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

Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Inc., Princeton, New Jersey

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 (q3dx6), 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. q3dx6, 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 q3dx6, 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.

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