A phase 3 study of trifluridine/tipiracil plus best supportive care (BSC) vs placebo plus BSC conducted in patients with metastatic gastric cancer who received at least two prior regimens of chemotherapy show the survival benefits and that trifluridine/tipiracil is an effective treatment option in such a heavily pretreated population. The results of the TAGS study (LBA-002), were presented at the 20th anniversary ESMO World Congress on Gastrointestinal Cancer (June 20-23 2018, Barcelona, Spain).

Trifluridine/tipiracil is an orally administered combination agent, currently approved for treatment in patients with refractory metastatic colorectal cancer. Trifluridine/tipiracil demonstrated promising clinical activity in a Japanese phase 2 trial in patients with refractory gastric cancer. These results prompted TAGS investigators to initiate the NCT02500043 study that evaluated the efficacy and safety of trifluridine/tipiracil in heavily pretreated metastatic gastric cancer.

The TAGS is a global phase 3 study that enrolled patients ≥18 years of age with histologically confirmed, non-resectable metastatic gastric cancer, including cancer of the gastro-esophageal junction. It was required that patients have a good performance status (PS) according to Eastern Cooperative Oncology Group (ECOG). The patients have received at least two prior regimens of chemotherapy, including fluoropyrimidines, platinum and a taxane- and/or irinotecan-containing regimen.

Patients were randomized 2:1 to receive trifluridine/tipiracil (35 mg/m² twice daily on days 1–5 and 8–12 of each 28-day cycle) plus BSC, or placebo plus BSC. Patients were stratified by region (Japan vs rest of world), ECOG PS (0 vs 1), and prior treatment with ramucirumab.

Between February 2016 and January 2018, the study team randomly assigned 507 patients to receive trifluridine/tipiracil (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 of March 31, 2018, a median overall survival (OS) was 5.7 months in the trifluridine/tipiracil group and 3.6 months in the placebo group (HR, 0.69; 95% CI 0.56, 0.85; one-sided p = 0.0003). Twelve-month OS rates were 21.2% in the trifluridine/tipiracil group and 13.0% in the placebo group.

Median progression-free survival (PFS) was 2.0 months in the trifluridine/tipiracil group and 1.8 months in the placebo group (HR, 0.57; 95% CI 0.47, 0.70; two-sided p < 0.0001). Four- and 6-month PFS rates were 26.8% and 14.6% in the trifluridine/tipiracil group vs 7.7% and 6.4% in the placebo group, respectively.

Grade 3 or higher adverse events occurred in 79.4% (266 of 335) of patients who received trifluridine/tipiracil and in 57.7% (97 of 168) of patients who received placebo. Grade 3/4 hematological side effects experienced by patients treated with trifluridine/tipiracil were neutropenia (38.1%), leukopenia (21.0%), anemia (18.6%), and lymphocytopenia (18.9%). Of the 38.1% of patients treated with trifluridine/tipiracil who experienced grade 3/4 neutropenia, 1.8% experienced febrile neutropenia (grade 3 or higher). No new safety signals were observed.