Work

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

Year: 2026

Type: review

Study designs: Systematic Review, Meta-Analysis

Abstract: Objective: 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. Methods: 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. Results: 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. Conclusions: 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. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420251275994, identifier CRD420251275994.

Source: Frontiers in Oncology

DOI: 10.3389/fonc.2026.1948508