790PA multicenter phase II study of TAS-114 in combination with S-1 in patients with pre-treated advanced gastric cancer (EPOC1604)

Abstract Background High deoxyuridine triphosphatase (dUTPase) in tumor tissue, as a gatekeeper enzyme for 5-fluorouracil (5-FU), is associated with 5-FU resistance. TAS-114 is an oral dUTPase inhibitor which enhance antitumor activity with 5-FU or fluoropyrimidines. Phase I study of TAS-114 in combination with S-1 showed its tolerability and preliminary antitumor signals for patients (pts) with non-small cell lung cancer and advanced gastric cancer (AGC). This phase II study has been conducted to evaluate efficacy and safety of TAS-114 and S-1 combination in pts with AGC. Methods The main eligibility criteria is pts with AGC after two or more previous chemotherapy regimens containing fluoropyrimidines, platinum agents, and taxanes or irinotecan. The primary endpoint is objective response rate (ORR) by investigators’ judgement. Using Simon’s optimal two-stage design, 29 pts were required, with one-sided a = 5% and power=80%. The threshold and expected ORRs were 5% and 25%. Protein expression levels of dUTPase and BRCA1 in tumor samples were determined by immunohistochemistry. Results The accrual was terminated in June 2018. Of all 20 enrolled pts, the ORR and disease control rate were 5.0% (95% confidence interval [CI], 0.1-24.9%) and 70.0% (95% CI, 45.7-88.1%), respectively. The median progression-free survival (PFS) and overall survival were 2.4 months (95% CI, 1.2-3.3 months) and 7.1 months (95% CI, 5.2-9.4 months), respectively. The median PFS in the groups with high and low dUTPase protein expression in the cytoplasm was 2.8 months (95% CI, 1.4–3.9) and 1.6 months (95% CI, 0.6–2.4), respectively (hazard ratio, 0.40 [95% CI, 0.16–1.04], P = 0.047). Grade 3 or higher treatment-related adverse events were anemia (20%), leucopenia (15%), neutropenia (10%), rash (10%), thrombocytopenia (5%), and Iymphopenia (5%). Conclusions TAS-114 with S-1 showed modest antitumor activity with acceptable safety profiles for heavily pretreated pts with AGC. Legal entity responsible for the study The authors. Funding Taiho. Disclosure D. Takahari: Research grant / Funding (self): Taiho Pharmaceutical Co; Research grant / Funding (self): Ono Pharmaceutical Co; Honoraria (self): Eli Lilly Japan; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Yakult Honsha Co; Honoraria (self): Chugai Pharmaceutical Co., Ltd. A. Kawazoe: Honoraria (self), Research grant / Funding (institution): Taiho. K. Shitara: Honoraria (self): Novartis; Honoraria (self): AbbVie; Honoraria (self): Yakult; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: MSD; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (self): Lilly; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Medi Science. All other authors have declared no conflicts of interest.