Ixabepilone and lapatinib for HER2-positive advanced breast cancer: Preclinical rationale and phase I trial.
Sub-category: Phase I Studies
Category: Developmental Therapeutics: Cytotoxic Chemotherapy
Meeting: 2009 ASCO Annual Meeting
Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 2582)
Abstract No: 2582
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Author(s):
P. N. Mainwaring, T. Nguyen, G. Price, D. Venter; Mater Health Services, South Brisbane, Australia
Abstract:
Trastuzumab with or without taxanes are the cytotoxic therapies of choice for advanced Her-2 positive breast cancer. Ixabepilone and lapatinib have demonstrated clinical efficacy in advanced breast cancer that is resistant to taxanes and trastuzumab. We have compared the therapeutic potential of ixabepilone, lapatinib, paclitaxel and trastuzumab, in vitro, prior to commencing a phase I clinical trial. Three different breast cancer cell lines SK-BR3, BT-474 and MCF-7 (control; non-Her-2 amplified), were seeded 96-well plates, cultured for 24 hours and different concentrations of ixabepilone or paclitaxel and trastuzumab or lapatinib were added. Experiments were performed in triplicate. A MTT viability assay was used to measure the activity of live cells after 0, 3, 24, 48 and 120 hours. The cells and vehicle control wells were averaged and normalized to 100% for comparison to the average value of the 6 replicate wells graphed over time for each cell line, drug concentration and cell density. Student-t test was used to determine the level of significance comparing the 0 hour time point in a pair-wise, pooled variance manner to each other time point. Paclitaxel + trastuzumab significantly reduced proliferation p < 0.001 at 120 hrs; Paclitaxel + lapatinib significantly reduced proliferation p < 0.001 at 120 hrs; Ixabepilone + trastuzumab significantly reduced proliferation p < 0.001 at 120 hrs; Ixabepilone + lapatinib significantly reduced proliferation p < 0.001 at 120 hrs; Dose response curves were clearly evident for all combinations. Of note
proliferation was reduced earlier and at lower drug concentrations with lapatinib combinations than with trastuzumab combinations. The drugs whose efficacy was proven in MCF-7 cells were studied in detail on the xCELLigence cell analysis system. These data recapitulated the MTT data and provided in depth detail of the rate of drug action. An international multicentre phase I trial of Ixabepilone with lapatinib ± capecitabine has commenced in patients with Her-2 positive taxane and trastuzumab resistant advanced breast cancer. Toxicity has been as previously described with fatigue, arthralgias, onycholysis and rash occurring. No DLTs have occurred. RECIST responses have been confirmed in 2 of the first 3 patients enrolled.
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