t have the medicines, what did they have?

They had what my colleagues and I had in 1981 and 1982—the ability to be there for our patients, to give hope and comfort. I’m certainly not saying that the human connection replaces the medicinal benefits of miraculous therapies like HAART, but as we learned from AIDS, when you combine human kindness with scientific drive, you pave the road for unlimited success.

Current Investigations What are your current research interests?

I’m very interested in the relationship between chronic inflammation and infections in the oncogenic pro-

AIDS Pandemic at a Glance ■■ 1981: generally given as start of HIV/AIDS epidemic ■■ 1982: gay-related immune deficiency (GRID) is term used by media ■■ 1985: at least one HIV/AIDS case reported in every region of the world ■■ 1986: President Reagan mentions AIDS for the first time in public; zidovudine (AZT) begins trials

■■ 1988: Florida court rules that a young girl with AIDS can attend school only if isolated in a glass enclosure

■■ 1995: FDA approves saquinavir (Invirase), beginning the era of HAART ■■ 1997: U.S. AIDS deaths drop by more than 40% ■■ 2002: HIV is leading cause of death worldwide in those aged 15 to 59 ■■ 2008: President-elect Obama calls for first-ever national HIV/AIDS strategy ■■ 2010: U.S. HIV/AIDS travel ban lifted meetings, but in the end, the FDA did not allow us to proceed. Jonas was employing concepts he used in developing the polio vaccine, and the younger scientists were dismissive, saying that they had genetic engineering and other high-tech tools at their disposal that were far more effective than older methods.

Now, we are more than 30 years into the AIDS pandemic and still no vaccine exists, leaving me to wonder if Jonas’s might have worked. I wish that we could have tested the vaccine

cess. That whole area of research is beyond fascinating to me, so that’s where much of my efforts will go.

It’s important to note that with the advent of HAART we saw a marked decrease in AIDS-related malignancies such as Kaposi sarcoma. However, we are now seeing an increase in non–AIDS-defining cancers in HIVpositive patients, such as anal, lung, and liver cancers. Our studies show that lifestyle issues partly contribute to that increase. For instance, we see that HIV-infected women are much more

■

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

Getting to Zero World AIDS Day, December 1, 2011 Zero new HIV infections.

Zero discrimination.

Zero AIDS-related deaths.

For more information, visit http://aids.gov/

The ASCO Post | NOVEMBER 15, 2011

PAGE 22

In the Clinic Novel Agents

Sunitinib and Everolimus: New Indications in Pancreatic Neuroendocrine Tumors

By Matthew Stenger

With In the Clinic, The ASCO Post provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Sunitinib Indication—The oral kinase inhibitor sunitinib (Sutent) was recently granted approval for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET, Fig. 1) in patients with unresectable, locally advanced or metastatic disease.

Sunitinib has earlier indications in gastrointestinal stromal tumors (GIST) after disease progression on imatinib (Gleevec) or in patients intolerant of imatinib and in advanced renal cell carcinoma.

Approval of sunitinib in pNET is based on a randomized trial comparing sunitinib at 37.5 mg/d (n = 86) vs placebo (n = 85) in patients with unresectable, locally advanced or metastatic well-differentiated pNET. Treatment with somatostatin analogs was allowed. A total of 69% of patients given placebo received sunitinib after progression. The trial was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group, as well as a difference in progression-free survival favoring sunitinib.

Sunitinib treatment significantly prolonged median progression-free survival, the trial’s primary endpoint, from 5.4 to 10.2 months, representing a 57% reduction in risk of progression (hazard ratio = 0.43, P < .001). Improved progression-free survival was seen in multiple patient subgroups,

Of Note Sunitinib inhibits cellular signaling by targeting multiple receptor tyrosine kinases and has been shown to delay tumor growth in a mouse model of pancreatic islet cell tumors by reducing endothelial cell density and pericyte coverage of tumor vessels.

including those with prior somatostatin analog treatment. Overall survival data were not mature at the time of analysis. The overall response rate with sunitinib was 9.3% (no complete responses).

How it works—Sunitinib inhibits cellular signaling by targeting multiple receptor tyrosine kinases.

Vascular endothelial growth factor (VEGF) is a key driver of angiogenesis in pancreatic neuroendocrine tumors, and malignant pancreatic endocrine tumors also show widespread expression of platelet-derived growth factor receptors (PDGFRs) α and β, stem-cell factor receptor (c-kit), and VEGF receptor (VEGFR)-2 and VEGFR-3. Sunitinib inhibits these kinases, and has been shown to delay tumor growth in a RIP1-Tag2 transgenic mouse model of pancreatic islet cell tumors by reducing endothelial cell density and pericyte coverage of tumor vessels.

How it is given—The recommended dose of sunitinib for pNET is 37.5 mg taken orally once daily continuously without a scheduled off-treatment period. Sunitinib can be taken with or without food. Patients with severe or intolerable adverse reactions may require temporary dose reductions to 25 mg/d or dose interruption.

Safety profile—Sunitinib has a boxed warning for hepatotoxicity.

During the double-blind phase of the trial supporting approval of sunitinib in pNET, the most common (≥ 30%) adverse reactions were diarrhea, nausea, asthenia, vomiting, and fatigue.

The most common (≥ 5%) grade 3/4 adverse reactions were neutropenia, hypertension, palmar-plantar erythrodysesthesia syndrome, and leukopenia. Five patients receiving sunitinib and nine receiving placebo died on-study; of the five sunitinib on-study deaths, one was due to cardiac failure and four were due to disease progression. An additional sunitinib patient was taken off study due to cardiac failure and died 2 months later.

Adverse events resulted in permanent discontinuation in 22% of sunitinib patients and in 17% of placebo patients. Dose delays or reductions were required in 61% and 23% of patients, respectively.

Sunitinib and Everolimus in Pancreatic Neuroendocrine Tumors Sunitinib

■■ Previously approved in gastrointestinal stromal tumor and renal

cell carcinoma, this oral kinase inhibitor is now also indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable, locally advanced or metastatic disease.

■■ The recommended dose of sunitinib for pNET is 37.5 mg taken once daily continuously, without a scheduled off-treatment period.

Everolimus

■■ Previously approved in renal cell carcinoma and subependymal giant cell astrocytoma, everolimus is another oral kinase (mTOR) inhibitor that has been approved for the treatment of progressive pNET that is unresectable, locally advanced or metastatic.

■■ The recommended dose of everolimus for pNET is 10 mg once daily.

Suggested Readings Kulke MH, Lenz HJ, Meropol NJ, et al: Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 26:3403-3410, 2008.

Raymond E, Dahan L, Raoul JL, et al: Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501-513, 2011.

SUTENT® (crizotinib capsules, oral) prescribing information. Pfizer Labs, May 2011. Available at http://labeling.pfizer. com/ShowLabeling.aspx?id=607.

Accessed October 24, 2011.

U.S. Food and Drug Administration: What’s New from the Office of Hematology Oncology Products: Sunitinib. Available at http://www.fda.gov/AboutFDA/

CentersOffices/CDER/ucm256499.htm.

Accessed October 24, 2011.

Everolimus Indication—The kinase inhibitor everolimus (Afinitor) was also recently approved for treatment of unresectable, locally advanced or metastatic progressive neuroendocrine tumors of pancreatic origin (pNET). The safety and efficacy of everolimus in treatment of carcinoid tumors have not been established. Everolimus has prior indications in advanced renal cell carcinoma after failure of sunitinib or sorafenib and in subependymal giant cell astrocytoma associated with tuberous sclerosis that

Fig. 1: Pancreatic neuroendocrine tumors (stained red in the histology slide above, magnified 20x) are composed of back-to-back cells of uniform size and shape. And, unlike tumors that begin in the cells that line the pancreas (adenocarcinomas), pancreatic neuroendocrine tumors don’t have an excessive build up of stromal cells around them. Image courtesy of Dr. Ralph Hruban of Johns Hopkins University.

ASCOPost.com | NOVEMBER 15, 2011

PAGE 23

In the Clinic

requires intervention but cannot be treated by curative resection.

Approval was based on a randomized trial of everolimus 10 mg/d (n = 207) vs placebo (n = 203) in patients with unresectable, locally advanced or metastatic pNET. Treatment with somatostatin analogs was allowed as part of best supportive care. In total, 73% of placebo patients crossed over to everolimus after disease progression, as permitted by study protocol. Median progressionfree survival, the primary endpoint of the trial, was increased from 4.6 to 11.0 months with everolimus, representing a 65% reduction in risk of progression (HR = 0.35, P < .001). Improvements in progression-free survival were observed across all patient subgroups, irrespective of prior somatostatin analog use. An interim analysis showed no difference between groups in overall survival (HR = 1.05, P = NS). The re-

Of Note Everolimus inhibits mTOR, which stimulates cell growth, proliferation, and angiogenesis. Inhibition of mTOR has been shown to result in an antiproliferative effect on pancreatic neuroendocrine tumor cells

dose of everolimus is 10 mg once daily; it should be taken at the same time of day and consistently with or without food.

Patients with severe or intolerable adverse reactions may require temporary dose reductions to 5 mg/d or dose interruption. The dose should be reduced to 5 mg once daily in patients with moderate (Child-Pugh class B) hepatic impair-

ment. The starting dose should be 2.5 mg once daily if treatment with drugs that are moderate inhibitors of CYP3A4 and/or P-glycoprotein is required; if tolerated, the dose can be increased to 5 mg once daily. If strong inducers of CYP3A4 are required, the dose can be increased in 5-mg increments to a maximum of 20 mg once daily.

Safety profile—Data from the trial supporting everolimus approval and 858 additional patients with advanced neuroendocrine tumors in the everolimus safety database indicate that the most common adverse reactions in patients receiving everolimus (> 30%) were stomatitis, rash, diarrhea, fatigue, continued on page 24

Community-based cancer care.

A precious resource.

At McKesson Specialty Health, our vision of helping independent, community-based oncology practices thrive means providing more solutions to meet your unique challenges.

Through the Onmark Select Program, you have access to proven clinical tools, integrated

sponse rate with everolimus was 4.8%, with no complete responses.

How it works—Everolimus inhibits mammalian target of rapamycin (mTOR), a serine-threonine kinase that stimulates cell growth, proliferation, and angiogenesis. Autocrine activation of the mTOR signaling pathway, which is mediated by insulin-like growth factor 1, is implicated in the proliferation of pancreatic neuroendocrine tumor cells, and inhibition of mTOR has been shown to result in an antiproliferative effect.

How it is given—The recommended

technology, revenue cycle and reimbursement solutions, all designed to help you strengthen your practice’s clinical services and business performance. With the Onmark Select Program, you have more choices than ever to support the success of your practice.

To learn more about McKesson Specialty Health, visit mckessonspecialtyhealth.com/oncology or contact us at: 800.482.6700, Option 4

Report Adverse Events

H

ealth-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www. fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

■

© 2011 McKesson Specialty Health. All rights reserved.

MSH193_PreciousResource_ASCO_7x10.indd 1

10/5/11 11:11 AM

The ASCO Post | NOVEMBER 15, 2011

PAGE 24

2011 European Multidisciplinary Cancer Congress Global Trials: Do Benefits Outweigh Pitfalls?

By Caroline Helwick

G

lobal clinical trials have many advantages and are essential in many disease settings, but there are also challenges that confront global industry-sponsored research, said Sandra Horning, MD, Senior Vice President and Global Head of Clinical Development in Hematology/Oncology for Genentech (Table 1).

ed Kingdom and Canada are dropping in the ranks.

The international flavor of trials is quickly becoming obvious. For example, the intriguing T-DM1 breast cancer data presented at this meeting (see The ASCO Post, November 1, page 8) came from a phase II Genentech-sponsored trial in which 75% of the participants were from outside the United States.2 “This is likely the way forward,” Dr. Horning said.

Table 1: Global Industry Trials: Benefits and Pitfalls Advantages

Disadvantages

■■ Global markets ■■ Shorter development timelines ■■ Earlier availability ■■ Increased population/sample

■■ Ethnic/cultural variability ■■ Efficacy, safety ■■ Different standards of care ■■ Regulatory requirements ■■ Limitations in operational

size

■■ Potential cost reduction

capacity and quality

■■ Rapidly changing environment, especially in developing countries

‘Wider Net Must Be Cast’

Sandra Horning, MD

International Impact of Cancer “Because cancer has an international public health impact, people with cancer in all regions of the world can benefit from the knowledge gained in global clinical research,” said Dr. Horning, who discussed the current state and future direction for global trials at the 2011 European Multidisciplinary Cancer Congress in Stockholm.1 The density of global trials is increasing outside of Europe and North America. The United States and Japan still host the most trials, but the landscape is shifting. China (where cancer is the leading cause of death) now ranks 3rd, having moved ahead of Germany, France, and Italy. Brazil is now ranked 7th, and India is expected to become the 8th most common site for clinical trials by 2015. Russia is also a fast-growing trials site, while the Unit-

Sunitinib and Everolimus continued from page 23

edema, abdominal pain, nausea, fever, and headache. The most common (≥ 5%) grade 3 or 4 adverse reactions were stomatitis and diarrhea. The most common (≥ 3%) grade 3 or 4 laboratory abnormalities were hyperglycemia, lymphopenia, decreased hemoglobin, hypophosphatemia, increased ALP, neutropenia, increased AST, decreased potassium, and thrombocytopenia.

During the trial, death occurred in 7 everolimus patients and 1 placebo patient. Causes of death in the everolimus group included acute renal failure, acute respiratory distress, cardiac ar-

As more is learned about the molecular heterogeneity within tumors, larger populations are needed from which to select subjects. “A wider net must be cast to target molecular subsets,” Dr. Horning noted. But while expanded populations and reduced cost are advantages to going global, industry faces many challenges in doing so.

Ethnic variability is a main concern.

Differences in disease biology can influence clinical outcomes and drug tolerability. This has been repeatedly shown in studies enrolling both Asian and Caucasian patients, such as trials of anti-EGFR agents in lung cancer and bevacizumab (Avastin) in gastric cancer, where outcomes have differed by ethnicity and/ or region. It is possible that biomarkers even differ by ethnicity, she said.

“Differences in the underlying biology of cancers and their hosts by ethnicity and geographic region are becoming apparent and require additional study. Biology is speaking to us,” she commented.

“We now include more pharmacokinetic and pharmacodynamic analyses in the early stage of drug development.”

While population demographics and genetics vary by site, so do medical

Courtesy of Sandra Horning, MD.

rest, death (cause unknown), hepatic failure, pneumonia, sepsis, and death from unknown cause. After crossover to open-label everolimus, there were 3 additional deaths, 1 due to hypoglycemia and cardiac arrest in a patient with insulinoma, 1 due to myocardial infarction with congestive heart failure, and 1 due to sudden death. Adverse events resulted in permanent discontinuation in 20% and 6% of patients in the everolimus and placebo groups, respectively. Dose delays or reductions were necessary in 61% of everolimus patients and 29% of placebo patients. Opportunistic infections in patients with advanced neuroendocrine tumors included hepatitis B reactivation

(resulting in death), mycobacterial infection, and invasive aspergillus. Pneumonitis was seen in 11% of patients (grade 3 or 4 in 1.7%) in the safety database.

practice and the available resources for care. Both can affect postprogression treatment and, therefore, prognosis.

“The world’s scientists must fully engage in collaborative research to better understand ethnic and regional differences in cancer biology, host responses, and therapeutic outcomes,” Dr. Horning commented.

Finally, regulatory requirements are not globally consistent. Clinical data requirements vary by country, as does the “scientific advice” that underlies all trials and the details regarding how trials are conducted.

“Variability in regulatory requirements represents a major challenge for timely industry-sponsored trials,” Dr. Horning said. This all comes together as “a balance of timelines, requirements, and markets.”

Global Trials ‘Here to Stay’ “Global trials are here to stay,” commented David Kerr, MD, Rhodes Professor of Clinical Pharmacology and Cancer Therapeutics at the University of Oxford, United Kingdom.

■

Suggested Readings AFINITOR® (everolimus) tablets prescribing information. Novartis Pharmaceuticals Corporation, July 2011. Available at http://www.pharma.us.novartis.com/ product/pi/pdf/afinitor.pdf.

Accessed October 24, 2011.

Missiaglia E, Dalai I, Barbi S, et al: Pancreatic endocrine tumors: Expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol 28:245-255, 2010.

U.S. Food and Drug Administration: What’s New from the Office of Hematolo-

“We have a celebration of diversity, ethnicity, and genetics in cancer research, but this leaves us with some questions,” he offered. “With such heterogeneity, we have to determine if global trial results are representative of all populations. Biology is king, and the more we understand that, the better our results will be.”

■

Disclosure: Dr. Kerr reported no potential conflicts of interest. Dr. Horning is Senior Vice President and Global Head of Clinical Development in Hematology/Oncology for Genentech.

References 1. Horning S: Industry-led global trials: Do benefits outweight pitfalls? 2011 European Multidisciplinary Cancer Congress. Abstract 329. Presented September 26, 2011.

2. Hurvitz S, Dirix L, Kocsis J, et al: Trastuzumab emtansine (T-DM1) versus trastuzumab plus docetaxel in previously untreated HER2-positive metastatic breast cancer: Primary results of a randomized multicenter open-label phase II study.

2011 European Multidisciplinary Cancer Congress. Abstract 5001. Presented September 25, 2011.

gy Oncology Products: Everolimus. Available at http://www.fda.gov/AboutFDA/ CentersOffices/CDER/ucm254392.htm.

Accessed October 24, 2011. von Wichert G, Jehle PM, Hoeflich A, et al: Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Cancer Res 60:4573-4581, 2000.

Yao JC, Lombard-Bohas C, Baudin E, et al: Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: A phase II trial. J Clin Oncol 28:69-76, 2010.

Yao JC, Shah MH, Ito T, et al: Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514-523, 2011.

Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

Fareston helps reduce the guess work FARESTON (toremifene citrate) 60 mg Tablets: indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.

ALREADY ACTIVE

500,000 PATIENT YEARS

UNIQUE METABOLISM

PATIENT SAVINGS

Parent compound binds to and blocks estrogen receptors

Metabolized principally by CYP3A4 CYP2D6 does not play a significant role in the activity of FARESTON No known drug interactions with SSRI antidepressants

Proven clinical profile Efficacy comparable to tamoxifen in head to head trials

Savings coupons offer up to $50 off each prescription for eligible patients Patient Assistance Program available for Medicare Part D and uninsured patients who qualify

Important safety information: FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. FARESTON is contraindicated in patients with known hypersensitivity to the drug. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively.

References: FARESTON® Prescribing Information, 2011. Data on file, GTx, Inc.

Please see brief summary of prescribing information including boxed warning on the following page.

For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

© 2011 GTx, Inc., Memphis, TN 38103. All rights reserved. FAR-P400-R0 October 2011

BRIEF SUMMARY OF PRESCRIBING INFORMATION WARNING: QT PROLONGATION FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [see Warnings and Precautions].

INDICATIONS AND USAGE FARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.

DOSAGE FORMS AND STRENGTHS Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side.

CONTRAINDICATIONS Hypersensitivity to the Drug FARESTON is contraindicated in patients with known hypersensitivity to the drug.

QT Prolongation, Hypokalemia, Hypomagnesemia Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia.

WARNINGS AND PRECAUTIONS Prolongation of the QT Interval Toremifene has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death.

Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions and Clinical Pharmacology].

Hypercalcemia and Tumor Flare As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, FARESTON treatment should be discontinued.

Tumorigenicity Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available.

Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology].

General Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment [see Warnings and Precautions]. Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.

Laboratory Tests Periodic complete blood counts, calcium levels, and liver function tests should be obtained.

Use in Pregnancy Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. 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 [see Use in Specific Populations].

Women of Childbearing Potential FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur.

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

Clinical Trials Experience Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment.

The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related.

North American Study FAR60 n = 221

TAM20 n = 215

Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4% Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).

Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below.

Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies].

Adverse Reactions Cardiac Cardiac Failure Myocardial Infarction Arrhythmia Angina Pectoris Ocular* Cataracts Dry Eyes Abnormal Visual Fields Corneal Keratopathy Glaucoma Abnormal Vision/Diplopia Thromboembolic Pulmonary Embolism Thrombophlebitis Thrombosis CVA/TIA Elevated Liver Tests** AST Alkaline Phosphatase Bilirubin Hypercalcemia

North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) 2 2 -

(1) (1)

1 (<1) 3 (1.5) -

1 1

22 20 8 4 3 -

(10) (9) (4) (2) (1.5)

16 (7.5) 16 (7.5) 10 (5) 2 (1) 2 (1) -

1 -

4 1

(2)

2 (1) 2 (1) 1 (<1) -

1 1 1 -

(<1) (<1) (<1)

4 24 4 6

30 16 2 1

(19) (10) (1) (<1)

(<1)

11 (5) 41 (19) 3 (1.5) 6 (3)

(2) (11) (2) (3)

(<1) (<1)

(<1)

1 (<1) 2 (1) -

2 (1) 3 (1.5) 1 (<1)

3 (1.5) 1 (<1) 1 (<1) 2 (1)

-

3 (1.5)

5 (3) 1 (<1) 1 (<1) -

(<1)

4 (2) 3 (1.5) 4 (2)

1 (<1) 3 (1.5) 4 (2) 4 (2)

22 (15) 13 (9) 1 (<1) -

32 (15) 18 (8) 2 (1) -

35 (17) 31 (15) 3 (1.5) -

1 1

(<1)

* Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual ophthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: AST >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: AST, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.

The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea.

Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.

Post-marketing Experience The following adverse reactions were identified during post approval use of FARESTON. 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.

Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge.

DRUG INTERACTIONS Drugs that Decrease Renal Calcium Excretion Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. Agents that Prolong QT The administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see Boxed Warning and Warnings and Precautions].

Effect of Strong CYP3A4 Inducers on Toremifene Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s Wort, lower the steady-state concentration of toremifene in serum.

Effect of Strong CYP3A4 Inhibitors on Toremifene In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively.

N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively.

The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning and Warnings and Precautions].

Effect of Toremifene on CYP3A4 Substrates In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and α-hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and α-hydroxymidazolam Cmax and AUC were reduced by less than 20%.

Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely.

Effect of Toremifene on CYP2C9 Substrates In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC. Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure).

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. 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.

In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies.

Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly.

Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits.

In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis).

Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero.

Nursing Mothers It is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FARESTON, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use There is no indication for use of FARESTON in pediatric patients.

Geriatric Use The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Renal Impairment The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.

Hepatic Impairment The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Race The pharmacokinetics of toremifene in patients of different races has not been studied.

Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted.

OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement.

Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.

Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

CLINICALPHARMACOLOGY Mechanism of Action Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor.

Pharmacodynamics Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH).

Effects on Cardiac Electrophysiology The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment [see Drug Interactions].

Dose and concentration-related increases in the QTc interval and T wave changes were observed (see Table 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration [see Boxed Warning and Warnings and Precautions].

Table 1: QTc Prolongation in Healthy Male Volunteers Treatment Arm Toremifene 20 mg (N = 47) Toremifene 80 mg (N = 47) Toremifene 300 mg (N = 48)

Mean (90% CI) ΔΔQTc, ms 7 (0.9, 13.6) 26 (21.1, 31.2) 65 (60.1, 69.2)

ΔQTc > 60 ms (n, %) 0 2 (4.3%) 43 (89.6%)

QTc > 500 ms (n, %) 0 0 5 (10.4%)

Pharmacokinetics Absorption – Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks.

Distribution – Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin.

Metabolism – Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state.

Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto- induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies.

Elimination – The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days.

Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation.

Renal insufficiency – The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function.

Hepatic insufficiency – The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients.

Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Geriatric patients – The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Food – The rate and extent of absorption of FARESTON are not influenced by food; thus FARESTON may be taken with or without food.

Race – The pharmacokinetics of toremifene in patients of different races has not been studied.

Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis).

Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests).

Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes).

Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks.

PATIENT COUNSELING INFORMATION Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs.

FARESTON may harm the fetus and increase the risk for pregnancy loss [see Warnings and Precautions and Use in Specific Populations].

Premenopausal women using FARESTON should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur [see Warnings and Precautions].

Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur.

Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner [see Boxed Warning, Warnings and Precautions, and Clinical Pharmacology].

Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during FARESTON treatment.

Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John’s Wort) and toremifene, can reduce concentrations of coadministered drugs [see Drug Interactions].

Distributed by GTx, Inc. Memphis, TN 38103, USA Product covered by Orion Product Patents and related patent numbers. © 2011 GTx, Inc. All rights reserved.

2E Rev. 03/2011

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Direct from ASCO

Oncology’s Only Benchmark Report, National Practice Benchmark, Is Now a Yearly JOP Supplement

W

ould it surprise you to learn that 40% of your peers in oncology who responded to a survey last year have a certified electronic medical record system in place? Or that 86% of them are in physician-owned practices?

Or that the average number of full-time equivalent hematology/ oncology physicians in oncology practices is 7.9?

Thomas R. Barr, MBA

After digesting your copy of National Practice Benchmark, 2011 Report on 2010 Data, none of these metrics will surprise you. A supplement to the November issue of the Journal of Oncology Practice ( JOP), the report contains the results from the only national benchmarking survey that focuses on the specialty of oncology, showing practices’ answers to questions such as: What pressures are impacting your business decisions? How are your drugs purchased or procured? How many staff members do you have, and what are their jobs?

ASCO Journal Apps Now Available for iPad and iPhone

U

New Metrics to Come Out Each Fall The new National Practice Benchmark supplement—which will be in your hands soon—officially kicks off the supplement’s annual status with JOP; going forward, each year a new report will be published along with a fall issue of JOP, providing a handy account of exactly how your peers are handling various sectors of their business, and giving you a tool to help manage your own practice.

Benchmarking is widely recognized as the most efficient way to look for opportunities to improve your practice and then monitor progress after corrective action is taken, said Thomas R. Barr, MBA, founder and General Manager of the Oncology Metrics division of Altos Solutions, which has for 6 years distributed the survey, analyzed the data collected, and published a report summarizing the findings.

sers of the market-leading mobile devices have been able to access optimized versions of the Journal of Clinical Oncology ( JCO) and Journal of Oncology Practice ( JOP) websites since the spring of 2011. Now, iPad and iPhone users can download free JCO and JOP apps from the iTunes store.

Smooth and Intuitive The apps give ASCO members and journal subscribers access to all of the latest clinical research and practice information, while taking discreet advantage of the technology and tools offered on the devices.

Readers can reach an issue’s table of contents with a tap, and scroll through the list of articles smoothly and intuitively. Article content is available in a wide array of useful forms and formats, from abstract and full text, to PDF and

a dedicated figure/table viewer.

Favorite articles can be noted and saved with a single touch, and items of interest can be e-mailed to colleagues easily via an integrated link.

Download the JCO and JOP apps today, for an enhanced and immersive journal experience.

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© 2011. American Society of Clinical Oncology. All Rights Reserved.

Statistics You Can Use “This is for folks interested in looking at the big picture and comparing what’s going on in their practice to what’s going on in other practices,” said Mr. Barr. “It’s a reference that practice administrators and managing physicians find useful in their assortment of tools used internally to improve their own opcontinued on page 28

2012 Gastrointestinal Cancers Symposium Science and Multidisciplinary Management 2012 Gastrointestinal of GI Malignancies

Cancers Symposium

Science and Multidisciplinary Management of GI Malignancies

January 19–21, 2012 San Francisco, California TARG E T I NG

C A NC E R

C A RE

The ASCO Post | NOVEMBER 15, 2011

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Direct from ASCO

National Practice Benchmark continued from page 27

erations.”

This year’s survey was returned by 117 practices in 37 states. The report’s author, Elaine L. Towle, CMPE, who had 25 years of experience in oncology practice management before joining Oncology Metrics as Director of Consulting Services, remarked that the benchmarks for revenue, expenses, and staffing are of particular interest year after year. This year for the first time, Oncology Metrics also asked practices for specifics about spending on information technology.

“We’ve known for several years that the impact of information technology on oncology practices is growing, but like most things, it creeps in slowly.

—Elaine L. Towle, CMPE

“We’ve known for several years that the impact of information

Elaine L. Towle, CMPE

technology on oncology practices is growing, but like most things, it creeps in slowly,” added Mr. Barr.

“Now, with meaningful-use objectives from the federal government requiring a certified electronic medical record, we recognize that this is a full-blown cost department. So we asked, what is your cost to maintain the technology and its connectivity?”

cisions. Interestingly, she said, it was virtually a dead heat between (1) competitive pressures (market competition); (2) cost pressures (drug costs, rent, staff costs, physician compensation, general operating costs); and (3) payer pressures (declining reimbursement rates, contracting, preauthorization/precertification requirements, retrospective denials, audits).

Given the current milieu of lower reimbursement, buyouts by hospitals, uncertainty about the future of Medicare, and general economic uneasiness, Ms. Towle said it was also a little surpris-

Volume 29, Issue 15

Official Journal of the American Society of Clinical Oncology

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al

Practices Identify Current Challenges Another new question this year, said Ms. Towle, centered on business challenges. Survey respondents were asked to rank the pressures that are currently affecting their business de-

ASCO in Action Online: Your Source for Policy News and Information

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

Top 10 most-accessed articles recently published in Journal of Clinical Oncology

JCO.org

1. Prostate Cancer: Evolution or Revolution?

Eric J. Small, et al 29(27): 3595

Andrew H. Ko 29(28): 3727

T

Polling on Policy With reader polling as an added feature on the site, ASCO in Action also gives ASCO members an easy way to help the Society decontinued on page 29

© 2011. American Society of Clinical Oncology. All rights reserved.

JCO

Great Leap Forward?

CEO Allen S. Lichter, MD. “ASCO members have been instrumental in explaining the impact of legislative proposals and public funding on future care and research. To make sure this continues, ASCO in Action gives oncologists and researchers timely information, more in depth analysis on critical issues, and a greater advocacy voice.”

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What’s Hot in

2. FOLFIRINOX: A Small Step or a

he recently enhanced ASCO in Action site ascoaction.asco.org is a one-stop source for the latest policy news related to quality cancer care and research. Whether it is information about legislation that affects cancer patients or oncology practices, easy links to ASCO’s recent policy positions, or a simple way to connect with elected leaders in Congress, ASCO in Action helps members stay informed and advocate for quality cancer care.

“Health-care policy being debated today has enormous implications for both oncology practices and patient health,” said ASCO

ing that many of the respondents said they expected their current business structure to remain unchanged and viable for at least the next 5 years.

“That contradicts what we hear all the time and see in the marketplace, which is that the current practice model that’s out there can’t continue to exist,” said Ms. Towle.

Look for your copy of the National Practice Benchmark with your November issue of JOP.

3. Flaxseed and Breast Cancer: What Should We Tell Our Patients?s Ruth E. Patterson 29(28): 3723

4. Can We Predict Who’s at Risk for Developing Bone Metastases in Breast Cancer?

Larissa A. Korde, et al 29(27): 3600

5. Nonestrogenic Management of Hot Flashes Charles L. Loprinzi, et al 29(29): 3842

6. Should the Presence of Germline BRCA1/2 Mutations Influence Treatment Selection in Breast Cancer?

Mark E. Robson 29(28): 3724 7. The End of an Era: Shall We Move Forward?

Chau Dang 29(29): 3849 8. Lost in Translation: A Fisherman’s Tale Michael J. Overman, et al 29(28): 3832 9. Chek2 DNA Damage Response Pathway and Inherited Breast Cancer Risk Nadine Tung, et al 29(28): 3813 10. The Study of Collaborative Practice Arrangements: Where Do We Go From Here?

Dean F. Bajorin, et al 29(27): 3599

ASCOPost.com | NOVEMBER 15, 2011

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ASCO in Action Online continued from page 28

velop policy positions and explain how various legislative proposals affect quality, access, and care. Recent polls on drug shortages and Medicare’s average sales price were fielded to help ASCO better understand how members feel about several proposed solutions to critical policy priorities.

who need clear, concise, and accurate information about the policy issues that matter the most,” explained Nicholas J. Vogelzang, MD, Chair of ASCO’s Communications Committee.

Stay Informed and Active In addition to its news content

and links, ASCO in Action will provide informational podcasts, videos, and policy forums for ASCO members.

“When it comesB:8.625 to inimproving patient health and cancer care in the T:7.625 in United States, we all have a stake and S:6.75 in an important role to play. Your voice really does matter, and I encourage

you to stay informed and active by regularly visiting ASCO in Action at ascoaction.asco.org, or signing up for ASCO in Action RRS feeds and important news updates,” Dr. Vogelzang said.

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© 2011. American Society of Clinical Oncology. All rights reserved.

Challenges and Opportunities “CurrentJOB#:legislative debate to 10157D control federal presents PROOF#:spending 1 Exelixis enormous CLIENT: challenges and opporDESC: Journal Ad 4C tunities thatColor:could either improve AD: TB quality andTRAFFIC: care EA or hurt patient VV access and OPERATOR: threaten the progress GALLEY#: 1 DATE: 9/19/11 - 8:35made PM against cancer being through CREATED: 9/15/11 - 9:08 PM publicly funded clinical trials,” said FONTS: Neo Sans Pro Medium, Neo Sans Pro Bold, Neo Sans Pro Richard L.Regular, Schilsky, MD, Chair Helvetica Neue LT Std of ASCO’s 77Government Bold Condensed, HelveticaRelations LT Std 47 Light Condensed, Committee.Neue Helvetica Neue LT Std 47 Light Condensedthan Oblique ever, we need “Now, more IMAGES: Exelixis_KO.eps, members who are both informed 10157_JA_twk.tif COLORS: C=24 M=0 Y=98 K=8, and engaged to help policymakers C=0 M=7 Y=80 K=0 NOTES: better understand the implications of DOC PATH: Macintosh the decisions they face,” Dr. Schilsky HD:Users:lakek:Desktop:EXL_ XLX_Q10157D_JA_M01.indd said.

DOC SIZE: 10” X 13” “The interactive PRINT SCALE: 100%capabilities of the new ASCO in Action will greatly benefit busy oncology professionals

Help Your Patients Understand Lung Cancer Despite advances in targeted cancer therapy,

an important escape pathway remains: MET Cosmos Communications 718.482.1800 1 Q1 LS 09.20.11 133 M8

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20402a

id you know that November is Lung Cancer Awareness Month? For an introduction to lung cancer, direct your patients to the fact sheet ASCO Answers: Lung Cancer at www.cancer.net/factsheets. For more detailed information, your patients can read the Cancer.Net Guide to Lung Cancer at www.cancer.net/ lung. If you would like to offer these materials in your office or waiting room, visit www.cancer.net/eStore to order copies.

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Q2

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© 2011. American Society of Clinical Oncology. All rights reserved.

Although advanced antitumor therapies have become available, many tumor types continue to evade treatment.1 Research has identified the MET pathway as one of the most critical escape pathways utilized by tumors. In most normal tissues, MET and its only known ligand, hepatocyte growth factor (HGF), are found in low levels. But in a range of malignancies—including thyroid, prostate, ovarian, lung, and breast cancers—MET is upregulated and drives more invasive and aggressive behavior of tumor cells, resulting in metastasis.2-7 Recent evidence also shows that inhibition of angiogenesis creates hypoxic conditions in the tumor that may further upregulate MET and ultimately promote disease progression.5,7 Exelixis is fully devoted to shutting down MET-driven escape in cancer. Therefore, we are investigating the dual targeting of the MET and VEGF pathways to simultaneously inhibit metastasis and angiogenesis in several cancers.

Visit www.METinhibition.com/asco to learn more about the role of MET in tumor escape.

References: 1. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, based on November 2010 SEER data submission, posted to the SEER Web site, 2011. http://seer.cancer.gov/csr/1975_2008/. Accessed May 10, 2011. 2. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth [draft manuscript]. 2011. Data on file, Exelixis, Inc. 3. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225:1-26. 4. Danilkovitch-Miagkova A, Zbar B. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest. 2002;109:863-867. 5. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3:347-361. 6. Capdevila J, Argiles G, Rodriguez-Frexinos V, Nuñez I, Tabernero J. New approaches in the management of radioiodine-refractory thyroid cancer: the molecular targeted therapy era. Discov Med. 2010;9:153-162. 7. Eder JP, Vande Woude GF, Boerner SA, LoRusso PM. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res. 2009;15:2207-2214.

© 2011 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 09/11

The ASCO Post | NOVEMBER 15, 2011

PAGE 30

54th ASTRO Annual Meeting Genitourinary Oncology

Hypofractionated Radiotherapy Effectively Controls High-risk Prostate Cancer

By Susan Reckling

T

he use of hypofractionated intensity-modulated radiotherapy (IMRT) appears to be a reasonable option for men with intermediate- to high-risk prostate cancer, 1 reported Alan Pollack, MD, Chairman of Radiation Oncology at the University of Miami Miller School of Medicine in Miami and lead investigator of the long-term Fox Chase trial. Five years after treatment, the shorter course of radiation treatment delivered via hypofractionated IMRT (in 2.5 weeks less time) was equally as effective as conventional IMRT in reducing

Alan Pollack, MD

biochemical failure in intermediateto high-risk patients with prostate cancer.

“We are still learning how best to apply hypofractionation, and the results in this trial show that the technique is very effective,” stated Dr. Pollack at the 53rd Annual Meeting of the American Society for Radiation Oncology (ASTRO) Plenary Session.

Between 2002 and 2006, a total of 307 patients took part in the study, with approximately half receiving conventional IMRT (76 Gy in 2.0 Gy fractions) and half receiving hypofractionated IMRT (70.2 Gy in

2.7 fractions). The high-risk patients also received hormone therapy for 2 years. Recurrences were determined by monitoring prostate-specific antigen levels. At 5 years after treatment, there was no significant difference in the rate of biochemical failure in the conventional and hypofractionated IMRT arms (about 22% each).

Rates for locoregional failure/distant metastasis were 1.0% and 1.3%, respectively, for the conventional and hypofractionated IMRT arms at 5 years.

Genitourinary Toxicity The rates of side effects were relatively low for both treatment methods, according to Dr. Pollack.

There were identical long-term rates of bowel/rectal reactions and the frequency of unsatisfactory erections. Although the number of grade 2+ rectal reactions was “quite low,” there was a significant increase in the number of grade 2+ genitourinary reactions among those who received hypofractionation.

At 5 years, 8.3% of patients treated with conventional IMRT experienced late grade 2+ genitourinary reactions, compared with 18.3% of patients treated with hypofractionated IMRT. There also was significantly higher bladder control in the conventionally fractionated arm than patients receiving hypofractionated therapy.

“Late urinary symptoms were higher with hypofractionation but were low overall,” declared Dr. Pollack, “particularly when the incidence of persistent urinary symptoms (< 10% at 5 years) was analyzed.”

Hypofractionated IMRT for Prostate Cancer ■■ Hypofractionated IMRT appears to be equally as effective as conventional IMRT in reducing biochemical failure in intermediate- to high-risk patients with prostate cancer.

■■ Grade 2+ rectal reactions were few, but there was a significantly increased frequency of grade 2+ genitourinary reactions with hypofractionation.

■■ The AUA symptom score may be the most significant predictor of genitourinary reactions.

■■ Good candidates for hypofractionated IMRT would be patients with an AUA score ≤ 10.

EXPERT POINT OF VIEW

T

he take-home message of the study findings from the Fox Chase trial reported at the 53rd ASTRO Annual Meeting plenary session supports the use of hypofractionated intensitymodulated radiotherapy as a more convenient and cost-effective alternative than conventional IMRT, according to formal discussant of this trial Patrick Kupelian, MD, of UCLA Jonsson Comprehensive Cancer Center.

Patrick Kupelian, MD In another positive randomized trial of hypofractionated IMRT for high-risk prostate cancer,1 the hypofractionated schedule was superior to the conventional schedule in terms of freedom from biochemical failure. However, the hypofractionated arm consisted of 62 Gy/20 fractions (3.1 Gy/fraction), whereas in the Fox Chase trial, it was 70.2 Gy in 2.0 fractions. “You might need higher doses per fraction to see changes or differences in efficacy,” Dr. Kupelian speculated.

The issue of late toxicity has been a major concern with hypofractionated IMRT. “A few years back, the concern was always rectal toxicity; amazingly, the events have been very few on this trial,” admitted Dr. Kupelian. Gastrointestinal toxicity was not a concern in this trial, and genitourinary toxicity consisted mostly of grade 2 events. Therefore, echoing the sentiments of Allan Pollack, MD, who presented the Fox Chase trial, Dr. Kupelian considers pretreatment urinary status to be an important predictor of genitourinary toxicity, more so with hypofractionated IMRT than with conventional IMRT.

■

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

Reference 1. Arcangeli G, Saracino B, Gomellini S, et al: A prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer. Int J Radiat Oncol Biol Phys 78:11-18, 2010.

AUA Score In addition, the role of the American Urological Association (AUA) symptom score was briefly explored. The median AUA score of study participants was 5. “We found the AUA symptom score to be the most significant predictor of genitourinary reactions, especially with > 10 being highly predictive of grade 2+ urinary side effects,” revealed Dr. Pollack. With the AUA pretreatment score being a strong determiner of outcome after fractionation, good candidates for hypofractionaed IMRT would have an AUA score ≤ 10.

The study investigators believe that their findings justify the rationale for phase III trials of hypofractionated IMRT in this population with prostate cancer. Similar regimens are

being tested in clinical trials, including the Cleveland Clinic study, and the results are eagerly awaited.

“Although [hypofractionated IMRT] is not yet adopted broadly because of the need for long-term follow-up, hypofractionation is rapidly gaining momentum for many types of cancer,” concluded Dr. Pollack. “The results presented here bring us much closer to effectively treating prostate cancer in a shorter period of time, with acceptable side effects.”

■

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

Reference 1. Pollack A, Walker G, Buyyounouski M, et al. Five year results of a randomized external beam radiotherapy hypofractionation trial for prostate cancer. 53rd ASTRO Annual Meeting. Abstract 1. Presented October 3, 2011.

ASCOPost.com | NOVEMBER 15, 2011

PAGE 31

Journal Spotlight

Tamoxifen vs Surgery Study Shows Older Patients with Breast Cancer Can Achieve a ‘Personal Cure’

By Charlotte Bath

A

truly final review—when all the patients in the trial have died and the cause of death is known for each—of a randomized trial comparing tamoxifen to surgery in patients over the age of 70 with operable breast cancer found no differences in the survival rates or deaths attributable to breast cancer. Patients in both groups continued to die from breast cancer over the 28 years of followup, but “almost two-thirds of the patients in this trial did not die of breast cancer” and thus achieved a personal cure, according to the final report published in the European Journal of Surgical Oncology.1 All trial participants had invasive ductal carcinoma and estrogen receptor (ER)-positive tumors proven at the time or retrospectively with the advent of immunologic assays.

Patients were randomized to two groups of 100 each to receive either tamoxifen, or surgery with wide local excision or partial or total mastectomy. The authors, Jean-Claude Gazet, MSc, FRCS, and Rosemary Sutcliffe of the Combined Breast Clinic, St. George’s Hospital in London, noted that the patients were “treated in an orthodox and ethical way in 1982,” when the trial began, “but now which could be considered outdated.”

‘Not an Alien Concept’ Deaths from breast cancer totaled 40 among the patients initially treated with tamoxifen and 43 among those receiving surgery (Table 1). “Absolute cure of any disease can be defined as when a patient dies from an unrelated condition. Thus it can be stated that 58.5% of this selected group of 200 patients achieved a personal cure from breast cancer,” the authors stated.

“Personal cure is the endpoint for a clinician,” Dr. Gazet explained to The ASCO Post. “However, the general population is well aware that cancer is a fatal condition SEE PAGE 60 and frequently re-

curs with no set time span. So the concept that a cure of cancer is indeed when they succumb to something else is not an alien concept and well understood.”

Crossover and Survival

Table 1: Causes of Death Among Patients Initially Treated With Surgery or Tamoxifen Cause of Death Surgery Cause

Tamoxifen

T1

T2

T3

T4

Total

T1

T2

T3

T4

Total

Breast carcinoma

8

20

12

3

43

3

16

11

10

40

Other carcinoma

1

4

0

1

6

2

5

1

0

8

Cardiovascular

6

12

6

3

27

7

16

2

2

27

Respiratory

2

8

4

0

14

3

9

2

1

15

0

2

0

0

2

2

4

1

1

8

17

52

17

14

100

Among the 79 CNS 1 0 1 0 2 patients (44 in the 4 4 0 0 8 tamoxifen arm, Other 35 in the surgical Total 22 48 23 7 100 arm) with local progression or lo- From Gazet JC, Sutcliffe R: Eur J Surg Oncol 37:754-757, 2011, with permission. cal recurrence as a regarding the management of breast first event without evidence of distant cancer in patients aged 70 and over. metastases, 38 in the tamoxifen arm Clinical practice ranged from inactivagreed to crossover to surgery and 34 ity, palliation or active management in the surgical arm agreed to crossover with endocrine therapy, surgery, rato tamoxifen. The authors reported diotherapy or a combination of all “no difference in survival between these therapies,” the authors noted, those who progressed on tamoxifen adding that “little has changed in and then had surgery or those who the treatment offered to this group recurred after surgery and then were of patients,” and citing more current treated with tamoxifen.” The average analyses of breast cancer treatment in survival times among the crossover the United Kingdom.2,3 “The problem patients were 80 and 83 months, reover the past few decades is that there spectively.

Present clinical practice confirms that there is no reason why age should be a consideration in the management of breast cancer.

“Likewise, there is no difference in survival between those who died of breast cancer having been treated with surgery or tamoxifen compared with those who died of other causes,” the authors noted. “However, when one compares all deaths whatever the cause in both arms of the trial, those who had surgery survived on average up to two years longer than those primarily treated with tamoxifen.”

Implications for Older Patients “Thirty years ago at the inception of this trial there was no consensus

has been a reluctance in the United States and United Kingdom to actively treat patients over 70 actively or in the same way as other groups, in spite of the overwhelming evidence that we have an aging population,” Dr. Gazet stated.

“Present clinical practice confirms that there is no reason why age should be a consideration in the management of breast cancer. If one accepts that the core treatment of breast cancer is a trinity of surgery, chemoendocrine therapy, and radiotherapy, then all patients should be treated only on this

basis,” according to the final report.

“Breast cancer in the elderly is a specific model. The tumours tend to be slow growing and ER positive.

The elderly have a short life expectancy, which allows accurate measurement of the value of any specific treatment,” the authors noted. “It would seem reasonable therefore to concentrate on active and aggressive treatment in the elderly in an attempt to reach a 100% personal cure,” they concluded.

■

Disclosure: Drs. Gazet and Sutcliffe reported no potential conflicts of interest.

References 1. Gazet JC, Sutcliffe R: A randomised trial comparing tamoxifen vs. surgery in patients over the age of 70 with operable breast cancer—final results after 28 years of follow-up. Eur J Surg Oncol 37:754-757, 2011.

2. Cheung S, Greenway N, Lagord C, et al: All Breast Cancer Report: A UK analysis of all symptomatic and screen detected breast cancers diagnosed in 2006. NHS Cancer Screening Programmes, 2009.

Available at http://www.cancerscreening. nhs.uk/breastscreen/all-breast-cancer-report.pdf. Accessed October 27, 2011.

3. UK Statistics Authority: Cancer statistics registrations: Registrations of cancer diagnosed in 2004, England (series MB1, no. 35). London, UK Statistics Authority, 2007.

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

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

These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

Important Safety Information WARNINGS AND PRECAUTIONS:

• Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Due to the risk of QT prolongation, ensure that potassium and magnesium are within the normal range before administration • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • Based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D) • ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).

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

The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%),

thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (n=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (n=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%).

Infections were the most common type of serious adverse event reported in both Study 1 (n=102) and Study 2 (n=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection.

The most common adverse reactions regardless of causality in Study 1 (n=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (n=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%).

DRUG INTERACTIONS: • ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible • Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors • Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives USE IN SPECIFIC POPULATIONS: • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

Introducing choice in treating PTCL ISTODAX® is now indicated for: • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated

Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages.

ISTODAX® is a registered trademark of Celgene Corporation. ©2011 Celgene Corporation 06/11 IST11004T

For more information: Please visit www.istodax.com or call 1-888-423-5436

The ASCO Post | NOVEMBER 15, 2011

PAGE 34

FDA Update

FDA Approves Molecular Test to Detect HPV

G

en-Probe recently announced that the FDA has approved its APTIMA HPV assay, an amplified nucleic acid test that detects high-risk strains of human papillomavirus (HPV) that are associated with cervical cancer and

precancerous lesions. The test has been approved to run on Gen-Probe’s fully automated, high-throughput TIGRIS instrument system.

The APTIMA HPV assay detects 14 high-risk HPV types associated

with cervical cancer and precancerous lesions. Testing is performed from ThinPrep liquid cytology specimens routinely used for Pap testing. Unlike other FDA-approved, DNA-based HPV tests, the APTIMA HPV assay

Only

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a brief summary only; see full prescribing information for complete product information.

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

• Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the therapy.

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

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

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

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

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

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

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

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

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

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

Due to the risk of QT prolongation, potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)].

detects messenger RNA overexpressed from two viral oncogenes that are integral to the development of cervical cancer.

“Most HPV infections clear up on their own, so it’s important to identify

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

5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. A study in rats did not expose pregnant animals to enough romidepsin to fully evaluate adverse outcomes.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)].

5.6 Use in Women of Childbearing Potential Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives. An in vitro binding assay determined that romidepsin competes with ß-estradiol for binding to estrogen receptors [See Nonclinical Toxicology (13.1)].

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

Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2.

The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1.

Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1.

Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) (continued)

ASCOPost.com | NOVEMBER 15, 2011

PAGE 35

FDA Update

those persistent, high-risk infections that are most likely to lead to cervical cancer,” said Tom Wright, MD, Professor of Pathology and Cell Biology at the Columbia University Medical Center. “In numerous clinical studies involving approximately 45,000 women, the APTIMA HPV assay has consistently shown similar sensitivity

and better specificity than the most frequently used DNA-based test.”

The APTIMA HPV assay is approved to test women age 21 and older

Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8)

Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%).

Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome.

Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesemia.

Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsorconducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles.

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

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

whose Pap tests showed atypical squamous cells of undetermined significance and to screen women age 30 and older as an adjunct to Pap testing.

FDA approval was based on data from the CLEAR (CLinical Evaluation of APTIMA HPV RNA) trial, which analyzed approximately 11,000 women undergoing routine Pap test-

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

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

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

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

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

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

7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors.

Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital)

ing at 18 U.S. clinics. In the study, the APTIMA HPV assay showed similar sensitivity for the detection of cervical disease as an FDA-approved, DNA-based test. However, the specificity of the APTIMA HPV assay was higher than that of the DNA-based test, and this advantage was statistically significant.

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The ASCO Post | NOVEMBER 15, 2011

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FDA Update

VGX-100 Investigational New Drug Application Approved

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he Australian biotechnology company Circadian Technologies announced that its subsidiary, Vegenics Pty Ltd, has received approval for its investigational new drug (IND) application from the FDA to initiate clinical trials of VGX-100. The first phase I trial

will study VGX-100 in patients with a variety of late-stage cancers.

VGX-100 is a human antibody that acts against the human vascular endothelial growth factor (VEGF)-C protein. Treatment for cancers, particularly glioblastoma and metastatic colorectal

may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort.

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

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

There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. A study in rats did not expose pregnant animals to enough romidepsin to fully evaluate adverse developmental outcomes. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential harm to the fetus.

In an animal reproductive study, pregnant rats received daily intravenous romidepsin during the period of organogenesis up to a dose of 0.06 mg/kg/day (0.36 mg/m2/day). This dose in rats is approximately equivalent to 18% the estimated human daily dose based on body surface area and resulted in 5% reduction in fetal weight. Embryofetal toxicities associated with the use of ISTODAX were not adequately assessed in this study.

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

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

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

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

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

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

Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of endstage renal disease on romidepsin pharmacokinetics has not been studied.

Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)].

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

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

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

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.

Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal

cancers, are the first target indications for VGX-100. Additionally, Circadian is developing VGX-100 for a number of other cancer indications, and as an agent to treat front-of the-eye diseases.

Studies in animal model studies across a wide range of tumor types

vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose.

Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.

16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [See References (15)].

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling.

17.1 Instructions • Nausea and Vomiting Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients.

Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)].

• Low Blood Counts Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)].

• Infections Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flulike symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2)].

• Tumor Lysis Syndrome Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)].

• Use in Women of Childbearing Potential If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling.

ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogencontaining contraceptives [See Warnings and Precautions (5.6)].

• Patients should be instructed to read the patient insert carefully.

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 ISTODAX® is a registered trademark of Celgene Corporation U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBVPI.002/PPI.002 06/11

have shown that when combined with bevacizumab (Avastin) and chemotherapy, VGX-100 can significantly reduce tumor growth and spread as well as significantly improve tumor inhibition, over and above that of bevacizumab and/or chemotherapy alone.

Recent studies have also implicated VEGF-C as a key mediator of disease progression during bevacizumab treatment, implying that combination therapy with VGX-100 and bevacizumab could significantly improve treatment outcomes in cancer patients.

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Test for AML Prognosis Cleared by FDA

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bbott announced today it has received 510(k) clearance from the FDA for a new in vitro diagnostic test to aid in determining the prognosis of patients with acute myeloid leukemia (AML) Abbott’s Vysis EGR1 FISH Probe Kit, the third Abbott fluorescence in situ hybridization (FISH) assay approved or cleared in the past 2 months by the FDA for oncology applications, detects a chromosomal deletion in bone marrow that is usually associated with an unfavorable prognosis for AML patients.

Published reports from several large clinical studies and the National Comprehensive Cancer Network guidelines suggest that chromosomal abnormalities associated with AML are valuable prognostic indicators. One study, conducted as part of an Eastern Cooperative Oncology Group (ECOG) clinical trial, demonstrated the utility of FISH technology to separate AML patients into risk categories based on chromosomal status or changes. Based on these categories, physicians are able to establish an effective disease management approach.

The Vysis EGR1 FISH Probe Kit is intended to detect deletion of LSI EGR1 probe target on chromosome 5q in bone marrow specimens and may be used, in addition to cytogenetics, other biomarkers, morphology and other clinical information, at the time of AML diagnosis as an aid in determining prognosis. Deletion of chromosome 5q has been associated with an unfavorable prognosis in AML patients.

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Drug Development

Biosimilars in Cancer Treatment: What Should the Oncology Community Expect?

By Caroline Helwick

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lternative versions of biologic agents, ie, “biosimilars,” will presumably be getting the green light by the FDA, giving oncologists more choices for treatments that come at lower costs to patients and society.

The FDA plans to issue its guidance on biosimilars by the end of this year, paving the way for drug development.

The National Comprehensive Cancer Network (NCCN) recently published a white paper written by a panel of stakeholders who identified key issues relevant to oncology.1 NCCN Guidelines panels will be evaluating data and, when appropriate, will incorporate biosimilars into guidelines.

The ASCO Post asked Gary Lyman, MD, MPH, who served on the NCCN white paper panel and recently coauthored an article on the topic,2 to describe the emerging landscape. Dr. Lyman is Director of Comparative Effectiveness and Outcomes Research at Duke University School of Medicine and Senior Fellow at the Duke Center for Clinical Health Policy Research.

Some recombinant protein drugs are a multibillion dollar global market. If it costs a few hundred million to do a phase III noninferiority trial and tap into this market, of course it could be worth it to industry.

—Mark Pegram, MD

Biosimilars vs Generics: The Hurdles Biosimilars are not generics.

Whereas generic agents duplicate the original product and can be produced with some consistency, it is technically unfeasible to make an exact copy of a biologic agent. Their production process is also proprietary; therefore, a company manufacturing a biosimilar must develop its own process. This can result in inadvertent chemical modifications that

may not produce clinically meaningful differences but could alter immunogenicity or other attributes, Dr. Lyman noted.

“Whether companies will be required to show comparability or true interchangeability remains to be seen,” Dr. Lyman said. Pharmacokinetic equivalence does not ensure comparability, and interchangeability is an even more stringent requirement, mandating that the new agent provide the same clinical result in any given patient. “Clearly,” he noted, “this is a high bar.”

It is believed that large phase III trials may be mandated, probably powered for noninferiority with the original product. This would mean an enormous investment for interested companies, “especially if the goal is to bring down the cost of drugs,” Dr. Lyman added.

Mark Pegram, MD, Professor of Medicine and Associate Director for Clinical Research, Sylvester Comprehensive Cancer Center at the University of Miami (Florida) Health System, suggested that the cost of conducting clinical trials would be offset by the potential for enormous profit.

“Some recombinant protein drugs are a multibillion dollar global market.

If it costs a few hundred million to do a phase III noninferiority trial and tap into this market, of course it could be worth it to industry. Even if the margins are thin, there is still a huge upside for the right investment,” Dr. Pegram maintained.

When to Expect Biosimilars Biosimilars will enter the marketplace as patents for agents near expiration. First among these are the hematopoietic growth factors and erythropoiesis-stimulating agents, for which biosimilars have already been approved in Europe. The European Union in 2004 introduced a new regulatory path for biosimilars and approved the first biosimilar in 2006.

Active treatment agents will follow, with rituximab the first monoclonal antibody biosimilar expected to be approved in Europe. Teva Pharmaceuticals announced it has an agent set to begin clinical trials in anticipation of the Rituxan patent expiration

in 2013.

“In the United States, we are still waiting for final FDA rules on what will be required for approval,” Dr. Lyman said.

The FDA is struggling to reconcile the science of biosimilar development with the new regulatory framework required by the Biologics Price Competition and Innovation (BPCI) Act of

gists’ comfort and experience with the older agent may influence decisions in clinical practice, Dr. Lyman maintained. “A large-scale move to biosimilars is not a foregone conclusion,” he said.

Dr. Pegram agreed. “Oncologists will be concerned about the safety of biosimilars. They will want to ensure that the chemistry, manufacturing,

Whether companies will be required to show comparability or true interchangeability remains to be seen.

­—Gary Lyman, MD, MPH

2009. The BPCI authorized the FDA to oversee an “abbreviated pathway” for approval of these agents. The many challenges were recently described in a New England Journal of Medicine article.3 “The FDA process for biosimilarity must consider the product’s complexity, its formulation, its stability, and the usefulness of biochemical and functional characterizations and incorporate these factors into a riskbased approach,” the authors noted.

“This is new territory for the FDA,” Dr. Lyman noted. “They may pull in external or expert consultants to help figure this all out.” The agency is expected to finalize regulations by the end of this year, which means some biosimilars could emerge on the market early next year, unless new clinical trials are mandated.

A number of companies are gearing up. Hospira, a leader in generic injectable drugs, recently announced the start of a U.S. phase I clinical trial of its biosimilar erythropoietin in patients with renal dysfunction, comparing Amgen’s epoetin alfa (Epogen) and Hospira’s erythropoietin. Hospira already sells biosimilar versions of erythropoietin and filgrastim in Europe.

Oncologists’ Concerns To what extent providers will embrace biosimilars is unclear. Oncolo-

and composition are on par with the labeled product,” he noted.

“I am sure the FDA, clinicians and patients themselves will be in tune with the safety issue and will be relying on very high quality controls,” he continued. “And I suspect the FDA will require noninferiority trials to assure not only safety but evidencebased efficacy.”

History supports their concern. “In Canada, a modification in a single amino acid chain SEE PAGE 60 of erythropoietin caused deaths from pure red cell aplasia. We can’t afford to repeat this catastrophe,” he said.

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Disclosure: Dr. Lyman is principal investigator on a research grant to Duke University from Amgen. Dr. Pegram reported no potential conflicts of interest.

References 1. Zelenetz AD, Ahmed I, Braud EL, et al: NCCN Biosimilars White Paper: Regulatory, Scientific, and Patient Safety Perspectives. J Natl Compr Canc Netw 9 Suppl 4:S1-S22, 2011.

2. Hirsch BR, Lyman GH: Biosimilars: Are they ready for prime time in the United States? J Natl Compr Canc Netw 9:934-943, 2011.

3. Kozlowski S, Woodcock J, Midthun K, et al: Developing the nation’s biosimilars program. N Engl J Med 365:385-388, 2011.

The ASCO Post | NOVEMBER 15, 2011

PAGE 38

Awards

American Society of Hematology Recognizes Christoph Klein, MD, PhD, with William Dameshek Prize

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he American Society of Hematology (ASH) will honor ­Christoph Klein, MD, PhD, of Children’s Hospital, Ludwig-Maximilians University in Munich, Germany, with

the 2011 William Dameshek Prize, at the upcoming Annual Meeting in San Diego.

Dr. Klein is being recognized by ASH for his many groundbreaking

contributions to hematology, including his landmark discovery of mutations in HAX1 genes in patients with severe congenital neutropenia (Kostmann disease) and his discovery of

­Christoph Klein, MD, PhD

human P14/ROBLD3 deficiency and G6PC3 deficiency, genetic defects that can cause severe congenital neutropenia.

Dr. Klein is Chair of Pediatrics at the Dr. von Hauner Children’s Hospital at Ludwig-Maximilians University.

Profound Impact on Medicine “The Society is honored to present this award to Dr. Klein for his pioneering research into the pathophysiology of rare diseases, which has had a direct and profound impact on clinical medicine,” said ASH President J. Evan Sadler, MD, PhD, of the Washington School of Medicine in St. Louis. “His discoveries have advanced our understanding of diseases that, until recently, were not well-understood, providing new hope to patients.”

Dr. Klein and his team’s recent contributions to hematology include his discovery that genetic mutations affecting the interleukin-10 receptor are associated with severe early-onset inflammatory bowel disease, leading him to use a stem cell transplant that successfully put one child’s inflammatory bowel disease into remission. A second recent accomplishment includes Dr. Klein’s application of gene therapy to treat Wiskott-Aldrich Syndrome, which succeeded in correcting symptoms of this rare, inherited disorder in 9 out of 10 children in a clinical trial.

What role may MUC1 play in NSCLC

It’s well-known that mucins protect healthy cells, but did you know that aberrant overexpression of mucin 1 (MUC1) by tumor cells may play a role in tumor cell survival?1-3 At EMD Serono, we’re investigating the significance of MUC1 and its impact on your patients with NSCLC.

About the Award

110715-130123

Visit www.emdserono.com to learn more about EMD Serono Oncology.

The William Dameshek Prize is named after the late William Dameshek, MD, a renowned hematologist, past president of ASH, and first editor of ASH’s journal Blood. It is awarded to an individual who has made a recent outstanding contribution to the field of hematology. The award will be presented to Dr. Klein on Tuesday, December 13, during the 53rd ASH Annual Meeting and Exposition.

1. Ahmad R, Raina D, Joshi MD, et al. MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res. 2009;69(17):7013-7021.

2. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42): 5667-5677. 3. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816.

EMD Serono Oncology | Combination is key™

EMD Serono, Inc. is an affiliate of Merck KGaA, Darmstadt, Germany

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AACR Frontiers in Basic Cancer Research Investigators Unlocking the Mysteries of Merkel Cell Carcinoma

By Barbara Boughton

esearchers at the University of Pittsburgh Cancer Institute have documented the molecular activity through which the Merkel cell polyomavirus contributes to 80% of cases of Merkel cell carcinoma—a finding that

holds promise for future therapies. The researchers are now working on testing more than 1,350 drugs to identify better methods to treat Merkel cell carcinoma, according to Patrick Moore, MD, MPH, who presented the University of Pittsburgh findings at the Second American Association for Cancer Research (AACR) Frontiers in Basic Cancer Research meeting in San Francisco.

“Our findings hold promise for development, in the near future, of rational chemotherapeutic targeting of Merkel cell carcinoma, an enigmatic and severe cancer,” Dr. Moore said.

uitous—everyone carries it in their skin.

“But if this is a ubiquitous infection and everyone is infected, why is Merkel cell carcinoma so rare?” Dr. Moore asked.

The researchers have recently made discoveries about the inner workings of the virus that help explain how it might transform healthy cells into cancer cells that result in skin cancer. When a patient develops T-cell immune deficiencies such as HIV, the virus increases its replication, making it more likely to fragment and integrate into the host cell. Normally, activities of the virus itself would kill the host cell. But if part of the T antigen of the virus is also mutated, uncontrolled viral oncogene expression can drive tumor cell proliferation, Dr. Moore explained. One of the viral oncogenes, called small T antigen, activates synthesis of cellular oncoproteins through a process called cap-dependent translation.1 Unlike other animal polyomaviruses that have served as classic models of cancer, MCV small T antigen’s targeting of cap-dependent translation can cause abnormal cell growth even after abolishing its ability to target PP2A and heat-shock proteins.

In the 3 years since discovering MCV, Dr. Moore and his colleagues have identified several unique characteristics of the virus.

Merkel Cell Polyomavirus

Unexpected Mechanisms

In 2008, Dr. Moore, his wife Dr. Yuan Chang, and their colleagues discovered Merkel cell polyomavirus (MCV), the virus that causes Merkel cell cancer. Only seven viruses are known to cause human cancers. This is the second human tumor virus discovered by Moore and Chang, after also discovering the virus causing Kaposi’s sarcoma in 1994. They then found that when MCV undergoes specific mutations, often in immunodeficient patients, it can generate Merkel cell carcinoma. These findings have now been verified in multiple studies.

In the past year, researchers have also found that the Merkel cell virus is ubiq-

“MCV induces cell transformation in unexpected ways, and Merkel cell carcinoma has been difficult to treat,” Dr. Moore said. “Discovery of the molecular causes of this cancer provides opportunities to directly target the cellular pathways that are perturbed by the virus.”

MCV is a member of a family of viruses capable of causing multiple tumors in animal models. “In the past 4 years, genomic technologies have led to discovery of six polyomaviruses besides MCV,” Dr. Moore said. “Prior to these discoveries, the only known human polyomaviruses were JC virus, which causes progressive multifocal leukoencephalopathy, and BK virus, which pri-

Patrick Moore, MD, MPH

Causes and Treatments for Merkel Cell Carcinoma ■■ Researchers have discovered unique characteristics of the Merkel cell

polyomavirus and how it promotes cancer in immunodeficient patients.

■■ Researchers are now investigating more than 1,300 drugs to find candidates for targeting Merkel cell carcinomas.

Impact of Basic Science Advances on Cancer Management Highlighted at AACR Conference

N

ew research in basic science labs coupled with advanced information technology is leading to a more sophisticated understanding of the causes of cancer, how it progresses, and potential methods of treatment, said Elizabeth H. Blackburn, PhD, Nobel Laureate and Chairperson of the Second Annual American Association for Cancer Research (AACR) International Conference on Frontiers in Basic Cancer Research, held recently in San Francisco. Such Elizabeth H. Blackburn, PhD basic research insights as well as novel methods of diagnosis and early research on potential treatments were showcased at the AACR conference. ”We’ve known for years that cancer is a complex set of diseases,” said Dr. Blackburn, Morris Herztein Professor of Biology and Physiology in the Department of Biochemistry and Biophysics at the University of California, San Francisco, and recipient of the 2009 Nobel Prize in Physiology or Medicine.

“Along with the sophistication of the science, conceptual research is advancing rapidly, moving ahead in ways that it hasn’t done before. It’s time for a new generation of cancer scientists to step out of their immediate research interest and look at what else is happening.”

As well as showcasing new research in the basic sciences, the AACR Frontiers in Basic Cancer Research conference exposed participants to new ideas about diagnosis and treatment. “Participants were clearly interested in thinking about things in ways they hadn’t previously considered. I’ve seen all sorts of interesting collaborations develop in real time,” Dr. Blackburn said. © Elisabeth Fall/fallfoto.com

R

Technology-driven Progress Dr. Blackburn noted that conference presentations dealt not only with tumor genetics and the molecular pathways that drive the oncogenic process, but also new imaging technologies in early development, which may be useful for early detection of tumors deep within the body. Technology-driven advances have enabled researchers to grapple with the disease in ways they could not have imagined as recently as 5 or 10 years ago, Dr. Blackburn said.

Molecularly targeted drugs are one example. “We’re clearly seeing how cancer alters blood vessel systems in ways that significantly affect the actions and efficacy of these drugs,” Dr. Blackburn said. The AACR conference was meant to provide information about some of the new insights into the cancer process that might result in exciting treatments in the near future, according to Dr. Blackburn. “It’s time for us to take advantage of our sophisticated knowledge about cancer in order to benefit the next generation of cancer treatment and research,” she said.

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

mary causes kidney and bladder disease among transplant patients.

“MCV, a natural component of human skin, is the first polyomavirus consistently associated with human cancer,” he said. “It is part of our flora and only causes cancer when a precise set of mutations occur in this otherwise harmless virus rather than the host cell. This is a new an unexected way for cancers to arise.” Discovery of six more human polyomaviruses opens the possibility

that still more cancers may be caused by this previously unknown and unrecognized group of viruses.

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Disclosure: Drs. Moore and Chang have patents related to MCV that they have assigned to the University of Pittsburgh.

Reference 1. Shuda M, Kwun HJ, Feng H, et al: Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator. J Clin Invest 121:3623-3653, 2011.

Oncology with soul At Eisai, human health care is our goal.

We give our first thoughts to patients and their families, and to increasing the benefits healthcare provides. Our therapies and diverse oncology pipeline are designed to make a difference and have an impact on patients’ lives. We are Eisai, where oncology is more than just our business—it’s our passion.

CORP82

©2011 Eisai Inc.

All rights reserved.

May 2011

www.Eisai.com/us

ASCOPost.com | NOVEMBER 15, 2011

PAGE 41

2011 European Multidisciplinary Cancer Congress Chemotherapy Generally Safe in Pregnancy

Fetal exposure to chemotherapy does not worsen outcomes.

By Caroline Helwick

T

he diagnosis of cancer in a pregnant woman causes concerns for both the mother and her unborn child. But studies suggest that most chemotherapy regimens can be delivered with reasonable safety after the first trimester. Cancer is diagnosed in about 1 per 1,000 to 2,000 pregnancies, mostly breast cancer, cervical cancer, and hematologic malignancies.

At the 2011 European Multidisciplinary Cancer Congress in Stockholm, George Pentheroudakis, MD, of the University of Ioannina in Greece, told attendees at the Presidential Session, “In addition to retrospective evidence, there is emerging prospective evidence that the mid- and long-term health of children born to mothers receiving chemotherapy after the first trimester is normal.”

Multicenter Prospective Study The prospective study to which Dr. Pentheroudakis referred was reported

C

at the Stockholm meeting by Frederic Amant, MD, of the University Hospitals Leuven in Belgium.1 “Fear of chemotherapy is not an indication to terminate pregnancy and not a reason to delay maternal treatment for cancer,” Dr. Amant agreed, based on the findings of a multicenter prospective study of 70 children exposed prenatally to chemotherapy (anthracycline-based in 78%). Children were examined at birth, 18 months, age 5 to 6, and every 3 years thereafter until age 18. The study is ongoing, and median follow-up is 22 months.

Testing comprised a clinical neurologic examination and age-appropriate testing of cognitive function (Bayley Scales of Infant Development, IQ test), learning, memory, behavior, and so forth. Children also received electro/ echocardiography and audiometry.

A total of 236 cycles of chemotherapy were administered during 68 pregnancies. Median gestational age

EXPERT POINT OF VIEW

hemotherapy delivered in the first trimester is associated with a 10% to 30% risk of abortion and 10% to 25% risk of malformations. Therefore, it should be postponed until the second or third trimester, when most regimens appear to be safe, according to Nicholas Pavlidis, MD, of the University of Ioannina in Greece, who is coauthor of Cancer and Pregnancy (Springer, 2008). At a lecture during the 2011 European Multidisciplinary Cancer Congress, Dr. Pavlidis offered his principles for Nicholas Pavlidis, MD safely giving chemotherapy to pregnant women: ■■ Medical oncologists should treat the mother and protect the fetus.

■■ Chemotherapy should not be allowed during the first trimester.

■■ Methotrexate should be avoided entirely.

■■ Endocrine therapy should also be avoided; tamoxifen has been associated with congenital defects in anecdotal reports.

■■ Targeted small molecules and monoclonal antibodies should be avoided due to lack of documented safety; trastuzumab (Herceptin) has been linked to an increased risk of maternal and fetal adverse outcomes.

■■ Risks associated with bisphosphonates are not clear, and therefore, they should be avoided.

Dr. Pavlidis referred oncologists to the recent recommendations of the European Society of Medical Oncology for the treatment of pregnant patients with malignancies.1

■

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

Reference 1. Pentheroudakis G, Orecchia R, Hoekstra HJ, et al: ESMO Guidelines Working Group. Cancer, fertility and pregnancy: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Ann Oncol 21(suppl 5):v266-v273, 2010.

at diagnosis was 18 weeks, and median gestational age at birth was 35.7 weeks; 9% were born between 32 and 34 weeks, and 7% between 28 and 32 weeks. Median birth weight was 2,612 g, and intrauterine growth retardation was observed in 21%.

Normal-range Outcomes The neonatal neurologic examination was normal in 64 infants (91.4%), and congenital malformations and other health problems did not occur in excess of the general population. The childrens’ behavior, general health, hearing, and growth during follow-up were also within normal ranges, and they demonstrated “age-adequate” neurologic development and cardiac function, Dr. Amant reported.

However, in children born prematurely, some impairment in cognitive development was recorded. Neurocognitive impairment (< 2 SD below the mean) was observed in 2% of children of gestational age ≥ 34 weeks but in 19% of those born at < 34 weeks.

“We have to take care to reduce iatrogenic prematurity,” he commented.

Hearing loss was documented in three children. Cardiac testing revealed no congenital heart malformation and normal functional parameters. Twins born prematurely constituted the “outliers” with serious mental/motor retardation and developmental delay, but a genetic syndrome was believed responsible for this.

Body of Data for Safety Dr. Pentheroudakis said the current study fits with what has been observed in retrospective studies.

In the European Registry of 315 pregnant women with breast cancer, those who received chemotherapy (51%) had neonatal outcomes no different from those who did not. Loibl et al2 concluded, in their report at the 2010 CTRC-AACR San Antonio Breast Cancer Symposium, “Pregnant patients with breast cancer should be treated as closely as possible to standard recommendations. Early delivery with the risk of prematurity of the newborns is unnecessary.”

Hahn et al3 evaluated 57 children exposed to CAF (cyclophosphamide, doxorubicin, fluorouracil) after the first trimester and found normal cogni-

tive and intellectual development and general health at 38 months, although two malformations were seen in three preterm deliveries. Aviles et al followed into adulthood 81 children exposed to anthracyclines4 and another 84 children whose mothers had hematologic malignancies (38 exposed to chemotherapy during the first trimester)5 and found all outcomes normal.

As for the current study, its strengths were its “meticulous methodology, large sample size for a rare clinical situation, cardiology follow-up in all patients, and neurocognitive tests in the majority,” Dr. Pentheroudakis said. However, he noted the follow-up period is short, and few children were observed long-term. Participation was refused for eight patients, and their neurocognitive status is unknown. Details were also lacking as to the mother’s cancer and treatment, and the cause of prematurity in 16 children.

“The take-home message is that abortion beyond the first trimester is not necessary and does not seem to improve maternal outcomes,” he said.

“The fetal risks, if any, do not outweigh the maternal risks stemming from no treatment, although prematurity is associated with neurocognitive impairment and should be avoided if possible.”

■

Disclosure: Drs. Pentheroudakis and Amant reported no potential conflicts of interest.

References 1. Amant F, Van Calsteren K, Halaska M, et al: Cognitive and cardiac outcome after prenatal exposure to chemotherapy in children 18 months or older. European Multidisciplinary Cancer Congress. Abstract 12LBA. Presented September 27, 2011.

2. Loibl S, Amant F, Kaufmann M, et al: 313 patients with breast cancer during pregnancy—results from a prospective and retrospective registry (GBG-20/ BIG02-03). Abstract S6-2. Breast Cancer Res Treat 70(24 suppl):91s, 2010.

3. Hahn KM, Johnson PH, Gordon N, et al: Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero. Cancer 107:1219-1226, 2006.

4. Aviles A, Neri N, Nambo MJ: Longterm evaluation of cardiac function in children who received anthracyclines during pregnancy. Ann Oncol 17:286-288, 2006.

5. Aviles A, Neri N: Hematological malignancies and pregnancy: A final report of 84 children who received chemotherapy in utero. Clin Lymphoma 2:173-177, 2001.

The ASCO Post | NOVEMBER 15, 2011

PAGE 42

Expert’s Corner

Geriatric Oncology, a Much Needed Discipline for Future Cancer Care

By Ronald Piana

T

he U.S. health-care system, with its rapidly aging population, faces a multitude of difficult clinical and financial challenges in caring for its burgeoning population of older patients with cancer. Moreover, age-related social and medical issues among older patients need to be addressed by a multidisciplinary approach, increasing the demand for oncologists who specialize in geriatric care.

A large question looms over the cancer community: With an impending oncology workforce shortage, will there be ample geriatric oncologists to care for the special needs of our elderly patients?

He cited overly strict inclusion criteria and lack of motivation to enroll older patients into trials as two reasons for this lack of participation. “However, another reason for lack of participation falls on the shoulders of physicians, many of whom are unjustifiably concerned about subjecting their older patients to treatment-related toxicities,” said Dr. Muss.

He pointed out that studies in geriatrics show that many older patients with cancer want access to the cuttingedge treatments afforded by clinical trials, and that with proper safety parameters, they fare just as well as their younger counterparts.

Education Needed The relatively new discipline of geriatric oncology remains challenged by misperceptions about treating older patients. “The average age of a patient with cancer in the United States is 66, and yet our age perception of cancer doesn’t really correspond with the reality. The view of patients with cancer presented in mass media is much younger—you rarely see an older patient in an advertisement,” said geriatric oncologist Hyman Muss, MD, speaking with The ASCO Post.

“The fact that 60% of cancer survivors in our nation are aged 65 years and older presents challenges that we need to address, in part, by educating physicians to recognize the special issues that pertain to older patients with cancer.

For instance, we don’t know how older people will respond to the newer chemotherapy regimens and biologics that have been tested in younger patients,” explained Dr. Muss.

According to Dr. Muss, despite the fact that they make up the majority of our cancer population, geriatric oncology patients are sorely underrepresented in cancer clinical trials. Studies looking at a number of demographic and socioeconomic factors show that patients aged 65 and older are less likely to be offered access to clinical trials. “That is a clear example of age bias,” said Dr. Muss.

Put simply, Dr. Muss contends that knowing what a patient is capable of doing—basic functional status—is the first step in evaluating proper qualityof-life measures. “Can the patient drive, cook, dress herself; is the family structure solid? A lot of oncologists have not learned how to do simple assessments of the elderly,” said Dr. Muss.

psychological problems such as anxiety, depression, and delirium. “We’ve developed effective tools to determine whether elderly patients are experiencing psychological problems, and we have good medications to treat these problems. It’s important to realize that older patients have different life expectations and concerns than patients who are still working and rearing a family. As doctors, we can

Geriatric Oncology and the Special Needs of Older Patients ■■ The average age of a U.S. patient with cancer is 66, yet the elderly remain underrepresented in clinical trials, in part, due to age bias.

■■ The definition of an “elderly” patient should be determined by functional age rather than chronologic age.

Age Barriers

Hyman Muss, MD

Quality-of-life Measures

Dr. Muss opined that although we have made progress in addressing issues of age bias, the phenomenon still exists within the cancer care community. He acknowledged that treatment decisions are more difficult in older patients, many of whom are frail and have serious comorbidities. “But if a 75-year-old patient with breast cancer is otherwise fit, she should be offered the same treatment options as a younger woman,” stressed Dr. Muss.

For instance, data indicate that older women with breast cancer are less likely to be offered treatment options such as lumpectomy or postoperative breast irradiation. “All of these women don’t need all of these treatment options, but a certain percentage do, and they shouldn’t be shortchanged because of age-only criteria,” said Dr. Muss.

Dr. Muss stressed that proper doctor-patient conversations about health-assessment and treatment goals are key to achieving optimal outcomes.

■■ More age-specific education and training, including an understanding of

comprehensive geriatric assessment (CGA) tools, is needed for oncologists to address the special needs of elderly patients.

■■ Elderly patients have different expectations than younger patients; knowing what these are helps tailor treatments.

He suggests implementing one of the various comprehensive geriatric assessment (CGA) instruments that are currently available. “A geriatric assessment tool helps the physician determine what therapies the patient will be able to undergo and benefit from,” said Dr. Muss.

Assessment instruments are also important tools in quality-of-life issues such as pain management. “Opioid fear among geriatric patients is another problematic issue, said Dr. Muss, adding, “Unwarranted alarm of addiction can lead patients to reject or neglect to adhere to opioid regimens.”

Dr. Muss said that any pain assessment must be tailored to the way in which age affects how a body processes drugs.

Changes in metabolic rates and blood

The fact that 60% of cancer survivors in our nation are aged 65 years and older presents challenges that we need to address, in part, by educating physicians to recognize the special issues that pertain to older patients with cancer.

—Hyman Muss, MD

“We need to analyze our elderly patients as individuals and be cognizant of the fact that age cannot be calculated as just a chronologic number.

Rather, we need to consider the way an individual’s health is related to his age-related physiologic and functional status,” commented Dr. Muss.

flow affect how geriatric patients absorb and eliminate opioids. “Also, because elderly patients usually take several medications, there is an increasing risk of toxicity and adverse drug interactions when managing their pain,” said Dr. Muss.

Proper symptom management should also include the assessment of

learn a lot from our elderly patients as we treat them; we just need to listen.”

A Career Change Dr. Muss said that he entered the field of geriatric oncology about 15 years ago, largely due to a request by pioneering geriatrician William Hazzard, MD, then department chair at Wake Forest University. “Dr. Hazzard asked me to work with a medical resident on a retrospective review of what was one of the first detailed breast cancer databases, comparing outcomes of women with metastatic breast cancer who received older agents vs outcomes using modern chemotherapy regimens, by age,” said Dr. Muss.

Early skepticism about the worth of the project was met with career-changing results. “Fortunately, we had data from trials that did not have an upper age limit, and we compared outcomes of older women with advanced disease to those of younger patients with breast cancer.

To our pleasant surprise, there was no difference in response rates among the different age groups,” explained Dr. Muss.

While preparing a subsequent manuscript that was accepted for publication in JAMA, Dr. Muss said that he became aware of how interesting and relevant the experience had been. “I was hooked. After a career as a breast cancer specialist I had reinvented myself as a geriatric oncologist.”

■

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

Finally in metastatic melanoma A PERSONALIZED

TREATMENT has come together

1

Introducing the first and only personalized treatment for unresectable or metastatic melanoma with the BRAFV600E mutation1,2

DECODE

metastatic melanoma

Indication and Usage ZELBORAF™ (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test.

ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma.

Important Safety Information Cutaneous squamous cell carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF. The incidence of cuSCC in ZELBORAF-treated patients in the Phase III study was 24%. The median time to first appearance of cuSCC was 7 to 8 weeks.

Potential risk factors included age ≥65 years, prior skin cancer, and chronic sun exposure.

All patients should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months following discontinuation of ZELBORAF. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care.

Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe reactions may include generalized rash and erythema or hypotension.

Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including 1 case of Stevens-Johnson syndrome and 1 case of toxic epidermal necrolysis in the Phase III study.

ZELBORAF treatment should be permanently discontinued in patients who experience a severe hypersensitivity or dermatologic reaction.

QT prolongation Exposure-dependent QT prolongation has been observed in patients treated with ZELBORAF, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes.

Treatment is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking medicines known to prolong the QT interval.

ECG and electrolytes should be monitored before initiating treatment with ZELBORAF and after dose modification and routinely during treatment (15 days after treatment initiation then monthly for first 3 months of treatment and every 3 months thereafter or as clinically indicated). If the QTc exceeds 500 ms, ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms. Permanent discontinuation is recommended if, after correction of associated risk factors, the QTc increase meets both a value of >500 ms and >60 ms change from pre-treatment values.

Liver laboratory abnormalities Liver laboratory abnormalities have occurred with ZELBORAF. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated.

Lab abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation.

Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials.

While taking ZELBORAF, all patients should be advised to avoid sun exposure and, when outdoors, to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥30). For intolerable grade 2 or greater photosensitivity, dose modifications are recommended.

Ophthalmologic Reactions In the Phase III study, 5 cases of uveitis were reported in patients treated with ZELBORAF.

EXTEND

survival

56% reduction in risk of death from any cause with ZELBORAF (95% CI, 0.33-0.59)

P<0.0001

OS=overall survival HR=hazard ratio CI=confidence interval * Median follow-up was 6.2 months (95% CI, 0.4-13.9) for ZELBORAF patients vs 4.5 months (95% CI <0.1-11.7) for those taking dacarbazine. † There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms respectively at the time of analysis.3

~4-month improvement in median progression-free survival (5.3 vs 1.6 months; HR=0.26, P<0.0001, 95% CI, 4.9-6.6 vs 1.6-1.7) Significant improvement in best overall response rate (48.4% vs 5.5%; P<0.0001, 95% CI, 41.6%-55.2% vs 2.8%-9.3%) There were 2 complete responses (1%) and 104 partial responses (PRs) (47.4%) with ZELBORAF vs 12 PRs (5.5%) with dacarbazine

The most common adverse reactions of any grade (≥30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma; the most common (≥5%) grade 3 adverse reactions were cutaneous squamous cell carcinoma and rash

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis.

Patients should be routinely monitored for signs and symptoms of uveitis.

Additionally, 5 cases each of blurry vision and iritis and 6 cases of photophobia were reported in the Phase III study. One case of retinal vein occlusion was reported in the Phase II study.

New Primary Malignant Melanoma Eight skin lesions in 7 patients were reported as new primary malignant melanoma in the Phase III study.

Cases were managed with excision and patients continued treatment without dose adjustment; monitoring for skin lesions should occur as outlined above [see cuSCC].

Use in Pregnancy: Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women.

If ZELBORAF is used during pregnancy or if the patient becomes pregnant while taking ZELBORAF, the patient should be apprised of the potential hazard to a fetus.

BRAF Testing Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for the selection of patients appropriate for ZELBORAF therapy. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma.

Most common adverse events The most common adverse reactions of any grade (≥30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.

The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was predefined as a grade 3 event.

Please see Brief Summary of Prescribing Information on the following page.

References: 1. Smalley KS, Sondak VK. Melanoma—an unlikely poster child for personalized cancer therapy. N Engl J Med. 2010;363:876-878. 2. Flaherty KT. Next generation therapies change the landscape in melanoma. F1000 Med Reports. 2011; 3:1-4. doi:10.3410/M3-8. 3. Data on file. Genentech, Inc.

© 2011 Genentech USA, Inc. All rights reserved. BRF0000653200 Printed in USA.

www.zelboraf.com

The ASCO Post | NOVEMBER 15, 2011

PAGE 46

FDA Update

FDA Approves Cetuximab to Treat Metastatic Head and Neck Cancer

O

n November 7, the FDA approved cetuximab (Erbitux) in combination with platinum-based therapy plus florouracil (5-FU) for the firstline treatment of patients with recurrent locoregional disease and/or metastatic squamous cell carcinoma of the head

human melanoma tissue. The safety and efficacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas ® 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits,for detailed information.

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

The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.

The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

cancer who were not suitable for potentially curative treatment with surgery or radiation.

The study used a European Union (EU)-approved cetuximab rather than the U.S.-approved

Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: dizziness, neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma Infections and infestations: folliculitis Investigations: weight decreased Eye disorders: retinal vein occlusion, uveitis Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 3 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4.

Table 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

-

* For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm.

7 DRUG INTERACTIONS Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes with ZELBORAF* Trial 2: Patients with Results from an in vivo drug-drug interaction study in patients with cancer Trial 1: Treatment Naive Patients Failure of at Least demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak One Prior Systemic CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)].

Concomitant use of ZELBORAF with agents with narrow therapeutic Therapy windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is ZELBORAF Dacarbazine ZELBORAF not recommended as ZELBORAF may alter their concentrations. If n= 336 n= 287 n= 132 coadministration cannot be avoided, exercise caution and consider a ADRs All Grade Grade All Grade Grade All Grade Grade dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug.

4 4 Grades 3 4 Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) (%) (%) (%) Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology Skin and (12.3)]. Exercise caution and consider additional INR monitoring when subcutaneous ZELBORAF is used concomitantly with warfarin. tissue disorders 7.2 Drugs that Inhibit or Induce CYP3A4 Rash 37 8 2 52 7 Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, Photosensitivity 33 3 4 49 3 atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, reaction nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, Alopecia 45 <1 2 36 rifampin, rifabutin, rifapentine, phenobarbital) should be used with Pruritis 23 1 1 30 2 caution when coadministered with ZELBORAF. Hyperkeratosis 24 1 <1 28 Rash maculo8 USE IN SPECIFIC POPULATIONS 9 2 <1 21 6 papular 8.1 Pregnancy Actinic keratosis 8 3 17 Pregnancy Category D [see Warnings and Precautions (5.9)].

Dry skin 19 1 16 ZELBORAF may cause fetal harm when administered to a pregnant Rash papular 5 <1 13 woman based on its mechanism of action.

Erythema 14 2 8 There are no adequate and well controlled studies in pregnant women.

Musculoskeletal Women of childbearing potential and men should be advised to use and connective appropriate contraceptive measures during ZELBORAF therapy and for tissue at least 2 months after discontinuation of ZELBORAF. If this drug is used disorders during pregnancy or if the patient becomes pregnant while taking this Arthralgia 53 4 3 <1 67 8 drug, the patient should be apprised of the potential hazard to a fetus.

Myalgia 13 <1 1 24 <1 8.3 Nursing Mothers Pain in extremity 18 <1 6 2 9 Musculoskeletal It is not known whether vemurafenib is excreted in human milk. Because 8 4 <1 11 pain many drugs are excreted in human milk and because of the potential for Back pain 8 <1 5 <1 11 <1 serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the General disorders drug, taking into account the importance of the drug to the mother. and administration site conditions 8.4 Pediatric Use Fatigue 38 2 33 2 54 4 Safety and efficacy in pediatric patients below the age of 18 have not Edema peripheral 17 <1 5 23 been established.

Pyrexia 19 <1 9 <1 17 2 8.5 Geriatric Use Asthenia 11 <1 9 <1 2 Ninety-four (28%) of 336 patients with unresectable or metastatic Gastrointestinal melanoma treated with ZELBORAF in Trial 1 were ≥ 65 years. Elderly disorders patients (≥ 65 years) may be more likely to experience some adverse Nausea 35 2 43 2 37 2 reactions, including cutaneous squamous cell carcinoma, nausea, Diarrhea 28 <1 13 <1 29 <1 decreased appetite, peripheral edema, keratoacanthoma and atrial Vomiting 18 1 26 1 26 2 fibrillation. The effects of ZELBORAF on overall survival, progressionConstipation 12 <1 24 16 free survival and best overall response rate were similar in the elderly as Nervous system compared to younger patients. disorders 8.6 Gender Headache 23 <1 10 27 The Grade 3 adverse events reported more frequently in females than Dysgeusia 14 3 11 males were rash, arthralgia, photosensitivity and increased creatinine.

Neoplasms The Grade 3 adverse events reported more frequently in males than benign, malignant females were keratoacanthoma, increased alkaline phosphatase and and unspecified increased total bilirubin. (includes cysts 8.7 Hepatic Impairment and polyps) No adjustment to the starting dose is needed for patients with Skin papilloma 21 <1 30 pre-existing mild and moderate hepatic impairment. ZELBORAF should Cutaneous SCC†# 24 22 <1 <1 24 24 Seborrheic be used with caution in patients with pre-existing severe hepatic 10 <1 1 14 keratosis impairment [see Clinical Pharmacology (12.3)].

8.8 Renal Impairment Investigations 5 3 <1 1 Gamma15 6 4 No adjustment to the starting dose is needed for patients with glutamyltransferase pre-existing mild and moderate renal impairment. increased ZELBORAF should be used with caution in patients with pre-existing Metabolism and severe renal impairment [see Clinical Pharmacology (12.3)]. nutrition disorders 10 OVERDOSAGE Decreased appetite 18 8 <1 21 There is no specific antidote for overdosage of ZELBORAF. Patients Respiratory, who develop adverse reactions should receive appropriate symptomatic thoracic and treatment. In case of suspected overdose, ZELBORAF should be mediastinal withheld and supportive care instituted. disorders Cough Injury, poisoning and procedural complications Sunburn

8

-

-

7

-

-

12

-

-

10

-

-

-

-

-

14

-

-

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required.

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

BRF0000422000 Initial U.S. Approval: August 2011 © 2011 Genentech, Inc

cetuximab (Erbitux). Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab; these pharmacokinetic data, together with the results of the study conducted in Europe and other clinical trial data using Erbitux establish the safety and efficacy of Erbitux at the recommended dose.

Study Details The trial enrolled 442 patients; 222 patients received cetuximab plus cisplatin (or carboplatin) with 5-FU and 220 patients received cisplatin (or carboplatin) with 5-FU. The median follow-up at the time of overall survival analysis was 19.1 and 18.2 months for the cetuximab-plus-chemotherapy arm and the chemotherapy-alone arm, respectively.

Overall survival was significantly improved in patients receiving cetuximab plus chemotherapy compared to those receiving chemotherapy alone (10.1 vs 7.4 months; HR = 0.80; 95% CI = 0.64–0.98; P = .034). Progressionfree survival was also significantly improved in patients receiving cetuximab plus chemotherapy (5.5 vs 3.3 months; HR = 0.57; 95% CI = 0.46–0.72; P < .0001). Objective response rates were 35.6% and 19.5% (odds ratio = 2.33; 95% CI = 1.50–3.60; P = .0001) in the cetuximab-plus-chemotherapy and the chemotherapy-alone arms, respectively.

Safety Precautions The most common adverse reactions in patients treated with cetuximab plus chemotherapy were nausea, anemia, vomiting, neutropenia, rash, asthenia, diarrhea, and anorexia. Other adverse reactions, sometimes severe, caused by cetuximab included infusion reactions, hypomagnesemia, hypocalcemia, and hypokalemia. Health care providers should closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after cetuximab administration.

The approved dose of Erbitux is 400 mg/m2 intravenously as an initial dose, followed by 250 mg/m2 intravenously weekly in combination with cisplatin or carboplatin plus continuous infusion 5-FU. Erbitux was first approved by the FDA in 2004 to treat epidermal growth factor receptor–positive late-stage colon cancer after patients stopped responding to chemotherapy, and has been approved since 2006 for treatment of nonmetastatic head and neck cancer.

Safety:10"

ZELBORAF™ (vemurafenib) tablet, oral Initial U.S. Approval: 2011 This is a brief summary of information about TRADENAME. Before prescribing, please refer to the full Prescribing Information.

1 INDICATIONS AND USAGE ZELBORAF™ is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS 5.1 Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment.

It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued.

5.3 Dermatologic Reactions Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued.

5.4 QT Prolongation Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval.

ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc > 500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both > 500 ms and > 60 ms change from pre-treatment values.

5.5 Liver Laboratory Abnormalities Liver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated.

Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)].

5.6 Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn.

For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration (2.2)].

5.7 Ophthalmologic Reactions In Trial 1, five cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2.

5.8 New Primary Malignant Melanoma There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)].

5.9 Use in Pregnancy Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

5.10 BRAF V600E Testing Confirmation of BRAF V600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom benefit has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas ® 4800 BRAF V600 Mutation Test [see Clinical Studies (14)]. This test is designed to detect BRAF V600E mutations in DNA isolated from formalin-fixed, paraffin-embedded

and neck. The approval was based primarily on the results of a multicenter clinical study conducted outside the United StatesSafety:7" in 442 patients with metastatic or locally recurrent head and neck

■

ASCOPost.com | NOVEMBER 15, 2011

PAGE 47

Expert’s Corner Palliative Care

A Conversation with Judith Redwing Keyssar, RN Lessening patients’ suffering at the end of life

By Jo Cavallo

Judith Redwing Keyssar, RN

T

a society unable to come to terms with our own mortality?

In our American culture today, the concept of impermanence is not one we can relate to easily. In other cultures, the fact that birth and death are part of the cycle of life and that we are only here briefly is much more accepted. Also, until the early- to mid-20th century, families took care of their loved ones who were dying at home, and death was more a part of everyday life. Today, people don’t see death in their world.

he number of patients seeking Slow Acceptance of Hospice hospice and palliative care has Do recent medical advances, especialgrown significantly since 1974, when ly in life-threatening diseases like cancer, the NCI funded the first hospice facontribute to making it more difficult for cility in Branford, Connecticut. Nevpatients—and physicians—to consider ertheless, according to the National hospice care?

Center for Health Statistics, 85% I think that’s absolutely true. I read of Americans still die in hospitals an article that said new treatments for or nursing homes. This prevalence cancer have delayed hospice referrals continues despite research from the because there is the hope that a new National Hospice Foundation showclinical trial or another treatment ing that nearly 80% of patients would might make a difference. And yet ofprefer to die in their homes, free of ten in the expectation and delivery pain and surrounded by their loved of more treatment, quality of life sufones. fers. How many times have we seen For more than 2 decades, Judith people being given chemotherapy up Redwing Keyssar, RN, has helped until a week or two before they die? dying patients maintain their qualWhen I hear a physician say a patient ity of life as they make the transition wants to keep refrom life to death. ceiving treatment, The Director of Hospice care is not it’s often because the Palliative and that’s what the End-of-Life Care just about facilitating a health-care proProgram at Sepeaceful and pain-free vider is suggesting niors at Home, a to the patient. If division of Jewish death. It’s also about life treatment is being Family and Chiland assisting patients in offered, patients dren’s Services of San Francisco, and having a high quality of life think there must be a good reason author of Last Acts for as long as possible. and that there of Kindness: Lesmust be hope that sons for the Living it’s going to make from the Bedsides them better. of the Dying (CreateSpace, 2010; But there comes a turning point www.lastactsofkindness.com), Keyswhen continuing treatment is futile sar talked with The ASCO Post about and sacrifices the patient’s quality of how oncologists and other medical life. Maybe the treatment will allow a professionals can use palliative care patient to stay alive an extra week or approaches to help ease the suffering month, but is that extra time going to of their terminally ill patients. give him the kind of quality of life he The Final Taboo would really appreciate?

You say in your book that death is the Most patients aren’t referred to final taboo in our culture. Why are we as hospice care until the last month or

EXPERT POINT OF VIEW

By Diane Meier, MD, FACP Director, Center to Advance Palliative Care and Hertzberg Palliative Care Institute Mount Sinai School of Medicine New York

I

n her interview with The ASCO Post, Judith Redwing Keyssar, RN, sheds light on easing the suffering of patients facing the end of life. Although what she says is appropriate for patients who are clearly dying, I would emphasize that palliative care is also pertinent to patients who are not terminally ill. An increasing body of evidence shows that delivering palliative care at the point of diagnosis of a serious illness not only improves quality of life for both patient and family, but also extends life. It does this by, among other things, helping patients avoid risky or harmful settings or unnecessary treatments.

The article speaks to an important but very narrow population of those who are dying imminently. However, it is vital for oncologists to be reminded of the added value of offering palliative care at the same time that diseasedirected treatment is initiated for their cancer patients.

■

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

two of their life and sometimes not until the last few days of their life. That is partly because health-care professionals still have a hard time accepting the fact that their patient is going to die, and they are not comfortable having that conversation with the patient. However, greater acceptance of palliative care approaches and the advent of palliative care physicians and specialty teams in hospitals are starting to make a big difference in helping initiate end-of-life care conversations with terminal patients. We have to acknowledge that having these conversations is as important to the patient’s clinical care as knowing how to do surgery to eliminate the cancer from the patient’s body.

Fear of Death Why are people so afraid of dying?

It’s like any other unknown we have to deal with. It’s scary because even though we’re all going to experience death and dying, we don’t talk openly about it and we don’t know what the process looks like. While hospice and palliative care practices have become more well known over the past 15 years, many people still don’t know the details of what

happens when a person dies so, of course, the concept is very scary. We have to get better at talking openly about death and dying and giving people more information so that it’s not so frightening. Death is a normal process, and we don’t need to be afraid of it.

Making the Transition How can oncologists help their patients make the transition from active treatment to end-of-life care?

It’s difficult because often there isn’t enough time in a typical office visit to address all the clinical issues and then discuss end-of-life care if treatment fails. It’s important to reassure patients that if conventional treatment fails, the palliative or hospice team will make sure that their life will be free from suffering and as high quality as possible and to dispel the myth that a referral to hospice care means death is imminent. Hospice care is not just about facilitating a peaceful and pain-free death. It’s also about life and assisting patients in having a high quality of life for as long as possible.

■

Disclosure: Ms. Keyssar reported no potential conflicts of interest.

The ASCO Post | NOVEMBER 15, 2011

PAGE 48

Journal Spotlight Thoracic Oncology

Improved Survival with Concurrent Chemotherapy plus Radiotherapy for Patients with Stage III Non–Small Cell Lung Cancer

By Charlotte Bath

F

ive-year survival was statistically significantly higher for patients with stage III non–small cell lung cancer (NSCLC) who received

concurrent rather than sequential cisplatin-based chemotherapy combined with thoracic radiotherapy, according to the phase III Radiation

Therapy Oncology Group (RTOG) 9410 trial. While acute toxicity, particularly esophagitis, was statistically significantly worse with concurrent

therapy, “long-term toxicity and treatment mortality are equivalent,” the inSEE PAGE 60 vestigators reported in the Journal of the National Cancer Institute.

Patients with inoperable stage II or III NSCLC were randomly assigned to two concurrent regimens and one sequential chemotherapy-plus–thoracic radiotherapy regimen. Patients in arm 1 (the sequential arm) received cisplatin at 100 mg/m2 on days 1 and

This study does support the hypothesis that concurrent therapy should be the standard nonoperative regimen for eligible patients.

29 and vinblastine at 5 mg/m2 per week for 5 weeks, with 60 Gy thoracic radiotherapy beginning on day 50. Patients in arm 2 followed the same chemotherapy regimen but with 60 Gy thoracic radiotherapy once daily beginning on day 1.

Patients in arm 3 received cisplatin at 50 mg/m2 on days 1, 8, 29, and 36, with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6, and with 69.6 Gy delivered as 1.2-Gy twice-daily fractions beginning on day 1.

Median survival times among the 577 patients eligible for analysis (95% of total enrollment) were 14.6 months for the sequential arm, 17 months for arm 2, and 15.6 months for arm 3.

Five-year survival rates were 10% (20 patients) in the sequential arm, 16% (31 patients) in concurrent arm 2, and 13% (22 patients) in concurrent arm 3.

Toxicity and Study Limitations “There were statistically significantly higher rates of acute esophagitis in both concurrent arms than in the sequential arm, with grade 3 or worse rates of 4%, 22%, and 45% for arms 1, 2, and 3 respectively,” the investigators reported. “Of interest was the lack of difference in late esophagitis rates among these arms, with rates of 1% to 4% among the three arms.

The authors pointed out that most continued on page 49

ASCOPost.com | NOVEMBER 15, 2011

PAGE 49

2011 European Multidisciplinary Cancer Congress Dermatologic Oncology

‘Breakthrough’ Approach to Advanced Basal Cell Carcinoma via Inhibition of Hedgehog Pathway

By Alice Goodman

T

he first-in-class Hedgehog pathway inhibitor vismodegib appears to be a successful treatment for advanced basal cell carcinoma, a disfiguring and debilitating disease, according to a pivotal multicenter nonrandomized trial presented as a Best Abstract at a Presidential Ses-

the face and head that resolved with treatment.

“It is hard to appreciate, unless you have seen the photos, how remarkable these results really are,” stated Sandra Horning, MD, Head of Clinical Development in Hematology/Oncology for Genentech, speaking to reporters at a press conference.

Data Breakdown

Luc Dirix, MD

sion during the recent European Multidisciplinary Cancer Congress in Stockholm.1 At present, there is no standard of care for the small minority of basal cell cancers that present as locally advanced or metastatic.

“This is an unmet need. Our study shows substantial benefit for advanced basal cell carcinoma with this new approach using a SEE PAGE 60 Hedgehog pathway inhibitor,” said Luc Dirix, MD, SintAugustinus Hospital, Antwerp, Belgium.

The data from the study were compelling, but perhaps more compelling were the photos of faces of patients with widespread ulcerated lesions of

The study population included 99 patients—33 with metastatic disease and 63 with locally advanced disease.

Treatment was with 150 mg/d of oral vismodegib until disease progression, unacceptable toxicity, or withdrawal from the study. The median age of patients was 62, and 100% were white.

Overall, 38% of patients’ lesions were inoperable, and 62% were not surgical candidates.

Among the group with metastatic basal cell cancer, overall response rate was 30%, and stable disease was observed in 63%. For those with locally advanced basal cell carcinoma, overall response rate was 43% and stable disease was observed in 40%.

Median progression-free survival at 10 months was identical in the two groups. Absence of basal cell cancer on biopsy was reported in 54% of the cohort with locally advanced disease.

Few serious adverse events were attributed to vismodegib. Of 26 (25%) serious adverse events, 4 (4%) were deemed drug-related. “The common adverse events were predominantly mild to moderate and related to inhi-

Vismodegib in Advanced Basal Cell Cancer ■■ First-in-class Hedgehog pathway inhibitor vismodegib showed dramatic resolution of advanced and metastatic basal cell cancer.

■■ These results suggest that this is a promising option for a disease with no standard of care.

Improved Survival for Stage III NSCLC Patients continued from page 48

patients with stage III NSCLC have functional status and comorbid conditions that would disqualify them from participating in the study and less able to tolerate the severe esophagitis observed with concurrent therapy.

“This study does support the hypothesis that concurrent therapy should be the standard nonoperative regimen for eligible patients,” the authors also noted. “Promising phase II reports of newer chemotherapeutic regimens, including taxane-based regimens, delivered concurrently with [thoracic radiotherapy] continue to be published and

EXPERT POINT OF VIEW

“V

ismodegib is a breakthrough for advanced basal cell carcinoma. These responses were convincing and spectacular, with a clinical benefit in more than 80% of patients and progression-free survival of 10 months,” said Caroline Robert, MD, Institut Gustav Roussy, Villejuif Paris-Sud, France, who was formal discussant for the paper by Dirix et al at the European Multidisciplinary Cancer Congress.

Basal cell cancer, though common, is usually Caroline Robert, MD a slow-growing cancer. “Despite this, we still see some patients with extensive advanced disease,” she said.

Phase II Trial Patients with Gorlin syndrome are “covered” with endless basal cell cancers, she continued. “Interim results of a phase II study of 41 patients with Gorlin syndrome showed a good clinical response with vismodegib, with almost no new tumor growth,” Dr. Robert told the audience.1 Despite the good clinical response, and the fact that serious adverse events are rare with this drug, long-term tolerance may be problematic, because 40% of the patients with Gorlin syndrome eventually stopped therapy in that trial.

“We need to continue to find treatment modalities that avoid side effects in high-risk patients,” Dr. Robert stated.

There may be a role for neoadjuvant vismodegib, she suggested, and surgery should remain in the treatment algorithm. The Hedgehog pathway is involved in stromal cell biology and angiogenesis, and the role of vismodegib should be explored in other tumors. It is presently being tested in pancreatic cancer and chondrosarcoma.

■

Disclosure: Dr. Robert is a consultant for Roche, GlaxoSmithKline, and Bristol-Myers Squibb.

Reference 1. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al: An investigator-initiated, phase II randomized, double-blind, placebo-controlled trial of GDC-0449 for prevention of BCCs in basal cell nevus syndrome (BCNS) patients. American Association for Cancer Research 102nd Annual Meeting, Abstract LB-1. Presented April 3, 2011.

Disclosure: Dr. Horning is Senior Vice President, Global Head of Clinical Development Hematology/Oncology for Genentech. Dr. Dirix reported no potential conflicts of interest.

Reference 1. Dirix L, Migden MR, Oro AR, et al: A pivotal multicenter trial evaluating efficacy and safety of the Hedgehog pathway inhibitor vismodegib in patients with advanced basal cell carcinoma. European Multidisciplinary Cancer Congress. Abstract 1BA. Presented September 24, 2011.

will require additional testing to define the optimal regimen.”

Send Us Your News

bition of the Hedgehog pathway, such as muscle spasms, alopecia, taste disturbance, weight loss, and fatigue,” he told listeners.

■

■

Reference 1. Curran WJ Jr, Paulus R, Langer CJ, et al: Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: Randomized phase III trial RTOG 9410. J Natl Cancer Inst 103:1452-1460, 2011.

Send your news of new appointments, awards, or significant events to The ASCO Post.

Write to editor@ASCOPost.com.

All submissions will be considered for publication.

The ASCO Post | NOVEMBER 15, 2011

PAGE 50

Patient’s Corner Gynecologic Oncology

Fighting to Get Back Control

Although my treatment is finished, all I think about is cancer.

By Mary Van Vlyman, as told to Jo Cavallo found that I had grade III endometrial cancer, I underwent a radical hysterectomy. The pathology report was grim: I had stage IIIC endometrial cancer and a uterine sarcoma.

Mary Van Vlyman

I

’ve had raging hormones since I was 18, when I was diagnosed with a benign pituitary adenoma. The tumor caused unpredictable menstrual cycles that remained constant throughout my life, even after it had been successfully treated. So 2 years ago, when I turned 40 and started having sudden bouts of heavy and frequent bleeding, I chalked it up to the beginning of perimenopause.

A year later, when the bleeding became even heavier and more frequent, I decided to see my gynecologist for a checkup. An examination revealed a vaginal polyp, and an ultrasound showed a thickening of the lining of my uterus. When a subsequent endometrial biopsy and tissue samples taken during a dilation and curettage (D&C)

hospitalized for several days.

Ever since I finished my chemotherapy treatment in May, the physical effects of having cancer have started to recede. Now, I’m battling the emotional turmoil I had so successfully reNo Time for Fear pressed while undergoing treatment.

Once the diagnosis was made, evAlthough I try to resist the impulse, I erything moved so quickly, I didn’t think about cancer 24/7. I’m trying to have time to be afraid. My oncologist regain control of my life, but it’s hard. recommended 5 weeks of daily pelvic While the good news is that my last external-beam radiotherapy and weekblood test results and CT scans were ly doses of cisnormal and my onplatin for 5 weeks, cologist assures me I wish I’d never had followed by three that “everything cancer, but it’s opened my looks good,” he still brachy therapy treatments and six hasn’t explained eyes to how precious life cycles of a regiexactly what my is and the importance of men of carboplaprognosis is. But tin and paclitaxel. from what I’ve read enjoying every day.

The effects of the on the Internet and treatment on my learned from other body were severe. In addition to hair endometrial cancer survivors in online loss, I had such uncontrollable nausea, chat rooms, there’s a very high likelithree different antiemtic medications hood that my cancer will recur. failed to bring me relief. But worst of Living for Today all was the intense pain I experienced My life will never be normal again from the radiation. Despite my mediand that’s a good thing. Before my dical team’s best efforts at management, agnosis I was rushing through life. A that pain was so unyielding, I had to be

CONQUERING

workaholic, I didn’t have time for family or friends or even a fun vacation or occasional outing. I’ve always wanted to go kayaking, a simple enough activity, but I kept putting it off. Now I make sure to get together with family and friends, and if there’s something I want to do, I do it.

After I got sick, I decided to join a support group so I could connect with other people going through a similar experience, but I found there weren’t any in my hometown that dealt with gynecologic cancers, so I’m in the process of starting one. No one should have to deal with a life-threatening disease alone.

I wish I’d never had cancer, but it’s opened my eyes to how precious life is and the importance of enjoying every day. I know I can’t say I’m cancer-free and that I’ll never have to deal with this disease again. But I also know that no one is guaranteed the promise of tomorrow. We only have today.

■

Mary Van Vlyman, 41, lives in Joliet, Illinois, and works in the medical and pharmacy billing department at a Walgreens Specialty Infusion Pharmacy.

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August 2011

The ASCO Post | NOVEMBER 15, 2011

PAGE 52

AACR Conference on Cancer Health Disparities Researchers Explore Reasons for Higher Risk of Triple-negative Breast Cancer in Underserved African-American Women

By Margot Fromer

T

riple-negative breast cancer, one of the most aggressive forms of the disease, has a bad reputation, and among socioeconomically disadvantaged black women, that reputation is especially well deserved.

In fact, according to Lisa A. Newman, MD, Director of the Breast Care Center, University of Michigan Comprehensive Cancer Center, among 156,570 subjects in the Women’s Health Initiative, the incidence of high-grade breast cancer was five times higher for black women than for whites. Mortality was higher for them as well. These were among the findings presented at the American Association for Cancer Research (AACR) 4th Annual Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, held September 18–21 in Washington, DC. Two other studies revealed a similarly skewed picture. The Carolina Breast Cancer Study reported increased prevalence of triple-negative breast cancer among premenopausal black women compared with postmenopausal women of the same race. The Southwest Oncology Group reported significantly worse outcomes in clinical trials for black women with triple-negative breast cancer molecular marker status than for whites.

Race Not the Only Factor Dr. Newman added that international breast cancer studies are now revealing an even higher risk of triple-negative breast cancer among sub-Saharan African women than among American women of African descent.

She noted that poverty and lack of health insurance are the two major barriers to any type of health care, but they are especially common among black and Hispanic women. Other factors include inadequate screening, which results in delayed diagnosis, lifestyle, diet, environment, culture, and genetics.

“Five-year survival is the lowest for the most impoverished women in American society,” she said.

These disparities have been well documented by the Surveillance, Epidemiology and End Results (SEER) program, the Centers for Disease Control and Prevention (CDC), and a variety of cancer registries, but the data are confounded by the fact that they rely on

self-reporting of race and ethnic background. This means that an individual’s lineage might actually include contributions from several populations. “The racial composition of the United States is shifting toward increased diversity, so an improved understanding of the multifactorial etiology of health-care disparities is critical for improved cancer control,” Dr. Newman said.

Genetics and Treatment James M. Ford, MD, Director of the Stanford Clinical Center Genetics Program, Stanford University School of Medicine, said that the genetics—and thus the treatment—of triple-negative breast cancer is still under investigation. The disease is a basal-like subtype that shares similar gene-expression profiles and DNA repair deficiencies with BRCA1-associated cancers. Those can-

Other Markers and Treatments Judy E. Garber, MD, Leader of the Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, echoed Dr. Ford’s thoughts. “We know that many factors contribute to the development of invasive breast cancer. The hormonal factors that have been studied for many years, like age at first period or use of hormone replacement, contribute to the development of hormone-driven breast cancers. We know much less about the risk factors for basal-like or ‘triple-negative’ breast cancers, over and above African-American ancestry, and little about risk factors for HER2-positive breast cancers.

We have identified other genes that confer risk of breast cancer, and are finding that certain genes increase the risk of specific breast cancer subtypes, but inherited forms of breast cancer are

The problem with triple-negative breast cancer is the lack of one specific target controlling the cancer cells in the majority of tumors. Once those targets are identified, new agents can be developed to treat this difficult disease.

— Judy E. Garber, MD

cers exhibit sensitivity to gemcitabine, cisplatin, and poly (ADP-ribose) polymerase (PARP) inhibition. Therefore, he and his colleagues hypothesized that triple-negative breast cancer could be treated with these drugs.

They found that to be the case.

Moreover, combination treatment indicated that PARP inhibition using smallmolecule inhibitors or siRNA knockdown was synergistic with gemcitabine and cisplatin in triple-negative breast cancer cells but not in luminal cancer cells. This suggested that the synergistic effect of PARP inhibition and gemcitabine or cisplatin reflected underlying DNA repair defects.

“Thus, the sensitivity to combination treatment seemed to be mediated by sustained DNA damage and inefficient DNA repair,” Dr. Ford said. “This may be a new therapeutic strategy to treat triple-negative breast cancer, an aggressive disease that lacks effective treatment options.”

uncommon, comprising no more than 5% to 10% of breast cancers overall.”

Regarding treatment, Dr. Garber said that efforts to understand the molecular biology—the genetic changes in the tumor cells—is leading to new treatments that target the cancer cells but spare the normal cells. Estrogen receptor and HER2 are examples of targets in some subsets of breast cancer.

The problem with triple-negative breast cancer is the lack of one specific target, a “driver mutation or critical pathway” that is controlling the cancer cells in the majority of triple-negative tumors.

Once those targets are identified, new agents can be developed to treat this difficult disease.

The Warburg Effect In another study presented at the AACR meeting, investigators looked at premenopausal African-American women at high risk of breast cancer because of family history.

“We found that in a high proportion of high-risk African-American women, precancerous cells were taking in a high amount of glucose, and they also had activation of insulin signaling,” said Victoria L. Seewaldt, MD, Professor of Medicine and Co-Director of the Breast and Ovarian Cancer Program at Duke University. “In these women, we would worry that if they had developed gestational diabetes, the condition could stimulate precancerous cells.” It is thus desirable to detect this effect as early as possible, she noted.

“We see a lot of triple-negative breast cancer among young AfricanAmerican women, and only 14% are alive 5 years after diagnosis,” Dr. Seewaldt said. “We already know that aggressive cancer cells actively consume glucose and produce lactic acid, even in the presence of adequate oxygen.

The cells break down the glucose, thus stimulating growth. This is known as the Warburg effect.”

New research has indicated that the Warburg effect occurs earlier than previously thought, even during cancer initiation, in young African-American women. Dr. Seewaldt and colleagues theorized that it might be testable and looked at 77 high-risk premenopausal women, 45% of whom were AfricanAmerican.

The signaling network most highly expressed in these women’s precancerous cells contained activated proteins associated with the Warburg effect (AKT/mTOR/P13K), insulin signaling (pACC, IRS-1), and epithelial-mesenchymal transition (interleukin‑6/ STAT3/vimentin). This meant that if they developed gestational diabetes, the precancerous cells would be easily stimulated.

This is the first evidence that abnormal glucose uptake and the Warburg effect occurs during breast cancer initiation in high-risk African-American women. “We can now identify the pertinent signaling networks associated with the effect, which means that we are more likely to be able to provide early detection and prevention. To some extent, this risk can be mitigated by exercise, weight loss, and administration of metformin,” said Dr. Seewaldt.

■

Disclosure: Drs. Garber and Seewaldt reported no potential conflicts of interest.

ASCOPost.com | NOVEMBER 15, 2011

PAGE 53

Expert’s Corner

A Conversation with Craig B. Thompson, MD

The President of Memorial Sloan-Kettering Cancer Center shares his thoughts on the future of cancer care.

By Jo Cavallo

Craig B. Thompson, MD

I

n November 2010, Craig B. Thompson, MD, was named President and CEO of Memorial Sloan-Kettering Cancer Center (MSK) in New York, succeeding Harold Varmus, MD, who is now Director of the NCI. A cancer clinician and researcher, before coming to Memorial Sloan-Kettering Dr. Thompson was Director of the Abramson Cancer Center at the University of Pennsylvania and Associate Vice President for Cancer Services of the University of Pennsylvania Health System.

As the 1-year anniversary of Dr. Thompson’s tenure approached, he talked with The ASCO Post about recent discoveries in more effective therapies for such deadly cancers as metastatic melanoma and the challenges that remain in advancing better targeted treatment for other currently incurable and difficult-to-treat cancers.

Ambitions and Challenges You’ve been President of Memorial Sloan-Kettering Cancer Center for a year.

Would you share some of your reflections

on that experience?

Joining MSK has been a transformative experience for me, both as a medical oncologist and as a cancer researcher. For a very long time I’ve been involved in trying to develop quality cancer care at matrix cancer centers embedded within tertiary care facilities. However, this is my first experience in a fully dedicated cancer hospital, and it has been an amazing experience.

What are some of the challenges you face?

Institutions like MSK and other dedicated freestanding cancer centers have really captured the world’s attention by showing that cancer is a

and cancers that have proven hard to treat like pancreatic, liver, kidney, and lung cancer, all of which are still difficult to diagnose early and for which treatment options are limited.

How do we most effectively continue to do research that deepens our understanding of this disease, and how do we deliver new therapies that can help these patients? That’s where the staff and I have redoubled our efforts at MSK.

Therapeutic Advances How would you describe the state of the art in medical oncology?

There are now three different treatment modalities—immunotherapy,

One of the things we think a dedicated cancer center should do is to mix and match these approaches in an effort to achieve the best possible outcomes. treatable disease and that we can push further and further into earlier, preemptive diagnoses.

The challenge going forward for freestanding disease-specific hospitals is to figure out how to survive, given the needed changes in American health care. Over the past 40 years, cancer treatment has improved to the point that, today, two-thirds of American patients with cancer are doing well 5 years after their diagnosis. And because their disease is either cured or largely controlled, they can get back to their normal lives.

Our mission now is to focus our attention on the one-third of patients with cancer who don’t do as well.

These are patients with rare cancers

oncogene-targeted inhibitory therapy, and chemotherapy exploiting the unique cellular dependencies created by oncogenic transformation—that are starting to deliver on the promise that came with the decoding of the human genome, our increased understanding of the basic biology of cancer, and how cancer interacts with the rest of the body.

For the first time, we are seeing immunotherapy make good on its potential. We have sipuleucel-T (Provenge), in which a vaccine approach has shown a survival benefit in prostate cancer.

And we see how blocking immune system inhibitors with drugs like ipilimumab (Yervoy) allow the immune system to mount a sustained attack on

cancer cells. The idea that we can harness the power of our own bodies to fight cancer represents a tremendous opportunity for cancer biologists. And it fits in with the other two advances that have also shown tremendous advantage this past year.

One is the development of targeted therapeutics beyond imatinib (Gleevec). For the first time, we see BRAF inhibitors such as vemurafenib (Zelboraf) successfully targeting RAFbased melanomas. We’ve also seen how ALK inhibitors can target oncogenic ALK rearrangements. Then there are therapies that exploit the unique properties of certain cancer cells—like the proteasome inhibitor bortezomib (Velcade)—that have proven effective in multiple myeloma.

So the question for us becomes, how do you use these therapies in combination? One of the things we think a dedicated cancer center should do is to mix and match these approaches in an effort to achieve the best possible outcomes.

For example, in melanoma we have the advances with vemurafenib, pioneered here by Paul Chapman, MD, and the work on ipilimumab,

by James Allison, PhD, Chair of the Sloan-Kettering Institute’s Immunology Program. Both of these agents have shown exciting therapeutic potential.

What’s interesting about the RAF inhibitors like vemurafenib is that nearly every patient with a RAF mutation experiences a benefit, but it only lasts 6 months to a year. In contrast, ipilimumab only helps a fraction of patients—between 25% and 35%— continued on page 54

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Expert’s Corner

Craig B. Thompson, MD continued from page 53

but some of those patients experience long-term disease-free survival.

So what’s making the difference? And how does one combine those two therapies so they are not antagonistic but are actually synergistic? These are the kinds of questions we are asking— and answering—at Memorial SloanKettering.

Collaborative Research Recently, researchers at MSK conducted a phase I trial of a novel T-cell– based gene therapy approach to treating chronic lymphocytic leukemia and B-cell acute lymphoblastic leukemia. A similar study was conducted at the University of Pennsylvania. Both studies showed promising results, and now researchers from the two institutions are launching a phase II study. Can you talk about the importance of this kind of collaborative work?

We have a grant from the NCI Special Translational Research Acceleration Project (STRAP) Program to demonstrate that two centers can work collaboratively and use the same protocols to launch a clinical trial. We’re developing the protocols here under lead investigator Renier Brentjens, MD, PhD, and working with Carl H. June, MD, Professor of Pathology and Laboratory Medicine at the University of Pennsylvania. I think we’re going to see more of these sorts of collaborations among cancer centers, because they can result in validating the reproducibility of new experimental approaches.

How we integrate this new approach into state-of-the-art patient

care is going to be extremely important. Similarly, how we incorporate advances in surgery, radiotherapy, and medical oncology and then disseminate that information to other hospitals will be critical. That’s our job: to develop these advances, with the ultimate goal of making them standard practice, so they can be adopted by other hospitals and clinicians.

Future of Oncology ASCO and other organizations have identified an impending shortage of oncologists. What advice would you offer to the next generation of clinicians and researchers to encourage the pursuit of a career in oncology?

I think this is a really exciting

Today, we understand much more about the molecular underpinnings of cancer and how surgery, radiotherapy, and medical oncology can be used in concert to increase treatment effectiveness and decrease side effects. The number of new chemotherapies that allow patients to live full, active lives with their cancer— dealing with it as a chronic disease— is unparalleled.

All these advances offer tremendous hope for patients, and they present tremendous opportunities for greater job satisfaction for physicians, who now have the chance to be part of the revolution that changes cancer from a death sentence into a manageable disease.

Physicians now have the chance to be part of the revolution that changes cancer from a death sentence into a manageable disease.

—Craig B. Thompson, MD

time in oncology for all the reasons that we’ve discussed. When you consider my generation of oncologists, whether we chose to practice surgery, radiotherapy, or medical oncology—we all came to our careers knowing that for the vast majority of cancers there weren’t a lot of effective therapies we could offer patients. We were giving nonspecific chemotherapeutic agents, performing big surgical procedures, and using nonmodulated radiation therapy, so the side effects were enormously debilitating to patients.

Cost of Care With the cost of cancer care so high and skyrocketing national deficits, can we afford to deliver the best possible cancer care for all Americans?

Analyzing what is affordable at this particular time in history is difficult. People wondered whether we could afford to build the tuberculosis sanitoriums that were set up around the country in the early 1900s. Then researchers discovered the antibiotics that eradicated TB—both as an individual disease and as a public health problem—and suddenly treating TB

became very inexpensive.

We are seeing the same sort of revolution in cardiovascular care. As the most effective cholesterol-lowering statins come off patents, the cost of these drugs is decreasing dramatically. With better control over heart disease, people with these onceterminal illnesses are living longer, healthier, and more productive lives, caring for their families, getting back into the workforce, and contributing to their communities. That’s really the goal, but it’s going to take economists to analyze whether the tradeoff is worth it.

New therapies to fight disease are always going to cost more money. As opposed to our cardiology colleagues, who have a number of strategies to control heart disease, we’re still at the halfway point in cancer. We can treat some cancers effectively, but there are others that we still don’t understand well enough to know the best ways to diagnose them early or to optimize care so that patients can fulfill their life goals.

We are not at the endgame. We need to continue to further our understanding of cancer so we can eliminate the problems of treatment toxicities and the damage that can still occur as a result of surgery and radiation therapy, even with modern techniques. In the final analysis, we need to make treatment of all kinds simpler and more effective. This will not only make things better for patients, but will also bring down the cost of care.

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

SAVE THE DATE Gastrointestinal Cancers Symposium January 19-21, 2012 Moscone West Building San Francisco, California

Multidisciplinary Head and Neck Cancer Symposium January 26-28, 2012 Arizona Biltmore Phoenix, Arizona

Genitourinary Cancers Symposium February 2-4, 2012 San Francisco Marriott Marquis San Francisco, California

ASCOPost.com | NOVEMBER 15, 2011

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SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE T HE 5 - Y E A R S UR VIVAL R ATE I S 17 % F O R PATIENTS W ITH M E TA S TATIC S OF T TIS S UE SA RC OMA , YE T SI G N IF ICANT THER APEUTIC A D VA N CE MENTS AR E LAG GING. 1

NEW TREATMENTS ARE URGENTLY NEEDED.

Reference: 1. National Cancer Institute. Surveillance Epidemiology and End Results. seer.cancer.gov/statfacts/html/soft.html. Accessed March 19, 2010.

Merck Oncology

Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1003549-0001

The ASCO Post | NOVEMBER 15, 2011

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In the News

Challenging Perceptions about Treatment Options for Younger Women with Early-stage Breast Cancer

By Charlotte Bath

In the News focuses on media reports that your patients may have questions about at their next visit.

This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

cancer (T1-2, N0-1, M0). The reported median follow-up was 5.7 years, but Dr. Mahmood pointed out that roughly 3,000 women had 10 years of followup and 1,000 women had 15 years of follow-up.

No Differences in Survival

After accounting for patient and tumor characteristics, multivariable analysis found that breast-conservahere is a perception out there tion therapy resulted in an overall surthat just because a woman is vival similar to that found with mastecyounger, she might not have as good tomy, according to an abstract of the an outcome with breast-conservastudy presented by Dr. Mahmood at tion therapy as with mastectomy,” acthe 2011 Breast Cancer Symposium.1 Matched-pair analysis, including 4,644 cording to Usama Mahmood, MD, breast-conservation therapy and masa radiation oncology fellow at The tectomy patients, confirmed no differUniversity of Texas MD Anderson ence in overall or cause-specific surCancer Center in Houston. That pervival. The overall survival rates at 5, 10, ception, however, is being challenged and 15 years were 92.5%, 83.5%, and by recent studies—including one led 77.0% for breast-conservation theraby Dr. Mahmood when he was at py and 91.9%, 83.6%, and 79.1% for the University of Maryland—that mastectomy. The found no differcause-specific surences in diseaseThe concern is that vival rates at 5, 10, free and overall and 15 years were survival among local control differences 93.3%, 85.5%, and women with earmay be large enough to 79.9% for breastly-stage breast cancer treated lead to survival difference, conservation therapy and 92.5%, with breast-conbut our study did not 85.5%, and 81.9% servation therapy show that. for mastectomy. vs mastectomy.

“Based on our Reassuring large database,” Option Dr. Mahmood told The ASCO Post, “Ours was the largest analysis to “we were able to show that at least in date, and we again didn’t show any these unselected patients, there was differences. So that is reassuring that no difference in terms of survival, rebreast-conservation therapy should gardless of type of local treatment that be an option,” Dr. Mahmood said in the women chose. That’s important, an interview with The ASCO Post. because a lot of retrospective studies Information from 14,764 women suggest that there might be some difenrolled in the Surveillance, Epidemiference in local control. So the concern ology, and End Results (SEER) datais that local control differences may be base was analyzed to compare overall large enough to lead to survival differsurvival and cause-specific survival ences, but our study did not show that.” among patients undergoing mastecRadiation Boost tomy (55%) or breast-conservation For patients opting for breast contherapy (lumpecservation therapy, “probably the optitomy and radiation mal treatment at this time would be treatment, 45%). whole-breast radiation with a boost,” The women were 20 Dr. Mahmood said. “The original to 39 years old with SEE PAGE 60 study looking at breast-conservation early-stage breast

“T

Expect Questions from Your Patients

Y

oung women with early-stage breast cancer “should be counseled appropriately regarding their treatment options, and should not choose a mastectomy based on the assumption of improved survival,” maintained investigators presenting a retrospective study at the 2011 Breast Cancer Symposium. Their conclusion was based on an analysis of data from 14,764 women treated with either breastconservation therapy (lumpectomy and radiation) or mastectomy.1 Usama Mahmood, MD But what should that counseling involve? Family history and genetic predispositions are major factors to consider in helping women chose the most appropriate treatment,” according to the study’s principal investigator, Usama Mahmood, MD. Depending on the results of genetic testing, particularly whether or not BRCA1 and BRCA2 mutations are identified, “women might choose to undergo prophylactic treatments, such as oophorectomies or mastectomies, or even tamoxifen therapy, and those are important issues to be considered with their physicians,” Dr. Mahmood said.

“Unfortunately, in our analysis, we weren’t able to include that information, but it certainly does play a big role,” he added.

Multidisciplinary Evaluation Is Key “Mammograms play a big role in the diagnosis and follow-up of women with breast cancer, and we are increasingly looking at the utilization of breast MRI. It would seem that especially for younger women with dense breast tissue that decreases the sensitivity of mammograms, it makes sense to use MRI,” he stated.

“In general, it is always good to emphasize the importance of multidisciplinary evaluation,” Dr. Mahmood continued. “For women with breast cancer, this plays even more of a role in these younger women because there is more controversy. It’s best for these women to be evaluated in a multidisciplinary setting where you have not just surgeons and radiation oncologists, but also medical oncologists and pathologists, plastic surgeons, everyone who is involved in breast cancer management.”

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therapy, National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06, used whole-breast irradiation alone. Since then, a European Organisation for Research and Treatment of Cancer (EORTC) trial has compared whole-breast radiation to wholebreast radiation plus a focal radiation boost to the area where the tumor was excised and the surrounding tissue.

They found that you could reduce local recurrence rates when you use the boost, and the women who benefit most are the youngest cohort,” Dr. Mahmood explained.

The SEER data used in the study

Dr. Mahmood recently reported did not include information on whether the women receiving radiation also had a boost. “They may or may not have,” he said.

■

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

Reference 1. Mahmood U, Morris CG, Neuner GA, et al: Equivalent survival with breast conservation therapy or mastectomy in the management of young women with early stage breast cancer. 2011 Breast Cancer Symposium. Abstract 85. Presented September 8, 2011.

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Journal Spotlight Breast Cancer

Adjuvant Trastuzumab in Nonanthracycline Regimen Studied

O

ne of four large, randomized trials to evaluate adjuvant trastuzumab (Herceptin) in early-stage HER2-positive breast cancer—and the only study to include a nonanthracycline chemotherapy regimen—found that regimen had similar efficacy to anthracycline-containing regimens, but with lower rates of cardiac dysfunction and leukemia.

The Breast Cancer International Research Group (BCIRG) 006 study compared doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), to the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), and to docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH).

The two regimens with trastuzumab were superior in efficacy to AC-T and had similar disease-free survival—84% among patients receiving AC-T plus trastuzumab and 81% among those receiving TCH— and overall survival—92% vs 91%.

“The risk–benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia,” the investigators stated in The New England Journal SEE PAGE 60 of Medicine.1

“These observations establish TCH as another (but not ‘the’) standard of care for adjuvant treatment of HER2positive early-stage breast cancer,” commented Daniel F. Hayes, MD, of the Breast Cancer Program, University of Michigan Comprehensive Cancer,

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References 1. Slamon D, et al: Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365:1273-1283, 2011.

2. Hayes DF: Steady progress against HER2-positive breast cancer. N Engl J Med 365:1336-1338, 2011.

What role may MUC1 play in NSCLC

MUC1 (mucin 1) is a transmembrane glycoprotein that is normally found on the apical surface of most simple secretory epithelial cells and is associated with a number of diverse cellular functions.1 The functions of the extracellular domain of MUC1 are largely dictated by the extent of its glycosylation.1,2 The cytoplasmic tail of MUC1 can serve as a scaffold for interactions with intracellular proteins that affect cell survival and proliferation and can have direct effects on transcription within the nucleus.1,2

Protocol-specified Analysis

Select functions of MUC1 in normal cells • Lubricates epithelial surfaces3 • Acts as a physical barrier against microbes3 • Protects against proteolytic degradation3 • Involved in adaptive immunity against pathogens4 • Mediates normal T-lymphocyte responses and regulates T-lymphocyte proliferation5 • Involved in signal transduction, which regulates cell survival and proliferation2 • Can directly affect transcription within the nucleus1

110718-140032

The 3,222 women participating in the study had HER2-positive, invasive, highrisk, node-negative or node-positive adenocarcinoma. Demographic and clinical characteristics, including cardiac risk factors, were similar among the women in the three treatment groups. At a median follow-up of 65 months, when 656 events triggered the protocol-specified analysis, the incidence of congestive heart failure was 2% in the group receiving AC-T plus trastuzumab, 0.7% in the AC-T group, and 0.4% in the TCH group.

“The incidence with AC-T plus trastuzumab as compared with TCH was increased by a factor of 5,” the authors reported. “The difference in rates of congestive heart failure between the two trastuzumab-containing regimens significantly favored TCH over AC-T plus trastuzumab (P < .001).” Seven cases of leukemia were reported in the groups receiving the anthracyclinebased regimens. The one case in the TCH group occurred in a woman who had received an anthracycline for the treatment of a B-cell lymphoma after breast cancer was diagnosed.

Ann Arbor, in an editorial accompanying the study.2 He added that newer studies, some testing agents “that target HER2 in different ways or target complementary pathways,” could make for a brighter future for patients with HER2-positive breast cancer.

Overexpression, altered distribution, and aberrant glycosylation of MUC1 have been observed in a variety of cancers, including non-small cell lung cancer (NSCLC).1,2,6 Aberrant overexpression of MUC1 by tumor cells is associated with several mechanisms of tumor cell survival.6-8 Overexpression of MUC1 may play a role in

abnormal cell signaling through interactions with regulatory proteins, such as with EGFR.2,7 In addition, the cytoplasmic tail of MUC1 can be targeted to the nucleus, where it interacts with transcription factors for genes related to invasion, angiogenesis, and metastasis.7,8 Furthermore, cells overexpressing tumor-associated MUC1 may escape the host immune response by suppression of the T-cell proliferation response and by failure to process and present MUC1 on class II major histocompatibility complexes.9,10 At EMD Serono, we’re investigating the significance of MUC1 and its impact on your patients with NSCLC. Visit www.emdserono.com to learn more about EMD Serono Oncology.

1. Hattrup CL, Gendler SJ. Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol. 2008;70:431-457. 2. Bafna S, Kaur S, Batra SK. Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells. Oncogene. 2010;29(20):2893-2904.

3. Carson DD. The cytoplasmic tail of MUC1: a very busy place. Sci Signaling. 2008;1(27):pe35.

4. McAuley JL, Linden SK, Png CW, et al. MUC1 cell surface mucin is a critical element of the mucosal barrier to infection. J Clin Invest. 2007;117(8):2313–2324. 5. Agrawal B, Longenecker BM. MUC1 mucin-mediated regulation of human T cells. Int Immunol. 2005;17(4):391-399.

6. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816. 7. Ahmad R, Raina D, Joshi MD, et al.

MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor.

Cancer Res. 2009;69(17):7013-7021. 8. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42):5667-5677. 9. Agrawal B, Krantz MJ, Reddish MA, Longenecker BM. Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2.

Nat Med. 1998;4(1):43-49. 10. Hiltbold EM, Vlad AM, Ciborowski P, Watkins SC, Finn OJ. The mechanism of unresponsiveness to circulating tumor antigen MUC1 is a block in intracellular sorting and processing by dendritic cells. J Immunol. 2000;165:3730-3741.

EMD Serono Oncology | Combination is key™

EMD Serono, Inc. is an affiliate of Merck KGaA, Darmstadt, Germany

003296_emddsa_de_muc1_lv_fa1.indd 1

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In the Literature

Emerging Clinical Data on Cancer Management COLORECTAL CANCER MRI Helps Predict Survival Outcomes in Patients with Rectal Cancer Magnetic resonance imaging (MRI) can be used after neoadjuvant therapy for rectal cancer to predict survival outcomes for good and poor responders and offer patients additional treatment options before definitive surgery, according to a study conducted at 11 specialist colorectal cancer units in five European countries. “This is the first time that a prospective study has demonstrated a correlation between radiologically determined tumor response and long-term outcomes,” the investigators reported in the Journal of Clinical Oncology.

In this prospective cohort study, 111 patients with rectal cancer treated by neoadjuvant therapy were assessed for response by MRI and pathology staging by tumor, node, and circumferential resection margin status. Tumor regression grade was also assessed by MRI. The study is a planned subgroup analysis of patients undergoing neoadjuvant therapy and total mesorectal excision surgery in the MERCURY (Magnetic Resonance Imaging in Rectal Cancer European Equivalence Study) trial.

Predictive Parameters Overall survival at 5 years for patients with poor tumor regression grade as assessed by MRI was 27% vs 72% for patients with good tumor regression grade on MRI (P= .001), while disease-free survival was 31% vs 64% (P = .007). “Preoperative MRI-predicted [circumferential resection margin] independently predicted local recurrence,” the researchers reported. Local recurrence rates at 5 years were 28% for patients with predicted circumferential resection margin involvment on MRI vs 12% for patients with a predicted clear margin on MRI (P = .013).

Postoperative histopathology assessment of circumferential resection margin was significant on multivariate analysis for overall survival, disease-free survival, and local recurrence.

Fiveyear survival for SEE PAGE 60 patients with poor

post-treatment pathologic T stage was 39% vs 76% for patients with good pathologic T stage (P= .001). “Pathology node status did not predict outcomes,” the investigators noted.

MRI assessment of tumor regression grade after preoperative therapy predicts disease-free and overall survival, and thus patient prognosis, before definitive surgery, the authors concluded. “Post-treatment MRI prediction of [circumferential resection margin] involvement also gives important prognostic information regarding the risk of [local recurrence].”

Patel UB, et al: J Clin Oncol 29:37533760, 2011.

Should Age at Initial Screening Colonoscopy Be Younger for Men? A study to investigate the most appropriate age for initial screening colonoscopy to improve detection of adenomas, advanced adenomas, and colorectal cancer, and lower colorectal cancer mortality found that the most appropriate age might be different for men and women.

“In our study, analysis of age- and sex-specific prevalence of adenomas, [advanced adenomas], and [colorectal cancer] indicates a significantly higher rate of these lesions among men compared with women in all age groups, suggesting that male sex constitutes an independent risk factor for colorectal carcinoma and indicating new sex-specific age recommendations for screening colonoscopy,” the researchers reported in the Journal of the American Medical Association.

Major Results Researchers from the Austrian Society for Gastroenterology and Hepatology and the Medical University of Vienna analyzed the results among 44,350 men and women participating in a national colonoscopy screening program. The median ages were 60.7 years for women, who constituted 51% of participants, and 60.6 years for men.

Adenomas were found in 19.7% of individuals screened, advanced adenomas in 6.3%, and colorectal cancer in 1.1%. The prevalence of adenomas was 24.9% for men and 14.8% for women; among 50- to 54-year-old men, the prevalence was 18.5%, which was greater than the prevalence among

women in the same age group (10.7%) but similar to the prevalence among 65- to 69-year-old women (17.9%).

The prevalence of advanced adenomas in 50- to 54-year-olds was 5.0% in men but 2.9% in women, with no statistically significance difference between men aged 45 to 49 years (3.8%) and women aged 55 to 59 years (3.8%). Colorectal cancer prevalence was twice as high among men, 1.5% vs 0.7% among women. Colorectal cancer prevalence among women aged 65 to 69 was 1.2%, similar to the 1.3% rate among men aged 55-to 59.

Screening Recommendations The authors noted that the age for referring average-risk patients to screening colonoscopy is 50 years for both men and women because of the increase in the prevalence of colorectal cancer in the sixth decade of life.

“Deciding whether to adjust the age at which screening begins also requires considering whether the recommended age for women should be older or the recommended age for men younger,” the researchers wrote.

In addition, the study offered support for complete colonoscopy. “In our study, 55% of polyps were found in the sigmoid colon or rectum and 45% proximal to the sigmoid colon or in both parts of colon,” they authors stated. “Approximately 50% of polyps would not be detected if only sigmoidoscopy were used for screening purposes. Therefore, our data support the importance of complete colonoscopy to cecum as a screening tool to find and remove all adenomas and [advanced adenomas].”

Ferlitsch M, et al: JAMA 306:13521358, 2011.

Oxaliplatin Improved Overall Survival in Patients under 70 The addition of oxaliplatin to fluorouracil (5-FU) plus leucovorin improved overall survival in patients younger than 70 years old participating in the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial. Patients eligible for the trial had either stage II or III colon cancer and had undergone potentially curative surgical resection with no evidence of residual malignant disease.

Of the 2,409 patients included in the analyses, 1,209 had been randomly

assigned to the 5-FU/leucovorin arm and 1,200 to the 5-FU/leucovorin plus oxaliplatin arm. “[Overall survival] did not differ significantly by treatment in the full cohort of this study,” according to updated NSABP C-07 trial results, including survival and subset analyses, published in the Journal of Clinical Oncology. The overall survival estimates at 5 years were 78.4% for 5-FU/leucovorin and 80.2% for 5-FU/leucovorin/ oxaliplatin, an absolute difference of 1.8%, favoring the oxaliplatin-containing regimen, the authors reported.

In an exploratory subset analysis by age, however, overall survival was significantly improved with 5-FU/ leucovorin/oxaliplatin compared with 5-FU/leucovorin for patients younger than 70 (HR = 0.80; 95% CI = 0.68– 0.95; P = .013). The 5-year overall survival estimates were 78.8% for 5-FU/ leucovorin and 81.8% with the addition of oxaliplatin, “a 3.1% improvement in patients younger than age 70 years,” the authors added.

Differences Related to Toxicity?

“Our finding that the effect of oxaliplatin differs by age group is provocative,” the authors stated. They suggest that the differences may be related to toxicity. Patients age 70 years or older were more likely to experience grade 4 or 5 toxicity with 5‑FU/leucovorin/oxaliplatin, while in younger patients the toxicity rates for the two treatments were similar. “These differences in toxicity are not conclusive, but they do suggest that older patients may be more likely to have adverse outcomes related to treatment with oxaliplatin,” the authors reported.

“Patients age 70 years or older received approximately 25% less oxaliplatin overall compared with younger patients, but dose intensities were similar, which suggests that older patients received fewer cycles,” they added.

“Although a chronologic age of at least 70 years may not be an ideal marker for the true cause of differences in outcome, it appears to be the best marker currently available.

In making treatment decisions for individual patients, we suggest that advanced age be one factor taken into account when oxaliplatin is being considered,” the authors continued.

They advised caution in selecting pacontinued on page 60

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In the Literature

Emerging Clinical Data continued from page 58

tients of advanced age for oxaliplatin therapy. “Consideration should be given to the patient’s overall state of health and potential for tolerating adverse events,” they concluded.

Yothers G, et al: J Clin Oncol 29:37683774, 2011.

BREAST CANCER Low-level Expression of ESR1 Tied to Tamoxifen Resistance Data from a retrospective analysis of two pivotal breast cancer studies suggest that the low-level expression of the estrogen receptor (ER) gene ESR1 “is a determinant of tamoxifen resistance in ER-positive breast cancer,” reported researchers in the Journal of Clinical Oncology.

“We performed gene expression

profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1),” the authors explained. Paraffin blocks with sufficient invasive breast cancer for RNA extraction were available from 645 of the 2,817 randomly assigned patients in the NSABP B-14 study and from 108 of the 13,338 patients in the P-1 study. In that study, “30% of ER-positive tumors were not prevented by tamoxifen,” the investigators noted.

“In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined,” the researchers found. “On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than

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two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression,” the investigators wrote.

Study Implications “The limitations of subset analysis have been detailed elsewhere and are always a concern in interpretation of data,” the authors acknowledged.

“However, the confirmation of B-14 results by P-1 results supports the conclusion that low levels of ER are at least in part responsible for tamoxifen resistance in breast cancer.”

The finding that tamoxifen is less effective in preventing ER-positive tumors with low levels of ESR1 means that “strategies should be developed to identify, treat, and prevent such tumors,” the researchers concluded.

Kim C, et al: J Clin Oncol Sept. 26, 2011 (early release online).

Fewer False-positives, Small Increased Risk of Late Diagnosis with Biennial Mammography Screening mammography every other year reduced false-positive recalls by about one-third compared to annual screening, but was associated with a small increase in the probability of latestage cancer diagnosis, according to a study funded by the NCI and published in Annals of Internal Medicine. To compare the cumulative probability of falsepositive results and stage of cancer diagnosis after 10 years of screening with either an annual or a biennial schedule, researchers analyzed data from 169,456 women who underwent first screening mammography at ages 40 to 59 and 4,492 women diagnosed with incident invasive breast.

“Cumulative probability of falsepositive biopsy recommendation was 7.0% (CI, 6.1% to 7.8%) with annual and 4.8% (CI, 4.4% to 5.2%) with biennial screening,” the researchers reported. “A non–statistically significant increase in the proportion of late-stage cancers was observed with biennial compared with annual screening (absolute increases, 3.3 percentage points [CI, −1.1 to 7.8 percentage points] for women age 40 to 49 years and 2.3 percentage points [CI, −1.0 to 5.7 percentage points] for women age 50 to 59 years) among women with incident breast cancer.”

The researchers concluded that after 10 years of annual screening, more than half of women will have at least

one false-positive recall, and 7% to 9% will have a false-positive biopsy recommendation. “Biennial screening appears to reduce the cumulative probability of false-positive results after 10 years but may be associated with a small absolute increase in the probability of late-stage cancer diagnosis,” they added.

Hubbard RA, et al: Ann Intern Med 155:481-492, 2011.

OVARIAN CANCER Alternative Treatment for Advanced Ovarian Cancer Reduces Neurotoxicity and Alopecia A randomized phase III clinical trial found that carboplatin/pegylated liposomal doxorubicin (Doxil) was not superior in prolonging progression compared to the standard carboplatin/paclitaxel as first-line therapy of patients with advanced ovarian cancer.

The carboplatin/liposomal doxorubicin regimen, however, “can be considered a reasonable alternative for first-line treatment of advanced ovarian cancer, particularly in patients at high risk of neurotoxicity or wishing to avoid alopecia,” the trial’s investigators concluded. “This choice, of course,” they noted, “should take into account patient’s [preferences] and consider limitations as a result of the lack of regulatory approval of [pegylated liposomal doxorubicin] for first-line treatment and its cost.”

In the Multicentre Italian Trials in Ovarian Cancer-2 (MITO-2), carboplatin/liposomal doxorubicin produced a response rate similar to the standard carboplatin/paclitaxel in chemotherapy-naive patients with stage IC to IV ovarian cancer. The patients were ≤ 75 years old with an Eastern Cooperative Oncology Group performance status ≤ 2.

“The favorable prognostic characteristics of the enrolled patients (significant proportion of patients with early-stage disease and of patients without residual disease after surgery)” resulted in “a dramatic decrease in the incidence of [progression-free survival] events,” the study investigators reported. Because getting the planned number of events would have required much more time and “non–ovarian cancer deaths might dilute [progression-free survival] differences,” the final MITO-2 analysis was performed with fewer events than planned, “but

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In the Literature

it is unlikely that this affected the results,” the researchers stated. Those results showed that median progressionfree survival was 16.8 months in the standard arm and 19.0 months in the experimental arm.

Multivariate Analysis “In multivariable analysis adjusted by stage, performance status, residual disease, age, and size of the institution, the difference between treatments remained not significant,” the authors wrote.

“Nonhematologic toxicity significantly differed between the arms, with hair loss and neurotoxicity being drastically less frequent in the experimental arm, but with this arm having more skin toxicity and stomatitis. Hematologic toxicity was also worse with experimental treatment but within acceptable limits for clinical practice,” they added.

42% to 32%. The 4-year survival rates were 51% for patients treated with total laryngectomy and 48% for those treated with chemoradiation.

“For the patient, choosing between [chemoradiation] and laryngectomy is not a trivial decision,” the authors noted. “Laryngectomy may result in a total loss of voice and sometimes impair-

ment of swallowing function, leading to a decreased quality of life. However, treating advanced laryngeal cancer with [chemoradiation] can result in complications such as renal failure and bone marrow suppression. Later complications, such as persistent dysphagia, gastrostomy tube dependency, pharyngoesophageal stenosis, chronic

lung aspiration, and permanent tracheotomy tracheotomy dependence, can occur.” The authors added that some patients receiving chemoradiation may still require a laryngectomy because of a dysfunctional larynx or persistent disease.

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Chen A, et al: Arch Otolaryngol Head Neck Surg 137:1017-1024, 2011.

2012 Gastrointestinal Cancers Symposium Science and Multidisciplinary Management of GI Malignancies

Pignata S, et al: J Clin Oncol 29:36283635, 2011.

HEAD AND NECK CANCER Rates of Surgery and Survival Increasing for Early-stage Cancers Surgery is increasingly being used to treat patients with early-stage laryngeal cancer in the United States, and chemotherapy in combination with radiation therapy is being used increasingly to treat patients in an advanced stage of the disease, according to a report in the October issue of Archives of Otolaryngology—Head & Neck Surgery.

Researchers from Emory University and the American Cancer Society analyzed data on 131,694 laryngeal cancer cases diagnosed from 1985 to 2007, identified from the National Cancer Database. The proportion of patients with early-stage disease receiving primary surgery increased from 20% in 1985 to 33% in 2007, while the use of radiation therapy decreased from 64% to 52%. The 4-year survival rate was higher for patients with early-stage laryngeal cancer treated with surgery than for those treated with radiation therapy (79% vs 71%), the investigators reported.

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Housing and Early Registration Deadline: December 14, 2011 at 11:59 PM (EST)

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• Fundamental themes in each track such as the etiology and prevention of cancer, risk and screening, clinical trial development, and targeted therapies • Multidisciplinary panel discussions featuring Surgical, Medical, and Radiation Oncologists’ perspectives • Keynote Lecture: On Being a Surgical Oncologist by Murray F. Brennan, MD of Memorial Sloan-Kettering Cancer Center

• Four concurrent morning and evening Meet the Professor Sessions on topics such as: > Novel Phase II Trial Designs for Biomarker-driven Studies > Daily Issues of Cancer Survivorship • Translational Research Sessions on Cancer Stem Cell Updates and the Biology and Potential Therapeutic Implications of Autophagy • New this year: Virtual Meeting and Mobile Meeting have been combined into one product and are included with registration

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Not a Trivial Decision Among patients with advancedstage cancer, the use of chemoradiation increased from less than 7% to 45%, the researchers found, whereas total laryngectomy decreased from

TARG E T I NG

C A NC E R

C A RE

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Health-care Policy Issues in Oncology

ASCO Supports the United Nations Political Declaration on Noncommunicable Diseases

Target goals include reducing tobacco and alcohol use and increasing access to affordable, quality medical care.

By Jo Cavallo

I

n September, government leaders from around the world as well as representatives from civil society, the private sector and academia gathered at the United Nations in New York for the first-ever summit on the growing economic and human crisis posed by noncommunicable diseases (NCDs), especially in low- and middle-income countries. According to data from the World Health Organization (WHO), noncommunicable diseases—mainly cancers, cardiovascular diseases, diabetes, and chronic respiratory diseases— are the world’s biggest killers, accounting for over 60% of all deaths globally, chiefly from cancer—7.6 million people annually. That figure represents more deaths than from HIV/AIDS, malaria, and tuberculosis combined.

Looming Crisis Unless interventions are put in place to alter this trend, warns WHO, mortality rates will rise by 17% over the next 10 years—with a projected increase of 24% in the poorest African countries.

The World Economic Forum puts the cost in lost productivity and medical care over the next 2 decades at $47 trillion. To avert this looming crisis, member nations attending the UN General Assembly High-level Meeting on the Prevention and Control of Noncommunicable Diseases voted unanimously to adopt the Political Declaration, which calls for the establishment of specific steps by 2013 to reduce the incidence of noncommunicable diseases and their devastating consequences.

“A very welcome and positive observation of the meeting was that all member states, regardless of socioeconomic status, showed a unity in supporting the guidelines and fighting the threat of NCDs. The Political Declaration also sets out the need for allocating more resources to control cancer and other NCDs, as well as optimal use of existing resources,” said Tanja Cufer, MD, PhD, Chair of ASCO’s International Affairs Committee and Professor of Oncology at Medical Faculty, University of Ljubljana in Slovenia.

Proposed Measures Some of the Declaration’s actions

include: ■■ National policies to prevent and control noncommunicable diseases ■■ Information systems for health planning and management and the development of population-based

efforts against them,” said ASCO CEO Allen S. Lichter, MD, in a statement.

Important Starting Point The Declaration is also being heralded by the Union for International

The power of ASCO is that its members are usually the best doctors in each country.

—Eduardo L. Cazap, MD, PhD

national registries to track noncommunicable disease incidences ■■ International agreements and legal and regulatory measures to reduce an individual’s risk factors for noncommunicable diseases, including restrictions on tobacco and alcohol use and the promotion of healthier diets and physical exercise ■■ Improvements in access to palliative care and to affordable, safe, effective, and quality medicines and technology ■■ Greater priority to early detection, screening, and diagnosis of noncommunicable diseases, especially cancer screening programs for breast and cervical cancers ■■ Increased access to hepatitis B and human papillomavirus vaccines as part of national immunization programs to prevent infection-related cancers ASCO immediately announced its support of the actions outlined in the Political Declaration. “For many years, ASCO has been aware of this growing issue [of noncommunicable diseases], particularly as it relates to cancer, and we are glad to see it recognized by our world leaders. The Political Declaration on NCDs is of enormous importance to the cancer community and organizations like ASCO in particular.

We look forward to establishment of the Declaration targets and identifying opportunities to match our ongoing

Cancer Control (UICC) as an important step in the global recognition of the threat posed by skyrocketing cancer and other noncommunicable disease rates, even though the document lacks specific target goals, such as reducing avoidable deaths from noncommunicable diseases by 25% by 2025 (as called for by WHO) and a system for evaluating progress.

“From the point of view of putting cancer and other NCDs on the global political agenda, the Declaration is a very important starting point for future actions. The UN summit was a success because now all the countries in the world will be obliged to fulfill the recommendations in the document,” said Eduardo L. Cazap, MD, PhD, President of the UICC, Co-chair of the UN Civil Society Task Force, and an ASCO board member. In addition, the Declaration provides cancer organizations, such as ASCO and UICC, with additional ammunition to have the reduction of the incidence of cancer and other noncommunicable diseases added to the UN’s Millennium Development Goals, which range from lowering rates of extreme poverty to stopping the spread of HIV/AIDS by 2015.

“There will be a review of the [target areas] in the Millennium Development Goals in 2013. Adding cancer to the list of targeted goals is a very important step because not having cancer includ-

ed is an obstacle to successfully reducing worldwide cancer incidence,” says Dr. Cazap. “For example, if a country is requesting support from the World Bank or other agencies, and the issue of cancer is not included in the Millennium Development Goals, it’s not a priority for international funding.”

Next Steps Now that the Declaration has been approved, participating countries—especially developing countries—have the task of putting in place the infrastructure necessary to implement the agreed upon actions contained in the document. To be effective in reducing the number of noncommunicable diseases, all areas of government, not just the public health sector, will have to be involved, including the departments of agriculture, finance, education, and transportation, says Dr. Cazap.

Another important component for success is the development of a global accountability framework to measure the implementation of policies to prevent cancer and other noncommunicable diseases and monitor progress. The NCD Alliance, which includes the UICC, World Heart Federation, International Diabetes Federation, and International Union Against Tuberculosis and Lung Disease, has asked WHO to establish a monitoring, evaluation, and accountability system for presentation at a meeting of the World Health Assembly scheduled in 2013.

ASCO, too, has an important role to play in the process of reducing cancer deaths globally. “The power of ASCO is that its members are usually the best doctors in each country. So my message to our members, especially to our nonU.S. members, is that they must be part of this action and work together with government and the medical society of the country they live in and try to make these resolutions real and applicable.

We now have an incredible tool to put pressure on a local level to achieve better cancer control in individual countries. And I think that is an important responsibility that comes with the power ASCO members have in countries around the world,” said Dr. Cazap.

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Disclosure: Drs. Cazap, Cufer, and Lichter reported no potential conflicts of intrest.

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Health-care Policy

Drug Shortages

To put it simply, Medicare reimburses physicians for chemotherapy cytarabine, the cure is 0%. This shortdrugs at 6% above an average sales age potentially affected thousands of price, whose calculation is flawed at patients who were diagnosed with best. When such a drug becomes geAML and treated in the approximately neric, initial competition reduces the 6-month period when cytarabine was price drastically, weeding out weaker out of stock. Today we face a shortage manufacturers and leaving fewer to of the second produce the drug. most important profit margin for Cytarabine-containing The drug in AML, these drugs is small chemotherapy regimens daunor ubicin. to begin with and Fortunately, this cure 40% of patients with can only be adjustdrug can be reed every 6 months.

AML; without cytarabine, Because there is no placed by idarubicin with potensuch rule in Europe, the cure is 0%. tially different the prices of generic ­—Hagop M. Kantarjian, MD toxicities. Still, drugs are slightly daunorubicin is higher than in the used in many of United States, and the leukemia clinical trials in AML in the prices of brand name drugs are this country, and its shortage has crelower (because of agreements beated havoc in AML research. tween governments and drug companies), ensuring an enduring and reaFollowing the Money sonable profit margin. No shortages Pundits and politicians wring of generic drugs have been reported their hands but offer few solutions. in Europe.

The solutions are, in fact, straightIn the United States, the solution forward if we look closer at the root is simple: Revise the Medicare rule so causes. So far, the shortages have that generic drugs could be priced at been explained by a variety of fac10% to 20% of the price of the brandtors, such as insufficient raw materiname equivalent, depending on the als, manufacturing flaws, overzealous price of the brand name, and allow FDA enforcement, regulatory rules for price adjustments of 10% to 20% leading to shutdown of plants, and every 6 months based on changes in consolidation of generic companies. the average sales price. This ensures There is little actual data to support manufacturers a reliable profit margin any of these reasons as the cause of and offers an incentive to continue the chemotherapy shortages. producing the drug.

Let us follow the money and conDrug Hoarding template two more plausible explanaThe hoarding of essential drugs— tions: (1) the Medicare “ASP+6” rule, and the resulting gray market—is and (2) hoarding of medications by another problem. Distributors of the distributors (politely referred to as a drugs have inside information on “gray market”). The ASP+6 rule was when the supply may be drying up, included in the 2003 Medicare legisallowing them lead time to stockpile lation, capping at 6% the amount over a supply. Once the shortage is wide the average sales price that Medicare enough, they can sell the drug at up reimburses physicians for drugs used to 100 times the original price. Such in their practices. The average sales price gouging was well documented price includes many pharmaceutiduring the cytarabine shortage. Becal company discounts and rebates cause Medicare does not allow upprovided to large buyers and can be date of the ASP but every 6 months, significantly less than the price paid doctors who bought the drug at high by a small-town oncology practice. prices to save their patients’ lives took This means that many doctors are ala bath. ready “underwater” when they buy Legislation proposed by U.S. Senathe drug, like homeowners who owe tors Amy Klobuchar (D-MN) and more money on their houses than Bob Casey (D-PA) would mandate they are worth. Medicare also manthat manufacturers inform the FDA dates that the price cannot increase at least 6 months ahead of a potential more than 6% every 6 months, leavshortage, but this could be a doubleing little flexibility for reimbursable edged sword: It would allow the FDA prices to adapt to a free market of supto seek alternative sources, but would ply and demand. continued from page 1

also alert distributors to start hoarding. This could be stopped with federal regulations making “scalping” of essential live-saving drugs in a blackmarket environment a criminal activity since it can cause the death of U.S. citizens.

The greatness of a civilized society is measured by how well it treats its

O

weakest members—the sick and the poor. In a nation such as the United States, it is a shame and it is shameful that we condone such drug shortages, which are entirely preventable and which can make a difference between life and death.

■

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

White House Issues Executive Order on Drug Shortage

n October 31, President Barack Obama issued an executive order instructing the FDA to broaden reporting of potential drug shortages, expedite reviews of applications to begin or modify production of these drugs, and provide more information to the Justice Department about possible cases of collusion or price gouging. The President also announced his support for House and Senate legislation that would require drug companies to notify the FDA 6 months ahead of a potenMichael Link, MD tial shortage.

In a statement released by ASCO, also on October 31, ASCO President Michael Link, MD, commented on the White House Executive Order on Drug Shortages, saying: The problem of cancer drug shortages continues to compromise the best possible patient care and is setting back the significant advancements being made in clinical cancer trials. ASCO has worked hard over the past year to raise awareness of these shortages and to find both immediate and permanent solutions.

The White House executive order is a good first step to addressing the problem.

ASCO stands ready to work with Congress and all oncology stakeholders on a comprehensive solution that puts patient health and research progress first.

To report information on how oncology drug shortages are affecting your practice, contact: ■■ ASCO at publicpolicy@asco.org or 571-483-1368 ■■ FDA at drugshortages@fda.hhs.gov ■■ ASHP at http://www.ashp.org/DrugShortages/Report/

■

© Christopher Weyant/The New Yorker Collection/www.cartoonbank.com

Antibody-drug conjugates (ADCs):

Can an ADC be greater than the sum of its parts?

Antibody-drug conjugates: Taking targeted therapy to the next level ADCs are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic agent and are designed to selectively kill cancer cells while minimizing effects on normal tissue.1-5

Monoclonal antibody

Stable linker

Cytotoxic agent

targets antigens that are preferentially or exclusively expressed on the surface of cancer cells and may retain anticancer effects1,3,6-8

designed to allow an ADC to remain inactive while in circulation1,2,7-9

incorporated into an ADC may be up to 1000-fold more potent than currently used chemotherapies7

These investigational ADCs have multiple proposed mechanisms of action, including antibody-mediated anticancer activities and targeted intracellular delivery of a potent cytotoxic agent.6 They may provide higher tumor selectivity, enhancing the cell-killing potential of monoclonal antibodies and improving tolerability.2,7,10

Visit www.ResearchADCs.com to learn more References:

1. Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146. 3. Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255. 4. Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925-932. 5. Ghose T, Blair AH. Antibody-linked cytotoxic agents in the treatment of cancer: current status and future prospects. J Natl Cancer Inst. 1978;61:657-676. 6. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169. 7. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107. 8. Oflazoglu E, Stone IJ, Gordon K, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171-6180. 9. Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852. 10. Ducry L, Stump B. Antibody窶電rug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21:5-13.

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