Epidermal growth factor receptors as a target for cancer treatment: the emerging role of IMC-C225 in the treatment of lung and head and neck cancers

Abstract

Epidermal growth factor receptor is one of four receptors critical to cellular proliferation, differentiation, and survival, and is widely expressed in malignant tissue, particularly in squamous cell carcinoma of the head and neck. Expression has been associated with malignant progression, inhibition of apoptosis, neoplastic angiogenesis, enhanced metastatic potential, and both chemoresistance and radioresistance. IMC-C225 is a chimeric monoclonal antibody that targets extracellular epidermal growth factor receptor; it has shown both in vitro and in vivo antitumor activity in tumor cells lines expressing epidermal growth factor receptor, including heightened radiation response in vitro in cultured human squamous cell carcinoma and enhancement of taxane- and platinum-induced cytotoxicity in non-small cell lung cancer xenografts. In A431 head and neck squamous cell xenografts, IMC-C225 administered both before and after radiation therapy yields a radiation enhancement factor of 3.62, attributable to both tumor necrosis and antiangiogenesis. In phase I pharmacokinetic studies, IMC-C225 has a long half-life, lending itself to convenient weekly administration. It has shown a favorable toxicity profile, limited primarily to allergic and dermatologic reactions, the latter characterized by a self-limited, sterile, acneiform rash. Anaphylaxis is rare. Standard treatment entails a loading dose of 400 mg/m(2) at week 1, followed by a maintenance dose of 250 mg/m(2) weekly. An ongoing phase III international multicenter, randomized study in locally advanced squamous cell carcinoma of the head and neck is evaluating therapeutic radiation therapy, either alone or in conjunction with IMC-C225. In a pilot trial, six of nine patients with platinum-exposed squamous cell carcinoma of the head and neck exhibited objective response. In an ongoing phase II trial in patients with stable or progressive disease on platinum-based therapy, the preliminary response rate is approximately 20%, far higher than one would expect with standard salvage regimens. The Eastern Cooperative Oncology Group has completed a placebo-controlled phase III registration trial assessing cisplatin 100 mg/m(2) every 4 weeks with or without IMC-C225. Three separate phase II trials in non-small cell lung cancer have been launched: one trial tests IMC-C225 in combination with standard paclitaxel/carboplatin; another integrates IMC-C225 into the gemcitabine/carboplatin combination in treatment-naive patients; and a third trial evaluates IMC-C225 in combination with docetaxel 75 mg/m(2) every 3 weeks in the second-line setting.