Pharmacy & Therapeutics - September 2008 - (Page 523)

DRUG FORECAST Ixabepilone (Ixempra), a Therapeutic Option for Locally Advanced or Metastatic Breast Cancer Nancy Egerton, PharmD, BCOP ABSTRACT Ixabepilone (Ixempra) is a member of a new class of cytotoxic agents, the epothilones. Epothilones promote tubulin polymerization in vitro and dem onstrate antitumor activity. This article reviews the preclinical and clinical data that have led to the approval of ixa bepilone for patients with locally advanced or metastatic breast cancer for whom anthracycline and taxane treatments have failed. Key words: ixabepilone, breast cancer, metastatic, locally advanced, epothilones, taxanes, anthracyclines, capecitabine INTRODUCTION In 2007, it was estimated that breast cancer would account for more than 40,000 deaths in the U.S.1 The outcome for patients with advanced breast cancer has improved significantly in recent years. Mortality rates have declined as a result of better mammography screening and improved therapies with the introduction of new medications.2–5 Of these agents, the taxanes and anthracyclines have emerged as the cornerstones of therapy for advanced disease as well as for early-stage breast cancer. Unfortunately, although taxanes and anthracyclines are highly active initially, treatment failure occurs in a substantial number of patients, and median survival for metastatic breast cancer is two to three years.3,6–8 In more than 90% of patients with metastatic cancer, treatment failure occurs as a result of the development of cross-resistance to antineoplastic agents.9 This multidrug resistance phenotype is thought to be conferred via the overexpression of efflux transporters, such as P-glycoprotein (P-gp), and other multidrug-resistant proteins that serve as efflux pumps, effectively removing anticancer agents from targeted tumor cells. Other mechanisms of anticancer drug resistance include alterations in target proteins, such as beta-tubulin, as in the case of taxanes.9–12 The fact that both anthracyclines and taxanes are susceptible to a range of multidrug resistance mechanisms represents a considerable limiting factor in breast cancer therapy. 13–15 The increased use of these agents in the adjuvant setting for earlierstage breast cancer means that fewer effective options are available for patients with advanced disease.2,4 For patients who no longer respond to anthracyclines and taxanes, cap ecitabine (Xeloda, Roche) is commonly used, but objective response rates (ORRs) are repor ted to be low (9%– 14%).16,17 Until recently, capecitabine was the only approved agent for patients with metastatic breast cancer that was resistant to paclitaxel (Taxol, Bristol-Myers Squibb) and to anthracyclines. Therefore, there is a significant unmet need for better therapeutic agents for late-stage breast cancer. Ixabepilone (Ixempra, Bristol-Myers Squibb), a member of the epothilone class, was approved by the U.S. Food and Drug Administration (FDA) on October 16, 2007, as monotherapy for patients Disclosure: Dr. Egerton has no conflict of interest to disclose regarding this manuscript and has no relationship to any of the companies that market epothilone derivatives. Editorial assistance from L. C. Shepherd, a medical writer, was funded by Bristol-Myers Squibb, but Dr. Egerton received no financial incentive for the writing of this article. with locally advanced or metastatic breast cancer in whom anthracyclines, taxanes, and capecitabine have failed and in combination with capecitabine for patients in whom an anthracycline and a taxane have failed.18 Ixabepilone was specifically developed for patients with disease that is resistant to other chemotherapies, because it has a low susceptibility to multiple mechanisms of drug resistance.10,19 This review summarizes results from the large clinical program for this promising agent. DATA SOURCES PubMed and the Proceedings of the American Society of Clinical Oncology were searched for any relevant material published between 2001 and September 2007. Ixabepilone and BMS-247550 were used as search terms. PHARMACOLOGY AND PRECLINICAL ACTIVITY The antineoplastic properties of taxanes are mediated through their ability to bind to and stabilize the tubulin subunits of cellular microtubules, resulting in mitotic arrest in the G2/M phase and apoptosis. The efficacy of taxanes in breast cancer has suggested that targeting of cell microtubules plays a critical role in treating this malignancy. This knowledge has led to a new generation of microtubule-targeted agents, of which epothilones represent a promising class.20 Natural epothilones are isolated from the soil-dwelling myxobacterium Sorangium cellulosum. It was believed that the natural epothilones occupied a common or overlapping binding site with the taxanes on beta-tubulin. However, electron cr ystallography data show that epo thilones bind to a common tubulin-binding site in a manner qualitatively different from that used by the taxanes.21,22 Because of this altered binding, epothilones are less susceptible to drugresistance mechanisms that limit the Dr. Egerton is the Manager of Pharmacy Services at New York Oncology Hematology, PC, in Albany, New York. Drug Forecast is a regular column coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi and Associates in New York, New York. Vol. 33 No. 9 • September 2008 • P&T® 523

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Pharmacy & Therapeutics - September 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Effect of Prescription Copays on Adherence and Treatment Failure with Oral Antidiabetic Medications Vaccine Declinations Present New Challenges for Public Health Universal Health Care in America Digestive Disease Week and American Diabetes Association Pharmaceutical Approval Update

Pharmacy & Therapeutics - September 2008

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