Phase I trial of sorafenib in combination with gefitinib in patients with refractory or recurrent non-small cell lung cancer.

PURPOSE To evaluate the combination of sorafenib and gefitinib in patients with advanced non-small cell lung cancer. EXPERIMENTAL DESIGN In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21 days followed by a 7-day washout with crossover to the other agent for an additional 21 days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed. RESULTS Thirty-one patients were treated (n=12, part A; n=19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib C(max) (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n=8, part A; n=12, part B) had stable disease >or=4 months. The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily. CONCLUSIONS Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non-small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.