Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Oct 1;9(10):1423-1431.
doi: 10.1001/jamaoncol.2023.3284.

Immune Checkpoint Inhibitors for Child-Pugh Class B Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Enrui Xie  1 , Yee Hui Yeo  2 , Bernhard Scheiner  3   4 , Yue Zhang  1   5 , Atsushi Hiraoka  6 , Xinxing Tantai  7 , Petros Fessas  3 , Tiago de Castro  8 , Antonio D'Alessio  3 , Claudia Angela Maria Fulgenzi  3 , Shuo Xu  9 , Hong-Ming Tsai  10 , Swetha Kambhampati Thiruvengadam  11 , Wenjun Wang  1 , Bridget P Keenan  12 , Xu Gao  1   7 , Zixuan Xing  1 , Matthias Pinter  4 , Yih-Jyh Lin  13 , Zhanjun Guo  9 , Arndt Vogel  8 , Takaaki Tanaka  6 , Hsin-Yu Kuo  14   15 , Robin K Kelley  12 , Masatoshi Kudo  16 , Ju Dong Yang  2   17 , David J Pinato  3   18 , Fanpu Ji  1   19   20   21
Affiliations

Immune Checkpoint Inhibitors for Child-Pugh Class B Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Enrui Xie et al. JAMA Oncol. .

Abstract

Importance: Immune checkpoint inhibitors (ICIs) are increasingly used in patients with advanced hepatocellular carcinoma (HCC). However, data on ICI therapy in patients with advanced HCC and impaired liver function are scarce.

Objective: To conduct a systematic review and meta-analysis to determine the efficacy and safety of ICI treatment for advanced HCC with Child-Pugh B liver function.

Data sources: PubMed, Embase, Web of Science, and Cochrane Library were searched for relevant studies from inception through June 15, 2022.

Study selection: Randomized clinical trials, cohort studies, or single-group studies that investigated the efficacy or safety of ICI therapy for Child-Pugh B advanced HCC were included.

Data extraction and synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline was followed to extract data. A random-effects model was adopted if the heterogeneity was significant (I2 > 50%); otherwise, a fixed-effect model was used.

Main outcomes and measures: The objective response rate (ORR) and overall survival (OS) were considered to be the primary efficacy outcomes of ICI treatment for Child-Pugh B advanced HCC, and the incidence of treatment-related adverse events (trAEs) was set as the primary measure for the safety outcome.

Results: A total of 22 studies including 699 patients with Child-Pugh B and 2114 with Child-Pugh A advanced HCC comprised the analytic sample (median age range, 53-73 years). Upon pooled analysis, patients treated with ICIs in the Child-Pugh B group had an ORR of 14% (95% CI, 11%-17%) and disease control rate (DCR) of 46% (95% CI, 36%-56%), with a median OS of 5.49 (95% CI, 3.57-7.42) months and median progression-free survival of 2.68 (95% CI, 1.85-3.52) months. The rate of any grade trAEs in the Child-Pugh B group was 40% (95% CI, 34%-47%) and of grade 3 or higher trAEs was 12% (95% CI, 6%-23%). Compared with the Child-Pugh A group, the ORR (odds ratio, 0.59; 95% CI, 0.43-0.81; P < .001) and DCR (odds ratio, 0.64; 95% CI, 0.50-0.81; P < .001) were lower in the Child-Pugh B group. Child-Pugh B was independently associated with worse OS in patients with advanced HCC treated with ICIs (hazard ratio, 2.72 [95% CI, 2.34-3.16]; adjusted hazard ratio, 2.33 [95% CI, 1.81-2.99]). However, ICIs were not associated with increased trAEs in the Child-Pugh B group.

Conclusions and relevance: The findings of this systematic review and meta-analysis suggest that although the safety of ICI treatment was comparable between patients with HCC with vs without advanced liver disease and the treatment resulted in a significant number of radiologic responses, survival outcomes are still inferior in patients with worse liver function. More study is needed to determine the effectiveness of ICI treatment in this population.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Scheiner reported receiving travel support from AbbVie, Ipsen, Gilead Sciences, and AstraZeneca outside the submitted work. Dr Hiraoka reported receiving lecture fees from Chugai Pharma, Eli Lilly, and AstraZeneca outside the submitted work. Dr de Castro reported receiving personal fees from Bristol Myers Squibb and nonfinancial support from MSD outside the submitted work. Dr D’Alessio reported receiving personal fees from Roche outside the submitted work. Dr Keenan reported receiving grants from Roche/Genentech and Partner Therapeutics, personal fees from Regeneron, and nonfinancial support from Roche/Genentech outside the submitted work. Dr Pinter reported receiving personal fees from Bayer, Eisai, Eli Lilly, Ipsen, MSD, Bristol Myers Squibb, Roche, and AstraZeneca outside the submitted work. Dr Vogel reported receiving consultant and advisory board fees from AstraZeneca, Amgen, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, BTG, Daiichi Sankyo, Eisai, Incyte, Ipsen, MSD, Pierre Fabre, Roche, Servier, Sirtex, Taiho, and Terumo and speaker fees from AstraZeneca, Amgen, Bristol Myers Squibb, Daiichi Sankyo, Eisai, GlaxoSmithKline, Incyte, Ipsen, MSD, Pierre Fabre, Roche, Servier, Sirtex, Taiho, and Terumo outside the submitted work. Dr Kelley reported receiving research support to her institution from AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Exelixis, Ipsen, Merck, Roche/Genentech, and Surface Oncology and personal fees from AstraZeneca, Regeneron, Exact Sciences, and Tyra Biosciences outside the submitted work. Prof Kudo reported receiving lecture fees from Chugai and Eisai; advisory board fees from Roche, Bristol Myers Squibb, Eisai, and MSD; and research grants from Ono and Otsuka outside the submitted work. Dr Pinato reported receiving consultant fees from ViiV Healthcare, Bayer Healthcare, Roche, Mursla, MiNa Therapeutics, Eisai, H3B, AstraZeneca, DaVolterra, Exact Sciences, Ipsen, Avamune, and Lift Biosciences and research grants to his institution from Bristol Myers Squibb, GlaxoSmithKline, and MSD outside the submitted work. Dr Ji reported receiving speaker and consultant fees from Gilead Sciences and MSD and speaker fees from Ascletis outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Immune Checkpoint Inhibitor Treatment in Patients With Advanced Hepatocellular Carcinoma (HCC) and Child-Pugh B Liver Function
Squares indicate estimates; size of squares, study weights; whiskers, 95% CIs; diamonds, mean estimates; DCR, disease control rate; OR, odds ratio; and ORR, objective response rate. aMantel-Haenszel test, fixed effects.
Figure 2.
Figure 2.. Estimated Overall Survival (OS) and Progression-Free Survival (PFS) in Patients With Advanced Hepatocellular Carcinoma and Child-Pugh B vs A Liver Function
Squares indicate estimates; size of squares, study weights; whiskers, 95% CIs; diamonds, mean estimates; AHR, adjusted hazard ratio; HR, hazard ratio; TE, estimate of treatment effect; and seTE, standard error of treatment effect estimate.
Figure 3.
Figure 3.. Association of Immune Checkpoint Inhibitors With Median Overall Survival (OS) and Progression-Free Survival (PFS) in Patients With Hepatocellular Carcinoma and Child-Pugh B Liver Function
Squares indicate estimates; size of squares, study weights; whiskers, 95% CIs; and diamonds, mean estimates. aWeights are from random-effects analysis.
See this image and copyright information in PMC

References

    1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi: 10.3322/caac.21660 - DOI - PubMed
    1. Arnold M, Abnet CC, Neale RE, et al. Global burden of 5 major types of gastrointestinal cancer. Gastroenterology. 2020;159(1):335-349.e15. doi: 10.1053/j.gastro.2020.02.068 - DOI - PMC - PubMed
    1. European Association for the Study of the Liver . Management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182-236. doi: 10.1016/j.jhep.2018.03.019 - DOI - PubMed
    1. Allemani C, Weir HK, Carreira H, et al. ; CONCORD Working Group . Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet. 2015;385(9972):977-1010. doi: 10.1016/S0140-6736(14)62038-9 - DOI - PMC - PubMed
    1. Grandhi MS, Kim AK, Ronnekleiv-Kelly SM, Kamel IR, Ghasebeh MA, Pawlik TM. Hepatocellular carcinoma: from diagnosis to treatment. Surg Oncol. 2016;25(2):74-85. doi: 10.1016/j.suronc.2016.03.002 - DOI - PubMed