Survival in unresectable hepatocellular carcinoma: Comparison of four treatments based on patients reconstructed from Kaplan-Meier curves of randomized trials.

BACKGROUND: The therapeutic landscape for unresectable hepatocellular carcinoma (HCC) has evolved with the advent of combinations of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI). However, the absence of direct comparisons in clinical trials makes it challenging to determine their relative efficacy. AIM: To explore the comparison between ICI and TKI in combination therapy and determine the relative efficacy. METHODS: We conducted a PubMed database search from inception to January 2026, selecting all first-line regimens supported by a randomized controlled trial (RCT). Overall survival (OS) was the endpoint. A series of indirect comparisons was performed across the selected regimens. To conduct our analysis, individual patient data (IPD) were reconstructed from Kaplan-Meier curves. Survival was assessed by the Cox univariate model. Hazard ratio (HR) and restricted mean survival time (RMST) were estimated. Heterogeneity between the sorafenib and lenvatinib control arms was assessed in two separate analyses. RESULTS: Based on our PubMed search, eight RCTs were included. Most combinations compared with sorafenib significantly improved OS, with camrelizumab plus rivoceranib showing the most favourable HR. This was followed by atezolizumab plus bevacizumab, tremelimumab plus durvalumab, toripalimab plus bevacizumab and anlotinib plus penpulimab. Cabozantinib plus atezolizumab did not demonstrate a clear benefit. Camrelizumab plus rivoceranib was superior to tremelimumab plus durvalumab (HR = 0.78; 95%CI: 0.61-0.99) and anlotinib plus penpulimab (HR = 0.73; 95%CI: 0.57-0.93). Compared with lenvatinib, nivolumab plus ipilimumab and pembrolizumab plus lenvatinib yielded modest improvements, with no significant difference between the two. RMST analyses suggested that nivolumab plus ipilimumab, lenvatinib and pembrolizumab plus lenvatinib produced similar results to those of camrelizumab plus rivoceranib. The choice of comparator meaningfully shapes the estimated treatment effect. CONCLUSION: Our study compared the efficacy of the main first-line treatments recommended for unresectable HCC. While we were able to rank the magnitude of efficacy across these treatments, the intrinsic limitations of our methods (primarily the reconstruction of IPD and the indirect nature of the treatment comparisons) should be borne in mind.