The EGFR as a target for anticancer therapy--focus on cetuximab

Abstract

The anti-epidermal-growth-factor-receptor (EGFR) monoclonal antibody cetuximab specifically binds to the EGFR with high affinity, blocking growth-factor binding, receptor activation and subsequent signal-transduction events leading to cell proliferation. Preclinical studies, both in vitro and in vivo, have shown that cetuximab enhances the antitumour effects of chemotherapy as well as radiotherapy by inhibiting cell proliferation, angiogenesis and metastasis and by promoting apoptosis. As of June 2000, 526 patients with advanced solid tumours were treated with cetuximab in phase I/II clinical trials. Analysis of the results of three phase I trials showed that cetuximab has non-linear pharmacokinetics, with saturation of drug-elimination pathways occurring at doses between 200 and 400 mg/m(2). Adverse-event data for 239 patients across most of the completed or ongoing phase I-III trials indicated that the antibody was generally well tolerated. Cetuximab has been evaluated both alone and in combination with radiotherapy and various cytotoxic chemotherapeutic agents in a series of phase I/II studies that primarily treated patients with either head and neck or colorectal cancer. Although not a primary objective of these studies, clinical responses to cetuximab were observed in many patients who had previously failed chemotherapy and/or radiotherapy or were otherwise unlikely to achieve a therapeutic outcome. Based on these promising results, additional phase II and phase III trials are currently underway in head and neck and colorectal cancer.