Comparative efficacy of fruquintinib, regorafenib or TAS-102 in patients with KRAS-mutant metastatic colorectal cancer: a systematic review and network meta-analysis
- 1Department of Laboratory Medicine, Beijing Hospital of Integrated Traditional Chinese and Western Medicine, Hospital of Integrated Traditional Chinese and Western Medicine, Beijing University of Chinese Medicine
- 2Department of Laboratory Medicine, National Health Commission (NHC) Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of National Health Commission, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University Third Hospital
- 3Department of Biology, The College of Life Sciences and Health, Wuhan University of Science and Technology
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.
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BibTeX
@article{zhou2026comparative,
title = {{Comparative efficacy of fruquintinib, regorafenib or TAS-102 in patients with KRAS-mutant metastatic colorectal cancer: a systematic review and network meta-analysis}},
author = {Yingyu Zhou and Shiqing Zhao and Xiaoyi Zheng and Yixuan Wang and Mingzhen Wang and Siyu Chen and Zhenan Wu and Dong Zang and Wenzhe Si},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1948508},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1948508/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Comparative efficacy of fruquintinib, regorafenib or TAS-102 in patients with KRAS-mutant metastatic colorectal cancer: a systematic review and network meta-analysis
AU - Yingyu Zhou
AU - Shiqing Zhao
AU - Xiaoyi Zheng
AU - Yixuan Wang
AU - Mingzhen Wang
AU - Siyu Chen
AU - Zhenan Wu
AU - Dong Zang
AU - Wenzhe Si
PY - 2026
DA - 2026/10/16
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1948508
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1948508/full
AB - 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.
SN - 2234-943X
ER -