Tumor epidermal growth factor receptor studies in patients with non-small-cell lung cancer or head and neck cancer treated with monoclonal antibody RG 83852.

Abstract

PURPOSE Tumor tyrosine kinase activity associated with the epidermal growth factor receptor (EGFR) and localization of anti-EGFR monoclonal antibody RG 83852 were studied in patients with non-small-cell lung cancer (NSCLC) and head and neck cancer. PATIENTS AND METHODS Fifteen patients were treated with escalating doses of RG 83852 by continuous intravenous infusion for 5 days. Fresh tumor specimens were obtained 24 hours after therapy in 10 patients (of whom five had a pretherapy sample taken). Tumor EGFR tyrosine kinase activity was determined in fresh tumor samples by autophosphorylation of EGFR isolated in immunocomplexes with RG 83852. Tumor EGFR saturation with RG 83852 was assessed semiquantitatively by comparing the EGFR tyrosine kinase activity in immunocomplexes of tumor specimens obtained after therapy with total EGFR tyrosine kinase activity assessed by exogenous addition of RG 83852 to tumor lysates. Modulation of EGFR tyrosine kinase activity after the administration of RG 83852 was assessed by comparing EGFR tyrosine kinase activity from the same malignant lesion obtained before and after therapy. Tumor localization of RG 83852 and EGFR saturation were also assessed by immunohistochemistry. RESULTS No significant side effects were observed up to a total dose of 600 mg/m2. Based on tyrosine kinase activity, a high degree of EGFR saturation (> or = 50%) was observed at doses > or = 200 mg/m2, and EGFR saturation was estimated to be 100% at a dose level of 600 mg/m2 both in tumor tissue and skin used as surrogate EGFR-positive tissue. Immunohistochemistry studies showed that RG 83852 localized in tumor tissue and skin, but not in stroma, at doses > or = 400 mg/m2, and high EGFR saturation was observed at 600 mg/m2. Tumor EGFR tyrosine kinase activity was studied in five patients (four with EGFR-positive tumors) before and 24 hours post-therapy; a threefold to fourfold upregulation of EGFR tyrosine kinase activity in posttherapy specimens was observed in two patients. Moderate upregulation of EGFR itself was suggested in both of these patients and in two additional patients by immunohistochemistry. CONCLUSION RG 83852 causes no toxic effects at doses that result in high tumor EGFR saturation. Treatment with RG 83852 may enhance EGFR tyrosine kinase activity and/or EGFR expression. Because high EGFR expression by tumors has been associated with increased sensitivity to cytotoxic therapy, the suggestion of antibody-mediated upregulation of EGFR by agents such as RG 83852 may prove useful in enhancing chemotherapeutic efficacy.