Survival outcomes with modern first-line systemic therapy in advanced hepatocellular carcinoma: A systematic review and meta-analysis.

e16218 Background: First-line systemic therapy for advanced hepatocellular carcinoma (HCC) has evolved from tyrosine kinase inhibitor (TKI) monotherapy to immune checkpoint inhibitor (ICI)–based strategies, including PD-1/PD-L1 inhibitors combined with anti-VEGF therapy and dual checkpoint blockade. We conducted a systematic review and meta-analysis to evaluate survival outcomes across contemporary first-line systemic regimens for advanced HCC. Methods: PubMed, Scopus, and Web of Science were searched for phase II–III studies evaluating first-line systemic therapy in advanced or unresectable HCC. Regimens included PD-1/PD-L1 inhibitors, CTLA-4 blockade, TKIs, anti-VEGF therapy, and investigational immunotherapy combinations, including TIGIT-based approaches. The primary endpoint was overall survival (OS); progression-free survival (PFS) was a secondary endpoint. Comparative outcomes were summarized as hazard ratios (HRs) with 95% confidence intervals (CIs), and pooled using random-effects models when available. Prespecified subgroup analyses were performed by regimen class. Single-arm studies and indirect comparisons were included in qualitative synthesis but excluded from pooled analyses. Heterogeneity was assessed using the I² statistic. Results: Fourteen studies met inclusion criteria, encompassing IO–VEGF combinations, dual checkpoint blockade, PD-1/PD-L1 monotherapy, TKIs, VEGF/EGFR-targeted strategies, and emerging investigational TIGIT-containing regimens. Comparative randomized trials contributed to pooled OS estimates, which favored experimental therapy over control within defined regimen classes, with heterogeneity reflecting treatment and design variability. PFS outcomes were synthesized using comparative HRs when available and summarized descriptively otherwise. Among single-arm studies, median PFS ranged from 4.0 months (pembrolizumab; 95% CI, 2–8) to 9.4 months (envafolimab plus lenvatinib; 95% CI, 1.6–15.6), with a 6-month PFS rate of 56.7% for envafolimab plus lenvatinib. In the ALTER-0802 phase II study of anlotinib, 24-week PFS rates were 54.2% (95% CI, 32.4–71.7) in TKI-naïve patients and 46.6% (95% CI, 24.4–66.2) in previously treated patients. Conclusions: Modern first-line systemic therapies for advanced HCC demonstrate favorable survival outcomes compared with control treatments within specific regimen classes, particularly among combination strategies. Variability across therapeutic approaches highlights the importance of biomarker-informed treatment selection and optimized sequencing. Together, these findings support a personalized first-line treatment approach informed by clinical and emerging biomarker data, while highlighting the need for biomarker-driven trials to optimize sequencing of combination therapies.