Comparative efficacy of fruquintinib, regorafenib or TAS-102 in patients with KRAS-mutant metastatic colorectal cancer: a systematic review and network meta-analysis

Abstract

This study aimed to synthesize evidence from recent randomized controlled trials (RCTs) evaluating the efficacy of regorafenib, fruquintinib, and TAS-102 in patients with metastatic colorectal cancer (mCRC). Using a network meta-analysis, we compared long-term survival outcomes (overall and progression-free survival) in the overall population and in patients with KRAS mutations, to guide treatment decisions and inform therapy selection in molecularly defined subgroups. We systematically searched PubMed, Embase, and the Cochrane Library up to 6 November 2025 for randomized controlled trials reporting overall survival (OS) and/or progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC). Risk of bias was assessed with the Cochrane RoB-2 tool and heterogeneity with I2. A Bayesian network meta-analysis using non-informative normal priors and a random-effects consistency model was fitted; convergence was assessed with the Gelman-Rubin diagnostic. Comparative safety was not formally meta-analyzed. Ten RCTs (n = 3959) were included, with no randomized head-to-head comparisons among the active treatments. Compared with placebo, all active treatments significantly improved overall survival (OS): fruquintinib HR 0.66 (95% CrI 0.53-0.84), regorafenib HR 0.69 (95% CrI 0.51-0.88), TAS-102 HR 0.69 (95% CrI 0.55-0.85), and TAS-102 plus bevacizumab HR 0.41 (95% CrI 0.28-0.59). Combination therapy ranked first; indirect differences among the three single agents were not consistently statistically significant. In patients with KRAS-mutant tumors, fruquintinib and TAS-102 were associated with numerically favorable OS estimates compared with placebo [HR 0.71 (95% CrI 0.51-1.01) and 0.74 (95% CrI 0.50-0.99), respectively], whereas regorafenib did not [HR 0.81 (95% CrI 0.52-1.19)]. These statistical differences versus placebo do not demonstrate superiority over regorafenib, and rank probabilities are exploratory. Fruquintinib and TAS-102 plus bevacizumab are effective later-line options for mCRC. In patients with KRAS-mutant CRC, fruquintinib may be a reasonable option, but available indirect evidence does not establish its superiority over TAS-102 or regorafenib. These findings provide a trial-level, KRAS-stratified synthesis of the available placebo-controlled RCT evidence and should be interpreted as hypothesis-generating, rather than as evidence of a predictive effect of KRAS status or of rank-based superiority among the agents. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420251275994 , identifier CRD420251275994.