Second-line treatment selection for advanced hepatocellular carcinoma: a network meta-analysis with reconstructed survival curves and integrated benefit–risk assessment

Background Optimal second-line systemic therapy for advanced hepatocellular carcinoma (HCC) remains uncertain. This study compared the efficacy and safety of available second-line treatments after tyrosine kinase inhibitor (TKI) failure and explored treatment strategies after immune checkpoint inhibitor (ICI) exposure. Methods Twelve phase III randomized controlled trials (RCTs) were included; 11 contributed to the primary post-TKI network, whereas REACH-2 contributed only to the exploratory alpha-fetoprotein (AFP) ≥400 ng/mL subgroup analysis. Reconstructed individual patient data from published Kaplan–Meier curves were used to generate descriptive pooled survival curves, whereas formal overall-survival (OS) comparisons were based on trial-reported hazard ratios in a frequentist random-effects network meta-analysis (NMA). Safety was evaluated using grade ≥3 adverse events (AEs), and benefit–risk profiles were explored using multidimensional distance to the corner (MDC). Seven observational studies were synthesized separately in an exploratory analysis of post-ICI strategies. Results In the random-effects NMA, regorafenib, cabozantinib and pembrolizumab significantly improved OS compared with placebo or best supportive care. No significant OS differences were observed between regorafenib and cabozantinib or pembrolizumab. Among patients with AFP ≥400 ng/mL, ramucirumab was associated with improved OS versus placebo or best supportive care in the exploratory subgroup analysis. Pembrolizumab had the lowest exploratory MDC (0.439), followed by regorafenib (0.693) and cabozantinib (0.908). The MDC ordering remained unchanged across alternative weighting and leave-one-out sensitivity analyses. The direction and statistical significance of the OS estimates were unchanged in the common-effects sensitivity analysis. In exploratory post-ICI analyses, regorafenib combined with ICIs was associated with improved OS compared with regorafenib monotherapy. Conclusions After TKI failure, several second-line agents improved OS, with differing safety profiles. Pembrolizumab showed the most favorable integrated efficacy–safety profile among treatments with demonstrated OS benefit and may be particularly relevant when tolerability is a priority, while ramucirumab remains a biomarker-directed option for patients with AFP ≥400 ng/mL. In the exploratory post-ICI analysis, combination therapy with regorafenib and ICI was associated with a potential survival benefit compared with regorafenib alone. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420261329202 , identifier CRD420261329202.