14-day versus 28-day trifluridine–tipiracil plus bevacizumab for refractory metastatic colorectal cancer (PRABITAS): a pragmatic, multicentre, open-label, randomised, phase 3, non-inferiority trial in Japan

BACKGROUND Trifluridine-tipiracil (FTD-TPI) plus bevacizumab is the standard treatment for refractory metastatic colorectal cancer. However, the conventional schedule is frequently associated with haematological and gastrointestinal toxicity, which is clinically significant and relevant to patients. A simplified 14-day schedule has been proposed to reduce toxicity, but whether this treatment preserves survival has not been established in a randomised trial. We therefore aimed to assess whether the 14-day schedule is non-inferior to the conventional schedule for overall survival. METHODS PRABITAS was a pragmatic, multicentre, open-label, randomised, phase 3, non-inferiority trial conducted in 178 hospitals in Japan. Patients with refractory metastatic colorectal cancer were randomly assigned (1:1) using a minimisation algorithm, stratified by Eastern Cooperative Oncology Group performance status, RAS mutational status, and institution, to FTD-TPI (35 mg/m2 orally twice daily) plus bevacizumab (5 mg/kg intravenously) on either a conventional 28-day (FTD-TPI on days 1-5 and 8-12; bevacizumab on days 1 and 15) or 14-day schedule (FTD-TPI on days 1-5; bevacizumab on day 1). Eligibility criteria were broadened compared with those of conventional explanatory trials, and trial procedures were aligned with routine clinical practice. The primary endpoint was overall survival, analysed in the intention-to-treat population, with a prespecified non-inferiority margin of 1·25. Safety was assessed in all patients who received at least one dose. Missing data were not imputed. This trial is registered with the Japan Registry of Clinical Trials, jRCTs041230120, and is closed to enrolment. FINDINGS Between Dec 26, 2023, and May 20, 2025, we randomly assigned 972 patients, of whom 970 (99%) constituted the intention-to-treat population after two were excluded because they were randomly assigned before site approval (486 [50%] to the 28-day treatment group, 292 [60%] men and 194 [40%] women]; and 484 [50%] to the 14-day treatment group, 264 [55%] men and 220 [45%] women). Median follow-up was 17·9 months (IQR 14·3-22·6). Median overall survival was 10·3 months (95% CI 9·5-11·6) in the 28-day group and 11·3 months (10·2-12·5) in the 14-day group (stratified hazard ratio 0·93 [95% CI 0·80-1·08]). The 12-month overall survival rates were 44·0% (95% CI 39·5-48·5) in the 28-day group and 47·5% (42·9-52·0) in the 14-day group. Neutropenia grade 3 or worse was reduced in the 14-day group (13% vs 39%; absolute difference 25 percentage points [95% CI 20-31]), as was anorexia grade 2 or worse (15% vs 26%; absolute difference 11 percentage points [6-16]). Two treatment-related deaths occurred in the 14-day group and none in the 28-day group. INTERPRETATION A 14-day schedule of FTD-TPI plus bevacizumab was non-inferior to the conventional 28-day schedule for overall survival, while reducing haematological and gastrointestinal toxicity. These findings support this simplified schedule as the new standard for FTD-TPI plus bevacizumab in refractory metastatic colorectal cancer.