Comparative analysis of immunotherapy-based combination in first-line management of hepatocellular carcinoma: A meta-analysis.

Abstract

581 Background: Hepatocellular carcinoma (HCC) is a highly fatal malignancy often diagnosed at an advanced stage, with limited treatment options and poor prognosis. Tyrosine kinase inhibitors (TKIs) have provided modest survival benefits, often limited by resistance. Immunotherapy, particularly combinations of immune checkpoint inhibitors (ICPIs), shows promise by overcoming immune evasion and improving efficacy in advanced HCC. This meta-analysis aims to compare the efficacy and safety of TKIs, ICPIs + TKIs, ICPIs + bevacizumab, and ICPIs duplet. Methods: A systemic search of PubMed, Scopus, Embase, and Google Scholar (2018 to 2025) was conducted to identify randomized clinical trials evaluating first-line treatment 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 4,040 patients with unresectable or metastatic HCC were included: 1,729 received TKIs, 878 received ICPIs + Bev, 728 received ICPIs duplet, and 705 received ICPIs + TKIs. Median OS was highest with ICPIs duplet (19.58 months), followed by ICPIs+ TKIs (19.2 months), ICPIs + Bev (19 months) and TKIs (15.3 months) (p<0.001), while median PFS was 5.5, 6.1, 5.7, 5.4 months, respectively (p<0.001). Grade 3/4 adverse events were highest with ICPI-TKI (72.4%) and lowest with ICPI duplet (32.7%) (p<0.0001), with hypertension and platelet abnormalities most frequent in ICPI-TKI and bilirubin elevation higher in ICPI-TKI. Conclusions: In advanced HCC, ICPI duplet achieved the longest OS with the lowest toxicity. ICPIs plus TKIs and ICPIs plus Bev provides comparable survival benefits but were associated with higher toxicity, particularly with ICPIs plus TKIs combinations, while TKIs alone showed inferior efficacy.