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

Abstract

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.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42024582268.

Keywords: PD-1/PD-L1 inhibitors; fruquintinib; meta-analysis; metastatic colorectal cancer; regorafenib.

Figure 1

Flow diagram of meta-analysis for study inclusion/exclusion.

Figure 2

Forest plot for pooled results of ORR (A) and DCR (B) in mCRC patients treated with regorafenib/fruquintinib plus PD-1/PD-L1.

Figure 3

Forest plot for pooled results of PFS (A) and OS (B) in mCRC patients receiving regorafenib/fruquintinib plus PD-1/PD-L1.

Figure 4

Forest plot of the subgroup analysis for ORR (A) and DCR (B) across different drug combination treatment groups (Regorafenib vs Fruquintinib).

Figure 5

Forest plot of the subgroup analysis for PFS (A) and OS (B) across different drug combination treatment groups (Regorafenib vs Fruquintinib).

Figure 6

Forest plot of the subgroup analysis for ORR (A) and PFS (B) across different groups (LM vs non-LM).

Figure 7

Forest plot of the subgroup analysis for ORR (A) and DCR (B) across different countries (East Asia vs North America).

Figure 8

Leave-one-out sensitivity analysis of ORR (A), DCR (B), PFS (C), and OS (D) for patients receiving regorafenib/fruquintinib plus PD-1/PD-L1.

Figure 9

Begg’s funnel plots for publication bias test with pseudo 95% confidence limits. (A) ORR, (B) DCR, (C) PFS, and (D) OS of Regorafenib/Fruquintinib in combination with PD-1/PD-L1 for mCRC.