Ixabepilone Plus Capecitabine for Metastatic Breast Cancer Progressing After Anthracycline and Taxane Treatment Eva S. Thomas, Henry L. Gomez, Rubi K. Li, Hyun-Cheol Chung, Luis E. Fein, Valorie F. Chan, Jacek Jassem, Xavier B. Pivot, Judith V. Klimovsky, Fernando Hurtado de Mendoza, Binghe Xu, Mario Campone, Guillermo L. Lerzo, Ronald A. Peck, Pralay Mukhopadhyay, Linda T. Vahdat, and Henri H. Roché A B S T R A C T Purpose Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demon- strated synergy with capecitabine in this setting. This study was designed to compare ixabepilone plus capecitabine versus capecitabine alone in anthracycline-pretreated or -resistant and taxane- resistant locally advanced or metastatic breast cancer. Patients and Methods Seven hundred fifty-two patients were randomly assigned to ixabepilone 40 mg/m 2 intrave- nously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m 2 orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m 2 on the same schedule, in this international phase III study. The primary end point was progression-free survival evaluated by blinded independent review. Results Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P = .0003). Objective response rate was also increased (35% v 14%; P  .0001). Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [ grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups. Conclusion Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes. J Clin Oncol 25:5210-5217. © 2007 by American Society of Clinical Oncology INTRODUCTION Breast cancer is the most prevalent malignancy in women and metastatic breast cancer is a leading cause of mortality, accounting for more than 400,000 deaths annually worldwide. 1 Even though anthracyclines and taxanes are the most active agents in breast cancer, treatment failure occurs in a substantial number of patients and median survival for metastatic breast cancer remains 2 to 3 years. 2-4 Resistance to antineoplastic agents, and in particular anthracyclines and taxanes, is a limiting factor in breast cancer therapy, either after metastatic or adjuvant treatment. 3,5 With increasing use of an- thracyclines and taxanes for early breast cancer, fewer effective options are available for patients with metastatic disease. 3,4 Capecitabine is com- monly used for the treatment of anthracycline- and/or taxane-pretreated metastatic breast can- cer; however, objective response rates in phase II studies are only 20% to 28%. 6,7 Therefore, there is an unmet need for new treatments of hormone- and chemotherapy-resistant, locally advanced, and metastatic breast cancer. The epothilones are a new class of antineoplas- tic agents that stabilize microtubule dynamics lead- ing to apoptotic cell death. They were developed to overcome tumor resistance mechanisms. Ixabepi- lone (BMS-247550; Bristol-Myers Squibb, New York, NY), a semisynthetic analog of epothilone B, is the first agent in this class and has been specifically designed to provide enhanced antitumor activity relative to other antineoplastic agents. In preclinical models, ixabepilone demonstrated low susceptibil- ity to mechanisms that confer tumor resistance, such as overexpression of efflux transporters (eg, From the M.D. Anderson Cancer Center, Houston, TX; Instituto Nacional de Enfermedades Neoplasicas; Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru; St Luke’s Medical Center; Veterans Memorial Medical Center, Quezon City, Philippines; Yonsei Cancer Center, Seoul, Republic of Korea; Centro de Oncologia Rosario, Sante Fe; Hospital de Oncologia ‘Maria Curie,’ Buenos Aires, Argentina; Medical University of Gdansk, Gdansk, Poland; C.H.U. Jean Minjoz, Besanc ¸ on; Centre Rene Gauducheau, Nantes; Institut Claudius Regaud, Toulouse, France; Bristol-Myers Squibb, Research and Development, Wallingford, CT; Cancer Hospital – Chinese Academy of Medical Sciences, Beijing, China; and Weill Medical College of Cornell University, New York, NY. Submitted May 30, 2007; accepted August 21, 2007; published online ahead of print at www.jco.org on October 29, 2007. Supported by Bristol-Myers Squibb. Interim efficacy and safety analyses were supervised by an independent data-monitoring committee. The authors vouch for the completeness and accuracy of results presented. Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 3, 2007, Chicago, IL. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Address reprint requests to Eva S. Thomas, MD, 280 West MacArthur Blvd, Oakland, CA 94611; e-mail: eva.s.thomas@kp.org. © 2007 by American Society of Clinical Oncology 0732-183X/07/2533-5210/$20.00 DOI: 10.1200/JCO.2007.12.6557 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 25  NUMBER 33  NOVEMBER 20 2007 5210 Downloaded from jco.ascopubs.org on May 7, 2012. For personal use only. No other uses without permission. Copyright © 2007 American Society of Clinical Oncology. All rights reserved.