A dual-level Bayesian network meta-analysis of first-line immunotherapy in advanced hepatocellular carcinoma: strategy-level and regimen-level evidence.

BACKGROUND: Phase III trials of first-line immunotherapy-based combinations for advanced hepatocellular carcinoma (HCC) have yielded heterogeneous results, and head-to-head comparisons remain scarce. We evaluated mechanism-based strategy classes and individual regimens using a dual-level Bayesian network meta-analysis to provide a structured interpretation of the current evidence. METHODS: We systematically searched the literature up to December 28, 2025, and identified 15 phase III randomised controlled trials. A dual-level Bayesian network meta-analysis was performed using separate models at the strategy level (PD-(L)1 plus VEGF monoclonal antibody (VEGF(Ab)), PD-(L)1 plus tyrosine kinase inhibitor (TKI), PD-(L)1 plus CTLA-4, and PD-(L)1 monotherapy) and the regimen level. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade ≥3 treatment-related adverse events (TRAEs). RESULTS: Fifteen trials comprising 9,792 patients were included. At the strategy level, PD-(L)1 plus VEGF(Ab) showed the most favourable OS effect versus TKI monotherapy and the highest efficacy-oriented ranking, followed by PD-(L)1 plus CTLA-4 and PD-(L)1 plus TKI. PD-(L)1 plus TKI also improved PFS but was associated with a higher toxicity and discontinuation burden, whereas PD-(L)1 monotherapy showed the most favourable tolerability profile. At the regimen level, atezolizumab plus bevacizumab, sintilimab plus IBI305, camrelizumab plus rivoceranib, and STRIDE showed OS benefit versus sorafenib. CONCLUSIONS: In this evidence network, PD-(L)1 plus VEGF(Ab) showed the most efficacy-oriented profile and was supported by relatively consistent regimen-level estimates. However, the clinical interpretation of strategy-level findings differed across classes: PD-(L)1 plus TKI required closer regimen-level assessment because of greater within-class variability and a less favourable toxicity profile, whereas PD-(L)1 plus CTLA-4 and PD-(L)1 monotherapy showed distinct benefit-risk patterns. This dual-level framework complements regimen-centric evidence by distinguishing strategy-level patterns from regimen-level findings and by supporting a structured interpretation of efficacy-toxicity trade-offs in first-line ICI-based therapy for advanced HCC. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251273309, identifier CRD420251273309.