The efficacy and safety of regorafenib/fruquintinib combined with PD-1/PD-L1 for metastatic colorectal cancer: a meta-analysis based on single-arm studies

Objective: The efficacy of regorafenib or fruquintinib in combination with PD-1/PD-L1 inhibitors for metastatic colorectal cancer (mCRC) treatment has not been elucidated. This study aims to systematically evaluate the efficacy and safety of this combination therapy. Methods: PubMed, Embase, Cochrane Library, and Web of Science were systematically retrieved until July 24, 2024. A meta-analysis was carried out for the overall objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the incidence of grade 3 or higher treatment-related adverse events (AEs). Non-overlapping 95% confidence intervals (CIs) were considered statistically significant. Results: 26 studies encompassing 1,409 patients were analyzed. Pooled analysis revealed an ORR of 6% (95% CI: 3%-12%), a DCR of 62% (95% CI: 55%-68%), a median PFS of 3.84 months (95% CI: 3.19-4.49 months), a median OS of 13.08 months (95% CI: 10.17-16.00 months), and an incidence rate of grade 3-4 AEs of 21% (95% CI: 15%-28%). In subgroup analyses, the fruquintinib-based regimen demonstrated significantly superior efficacy compared to regorafenib-based therapy, with higher ORR (16% [95% CI: 13%-21%] vs 3% [95% CI: 1%-9%]), DCR (79% [95% CI: 72%-85%] vs 54% [95% CI: 47%-61%]), and median PFS (5.40 months [95% CI: 4.60-6.19] vs 3.00 months [95% CI: 2.47-3.52]). Median OS was numerically but not significantly longer with fruquintinib (14.35 months [95% CI: 10.68-18.02] vs 12.70 months [95% CI: 8.79-16.61]). Liver metastasis status strongly influenced outcomes, with significantly lower ORR (3% [95% CI: 1%-13%] vs 49% [95% CI: 32%-76%]) and shorter median PFS (2.37 months [95% CI: 1.77-2.96] vs 3.50 months [95% CI: 3.09-3.91]) in patients with liver involvement. Conclusion: The combination of regorafenib or fruquintinib with PD-1/PD-L1 shows moderate efficacy and acceptable safety in the treatment of mCRC. The fruquintinib-based regimen may be superior to the regorafenib-based regimen, and patients without liver metastasis may derive greater benefits. These findings offer new insights for treating mCRC, although they should be validated through large randomized controlled trials.