Background: A phase I dose-escalation study was performed to investigate the safety and pharmacokinetics of the combination of S-1 and gefitinib in patients with pulmonary adenocarcinoma who had failed previous chemotherapy. Methods: Patients received gefitinib at a fixed daily oral dose of 250 mg, and S-1 was administered on days 1-14 every 21 days at doses starting at 60 mg/m2 (level 1) and escalating to 80 mg/m2 (level 2). The primary end point of the study was determination of the recommended dose for S-1 given in combination with a fixed dose of gefitinib. Results: Twenty patients were enrolled in the study. Two of the first six patients at dose level 2 experienced a dose-limiting toxicity (elevation of alkaline phosphatase of grade 3 in one patient; elevations of aspartate and alanine aminotransferases of grade 3 in the other). The recommended dose was thus determined as level 2, and an additional 11 patients were assigned to this level. All observed adverse events were well managed. The response rate was 50 % (10 of 20 patients), and the median progression-free survival (PFS) and overall survival times were 10.5 and 21.2 months, respectively. In EGFR mutation-positive patients (n = 9), seven patients achieved an objective response and the median PFS was 12.4 months, whereas none with wild-type EGFR (n = 6) responded. No pharmacokinetic interaction between S-1 and gefitinib was detected. Conclusions: The combination of S-1 and gefitinib is well tolerated and appears to possess activity against EGFR mutation-positive NSCLC.
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