Efficacy and safety of immune checkpoint inhibitors combined with anti-angiogenic agents compared to sorafenib or lenvatinib in the treatment of unresectable or advanced hepatocellular carcinoma a pairwise meta-analysis of randomized controlled trials

Background: This study evaluates the effectiveness and safety of immune checkpoint inhibitors (ICIs) combined with anti-angiogenic agents compared to sorafenib or lenvatinib monotherapy for unresectable or advanced hepatocellular carcinoma (HCC) and assesses the benefits of combination therapy across various high-risk subgroups. Methods: We systematically reviewed randomized controlled trials (RCTs) from PubMed, Embase, and the Cochrane Library involving PD-1/PD-L1 inhibitors combined with anti-angiogenic agents as first-line therapy for unresectable or advanced HCC. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs). Hazard ratios (HR), odds ratios (OR), and 95% confidence intervals (CI) were extracted for meta-analysis using STATA (version 15). Results: Analysis of 4,020 patients from seven RCTs showed that combination therapy significantly improved PFS (HR = 0.64, 95% CI: 0.55-0.74, P < 0.001), OS (HR = 0.73, 95% CI: 0.64-0.84, P < 0.001), ORR (OR = 3.86, 95% CI: 2.43-6.13, P < 0.001), and DCR (OR = 1.84, 95% CI: 1.43-2.37, P < 0.001). Subgroup analyses revealed substantial benefits in patients with macrovascular invasion, extrahepatic metastasis, hepatitis B-related HCC, and elevated AFP (≥400 ng/mL). Efficacy was more consistent and pronounced in Asian populations and with VEGF monoclonal antibody-based regimens. A pre-specified blinding-risk subgroup analysis demonstrated that treatment effects for PFS and ORR were attenuated in the single double-blind trial, suggesting a more conservative estimate of benefit for these endpoints. Safety analysis showed combination therapy increased grade ≥3 TRAEs (OR = 1.50, 95% CI: 1.04-2.17, P = 0.030) and serious adverse events (OR = 2.03, 95% CI: 1.56-2.65, P < 0.001), with heightened risks of decreased platelet count, increased blood bilirubin, proteinuria, decreased neutrophil count, and hypertension. Conclusion: This meta-analysis establishes immune checkpoint inhibitors combined with anti-angiogenic agents as a superior first-line treatment for advanced hepatocellular carcinoma, providing significant survival benefits over sorafenib or lenvatinib monotherapy. The efficacy is particularly robust in high-risk subgroups and is meaningfully influenced by the choice of anti-angiogenic partner. Despite an increased risk of specific toxicities, the profound survival advantage and superior tumor response firmly support this combination in redefining the standard of care, with optimal application guided by patient profile and drug class selection.