Shitara K, et al. - Given that, in pretreated patients with advanced gastric cancer, trifluridine/tipiracil showed activity and was well tolerated in a phase 2 study done in Japan, researchers determined if, in a global population, the treatment was effective vs placebo. In a heavily pretreated population of patients with advanced gastric cancer, a significantly improved overall survival was seen with trifluridine/tipiracil vs placebo. Trifluridine/tipiracil was well tolerated. This population represents a high unmet medical need, so the potential of trifluridine/tipiracil to be a new treatment option is welcomed.

Methods

• For a randomized, double-blind, placebo-controlled, phase 3 trial conducted in 110 academic hospitals in 17 countries, eligible patients were those aged 18 years or older with histologically confirmed, non-resectable, metastatic gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) as defined by the American Joint Committee on Cancer staging classification (7th edition) who had received at least two previous chemotherapy regimens and had experienced radiological disease progression.
• Either oral trifluridine/tipiracil (35 mg/m² twice daily on days 1-5 and days 8-12 every 28 days) plus best supportive care or placebo plus best supportive care was given to randomly assigned (2:1) patients; dynamic randomization from a centralized interactive voice-response system was used.
• Study-site personnel allocated participants to groups.
• By region (Japan vs rest of world), ECOG performance status (0 vs 1), and previous treatment with ramucirumab (yes vs no), randomization was stratified.
• Both patients and investigators were masked to treatment allocation.
• Overall survival was assessed as primary endpoint.
• The intention-to-treat population was examined for effectiveness, and safety was assessed in all patients who received at least one dose of treatment.

Results

• A total of 507 patients were enrolled and randomly assigned, 337 to the trifluridine/tipiracil group and 170 to the placebo group between February 24, 2016 and January 5, 2018.
• In the trifluridine/tipiracil group and in the placebo group, the median overall survival was 5.7 months (95% CI 4.8–6.2) and 3.6 months (3.1–4.1), respectively (hazard ratio 0.69 [95% CI 0.56–0.85]; one-sided p=0.00029, two-sided p=0.00058).
• In the trifluridine/tipiracil group and in the placebo group, grade 3 or worse adverse events of any cause were experienced by 267 (80%) patients and 97 (58%) patients, respectively.
• Neutropenia (n=114 [34%]) and anemia (n=64 [19%]) were documented as the most frequent grade 3 or worse adverse events of any cause in the trifluridine/tipiracil group, whereas, abdominal pain (n=15 [9%]) and general deterioration of physical health (n=15 [9%]) were the most frequent grade 3 or worse adverse events of any cause in the placebo group.
• In the trifluridine/tipiracil group and in the placebo group, 143 (43%) patients and 70 (42%) patients, respectively, suffered serious adverse events of any cause.
• In each group, the occurrence of one treatment-related death was documented (because of cardiopulmonary arrest in the trifluridine/tipiracil group and because of toxic hepatitis in the placebo group).