Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer

C225, a human-mouse chimerized monoclonal antibody directed against the epi dermal growth factor receptor (EGFr), has a synergistic effect with cisplat in in xenograft models, To determine the tumor EGFr saturation dose with C2 25 and the fate of infused C225, we conducted a Phase Ib study,with C225 in combination with cisplatin in patients with recurrent squamous cell carcin oma of the head and neck. Using tumor samples, we assessed tumor EGFr satur ation by antibody using immunohistochemistry studies, the EGFr tyrosine kin ase assay, and detection of the EGFr/C225 complex formation by immunoblot. Potential candidates were screened for EGFr expression in their tumors, and 12 patients who had high levels of EGFr expression and tumors easily acces sible for repeated biopsies (pretherapy, 24 h after first C225 infusion, 24 h before third C225 infusion) were entered at three different dose levels of C225 with a fixed dose of cisplatin, The median value of tumor EGFr satu ration increased to 95% at the higher dose levels. EGFr tyrosine kinase act ivity was significantly reduced after C225 infusion, and EGFr/C225 complexe s were also detected at higher doses of C225. The Loading dose of C225 at 4 00 mg/m(2) with a maintenance dose at 250 mg/m(2) achieved a high percentag e of saturation of EGFr in tumor tissue, and these doses were recommended f or Phases II or Hi clinical trials, Sir: (67%) of nine evaluable patients a chieved major responses, including two (22%) complete responses. Mild to mo derate degrees of allergic reaction and folliculitis-like skin reactions we re demonstrated. We conclude that infused C225 binds and significantly satu rates tumor EGFr, which may render a high degree of antitumor activity, and provides a novel mechanism for targeting cancer therapy for patients who h ave EGFr expression in their tumors.