Therapeutic Synergy of Oral Taxane BMS-275183 and Cetuximab versus Human Tumor Xenografts

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Abstract
Purpose: Combination therapy consisting of an oral taxane, BMS-275183, and the anti-epidermal growth factor receptor monoclonal antibody, cetuximab, was assessed for enhanced therapeutic benefit in preclinical tumor models. Experimental Design: Mice bearing human tumor xenografts, either L2987 lung or GEO colon carcinoma, were administered the aforementioned treatments singly or in combination regimens. Delays in tumor growth and tumor-free status were evaluated and combination treatments were assessed relative to optimal solo treatments. Results: Combination therapies with the oral taxane plus cetuximab were tolerated and therapeutic synergistic outcomes obtained. The therapeutic enhancements were >1 log cell kill greater than the antitumor effect caused by either solo agent applied optimally. For example, at the maximum-tolerated dose of BMS-275183, 60 mg/kg/administration, given p.o. once every 3 days for a total of six administrations (q3d×6), 1.0 gross log cell kill was achieved in mice bearing well established (100 to 200 mg) s.c. implanted L2987 tumors. Cetuximab, at an optimal dose of 1 mg/mouse, given i.p. q3d×6, produced 1.3 log cell kill. When cetuximab, 1 mg/mouse, i.p., plus BMS-275183, 25 mg/kg/administration, p.o., were both given q3d×6, the result was 2.6 log cell kill with three of eight mice cured (P < 0.01). Similar efficacy benefits were obtained in the GEO tumor model. Conclusions: The combination of oral taxane BMS-275183 plus cetuximab provided therapeutically synergistic antitumor activity in two different human tumor xenograft models. Clinical evaluation of this combination is recommended.