PD-1/PD-L1 inhibitors in the treatment of pMMR mCRC: a meta-analysis based on randomized controlled trials

Background The clinical efficacy of PD-1/PD-L1 inhibitors combined with chemotherapy (± targeted agents) in patients with proficient mismatch repair (pMMR) metastatic colorectal cancer (mCRC) remains unclear. This study systematically evaluated the efficacy of this regimen. Methods We searched PubMed, Web of Science, Embase, the Cochrane Library, and ClinicalTrials.gov for relevant randomized controlled trials (RCTs) published up to May 2026. The primary outcomes were progression-free survival (PFS) and overall survival (OS); effect sizes were estimated as hazard ratios (HRs) and 95% confidence intervals (95%CIs). Results Six RCTs comprising 1,165 participants were included. The addition of PD-1/PD-L1 inhibitors to chemotherapy, with or without anti-VEGF agents, was associated with prolonged PFS (HR = 0.84, 95%CI [0.73, 0.95], P = 0.007) and OS (HR = 0.83, 95%CI [0.73, 0.94], P = 0.004). Subgroup analyses for PFS preliminarily suggested greater benefit in male patients (HR = 0.77, 95%CI [0.64, 0.94], P = 0.010), those with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (HR = 0.73, 95%CI [0.56, 0.95], P = 0.018), those with liver metastases (HR = 0.82, 95%CI [0.68, 0.98], P = 0.027), those without prior adjuvant therapy (HR = 0.81, 95%CI [0.67, 0.98], P = 0.030), those with a PD-L1 combined positive score (CPS) < 1 (HR = 0.53, 95%CI [0.30, 0.95], P = 0.032), those with synchronous metastases (HR = 0.79, 95%CI [0.63, 0.99], P = 0.037), and those with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations (HR = 0.49, 95%CI [0.30, 0.80], P=0.005). These subgroup findings are exploratory, and interaction tests were not performed. Conclusions PD-1/PD-L1 inhibitors combined with chemotherapy (with or without targeted agents) may improve the prognosis of patients with pMMR mCRC and represent a potential first-line treatment option. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420261330186.