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The Epothilones Are Coming!

Four phase II reports plus preliminary data from a randomized phase III study suggest that the semisynthetic epothilone ixabepilone is tolerable and beneficial for women with metastatic breast cancer.

Microtubules (intracellular organelles that are composed of ß-tubulin heterodimers) play a pivotal role in cell division. Equilibrium of ß-tubulin polymerization and depolymerization is required for normal cell function and division. Several chemotherapy drugs target microtubules (e.g., taxanes induce mitotic arrest by stabilizing microtubules). The epothilones are a new class of microtubule-stabilizing agents that induce apoptosis and promote cell death. They interact with microtubules differently than do taxanes, and mechanisms of cellular resistance also appear to be distinct from those that inhibit taxanes. Naturally occurring epothilones are derived from the myxobacterium Sorangium cellulosum, but semisynthetic analogues of epothilones are being developed: Ixabepilone (BMS-247550) is furthest along in clinical trials. In preclinical models, ixabepilone demonstrated consistent antitumor activity in chemotherapy-resistant cell lines and xenograft models. Numerous phase II clinical trials involving ixabepilone have been completed (four are summarized below), and results from the pivotal phase III trial, in which capecitabine alone was compared with capecitabine plus ixabepilone, were reported at the 2007 ASCO meeting (ASCO abstract).

One group reported on the efficacy and safety of ixabepilone in an industry-sponsored international trial of 113 patients with metastatic breast cancer that was resistant to anthracyclines, taxane, and capecitabine (resistance was defined as disease progression during therapy in the metastatic setting or recurrence within 6 months of adjuvant or neoadjuvant anthracycline or taxane therapy). Approximately 90% of patients had undergone two or more chemotherapy regimens for metastatic disease before they were enrolled. Ixabepilone (40 mg/m²) was administered as single 3-hour infusions every 3 weeks (median, 4 cycles). The investigator-assessed objective response rate was 12%, and an additional 14% of patients maintained stable disease for 6 months or longer. Grade 3 or 4 sensory peripheral neuropathy developed in 14% of patients and resolved (to baseline or grade 1) after a median of 5.4 weeks. Grade 3 or 4 fatigue, myalgia, and mucositis occurred in 13%, 8%, and 6% of patients, respectively.

In another industry-sponsored international trial, 49 patients with metastatic breast cancer were evaluated. Most patients (86%) had undergone at least two prior chemotherapy regimens, and all had undergone at least one taxane-containing regimen (98% had received taxanes as their most recent treatment for metastatic disease, and 73% had developed progressive disease within 1 month of their last taxane dose). In this heavily pretreated patient population, ixabepilone treatment (40 mg/m², administered as a 3-hour infusion every 3 weeks; median, 3 cycles) resulted in an objective response rate of 12%; median time to disease progression was 2.2 months. Grade 3 sensory neuropathy occurred in 12% of patients and subsequently resolved in 83% of those. Other adverse events were primarily grade 1 or 2.

Researchers conducted a single-center trial in 23 patients with metastatic breast cancer who had not received taxanes previously (70% had received prior chemotherapy, and 52% had received prior anthracycline therapy). Ixabepilone (6 mg/m², 1-hour infusion) was administered on days 1 through 5 every 3 weeks (median, 8 cycles). In this small group, the objective response rate was 57%, and the median time to progression was 5.5 months. In six paired samples (biopsy material collected pre- and post-ixabepilone therapy), increased acetylation of -tubulin (a marker of tubulin stabilization) was noted in post-ixabepilone samples, regardless of tumor response. Only one patient developed motor neuropathy (grade 3).

Finally, a fourth group reported the results of an industry-sponsored international trial in which 65 patients received ixabepilone (40 mg/m², 3-hour infusion every 3 weeks; median, 6 cycles) as first-line therapy for metastatic disease. All patients had received prior adjuvant anthracycline-based therapy, and 83% had received taxanes as a component of adjuvant therapy (at least 12 months earlier). The objective response rate was 41.5%, and the median response duration was 8.2 months. The median time to response was 6 weeks. Most adverse events (51%) were grade 1 or 2. Grade 3 sensory neuropathy occurred in 20% of patients, and 28% of patients discontinued therapy due to sensory neuropathy.

Comment: At the 2007 ASCO meeting, results were reported from a phase III trial in which capecitabine alone was compared with capecitabine plus ixabepilone in patients with metastatic breast cancer. The authors of this ASCO presentation suggested that combination therapy was associated with improvements in objective response rates and modest improvements in time to disease progression. This randomized trial represents a key (and obligatory) component of FDA approval of ixabepilone for treatment of advanced breast cancer. The phase II results reported above add to the body of evidence showing that ixabepilone has antitumor activity in both patients who are relatively chemotherapy naive and in those who have received numerous previous treatments, including taxanes. The main issue for ixabepilone relates to its toxicity profile and its position within standard treatment algorithms. In particular, defining ixabepilone’s antitumor activity relative to taxane therapy is vital. Equally important will be assessing the relative differences in adverse events among patients with metastatic disease who receive ixabepilone versus other treatments. Ixabepilone will likely be approved as a new treatment option for patients with advanced breast cancer; its optimal position within the spectrum of treatment options remains to be defined.

— William J. Gradishar, MD

Published in Journal Watch Oncology and Hematology August 28, 2007

Citation(s):

Perez EA et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 2007 Aug 10; 25:3407-14.

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• Medline abstract (Free)

Thomas E et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol 2007 Aug 10; 25:3399-406.

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• Medline abstract (Free)

Denduluri N et al. Phase II trial of ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previously untreated with taxanes. J Clin Oncol 2007 Aug 10; 25:3421-7.

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• Medline abstract (Free)

Roché H et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy. J Clin Oncol 2007 Aug 10; 25:3415-20.

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• Medline abstract (Free)