Efficacy and safety of trifluridine/tipiracil plus bevacizumab across different subgroups of patients with refractory colorectal cancer: a meta-analysis

Introduction: Metastatic colorectal cancer (mCRC) patients who are refractory to initial treatment lines exhibit a challenging clinical scenario characterised by a poor prognosis and constrained therapeutic options. This systematic review and meta-analysis assess the integration of bevacizumab into trifluridine-tipiracil (TFD/TPI) therapy for mCRC, examining its benefits across patient subgroups and evaluating safety relative to TFD/ TPI monotherapy. Materials and methods: Following preferred reporting items for systematic reviews and meta-analysis statements, we conducted a thorough literature search from 15 October to 11 November 2023, covering MEDLINE, Embase and the Cochrane database. Data extraction and quality assessment followed Cochrane guidelines, and hazard or odds ratios with 95% confidence intervals (CI) were pooled ( p < 0.05 significance threshold). The study protocol is registered in PROSPERO (CRD42023484695). Results: Analysing 770 database results, we included two randomised controlled trials and five observational studies covering over 4,000 patients. Combined therapy exhibited significant improvements in overall survival (OS) hazard ratios (HR 0.60; 95% CI 0.49- 0.72; p < 0.01) and progression-free survival (HR 0.48; 95% CI 0.40-0.59; p < 0.01). Subgroups, including prior bevacizumab exposure (HR 0.70; 95% CI 0.64-0.77; p < 0.01) and mutated RAS gene (HR 0.64; 95% CI 0.53-0.77; p < 0.01), demonstrated improvements in OSwith bevacizumab. Conclusion: This meta-analysis underscores the heightened efficacy of TFD/TPI combined with bevacizumab for refractory mCRC compared to TFD/TPI monotherapy across diverse subgroups. Combined therapy has increased grade >= 3 neutropenia and hyperten- sion, while monotherapy is associated with fatigue and anemia.