Optimizing ixabepilone treatment schedules in patients with advanced or metastatic breast cancer

The epothilone B analog, ixabepilone, demonstrates low susceptibility to drug resistance mechanisms and has demonstrated clinically meaningful efficacy in patients refractory to other chemotherapeutic options. Ixabepilone is approved by the FDA for treatment of patients with metastatic breast cancer (MBC) progressing after taxanes and anthracyclines, either in combination with capecitabine or as monotherapy if the patient has already progressed on capecitabine. Ixabepilone is generally well tolerated at the approved dose and administration schedule of 40 mg/m(2) every 3 weeks. The most commonly observed dose-limiting adverse events (AEs) associated with ixabepilone are myelosuppression and peripheral neuropathy. Dose modification including dose reduction and dosing schedule modification may be utilized to manage toxicities, but this must be based on careful hematologic, neurologic, and liver function monitoring. Other ixabepilone dose schedules are being evaluated to further improve the risk/benefit profile. Weekly and daily schedules of ixabepilone have shown useful efficacy and reasonable tolerability. A recent phase II trial compared the tolerability of ixabepilone dosed once weekly (16 mg/m(2) on Days 1, 8, and 15 of each 28-day cycle) or every 3 weeks (40 mg/m(2) on Day 1 of each 21-day cycle) in patients with MBC. Preliminary data showed that both dosing schedules had an acceptable safety profile; however, more AEs were reported in patients receiving ixabepilone every 3 weeks. Ixabepilone is also being evaluated in combination with other anticancer agents (e.g., bevacizumab and lapatinib), in earlier breast cancer settings and in other indications.