TAS-102 plus bevacizumab in refractory metastatic colorectal cancer: A systematic review and meta-analysis of randomized trials with validation from prospective single-arm studies.

Abstract

174 Background: TAS-102 (trifluridine–tipiracil) provides modest benefit in refractory metastatic colorectal cancer (mCRC). The addition of bevacizumab has shown encouraging activity in randomized and single-arm studies. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) and summarized outcomes from prospective single-arm series. Methods: A systematic search of PubMed, Embase, and major oncology meeting abstracts through September 2025 was performed to identify eligible studies. RCTs of TAS-102 with or without bevacizumab were included in the meta-analysis, and prospective single-arm phase I/II studies were summarized qualitatively. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) for safety outcomes were extracted. Pooled estimates were generated using fixed-effects models, with random-effects analyses performed for sensitivity. Results: Two RCTs met eligibility criteria: the phase III SUNLIGHT trial (N=492) and the phase II trial by Pfeiffer et al. (N=93), for a combined total of 585 patients. In the pooled analysis, TAS-102 plus bevacizumab significantly reduced the risk of death compared with TAS-102 alone (HR 0.60, 95% CI 0.49–0.74). Progression-free survival was likewise improved (HR 0.44, 95% CI 0.37–0.53). Grade ≥3 neutropenia was more frequent with the combination (RR 1.28, 95% CI 1.03–1.60), although other toxicities were generally manageable. Four additional prospective single-arm studies conducted between 2017 and 2022, including C-TASK FORCE, BiTS, TAS-CC4, and Yoshida et al., enrolled 25 to 46 patients each. These consistently demonstrated median PFS ranging from 3.7 to 4.6 months and median OS ranging from 9.3 to 11.4 months, reinforcing the reproducibility of RCT findings in diverse cohorts. Conclusions: Pooled evidence from two randomized trials demonstrates that TAS-102 plus bevacizumab significantly improves both OS and PFS compared with TAS-102 alone in refractory mCRC, at the cost of increased but manageable neutropenia. Prospective single-arm studies further validate these results, showing consistent survival outcomes across independent settings. This systematic review and meta-analysis provide comprehensive synthesis and support TAS-102 plus bevacizumab as an evidence-based treatment option in refractory mCRC. Summary of included randomized trials of TAS-102 + bevacizumab in refractory mCRC. Trial Phase N Backbone Median OS (mo) HR OS (95% CI) Median PFS (mo) HR PFS (95% CI) ≥G3 neutropenia (%) Combo vs Control SUNLIGHT (2023) III 492 FTD–TPI ± Bev 10.8 vs 7.5 0.61 (0.49–0.77) 5.6 vs 2.4 0.44 (0.36–0.54) 43.1 vs 32.1 Pfeiffer et al. (2020) II 93 FTD–TPI ± Bev 9.4 vs 6.7 0.55 (0.32–0.94) 4.6 vs 2.6 0.45 (0.29–0.72) 67.4 vs 38.3