Overall survival results from a phase III trial of trifluridine/tipiracil versus placebo in patients with metastatic gastric cancer refractory to standard therapies (TAGS)

Background: Trifluridine/tipiracil (FTD/TPI), an orally administered combination agent approved for patients with refractory metastatic colorectal cancer, demonstrated promising clinical activity in a refractory gastric cancer Japanese Phase II trial. Therefore, we initiated the TAGS study (NCT02500043) to evaluate the efficacy and safety of FTD/TPI in patients with heavily pretreated metastatic gastric cancer (mGC). Methods: This global Phase III study enrolled patients ≥18 years of age with: histologically confirmed, non-resectable mGC, including cancer of the gastro-oesophageal junction; an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; and at least two prior regimens of chemotherapy, including fluoropyrimidines, platinum and a taxane- and/or irinotecan-containing regimen. Patients were randomised 2:1 to receive FTD/TPI (35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle) plus best supportive care, or placebo plus best supportive care. Patients were stratified by region (Japan versus rest of world), ECOG PS (0 versus 1) and prior treatment with ramucirumab. Results: Between 24 February 2016 and 5 January 2018, we randomly assigned 507 patients to receive FTD/TPI (n = 337) or placebo (n = 170). Baseline patient and disease characteristics were balanced across treatment groups, with all patients receiving platinum and either irinotecan and/or taxanes, and all but one receiving fluoropyrimidine. At the data cut-off (31 March 2018), median overall survival was 5.7 months in the FTD/TPI group and 3.6 months in the placebo group (hazard ratio 0.69; 95% confidence interval [CI] 0.56, 0.85; one-sided p = 0.0003). Twelve-month overall survival rates were 21.2% in the FTD/TPI group and 13.0% in the placebo group. Median progression-free survival was 2.0 months in the FTD/TPI group and 1.8 months in the placebo group (hazard ratio 0.57; 95% CI 0.47, 0.70; two-sided p < 0.0001). Four- and 6-month progression-free survival rates were 26.8% and 14.6% in the FTD/TPI group versus 7.7% and 6.4% in the placebo group, respectively. Grade 3 or higher adverse events occurred in 266 of 335 (79.4%) treated patients who received FTD/TPI and 97 of 168 (57.7%) treated patients who received placebo. Grade 3/4 haematological laboratory abnormalities of special interest experienced by patients treated with FTD/TPI included neutropenia (38.1%), leucopenia (21.0%), anaemia (18.6%) and lymphocytopenia (18.9%). Of the 38.1% of patients who experienced grade 3/4 neutropenia when treated with FTD/TPI, six (1.8%) experienced febrile neutropenia (grade 3 or higher). No new safety signals were observed. Conclusions: In this Phase III study, the survival benefits (31% reduction in risk of death associated with a 2.1-month improvement in median survival) demonstrated that FTD/TPI is an effective treatment option for patients with heavily pretreated mGC.