Background
Phase III double-blind RCT, N=507 (2:1 allocation), heavily pretreated metastatic gastric or GEJ adenocarcinoma (≥2 prior chemotherapy regimens including platinum and fluoropyrimidine). 17 countries; included both Asian and non-Asian patients. TAGS = TAS-102 Gastric Study.
Interventions and follow up
Arm A: Trifluridine/tipiracil (TAS-102) 35 mg/m² bid days 1–5 and 8–12 of each 28-day cycle + best supportive care (BSC) — 337 patients
Arm B: Placebo + best supportive care (BSC) — 170 patients
Primary endpoint: Overall survival
Follow-up: 10.6 mo
Arm B: Placebo + best supportive care (BSC) — 170 patients
Primary endpoint: Overall survival
Follow-up: 10.6 mo
Results
mOS: 5.7 vs 3.6 mo, HR 0.69, 95% CI 0.56–0.85, P=.00058
mPFS: 2.0 vs 1.8 mo, HR 0.57, 95% CI 0.47–0.70, P<.0001
DCR: 44% vs 14%
mPFS: 2.0 vs 1.8 mo, HR 0.57, 95% CI 0.47–0.70, P<.0001
DCR: 44% vs 14%
Adverse events
Grade ≥3 hematologic: neutropenia 34%, anaemia 19%, leukopenia 11%; febrile neutropenia 4%.
Overall grade ≥3 / deaths: any-cause grade ≥3 80% (TAS-102) vs 58% (placebo); one treatment-related death in each arm.
Overall grade ≥3 / deaths: any-cause grade ≥3 80% (TAS-102) vs 58% (placebo); one treatment-related death in each arm.
Conclusions
Trifluridine/tipiracil significantly improved OS vs placebo in heavily pretreated metastatic gastric cancer (mOS 5.7 vs 3.6 mo, HR 0.69), establishing TAS-102 as a third-line option in gastric cancer analogous to its role in colorectal cancer.
Key Limitations
Modest absolute survival gain (2.1 mo) in a heavily pretreated population with very short survival. Control arm (placebo + BSC) does not include active comparators like ramucirumab or irinotecan. Hematologic toxicity is significant. PD-L1 and HER2 status were not prospectively analyzed as biomarkers. The role of TAS-102 in the context of modern first-line IO + chemo regimens is evolving.
Clinical Context
FDA approved trifluridine/tipiracil for HER2-negative metastatic gastric or GEJ cancer after ≥2 prior lines, analogous to RECOURSE in colorectal cancer. Alternative later-line options include ramucirumab monotherapy and irinotecan-based regimens. SUNLIGHT showed TAS-102 + bevacizumab improved CRC outcomes; similar combinations are not validated in gastric. MSI-H patients may benefit more from pembrolizumab monotherapy in this setting.