Ixabepilone: A Novel Microtubule Inhibitor for the Treatment of Locally Advanced or Metastatic Breast Cancer

Background: Ixabepilone is the first member of the epothilones, a new class of anticancer drugs. It is approved for use as monotherapy in patients with locally advanced or metastatic breast cancer that has failed to respond to therapy with a taxane, an anthracycline, and capecitabine, or in combination with capecitabine in patients with locally advanced or metastatic breast cancer that has failed to respond to therapy with a taxane and an anthracycline. Objectives: This paper reviews available information on the pharmacokinetics, pharmacodynamics, clinical efficacy, and tolerability of ixabepilone when used for its approved indication. It also reviews clinical studies of ixabepilone in other cancers, including prostate, lung, and ovarian cancers, sarcoma, and lymphoma. Finally, the dosing and administration of ixabepilone and pharmacoeconomic considerations are discussed. Methods: MEDLINE and EMBASE (1950-present) were searched in November 2007 and again in March and June 2008 to identify clinical trials, abstracts, and case reports involving ixabepilone. The search terms included ixabepilone, BMS-247550, and epothilone. The reference lists of identified articles and meeting abstracts were reviewed to identify additional publications. Results: In a Phase III trial of the combination of ixabepilone 40 mg/m(2) IV + capecitabine 1000 mg/m(2) PO BID versus capecitabine 1250 mg/m(2) PO BID, both given on days I through 14 of a 21-day cycle, the combination arm had significantly greater progression-free survival (5.8 vs 4.2 months, respectively; P < 0.001) and a significantly greater objective response rate (32% vs 14%; P < 0.001). In a Phase 11 trial of monotherapy with ixabepilone 40 mg/m(2) IV given every 21 days, 50% of patients had stable disease, with a median progress on-free survival of 3.1 months. Grade 3/4 hematologic adverse effects occurring during use of ixabepilone included neutropenia (54%), leukopenia (49%), anemia (8%), and thrombocytopenia (7%). The most common nonhematologic adverse effects included peripheral neuropathy (72%), fatigue (56%), myalgia/arthralgia (49%), alopecia (48%), nausea (42%), stomatitis/mucositis (29%), vomiting (29%), diarrhea (22%), and musculoskeletal pain (20%). Dose adjustment is required in the presence of toxicity (grade 2 or higher neuropathy; grade 3 or higher myalgia/arthralgia, fatigue, or palmar-plantar erythrodysesthesia; prolonged neutropenia, febrile neutropenia, or severe thrombocytopenia). Use of ixabepilone is contraindicated in patients with hepatic impairment. Conclusions: Ixabepilone, a new antineoplastic agent with antimitotic capabilities, is approved for use with or without capecitabine in the management of metastatic or locally advanced breast cancer. It has also been evaluated for antitumor activity in a number of other cancers. The potential for significant toxicity with ixabepilone requires close clinical observation to assess the need for dose adjustment. (Clin Ther. 2008;30:1590-16-17) (C) 2008 Excerpta Medica Inc.