Phase I dose-escalation study on irinotecan, cisplatin, and S-1 combination in chemotherapy-naïve patients with HER2-negative advanced gastric cancer (HERBIS-4B, OGSG 1106).

Abstract

The development of triplet regimens for advanced gastric cancer is challenging. The aim of this phase I dose-escalation study was to determine the maximum tolerated dose and recommended dose of the combination of irinotecan, cisplatin, and S-1 in chemotherapy-naïve patients with HER2-negative advanced gastric cancer. The 3 + 3 design was adopted. Every 4weeks, patients received an escalating dose of intravenous irinotecan (100-150mg/m2) on day 1 and fixed doses of intravenous cisplatin (60mg/m2) on day 1 and oral S-1 (80mg/m2) on days 1 to 14. Twelve patients were enrolled in two dose level cohorts. In the level 1 cohort (irinotecan 100mg/m2, cisplatin 60mg/m2, and S-1 80mg/m2), dose-limiting toxicity including grade 4 neutropenia and febrile neutropenia occurred in one of six patients, whereas in the level 2 cohort (irinotecan 125mg/m2, cisplatin 60mg/m2, and S-1 80mg/m2), dose-limiting toxicities including grade 4 neutropenia developed in two of six patients. Thus, the level 1 and 2 doses were determined to be the recommended and maximum tolerated doses, respectively. Common grade 3 or higher adverse events were neutropenia (75%; n = 9), anemia (25%; n = 3), anorexia (8%; n = 1), and febrile neutropenia (17%; n = 2). Irinotecan, cisplatin, and S-1 combination therapy achieved an overall response rate of 67% with a median progression-free survival and overall survival of 19.3 and 22.4months, respectively. The potential treatment efficacy of this triplet regimen in HER2-negative advanced gastric cancer warrants further evaluation, especially in patients requiring intensive chemotherapy.