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World J Gastrointest Pharmacol Ther. Sep 5, 2026; 17(3): 120377
Published online Sep 5, 2026. doi: 10.4292/wjgpt.120377
Survival in unresectable hepatocellular carcinoma: Comparison of four treatments based on patients reconstructed from Kaplan–Meier curves of randomized trials
Vera Damuzzo, Stefano Vecchia, Lorenzo Gasperoni, Luna Del Bono, Andrea Ossato, Elena Orlandi, Andrea Messori
Vera Damuzzo, Department of Pharmacy, Vittorio Veneto Hospital, AULSS2 Marca Trevigiana, Vittorio Veneto 31029, Italy
Stefano Vecchia, Department of Pharmacy, AUSL Piacenza Guglielmo da Saliceto Hospital, Piacenza 29121, Italy
Lorenzo Gasperoni, Department of Pharmaceutical, USL Toscana Centro, Prato 59100, Italy
Luna Del Bono, Department of Pharmacy, University of Pisa, Pisa 56126, Italy
Andrea Ossato, UOC Territorial Pharmaceutical Service, Azienda ULSS 8 Berica, Vicenza 36100, Italy
Elena Orlandi, Department of Oncology-Haematology, Piacenza General Hospital, Piacenza 29191, Italy
Andrea Messori, Osservatorio Innovazione Section, HTA Regione Toscana, Firenze 50139, Italy
Co-first authors: Vera Damuzzo and Stefano Vecchia.
Author contributions: Damuzzo V and Vecchia S contributed to conceptualization, data curation, formal analysis, investigation, methodology, software, supervision, validation, writing-original draft, writing-review and editing, both authors have made crucial and indispensable contributions towards the completion of the project and thus qualified as the co-first authors of the paper; Gasperoni L, Del Bono L, Ossato A, Orlandi E, Messori A contributed to conceptualization, data curation, formal analysis, investigation, methodology, supervision, validation, writing-original draft, writing-review and editing.
AI contribution statement: AI tools (specifically ChatGPT) were used solely for linguistic refinement and formatting assistance. No AI tool was involved in the generation of research data, interpretation of results, or formulation of conclusions. All AI-generated outputs were critically reviewed and revised by the authors.
Conflict-of-interest statement: The authors declare no conflict of interests.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Received: February 27, 2026
Revised: April 30, 2026
Accepted: May 22, 2026
Published online: September 5, 2026
Processing time: 184 Days and 9.6 Hours
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.
Core Tip: In the absence of head-to-head trials for first-line unresectable hepatocellular carcinoma, we reconstructed individual patient data from eight phase III trials to indirectly compare immune checkpoint inhibitor and tyrosine kinase inhibitor combinations. Most regimens outperformed sorafenib, with camrelizumab plus rivoceranib emerging as the most effective option, demonstrating superiority over tremelimumab plus durvalumab and anlotinib plus penpulimab. Restricted mean survival time analyses revealed that nivolumab plus ipilimumab, lenvatinib, and pembrolizumab plus lenvatinib achieved results similar to those of camrelizumab plus rivoceranib. These findings provide a practical framework for treatment positioning and underscore the critical influence of comparator on estimated efficacy.
