Tislelizumab plus tyrosine kinase inhibitors with TACE improves survival in unresectable hepatocellular carcinoma with clinical predictors and manageable safety

Background Aims The survival benefit of adding transarterial chemoembolization (TACE) to systemic therapy (tislelizumab plus tyrosine kinase inhibitors TKIs) for unresectable hepatocellular carcinoma (HCC) requires validation. This retrospective study compared the efficacy and safety of tislelizumab-TKIs with or without TACE and identified clinical predictors of benefit. Methods This retrospective analysis included 283 unresectable HCC patients: systemic therapy alone (STG, n=98; tislelizumab plus TKIs) versus combination therapy (CTG, n=185; tislelizumab plus TKIs and TACE). Primary endpoints were overall survival (OS) and progression-free survival (PFS), analyzed by Cox regression. Propensity score matching (PSM) was used to reduce baseline differences between the two groups. Results After PSM, CTG significantly improved median OS (22.5 95% confidence interval (CI): 19.0–34.4 vs . 14.0 12.1–18.6 months; hazard ratio (HR) 0.53, p0.001) and PFS (14.6 12.1–19.1 vs . 9.5 7.8–12.5 months; HR 0.59, p0.001) versus STG. Multivariate analysis identified independent predictors of poor OS: age 60 years, extrahepatic spread, portal vein thrombus, alpha-fetoprotein (AFP) ≥400 ng/mL, and elevated gamma-glutamyl transferase (GGT). Subgroups with maximal CTG benefit included patients aged ≥60 years, no extrahepatic spread, AFP 400 ng/mL, and normal GGT. CTG had higher all-grade adverse events (79.6% vs . 67.0%, p=0.021) and grade ≥3 events (23.5% vs . 14.1%, p=0.038), primarily manageable liver toxicity and hematological abnormalities. Conclusion Combining TACE with tislelizumab-TKIs significantly improves survival over systemic therapy alone in unresectable HCC, with maximal benefit observed in patients aged ≥60 years, without extrahepatic spread, with AFP 400 ng/mL, or normal GGT, despite increased manageable toxicity.