Clinical development of ixabepilone and other epothilones in patients with advanced solid tumors

Area of Science:

• Oncology
• Pharmacology
• Cancer Biology

Background:

• Multidrug resistance (MDR) significantly limits chemotherapy efficacy in solid tumors.
• Epothilones, a class of microtubule inhibitors, exhibit reduced susceptibility to MDR and activity in taxane-resistant cancers.
• Ixabepilone is the first approved epothilone B analogue, demonstrating preclinical and clinical activity.

Purpose of the Study:

• To review the challenges posed by multidrug resistance in solid tumors.
• To discuss the role and efficacy of epothilones, particularly ixabepilone, in overcoming drug resistance.
• To highlight ixabepilone's clinical activity in various solid malignancies.

Main Methods:

• Preclinical evaluation of ixabepilone in chemotherapy-sensitive and resistant tumor models.
• Clinical trials assessing single-agent ixabepilone and combination therapy in solid tumors.
• Review of phase III trial data for ixabepilone plus capecitabine in metastatic breast cancer.

Main Results:

• Ixabepilone demonstrated preclinical synergistic antitumor activity with other agents.
• Clinical activity was observed in advanced breast, lung, prostate, pancreatic, renal cell, and ovarian cancers.
• A phase III trial showed superior disease control with ixabepilone plus capecitabine in resistant metastatic breast cancer.

Conclusions:

• Ixabepilone is an effective treatment option for patients with solid tumors, especially those with multidrug resistance.
• Its efficacy extends to taxane-resistant and anthracycline-resistant metastatic breast cancer.
• Ixabepilone is also active in hormone-refractory prostate cancer and platinum-resistant non-small cell lung cancer, with neutropenia and neuropathy as primary adverse events.