Aetiology of liver disease and response to immune checkpoint inhibitors: An updated meta-analysis confirms benefit in those with non-viral liver disease

Clinical outcomes for advanced hepatocellular carcinoma (HCC) have significantly improved with the introduction of immune checkpoint inhibitors (ICIs), but results from initial trials have suggested that the aetiology of liver disease may be a predictive marker of clinical benefit, and stratification based on aetiology has been recommended. The differential response has been supported by preclinical models and reinforced in the recent review.[1]Pfister D. Nunez N.G. Pinyol R. Govaere O. Pinter M. Szydlowska M. et al.NASH limits anti-tumour surveillance in immunotherapy-treated HCC.Nature. 2021; 592: 450-456Crossref PubMed Scopus (524) Google Scholar,[2]Yahoo N. Dudek M. Knolle P. Heikenwalder M. Role of immune responses for development of NAFLD-associated liver cancer and prospects for therapeutic modulation.J Hepatol. 2023; Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar But as more clinical data emerge, the association between liver disease aetiology and response to ICI-based therapy has become less clear. The possibility that aetiology was an important factor for response to ICI-based therapy was raised by the subgroup analysis of the IMbrave 150 trial.[3]Finn R.S. Qin S. Ikeda M. Galle P.R. Ducreux M. Kim T.Y. et al.Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.N Engl J Med. 2020; 382: 1894-1905Crossref PubMed Scopus (3215) Google Scholar The trial met its endpoint demonstrating an overall survival advantage for atezolizumab+bevacizumab compared with sorafenib (hazard ratio [HR] 0.58; 95% CI 0.42 to 0.79; p <0.001), but in the non-viral sub-group, the HR was only 0.91 (0.52-1.60), comparing unfavourably with the hepatitis B and C cohort with HRs of 0.51 and 0.43, respectively. But what is also striking in the subgroup analysis is that the median overall survival for the 53 non-viral, sorafenib-treated patients was 18 months, considerably better than the 12.4 and 12.6 months for the hepatitis B and C cohort.[4]Cheng A.L. Qin S. Ikeda M. Galle P.R. Ducreux M. Kim T.Y. et al.Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma.J Hepatol. 2022; 76: 862-873Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar Initial studies have not suggested that patients with non-viral HCC have a better prognosis with sorafenib than those with viral aetiology; in fact, if anything, the data indicates that those with HCV do better.[5]Bruix J. Raoul J.L. Sherman M. Mazzaferro V. Bolondi L. Craxi A. et al.Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial.J Hepatol. 2012; 57: 821-829Abstract Full Text Full Text PDF PubMed Scopus (667) Google Scholar Hence, the overperformance of the control group in the subgroup analysis of IMbrave 150 trial may explain, at least in part, the apparent lack of benefit of atezolizumab+bevacizumab in non-viral patients. Additionally, the response rate of 27% in the non-viral cohort was similar to that reported for non-viral cohorts in the initial studies of single-agent PD-1 inhibitors.[6]El-Khoueiry A.B. Sangro B. Yau T. Crocenzi T.S. Kudo M. Hsu C. et al.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.Lancet. 2017; 389: 2492-2502Abstract Full Text Full Text PDF PubMed Scopus (2918) Google Scholar,[7]Finn R.S. Ikeda M. Zhu A.X. Sung M.W. Baron A.D. Kudo M. et al.Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma.J Clin Oncol. 2020; JCO2000808Crossref Scopus (663) Google Scholar However, a subsequent meta-analysis, including data from IMbrave 150, CheckMate 459 and KEYNOTE-240, concluded that immunotherapy was superior to control in those with viral aetiology but provided no survival advantage in those of non-viral aetiology.[1]Pfister D. Nunez N.G. Pinyol R. Govaere O. Pinter M. Szydlowska M. et al.NASH limits anti-tumour surveillance in immunotherapy-treated HCC.Nature. 2021; 592: 450-456Crossref PubMed Scopus (524) Google Scholar Since then a further six randomised-controlled trials have been reported; COSMIC-312[8]Kelley R.K. Rimassa L. Cheng A.L. Kaseb A. Qin S. Zhu A.X. et al.Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial.Lancet Oncol. 2022; 23: 995-1008Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, HIMALAYA[9]Abou-Alfa G.K. Chan S.L. Kudo M. Lau G. Kelley R.K. Furuse J. et al.Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA.J Clin Oncol. 2022; 40: 379Crossref Google Scholar, LEAP-002[10]Finn R.S. Kudo M. Merle P. Meyer T. Qin S. Ikeda M. et al.Primary results from the phase III LEAP-002 study: lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC).Ann Oncol. 2022; 33: S808-S869Abstract Full Text Full Text PDF Google Scholar, RATIONALE-301[11]Qin S. Kudo M. Meyer T. Finn R.S. Vogel V. Bai Y. et al.Final analysis of RATIONALE-301: randomized, phase III study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma.Ann Oncol. 2022; 33: S808-S869Google Scholar, Camrelizumab and rivoceranib[12]Qin S. Chan L.S. Gu S. Bai Y Y. Ren Z. Lin X. et al.Camrelizumab (C) plus rivoceranib (R) vs. sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): a randomized, phase III trial.Ann Oncol. 2022; 33: S808-S869Google Scholar and ORIENT-32[13]Ren Z. Xu J. Bai Y. Xu A. Cang S. Du C. et al.Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.Lancet Oncol. 2021; 22: 977-990Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar. We have performed an updated meta-analysis to explore the relationship between liver disease aetiology and clinical outcome for patients treated with ICI-based therapy (Fig. 1). We excluded the ORIENT-32 trial since it was conducted exclusively in China in a population in which 94% had hepatitis B infection. The meta-analysis used a restricted maximum likelihood random effects model. A low degree of heterogeneity in the HRs is indicated by I2 = 26% and T2 = 0.01. The findings reveal a significant survival advantage across both non-viral and viral aetiologies (HR 0.79, 95% CI 0.72 to 0.86, p <0.001), with the largest estimated benefit for those with hepatitis B (hepatitis B: HR 0.70, p <0.001; hepatitis C: HR 0.78, p = 0.04; non-viral: HR 0.87, p = 0.02). For the non-viral subgroup, the HIMALAYA trial reported the most significant benefit with ICIs, indicating the potential importance of CTLA-4 inhibition in this subpopulation. In this respect, publication of the CheckMate 9DW trial comparing nivolumab and ipilimumab with sorafenib, is eagerly awaited. Based on this analysis, it is premature to conclude that patients with non-viral liver disease do not benefit from ICI-based therapy. In addition to all the potential pitfalls of post hoc analysis, it has to be acknowledged that in the majority of cases, HCC development is multifactorial and includes demographic factors, severity and activity of the underlying disease, metabolic factors (diabetes, obesity), and lifestyle factors (alcohol intake, smoking). Specifically, the distinction of NASH/NAFLD and ASH can be challenging in light of recent data indicating that harmful drinking can be observed in up to 30% of obese patients.[14]Staufer K. Huber-Schonauer U. Strebinger G. Pimingstorfer P. Suesse S. Scherzer T.M. et al.Ethyl glucuronide in hair detects a high rate of harmful alcohol consumption in presumed non-alcoholic fatty liver disease.J Hepatol. 2022; 77: 918-930Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Overall, these issues complicate the (post hoc) evaluation of how “one” underlying liver disease might influence the effectiveness of a specific therapy. In this context, preclinical models can be very helpful not only to understand the molecular mechanisms that may underlie differential efficacies, but also to develop hypothesis-based strategies to improve the efficacy of therapy in a specific sup-group such as patients with fatty liver. The authors received no financial support to produce this manuscript. TM Consultancy: Eisai, BMS, Adaptimmune. Ipsen, Roche, AstraZeneca, MSD, Beigene Funding: MSD. AV Consultancy/Speaker: AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, BTG, Daichi-Sankyo, EISAI, Incyte, Ipsen, MSD, PierreFabre, Roche, Servier, Sirtex, Tahio, Terumo. Please refer to the accompanying ICMJE disclosure forms for further details. TM: Concept and design, collection of data, interpretation of data, drafting and reviewing and approving final manuscript. SG: Analysis of data, interpretation of data, reviewing final manuscript. AL: Analysis of data, interpretation of data, reviewing final manuscript. 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