TAGS: A phase III, randomised, double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory metastatic gastric cancer

Abstract

Background: Trifluridine/tipiracil (FTD/TPI) demonstrated promising efficacy and was well tolerated in a Japanese phase 2 trial of pretreated patients (pts) with advanced gastric cancer. TAGS (NCT02500043) was conducted to confirm these findings. Method(s): This global phase 3 study enrolled pts aged >=18 y with histologically confirmed, non-resectable metastatic gastric cancer (mGC), Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1, and >=2 prior chemotherapy regimens. Pts were randomised 2:1 to receive FTD/TPI (35 mg/m2 BID on days 1-5 and 8- 12 of each 28-day cycle) or placebo, plus best supportive care. Result(s): Between Feb 2016 and Jan 2018, 507 pts were randomised to receive FTD/TPI (n=337) or placebo (n=170). Baseline pt characteristics were balanced across treatment groups; 317 pts (63%) had received >=3 lines of prior systemic therapy. At data cut-off (31 Mar 2018), median follow-up was 10.7 mo and the primary endpoint was met: the risk of death was lower with FTD/TPI vs placebo (HR 0.69; 95% CI 0.56-0.85; P=0.0003; median overall survival [OS] 5.7 vs 3.6 mo). Subgroup OS analyses favored FTD/TPI over placebo in most prespecified subgroups (eg, ethnicity, geographic region, ECOG PS, number of prior regimens). FTD/TPI vs placebo was associated with a lower risk of disease progression or death (HR 0.57; 95% CI 0.47-0.70; P<0.0001). Progression-free survival was longer with FTD/TPI vs placebo in all subgroups. Pts in the FTD/TPI group had a higher disease control rate (44% vs 14%; P<0.0001) and lower risk of ECOG PS deterioration to >=2 (HR 0.69; 95% CI 0.56-0.85; P=0.0005). Grade >=3 any-cause adverse events (AEs) were reported in 267/335 (80%) FTD/TPItreated pts and 97/168 (58%) placebo-treated pts. Any-grade AEs led to dosing delay/ dose reduction in 195 (58%) FTD/TPI-treated and 37 (22%) placebo-treated pts. Dosing delays were used more often than dose reduction to manage AEs. One treatment- related death was reported in each treatment group. No new safety signals were noted. Conclusion(s): In this phase 3 study, FTD/TPI provided clinically meaningful and statistically significant prolongation in OS (31% reduction in risk of death) and was well tolerated in pts with heavily pretreated mGC.