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

Abstract

580 Background: Hepatocellular carcinoma (HCC) is a highly fatal malignancy often diagnosed at advanced stage, with limited therapeutic options and poor prognosis. For over a decade, tyrosine kinase inhibitors (TKIs) have offered limited survival benefits in HCC due to resistance. Immunotherapy, particularly combination strategies with multiple immune checkpoint inhibitors (ICPIs), shows promise by overcoming immune evasion and enhancing treatment efficacy in advanced HCC. However, direct comparisons of the first-line ICPIs combined with TKIs versus ICPIs duplet are limited. To address this, we conducted a meta-analysis to evaluate the efficacy and safety of these regimens in advanced HCC. Methods: A systemic search of PubMed, Scopus, Embase, and Google Scholar (2018 to 2025) was conducted to identify randomized clinical trials evaluating first-line ICPIs combined with TKIs versus ICPIs duplet with advanced or metastatic HCC. The primary endpoint was overall survival (OS, 95% CI), with secondary endpoints including progression-free survival (PFS, 95% CI) and safety. When Kaplan-Meier curves were presented, individual patient data (IPD) reconstruction tools were used to extract outcome data. Results: A total of 3,162 patients with unresectable or metastatic HCC were included: 1,729 received TKIs, 728 received ICPIs duplet, and 705 received ICPIs + TKIs. Median age ranged 57–65 years, and 82–86% were male. Median OS was highest with ICPIs duplet (19.5 months), followed by ICPIs+ TKIs (19.2 months) and TKIs (15.2 months) (p<0.001), while median PFS was 5.5, 6.1, 5.4 months, respectively (p<0.001). Grade 3/4 adverse events were highest with ICPIs + TKI (72.4%) versus TKIs (42.7%) and ICPIs duplet (32.7%) (p=0.055). Hypertension and platelet abnormalities were most frequent with ICPIs + TKIs, while bilirubin elevation was higher in ICPIs duplet. Other toxicities were similar across groups, indicating greater overall toxicity with ICPIs + TKIs. Conclusions: In advanced HCC, ICPIs duplet offers the longest survival with lower toxicity, while ICPIs + TKIs shows similar survival but higher adverse events. TKIs alone provided shorter survival with moderate toxicity, with ICPIs duplet emerging as the safer option.