204P Phase II trial of S-1 plus leucovorin in patients with advanced gastric cancer and clinical prediction by S-1 pharmacogenetic pathway

Abstract

Aim/Background: As the first phase II trial, it aimed to evaluate and predict the efficacy and safety of S-1 combined with oral leucovorin (S-1/LV) as first-line chemotherapy for patients with advanced gastric cancer (AGC), using S-1 pharmacogenetic pathway approach. Method(s): 39 patients orally took S-1 at conventional dose and LV simultaneously at a dose of 25 mg twice daily for a week, within a 2-week cycle. The endpoints were overall response rate (ORR), progression-free survival (PFS), time to failure (TTF), overall survival (OS), disease control rate (DCR), and adverse events (AEs). Peripheral blood was sampled prospectively for baseline plasmic expression of dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and thymidylate synthase (TS), CYP2A6 gene polymorphisms, and 5-FU pharmacokinetics. Result(s): The ORR and the DCR were 41.0% and 76.9%. The median PFS, median TTF, and median OS were 4.13 (95% CI, 3.44-4.83), 3.70 (2.60-4.80), and 11.40 (7.76-15.05) months. Grade 3 ~ 4 AEs occurred in only 13 patients, and grade 4 AE (neutropenia) occurred in only one of them. High OPRT/TS (Odd Ratio (OR) 16.962 (1.781-161.581), P = 0.014) and peritoneal metastasis (OR 25.604 (1.852-353.979), P = 0.016) independently predicted responding. High OPRT/DPD (OR 15.566 (1.490-162.605), P = 0.022) independently predicted grade 3 ~ 4 AEs. Response to S-1/ LV (Hazards Ratio (HR) 0.275 (0.124-0.609), P = 0.001) and high area under the curve (AUC0-24h) of 5-FU (HR 0.272 (0.114-0.645), P = 0.003) independently predicted prolonged PFS. Low baseline plasmic DPD (HR 2.726 (1.045-7.113), P = 0.040) and second-line treatment (HR 0.259 (0.091-0.736), P = 0.011) independently predicted prolonged OS. See table. Conclusion(s): S-1/LV demonstrated promising efficacy and satisfactory safety in AGC. Patients with high OPRT/TS, high AUC0-24h of 5-FU, low DPD and second-line chemotherapy may benefit most from S-1/LV.