Transarterial chemoembolization combined with immunotherapy and targeted therapy as first-line treatment for unresectable and non-metastatic hepatocellular carcinoma: a meta-analysis of phase III trials

Background: The current standard treatment paradigm for patients with unresectable and non-metastatic hepatocellular carcinoma (HCC) involves transarterial chemoembolization (TACE) as the primary local therapeutic modality, followed by systemic therapy upon disease progression. Emerging evidence suggests that the concurrent integration of immunotherapy and targeted therapy with TACE may yield synergistic therapeutic effects. Recent phase III trials—including EMERALD-1, LEAP-012, and TALENTACE—have provided important insights into the efficacy and safety of this multimodal approach. Objectives: This meta-analysis aimed to quantitatively synthesize the efficacy and safety of first-line TACE combined with immunotherapy and targeted therapy versus TACE alone in patients with unresectable, non-metastatic HCC. Design: Systematic review and meta-analysis of phase III randomized controlled trials (RCTs). Data sources and methods: A systematic search of PubMed and major conference proceedings was conducted up to July 6, 2025. Three phase III trials (EMERALD-1, LEAP-012, TALENTACE) were included. Pooled hazard ratios (HRs) for progression-free survival (PFS), odds ratios (ORs) for objective response rate (ORR), and risk ratios (RRs) for adverse events (AEs) were calculated using fixed-effect or random-effects models. Results: The combination of TACE with immunotherapy and targeted therapy demonstrated superior efficacy compared to TACE monotherapy. The pooled HR for PFS was 0.69 (95% confidence interval (CI): 0.60–0.79), indicating a significant delay in disease progression. The pooled OR for ORR was 1.83 (95% CI: 1.45–2.31), reflecting a markedly improved tumor response rate. However, overall survival (OS) data remain immature, and no statistically significant difference in OS was observed at this stage. In terms of safety, the combination therapy was associated with a higher incidence of AEs. Specifically, it significantly increased the risk of grade 3–5 AEs (RR: 1.88, 95% CI: 1.48–2.40) and serious AEs (RR: 1.65, 95% CI: 1.31–2.07). Conclusion: First-line treatment with TACE combined with immunotherapy and targeted therapy significantly improves tumor response and prolongs PFS in patients with unresectable and non-metastatic HCC, albeit at the cost of increased toxicity. This combination strategy represents a promising advancement in the therapeutic landscape for HCC, offering meaningful improvements in oncologic outcomes while highlighting the need for careful toxicity management. Trial registration: International Prospective Register of Systematic Reviews (PROSPERO; CRD420250652613).