Efficacy and safety of TACE combined with immune checkpoint inhibitors and VEGF inhibitors in hepatocellular carcinoma: A systematic review and meta-analysis.

e16300 Background: Transarterial chemoembolization (TACE) remains the standard of care for intermediate stage hepatocellular carcinoma (HCC), yet long term survival is limited by high rates of recurrence and progression. The addition of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) with TACE has recently emerged as a promising strategy. This meta-analysis evaluates the efficacy and safety of TACE plus systemic combination therapy compared to TACE alone. Methods: A systematic review and meta-analysis was conducted according to PRISMA guidelines. Studies evaluating TACE combined with dual systemic therapy (ICI + TKI/VEGF inhibitor) were identified through major databases up to January 2026. Pooled odds ratios (ORs) and Hazards Ratio (HRs) were calculated using fixed effects models as appropriate. Results: Five studies (4 RCTs, 1 cohort) comprising 1964 patients were included. Progression-free survival was significantly longer with TACE combined with dual systemic therapy compared with TACE alone (mean difference 4.12 months, 95% CI 2.86-5.37; p < 0.00001; I² = 73%). The objective response rate was also significantly higher with TACE combination therapy (OR 2.66, 95% CI 2.17-3.26; p < 0.00001), despite substantial heterogeneity (I² = 83%). Grade 3/4 adverse events were significantly more frequent with TACE combination therapy (OR 3.36, 95% CI 2.66-4.25; p < 0.00001; I² = 68%). The most common severe toxicities included Hypertension (16.2%), Immune-mediated Hepatitis (9.6%), and Proteinuria (8.8%). Hypertension occurred significantly more often with TACE combination therapy than with TACE alone (pooled OR 9.52, 95% CI 1.83-49.62; p = 0.007; I² = 51%). Conclusions: The addition of ICI and TKI/VEGF inhibitors to TACE provides consistent, statistically significant and clinically meaningful improvement in disease control for unresectable HCC. This can be explained on the basis of complementary biological mechanisms, including enhanced tumor antigen exposure following TACE, restoration of antitumor T cell activity with ICI, and suppression of TACE induced angiogenesis through VEGF pathway blockade. While the efficacy benefit is robust across trials, safety profiles vary significantly by regimen.The higher rate of grade ¾ adverse effects, especially hypertension and immune-mediated hepatitis, is mainly due to the biological effects of VEGF inhibitors on blood vessels and the increased immune activation caused by immune checkpoint inhibitors. Despite a higher incidence of grade 3/4 toxicities, adverse events were generally manageable with standard supportive care and dose modifications. Overall, these findings support the use of TACE-systemic combinations as a new potential standard of care, with careful patient selection and toxicity monitoring.