Integrating efficacy and safety profile in advanced HCC: A network meta-analysis of first-line systemic therapies

BACKGROUND: Hepatocellular carcinoma(HCC) is the sixth most common cancer and the third leading cause of cancer-related death worldwide. Our updated network meta-analysis aims to compare and rank first-line treatment regimens for advanced HCC. METHODS: We searched PubMed, EMBASE, Scopus, and Cochrane from inception to May 2025 for phase III RCTs investigating first-line systemic therapies for advanced HCC. Derived hazard ratios(HRs) for each study were pooled in a random-effects NMA. The primary outcome was overall survival(OS), progression-free survival(PFS), objective response rate(ORR), and ≥ Grade 3 treatment-related adverse events(TRAE) of the assessed treatment in comparison to Sorafenib and Lenvatinib. Subgroup analysis for OS and PFS was conducted using study-level HRs. P-scores were used to rank the treatment strategies numerically. RESULTS: Seventeen studies involving 12,727 patients were included in the final analysis. Nivolumab-Ipilimumab(HR:0.61,95%CI:0.44-0.84), Atezolizumab-Bevacizumab(HR:0.66,95%CI:0.48-0.90), Durvalumab-Tremelimuma(HR:0.76,95%CI:0.59-0.97), Sintilimab-BevSim(HR:0.57,95%CI:0.41-0.80), and Camrelizumab-Rivoceranib(HR:0.62,95%CI:0.45-0.85) had superior OS compared to Sorafenib. Only Sintilimab-BevSim(HR:0.66,95%CI:0.44-0.99) and Nivolumab-Ipilimumab(HR:0.70,95%CI:0.54-0.92) had superior OS compared to Lenvatinib. Based on p-score rankings only, Nivolumab-Ipilimumab had the highest p-score for OS, PFS, and ORR among the three FDA and EMA approved combination regimens, with similar ≥ Grade 3 TRAE compared to Sorafenib. In the subgroup analysis, Atezolizumab-Cabozantinib has the highest p-score for HBV, Atezolizumab-Bevacizumab the highest for HCV, Durvalumab-Tremelimumab for non-viral aetiology, and Pembrolizumab-Lenvatinib for AFP≥400. CONCLUSION: Our NMA comprehensively compares therapeutic regimens across key clinical outcomes, including OS, PFS, ORR, and ≥ Grade 3 TRAE. The heterogeneity in treatment responses across patient subgroups underscores the importance of personalized approaches in managing HCC.