Efficacy of PD-1/PD-L1 inhibitors combined with multi-targeted anti-angiogenic TKIs in advanced or metastatic NSCLC: A meta-analysis based on RCTs

Background: The efficacy of combining programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors with multi-targeted anti-angiogenic tyrosine kinase inhibitors (TKIs) in advanced or metastatic non-small cell lung cancer (NSCLC) remains controversial. This study therefore aimed to systematically evaluate the efficacy of this combination regimen in patients with advanced or metastatic NSCLC. Methods: We systematically searched PubMed, EMBASE, Web of Science, ClinicalTrials.gov, and the Cochrane Library databases for relevant randomized controlled trials (RCTs) up to July 2025. The primary outcomes were progression-free survival (PFS) and overall survival (OS), analyzed using the hazard ratio (HR) and 95% confidence interval (95%CI). Results: A total of six RCTs were included, involving 2,787 participants. Results demonstrated that the intervention group receiving PD-1/PD-L1 inhibitors combined with anti-angiogenic TKIs showed improved PFS compared with the control group (HR = 0.82, 95%CI: 0.69-0.97, p=0.021). However, no statistically significant difference was observed between the two groups in OS (HR = 0.97, 95%CI: 0.88-1.07, p=0.554). Subgroup analyses indicated that the PFS benefit was more pronounced in patients aged<65 years (HR = 0.78, 95%CI: 0.64-0.94), female (HR = 0.73, 95%CI: 0.57-0.92), never-smokers (HR = 0.72, 95%CI: 0.53-0.98), white people (HR = 0.85, 95%CI: 0.72-0.99), with non-squamous NSCLC (HR = 0.82, 95%CI: 0.66-1.01, p=0.064), high PD-L1 expression (tumor proportion score (TPS)≥50%) (HR = 0.78, 95%CI: 0.63-0.96), Eastern Cooperative Oncology Group (ECOG) performance status (PS)=1 (HR = 0.78, 95%CI: 0.64-0.96), no liver (HR = 0.78, 95%CI: 0.64-0.96) or brain (HR = 0.73, 95%CI: 0.53-1.00, p=0.054) metastases, and those receiving first-line therapy (HR = 0.72, 95%CI: 0.54-0.97). No significant difference in OS was observed in all subgroups (all p>0.05). Conclusion: The combination of PD-1/PD-L1 inhibitors and anti-angiogenic TKIs significantly improved PFS in patients with advanced or metastatic NSCLC but did not translate into an OS benefit. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251126527.