Comparing first-line immune checkpoint inhibitor combinations in advanced hepatocellular carcinoma: A meta-analysis.

Abstract

578 Background: Liver metastasis is a common manifestation of advanced malignancy. In recent years, novel therapeutic strategies, particularly combination regimens involving immune checkpoint inhibitors (ICPIs), have emerged for advanced hepatocellular carcinoma (HCC). However, direct head-to-head comparisons of the first-line ICPIs are limited. To evaluate their clinical impact, we conducted a meta-analysis assessing the efficacy and safety of all Food and Drug Administration (FDA)-approved first-line ICPIs in patients with advanced or metastatic HCC. Methods: A comprehensive search of PubMed, Scopus, Embase, and Google Scholar for studies published between 2018 to 2025. Eligible studies included randomized clinical trials evaluating FDA- approved ICPIs as first-line treatment for advanced or metastatic HCC. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS) and safety. For studies presenting Kaplan-Meier survival curves, individual patient data (IPD) reconstruction tools were used to extract outcome data. Results: A total of 1,064 patients with Unresectable or metastatic HCC from STRIDE, IMbrave150, and CheckMate 9DW were included, with a median age of 64-65 years and 81-83% being male across the three treatment groups: Tremelimumab + Durvalumab (Durva/Treme, n=393), Atezolizumab + Bevacizumab (Atezo/Bev, n=336), and Nivolumab + Ipilimumab (Nivo/Ipi, n=335). The meta-analysis showed that median OS was highest with Nivo/Ipi (24 months), followed by Atezo/Bev (19 months) and Durva/Treme (16.7 months) (p=0.046), while median PFS was 9.3, 6.8, and 3.8 months, respectively (p<0.001). Grade 3/4 adverse events were lowest with Durva/Treme (25.5%) compared with Atezo/Bev (42.6%) and Nivo/Ipi (40.9%) (p<0.0001). Fatigue and diarrhea were slightly more frequent with Durva/Treme, whereas hypertension was most common with Atezo/Bev; other toxicities were comparable across groups. Conclusions: First-line ICPIs combination for advanced HCC shows distinct profiles: Nivo/Ipi offers the longest survival, Durva/Treme has the lowest severe toxicity. These findings suggest that first-line ICPIs selection in advanced HCC should balance efficacy and safety, supporting individualized treatment decisions.