Triplet chemotherapy with Gemcitabine, Nab-paclitaxel, and S-1 achieves high response and conversion rates in advanced pancreatic cancer: A multicenter phase II study (GeNeS1S trial).

BACKGROUND: S-1 has demonstrated non-inferiority to gemcitabine (GEM) in overall survival (OS) in advanced pancreatic cancer and superiority in the adjuvant setting for resectable disease. This study evaluated the efficacy and safety of S-1 combined with GEM plus nab-paclitaxel (nPTX) in advanced pancreatic cancer. METHODS: This multicenter, single-arm, phase II study enrolled patients with previously untreated locally advanced, recurrent, or metastatic pancreatic cancer. Treatment consisted of GEM (600 mg/m²) and nPTX (90 mg/m²) on days 1 and 8 plus oral S-1 (50/70/80 mg/day according to body surface area) on days 1-14 of a 3-week cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), OS, duration of response (DoR), primary tumor response, conversion rate, and safety. RESULTS: Between September 2018 and April 2024, 30 patients were enrolled. ORR was 63.3% (95% CI, 45.5-78.2), meeting the prespecified primary endpoint. PD was observed in only 6.7% of patients, resulting in a DCR of 86.7%. Median PFS and OS were 9.0 (95% CI, 7.5-10.5) and 15.0 months (12.6-17.4), respectively, and median DoR was 8.6 months (95% CI, 4.7-12.5). In locally advanced disease, ORR was 100.0%, and three of five patients (60.0%) underwent conversion surgery. Grade ≥ 3 adverse events were mainly hematologic, including neutropenia (43.3%), anorexia (6.7%), and biliary tract infection (6.7%), with no treatment-related deaths. CONCLUSION: The addition of S-1 to GEM plus nPTX demonstrated high antitumor activity, durable disease control, and encouraging conversion to resection, supporting further evaluation of this regimen, particularly in borderline resectable or locally advanced pancreatic cancer.