Multi-Institutional Phase II Study of S-1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations

This study describes the first phase II study of S-1, a novel oral fluoropyrimidine, in a non-Japanese Asian population with advanced gastric cancer. S-1 was administered twice daily for 28 days every 6 weeks. A pharmacokinetic study was performed on day 28 of cycles 1 and 3. Genomic DNA from peripheral mononuclear cells was analyzed using a cDNA microarraybased comparative genomic hybridization (CGH) method. Thirty-one patients were initially given a dose of 35 mg/m 2 twice daily (bid) (group 1); then, the protocol was amended by increasing the dose to 40 mg/m 2 bid for an additional 31 patients (group 2) because of good tolerability to S-1. The overall response rate was 19.3% (95%confidenceinterval,9.2%–29.5%).Overamedian follow-up duration of 265 days, the median time to progression and overall survival time were 126 and 264 days, respectively. The 1-year survival rate was 34%. Therewasnograde4toxicityandthemajoradverseevent was anemia. Pharmacokinetic parameters were similar to those of the previous Japanese reports. Microarray CGH identified 18 genes with copy number changes that were associated with hemoglobin reduction with S-1 treatment. A logistic regression analysis, integrating one clinical parameter(initialhemoglobinlevel)combinedwiththreegenetic copy number variations (HIST1H2BL, C10orf127, andXPNPEP2),providedapredictivemodelforthedevelopment of severe hemoglobin reduction. In conclusion, this study showed the feasibility of using S-1 at 35 mg/m 2 bid in gastric cancer. We suggest that the pharmacogenomic markers identified in this study may be potential candidates for predicting anemia after S-1 treatment. The Oncologist 2007;12:543–554