Treatment-related deaths with immune checkpoint inhibitor–based combinations versus tyrosine kinase inhibitor monotherapy in hepatocellular carcinoma: A systematic review and meta-analysis

BACKGROUND: The therapeutic landscape of HCC has evolved, with ICI-based combinations progressively replacing TKI monotherapy as standard first-line treatment, although concerns remain regarding their safety profile. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing ICI-based combinations with TKI monotherapy as first-line treatment for advanced HCC. MEDLINE/PubMed, Scopus and the Cochrane Library were searched through December 1, 2025. The primary endpoint was the relative risk (RR) of treatment-related death (TRD). RESULTS: 5751 patients from ten RCTs were included: 3349 received ICI-based therapies and 2402 TKI. TRD occurred in 50 patients treated with ICI combinations (1.49%) and in 17 receiving TKI (0.71%). ICI combinations were associated with a significantly increased risk of TRD compared with TKI monotherapy (RR 2.07, 95% CI 1.18-3.65, p = 0.01). In a subgroup analysis according to type of ICI combination, dual ICI therapy showed a significantly increased risk of TRD (RR 3.38; p = 0.008), whereas anti-PD-1 + anti-VEGF(R) (RR 1.23; p = 0.62) and anti-PD-L1 + anti-VEGF(R) (RR 2.87; p = 0.17) did not reach statistically significance. In the subgroup analysis based on baseline liver function, ICI combinations were associated with a significantly higher risk of TRD in patients with ALBI grade 1 (RR 4.76; p = 0.02), while only a non-significant trend was observed in those with ALBI 2 (RR 2.25; p = 0.12). CONCLUSION: ICI combinations were associated with an increased risk of TRD compared with TKI monotherapy, (particularly the dual ICI combinations). The impact of liver function on fatal toxicity remains uncertain and warrants further investigation.