Outcomes of first-line immune checkpoint inhibitor combinations versus tyrosine kinase inhibitors in advanced hepatocellular carcinoma: A meta-analysis.

Abstract

e16243 Background: This meta-analysis compares survival and safety outcomes of FDA-approved first-line ICI combinations versus TKI monotherapy and ICI monotherapy in advanced HCC. Methods: Following PRISMA guidelines, we searched PubMed, Embase, Scopus, and Google Scholar for randomized controlled trials (2018–2025) evaluating first-line systemic therapies in unresectable/metastatic HCC. Primary endpoint: progression-free survival (PFS) and overall survival (OS) . Secondary: grade 3/4 adverse events (AEs) per CTCAE. Kaplan-Meier curves were digitized, and individual patient data (IPD) reconstructed for pooled estimates using random-effects models to derive hazard ratios (HRs), median survivals (with 95% CIs), and heterogeneity (I²). Results: A total of 4,429 patients were included across key trials. Pooled median PFS (95% CI) and OS (95% CI) were: dual ICI (nivolumab/ipilimumab, tremelimumab/durvalumab) 5.51 months (4.75-5.76) and 19.58 months (17.56-23.32); ICI + bevacizumab (atezolizumab/bevacizumab) 5.75 months (5.55-6.74) and 19.09 months (17.10-21.27); ICI + TKI 6.17 months (5.58-7.07) and 19.23 months (16.82-21.88); TKI monotherapy 5.42 months (4.76-5.51) and 15.30 months (13.96-16.27); ICI monotherapy 3.73 months (3.34-3.89) and 16.84 months (13.85-not estimable). All ICI combinations significantly improved OS versus TKI monotherapy (p < 0.001); PFS benefits were variable but generally favored combinations. Among dual ICIs, nivolumab/ipilimumab showed the highest median PFS (9.33 months) and OS (24 months) compared with tremelimumab/durvalumab (PFS 3.84 months, OS 16.7 months) and atezolizumab/bevacizumab (PFS 6.86 months, OS 19.09 months). Versus tremelimumab/durvalumab, atezolizumab/bevacizumab and nivolumab/ipilimumab had favorable PFS (HR 0.76, 95% CI 0.64-0.89, p < 0.05; HR 0.60, 95% CI 0.51-0.72, p < 0.05) and OS (HR 0.93, 95% CI 0.76-1.13, p = 0.4; HR 0.79, 95% CI 0.65-0.95, p < 0.05). Grade 3/4 AEs were highest with ICI + TKI (72.4%), followed by TKI monotherapy (42.7%), ICI + bevacizumab (38.7%), and lowest with dual ICI (32.7%). Notable toxicities included hypertension/platelet abnormalities (ICI + TKI), diarrhea (TKI monotherapy/dual ICI), bilirubin elevation/fatigue (dual ICI), and anemia (ICI + bevacizumab). Conclusions: First-line ICI-based combinations significantly improve survival over TKI monotherapy in advanced HCC, with dual ICI and ICI + bevacizumab regimens showing comparable OS benefits and more favorable toxicity profiles than ICI + TKI approaches. Dual ICI offers an optimal efficacy-toxicity balance in this pooled analysis. These findings support personalized first-line selection based on patient-specific efficacy expectations and tolerability risks, warranting further head-to-head and biomarker-driven studies.