Efficacy and safety of regorafenib plus PD-1/PD-L1 inhibitors for metastatic colorectal cancer: a systematic review and meta-analysis

Regorafenib is an approved later-line therapy for metastatic colorectal cancer (mCRC). Combining regorafenib with PD-1/PD-L1 blockade may enhance antitumor immunity by modifying the tumor microenvironment. This meta-analysis compared the combination with regorafenib monotherapy and explored preliminary treatment signals in microsatellite-stable/proficient mismatch repair (MSS/pMMR) mCRC. A comprehensive search was performed in PubMed, Cochrane Library, Embase, Web of Science, and Chinese databases (Wanfang, VIP, CNKI, CBM) up to February 20, 2026. RCTs and RCSs comparing combination therapy with monotherapy were included. Outcomes were ORR, DCR, PFS, and OS, etc. Study quality was assessed using the Cochrane risk-of-bias tool for randomized trials and the Newcastle–Ottawa Scale (NOS) for observational studies. Analyses were performed using RevMan 5.4, with RR/HR and 95% CIs. Heterogeneity was assessed using I², publication bias via funnel plots, and Egger’s/Begg’s tests when applicable. Evidence certainty was graded using GRADE. Eight studies (two RCTs and six RCSs; 992 patients) were included. Compared with regorafenib monotherapy, combination therapy improved ORR (RR = 1.81, 95% CI: 1.15–2.85), DCR (RR = 1.34, 95% CI: 1.10–1.62), and PR (RR = 1.66, 95% CI: 1.07–2.59), and reduced the proportion of patients with PD at tumor assessment (RR = 0.65, 95% CI: 0.50–0.86). Combination therapy was also associated with longer PFS (HR = 0.57, 95% CI: 0.37–0.87), whereas the OS estimate was borderline and did not establish a robust survival benefit (HR = 0.73, 95% CI: 0.54–1.00; P = 0.05). Post hoc exploratory analyses based on extractable MSS/pMMR data suggested possible improvements in disease control. Combination therapy was associated with increased odds of hypertension, hypothyroidism, hand-foot skin reaction, liver function abnormalities, and nausea; however, comparative evidence for grade ≥ 3 toxicity was insufficient because reporting was inconsistent. Regorafenib plus PD-1/PD-L1 inhibitors may improve tumor response and PFS compared with regorafenib monotherapy in refractory mCRC, but a definitive OS advantage has not been established. The MSS/pMMR findings remain exploratory and hypothesis-generating. Adequately powered, biomarker-stratified randomized trials with standardized MSI/MMR assessment, consistent safety reporting, and longer follow-up are required before this combination can be considered a standard later-line treatment.