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Introduction: This study investigated the efficacy and safety of S-1 vs. capecitabine in elderly patients (pts) with metastatic gastric cancer (MGC) with/without poor performance status (PS), and examined the association between CYP2A6 polymorphisms and treatment outcomes. Methods: Eligibility criteria included MGC, measurable lesion(s), no prior chemotherapy for MGC, and age of 70-85 yrs with ECOG PS 0-2 or age ≥ 65 and < 70 yrs with PS 2. Pts were randomized to receive S-1 40 mg/m2 bid or capecitabine 1250 mg/m2 bid on days 1-14 every 3 weeks. The primary endpoint was overall response rate (ORR) with time to progression (TTP), overall survival (OS), quality of life (QOL), safety, and the association between CYP2A6 genotypes (*1, *4, *7, *9, *10) and treatment outcomes as secondary endpoints. Results: From May 2007 to July 2010, 107 pts were randomized to receive either S-1 (n=53) or capecitabine (n=54). Baseline characteristics were well balanced between the two arms (S-1:capecitabine): median age, 72 yrs (range, 64-81):71 yrs (65-78); male, 74%:81%; and PS 0/1, 85%:83%. The median number of cycles was 4 (range, 1-26) in S-1 arm and 5 (1-32) in capecitabine arm. The incidence of G3/4 neutropenia was 3.8% in each arm, and the most common G3/4 non-hematological toxicities included anorexia (21.2% with S-1 vs. 7.5% with capecitabine), fatigue (13.5% vs. 15.1%), and nausea (7.7% vs. 1.9%). S-1 arm had higher incidences of vomiting (40.4% vs. 17.0%; P=0.010) and tearing (51.9% vs. 28.3%; P=0.017), and lower incidence of HFS (25.0% vs. 58.5%; P=0.001) than capecitabine arm. Of the 49 pts assessable for response in each arm, the ORR was 28.6% (95% CI, 15.9-41.3%) in S-1 arm and 26.5% (95% CI, 14.1-38.9%) in capecitabine arm. The median TTP was 3.2 months (95% CI, 1.6-4.8 months) in S-1 arm and 3.4 months (95% CI, 2.5-4.3 months) in capecitabine arm (P=0.825), and median OS was 8.5 months (95% CI, 6.1-10.9 months) and 10.3 months (95% CI, 7.1-13.5 months), respectively (P=0.691). CYP2A6 polymorphisms were associated with the efficacy of S-1. Pts having two variant alleles (V/V) had inferior efficacy to those having no or one variant allele (W/W or W/V): median TTP 2.3 vs. 4.1 months (P=0.062), and median OS 6.4 vs. 11.5 months (P=0.034). However, the efficacy of capecitabine did not differ according to CYP2A6 genotypes: median TTP was 3.6 months in V/V pts vs. 3.3 in W/W or W/V (P=0.257), and median OS was 11.6 vs. 10.2 months (P=0.756), respectively. In pts with V/V genotype, capecitabine arm had better TTP (median, 3.6 vs. 2.3 months; P=0.062) and OS (median, 11.6 vs. 6.5 months; P=0.090) than S-1 arm. Conclusions: Both S-1 and capecitabine were active and tolerable for elderly MGC pts with/without poor PS with different toxicity profiles. Genotyping for CYP2A6 might provide useful information for treatment selection. Citation Format: Sook Ryun Park, Sun-Young Kong, Mi-Jung Kim, Min Kyeong Kim, Byung-Ho Nam, Mihee Choi, Young-Iee Park. A randomized phase II study of S-1 versus capecitabine as first-line chemotherapy in the elderly metastatic gastric cancer patients with/without poor performance status: clinical and pharmacogenetic results. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-172. doi:10.1158/1538-7445.AM2013-LB-172

Introduction: S-1 contains tegafur, which is converted to 5-fluorouracil by CYP2A6. We evaluated the association between polymorphisms of CYP2A6, ERCC1 and XRCC1 and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin. Methods: Among chemonaive MGC patients (n=108) who received S-1 40 mg/m2 b.i.d. on days 1-14 and cisplatin 60 mg/m2 on day 1 of a 3-week cycle, we analyzed the wild-type allele [W] (CYP2A6*1), four CYP2A6 variants [V] that abolish (CYP2A6*4) or reduce (CYP2A6*7, *9, *10) enzyme activity, and the polymorphisms of ERCC1 [8525C>T (rs11615), 19442C>A (rs3212986)] and XRCC1 [1196G>A (rs25487)]. Results: Patients having fewer CYP2A6 variants had significantly better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4 = 66.7% vs 58.3% vs 32.3%; P=0.008), time to progression (TTP) (median, 7.2 vs 6.1 vs 3.5 months, P=0.021), and overall survival (median, 23.2 vs 15.4 vs 12.0 months, P=0.004). ERCC1 19442C>A was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P=0.048) and TTP (median, 4.4 vs 7.6 vs 7.9 months) (P=0.012). When we classified patients according to the number of risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C>A (C/C), patients carrying two vs those carrying none showed an adjusted odds ratio of 0.113 (95% CI, 0.025-0.509) (P=0.004) for response and adjusted hazard ratios of 3.748 (95% CI, 1.900-7.393) (P=0.0001) for TTP and 2.961 (95% CI, 1.371-6.393) (P=0.006) for death.Conclusion: CYP2A6 and ERCC1 19442C>A polymorphisms are important predictors for the efficacy of S-1/cisplatin in MGC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5450. doi:10.1158/1538-7445.AM2011-5450

Introduction: This study investigated the efficacy and safety of S-1 plus irinotecan and oxaliplatin (TIROX) in metastatic gastric cancer (MGC) and examined the association between uridine diphosphate-glucuronosyltransferase (UGT) 1A polymorphisms and treatment outcomes. Methods: Patients with previously untreated MGC received S-1 40 mg/m2 b.i.d. on days 1-14, irinotecan 150 mg/m2 and oxaliplatin 85 mg/m2 on day 1 every 3 weeks. We analyzed the association of UGT1A genotypes and clinical outcomes. Results: Forty-four patients were enrolled on study and received a median of 11 cycles (range, 1-12). Of the 42 patients assessable for response, the objective response rate was 79% (95% CI, 66% to 91%); complete response (CR) (14%) and partial response (64%). The median time to progression (TTP) and overall survival (OS) was 10.2 months (95% CI, 7.7 to 12.7) and 17.6 months (95% CI, 9.0 to 26.2), respectively. Ten (26%) of 39 patients with primary gastric tumor showed a biopsy-proven gastric CR. Grade 3/4 neutropenia developed in 66% of patients and grade 3 febrile neutropenia in 16%. Non-hematological toxicities were modest and manageable. The most common grade 3 non-hematological toxicity was abdominal pain (18%), followed by anorexia (16%) and diarrhea (14%). UGT1A polymorphisms was associated with significantly higher incidence of grade 4 leukopenia (UGT1A1*6), neutropenia (UGT1A1*6, UGT1A6*2, or UGT1A7*3), grade 3/4 febrile neutropenia (UGT1A1*6), or grade 3 abdominal pain (UGT1A1*6). Conclusions: TIROX is a highly active regimen inducing marked tumor reduction and promising survival with a manageable toxicity profile in MGC patients. Genotyping for UGT1A might predict severe toxicity for TIROX.Association of UGT1A Genotypes with Toxicity during Cycle 1 G4 leukopeniaG4 neutropeniaG3/4 febrile neutropeniaG3 abdominal pain No.(%)PNo.(%)PNo.(%)PNo.(%)PUGT1A1*6 0.042 0.013 0.042 0.042absence0/28 (0) 0/28 (0) 0/28 (0) 0/28 (0) presence3/16 (19) 4/16 (25) 3/16 (19) 3/16 (19) UGT1A1*28 1.000 1.000 1.000 1.000absence3/35 (9) 3/35 (9) 3/35 (9) 3/35 (9) presence0/9 (0) 1/9 (11) 0/9 (0) 0/9 (0) UGT1A1*60 0.258 0.634 0.258 0.258absence3/26 (12) 3/26 (12) 3/26 (12) 3/26 (12) presence0/18 (0) 1/18 (6) 0/18 (0) 0/18 (0) UGT1A6*2 0.100 0.044 0.100 0.100absence0/23 (0) 0/23 (0) 0/23 (0) 0/23 (0) presence3/21 (14) 4/21 (19) 3/21 (14) 3/21 (14) UGT1A7*3 0.100 0.044 0.100 0.100absence0/23 (0) 0/23 (0) 0/23 (0) 0/23 (0) presence3/21 (14) 4/21 (19) 3/21 (14) 3/21 (14) Toxicity grade by National Cancer Institute Common Toxicity Criteria version 3.0 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3719.