Efficacy of immune-based combinations across treatment lines in advanced hepatocellular carcinoma: a systematic review and network meta-analysis

Background With the rapid introduction of immune checkpoint inhibitors (ICIs) for advanced hepatocellular carcinoma (HCC), optimal treatment sequencing remains unclear. Lacking direct comparisons, we aimed to evaluate the efficacy and safety of systemic therapies across first- and second-line settings. Methods A frequentist network meta-analysis (PROSPERO: CRD420261296427) was performed using phase III RCTs from PubMed, Embase, Cochrane, and Web of Science (up to January 2026) evaluating systemic HCC therapies. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and Grade ≥3 treatment-related adverse events (TRAEs). Subgroup analysis compared treatment-naïve versus refractory populations. Results Twelve RCTs comprising 8,138 patients were analyzed. For OS, ICI-anti-angiogenic combinations ranked highest, notably sintilimab plus IBI305 (HR = 0.57 vs. sorafenib; SUCRA = 0.94) and camrelizumab plus rivoceranib (HR = 0.62 vs. sorafenib; SUCRA = 0.89). Combinations consistently outperformed monotherapies in PFS and ORR. Crucially, subgroup analysis revealed a statistically significant difference in the magnitude of survival benefit between first-line (HR = 0.74, 95% CI: 0.65–0.83) and second-line settings (HR = 1.09, 95%CI: 0.90–1.30) when compared to sorafenib (P = 0.0006). Regarding safety, ICI monotherapy/dual-blockade (e.g., pembrolizumab, nivolumab + ipilimumab) demonstrated better tolerability, whereas TKI-based combinations significantly increased Grade ≥3 TRAE rates. Conclusion ICI-based combinations offer the most robust survival benefits in HCC via pharmacodynamic synergy, albeit with higher cumulative toxicity. The differing magnitude of survival benefit between first- and second-line settings when compared to sorafenib highlights their distinct clinical contexts. These findings support a tailored continuum of care, guiding optimal sequencing based on pharmacological efficacy and safety profiles. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420261296427 , identifier CRD420261296427.