Epidermal growth factor receptor inhibitors in clinical development

In cancer cells, aberrant signaling through the epidermal growth factor receptor (EGFR) activates pathways that stimulate many of the properties associated with neoplasia, including proliferation, migration, stromal invasion, tumor angiogenesis, and resistance to cell death-inducing signals. Because of the frequency of abnormalities in receptor signaling in human cancers, the EGFR is an attractive target for therapeutic development. Monoclonal antibodies and small molecule tyrosine kinase inhibitors are the two classes of agents that are the furthest advanced in clinical development. Although pharmacologic and mechanistic differences exist between the two classes, the results of preclinical studies suggest that both inhibit proliferation, have little normal tissue toxicity, and are additive/synergistic with standard therapies. The results from early clinical trials have indicated that both classes of agents are well tolerated and have antitumor activity. However, the first Phase III studies to be completed have not shown an improvement in survival with the addition of the monoclonal antibody C225 to cisplatin in patients with head-and-neck carcinoma or the addition of the kinase inhibitor ZD1839 to chemotherapy in patients with advanced lung cancer. Ongoing and future studies must address issues related to the selection of patients for study, dose and schedule of administration, monotherapy vs. combination treatment, and combinations with standard and investigational agents