A phase I/II trial of erlotinib S-1 therapy in patients with non-small cell lung carcinoma: Thoracic Oncology Reseach Group (TORG) 0808/0913.
e18099 Background: Gefitinib has been shown in basic studies to reduce the expression of thymidilate synthase, the target enzyme for the 5-FU-based chemotherapy, at the protein and mRNA levels, and synergistic effects of gefitinib used in combination with S-1 have been reported. Erlotinib also reduced TS expression and activity. The present studies were designed as study aimed at evaluating the efficacy and safety of erlotinib/ S-1 combination therapy as a 2nd/3rd-line therapy for recurrent/advanced NSCLC. Methods: Chemotherapy consisted of two 3-week cycles of erlotinib and S-1 treatment. Erlotinib was orally administered once daily at a dose of 150 mg/body, and patients received an oral dose of S-1 twice daily after meals from days 1 to 14 of each 21-day cycle. In phase I trial(TORG0808), the primary endpoint was to evaluate the DLT and the MTD for the following phase II study, and the secondary endpoint was to evaluate the antitumor activity and safety. Based on the phase I trial, we conducted a phase II trial (TORG0913) of this combination with pretreated EGFR negative NSCLC to determine the ORR. The secondary endpoints were PFS, disease control rate, OS, and safety. Results: 7 patients with good PS (0 or 1) and 10 patients with PS 0-2 participated in phase I and phase II trial. In phase I trial, the recommended doses for the phase II study were determined to be 150mg/body and 80mg/m2. The ORR was 67%, and 3/4 responders are EGFR positive patients. In phase II trial, the ORR was very low (only one patient).Myelosuppression was relatively mild, but Grade 3 or worse non-hematological toxicities including diarrhea, mucositis, and dermatitis were observed in 6 patients, which resulted in two treatment-related deaths. Data and Safety Monitoring Committee recommended the early termination, and the clinical trial was terminated due to adverse events. Conclusions: Phase I study showed the favorable efficacy and moderate safety profiles of this combination especially in EGFR positive patients, but less effective and too toxic in EGFR negative patients in phase II trial.