Efficacy of PD-1/PD-L1 inhibitors combined with anti-VEGF/TKIs and TACE in uHCC: a meta-analysis

Background This study evaluated the efficacy of transarterial chemoembolization (TACE) combined with anti-vascular endothelial growth factor (VEGF)/tyrosine kinase inhibitors (TKIs) and programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) inhibitors in the treatment of unresectable hepatocellular carcinoma (uHCC). Methods Four databases were searched for studies evaluating the efficacy of TACE combined with anti-VEGF/TKIs and PD-1/PD-L1 inhibitors in uHCC. Pooled data were analyzed using random-effects models, with hazard ratio (HR) and 95% confidence intervals reported. Overall survival (OS) was the primary outcome, and progression-free survival (PFS) was a secondary outcome. Subgroup analyses were performed based on treatment regimens, therapy setting, and the sequencing of TACE and systemic therapy. Results A total of 53 studies (3 multicentre randomized controlled trials (RCTs) and 50 cohort studies) comprising over 10, 000 patients were included. Patients receiving triple therapy may derive greater OS (HR = 0.47, p<0.001) and PFS (HR = 0.52, p<0.001) benefits than those receiving other regimens. In OS subgroups, across various combinations, the TACE-bevacizumab-atezolizumab (HR = 0.44, p<0.001) and TACE-lenvatinib-tislelizumab regimens (HR = 0.44, p<0.001) appear to derive greater benefit. In contrast, the TACE-lenvatinib-pembrolizumab combination appears to show less benefit (HR = 0.67, p<0.001). Additionally, patients could potentially carry greater OS benefit with triple therapy, regardless of whether TACE was performed first (HR = 0.46, p<0.001) or systemic therapy was followed by TACE (HR = 0.42, p=0.001). Regarding treatment setting, the first-line group may obtain greater OS benefit (HR = 0.47, p<0.001), and the non-first-line group may also derive greater benefit (HR = 0.34, p=0.001). Conclusion Triple therapy (TACE with anti-VEGF/TKIs and PD-1/PD-L1 inhibitors) could significantly improve prognosis in uHCC, and its efficacy may vary depending on the treatment regimen, including the drug combination, treatment sequence, and lines. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251151703 , identifier CRD420251151703.