Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis of published data

Although existing evidence from clinical trials has demonstrated manifestation of hepatic adverse events with the use of immune checkpoint inhibitors (ICPIs), overall risks have yet to be reported. Therefore, we assessed the risk of hepatotoxicity associated with inhibitors of the immune checkpoint. We examined data from the Pubmed, Medline and Google Scholar databases. We also examined original studies and review articles for crossreferences Eligible studies included randomized Phase II to Phase III trials of cancer patients treated with nivolumab, pembrolizumab, ipilimumab, tremelimumab. The authors extracted relevant information on participants' characteristics, all-grade and high-grade hepatotoxicity and information on the methodology of the studies. In total, 17 trials were considered eligible for the meta-analysis. The odds ratio for all-grade hepatotoxicity for CTLA-4 inhibitors (Ipilimumab and tremelimumab) was 1.24 (95% confidence interval 0.75, 2.05; p = 0.39) and for high-grade hepatotoxicity was 1.93 (95% confidence interval 0.84, 4.44; p =0.12). Moreover, the odds ratio for all-grade hepatotoxicity for PD-1 inhibitors was 1.52 (95% confidence interval 1.24, 1.86; p < 0.0001) and for high-grade hepatotoxicity was 0.48 (95% confidence interval 0.29, 0.80; p =0.005). The analysis of data showed that CTLA-4 inhibitors seem to be associated with a higher risk of all- and high-grade hepatotoxicity compared with control regimens, whereas PD-1 inhibitors seem to be associated with a lower risk of all- and high-grade hepatotoxicity compared with control regimens.