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Breast Cancer

Clinical Development of Ixabepilone and Other Epothilones in Patients with Advanced Solid Tumors

^aThe Methodist Hospital/Weill Cornell University, Houston, Texas, USA; ^bUniversity of California Davis Cancer Center, Sacramento, California, USA

Key Words. Epothilones • Ixabepilone • Multidrug resistance • Breast cancer • Prostate cancer

Correspondence: Edgardo Rivera, M.D., The Methodist Hospital/Weill Cornell University, 6550 Fannin Street, SM701, Houston, Texas 77030, USA. Telephone: 713-441-6710; Fax: 713-790-3038; e-mail: erivera1{at}tmhs.org

Received July 3, 2008; accepted for publication November 7, 2008; first published online in THE ONCOLOGIST Express on December 16, 2008.

Disclosure: Employment/leadership position: None; Intellectual property rights/inventor/patent holder: None; Consultant/advisory role: None; Honoraria: Edgardo Rivera, Bristol-Myers Squibb, Abraxis Oncology; Research funding/contracted research: Edgardo Rivera, Tragara Pharmaceuticals, Bristol-Myers Squibb; Ownership interest: None; Expert testimony: None; Other: None.

The article discusses unlabeled, investigational, or alternative use(s) of a product, device or technique: ixabepilone (Bristol-Myers Squibb), all tumors other than breast cancer; patupilone (Bristol-Myers Squibb/Novartis), solid tumors; sagopilone #4, KOS-1584 (Bayer) solid tumors.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.

Chemotherapy efficacy in patients with solid tumors is influenced by primary and acquired multidrug resistance (MDR). Epothilones represent a novel class of microtubule inhibitors with lower susceptibility to drug resistance and efficacy in taxane-resistant tumors. While other epothilones are currently under investigation, ixabepilone is the first epothilone B analogue approved by the U.S. Food and Drug Administration. Ixabepilone has been shown to have preclinical activity in chemotherapy-sensitive and chemotherapy-resistant tumor models, and synergistic antitumor activity with other chemotherapeutic and targeted agents. Single-agent ixabepilone has demonstrated clinical activity in multiple solid tumors including advanced breast, lung, prostate, pancreatic, renal cell, and ovarian cancers. Most notably, efficacy has been demonstrated in patients with metastatic breast cancer (MBC) progressing after treatment with anthracyclines and taxanes. A phase III trial in anthracycline- and taxane-resistant MBC showed superior disease control with ixabepilone plus capecitabine versus capecitabine monotherapy, resulting in its approval. Ixabepilone is also active in chemotherapy-naïve and taxane-resistant hormone-refractory prostate cancer and platinum-resistant non-small cell lung cancer. Neutropenia and peripheral sensory neuropathy are the most common adverse events associated with treatment. This review discusses the challenges of MDR and the data that support the use of epothilones in this setting, focusing on ixabepilone.

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