Objective To systematically evaluate the efficacy and safety of regorafenib and fruquintinib as third-line or later-line treatment for metastatic colorectal cancer (mCRC).

Methods PubMed, the Cochrane Library, Embase, Web of Science, CNKI, and Wanfang Data were systematically searched for relevant randomized controlled trials (RCTs) published from January 1, 2012 to March 31, 2025. Conventional Meta-analyses were performed using the Paule-Mandel random-effects model. Random-effects network Meta-analyses were conducted for disease control rate (DCR), objective response rate (ORR), and serious adverse events (SAEs).

Results A total of 6 RCTs were included. Of these, 5 RCTs involving 2,142 patients met the eligibility criteria for the primary analysis, whereas one RCT evaluating second-line combination therapy was included only in the sensitivity analysis. In the primary analysis, compared with placebo, both regorafenib and fruquintinib were associated with improved overall survival, with HRs of 0.67 [95%CI (0.48, 0.93)] and 0.66 [95%CI (0.57, 0.76)], respectively. For progression-free survival, the corresponding HRs were 0.40 [95%CI (0.26, 0.63)] and 0.30 [95%CI (0.26, 0.34)], respectively, also significantly favoring active treatment. For DCR, the ORs versus placebo were 6.69 [95%CI (2.06, 21.74)] for regorafenib and 8.14 [95%CI (5.59, 11.86)] for fruquintinib. No statistically significant differences in the incidence of any SAEs were observed between regorafenib and placebo, or between fruquintinib and placebo [OR=1.21, 95%CI (0.92, 1.60); OR=1.46, 95% CI (0.75, 2.87)]. Network Meta-analysis showed no statistically significant differences between fruquintinib and regorafenib in DCR [OR=1.41, 95%CI (0.54, 3.70)], ORR [OR=1.70, 95%CI (0.15, 19.32)], or SAEs [OR=1.14, 95%CI (0.52, 2.51)]. Some estimates were affected by heterogeneity, imprecision, or sensitivity to the analytical methods used.

Conclusion Current evidence from RCTs suggests that both regorafenib and fruquintinib may provide clinical benefit as later-line treatment options for patients with mCRC who have experienced failure of prior standard therapies. However, due to the lack of head-to-head RCTs, sparse evidence network and uncertainty in some effect estimates, the available evidence is insufficient to establish the comparative efficacy or safety advantages of either drug or to determine a preferred treatment sequence.

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