Hepatic failure associated with immune checkpoint inhibitors: An analysis of the Food and Drug Administration Adverse Event Reporting System database

Abstract Background Hepatic failure induced by immune checkpoint inhibitors (ICIs) has been reported in only a few case series and case reports. Objective We aimed to explore the association between ICIs and hepatic failure and characterize the clinical features of ICI‐associated hepatic failure in the pharmacovigilance database. Methods Data from the first quarter (Q1) of 2015 to the fourth quarter (Q4) of 2021 in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database were retrieved for disproportionality and Bayesian analysis. Reporting odds ratios (ROR) and information component (IC) were used to evaluate correlations between ICIs and hepatic failure. Results Hepatic failure occurred in 0.19% (18,454/9,647,655) of all cases in the FAERS database, of which 654 cases were associated with ICIs. The overall median time from ICIs initiation to hepatic failure onset was 38 days, 72.3% of the adverse events occurred within the first 3 months, and 68.65% of the cases died after developing hepatic failure. In general, a strong signal was shown between ICIs and hepatic failure (ROR 025 = 2.70, IC 025 = 1.39). For the three categories of ICIs, programmed cell death 1 ligand 1 inhibitors (ROR 025 = 3.09, IC 025 = 1.57) had a higher risk signal than programmed cell death protein 1 inhibitors and cytotoxic T lymphocyte‐associated protein 4 inhibitors. For monotherapy, atezolizumab showed the strongest risk signal (ROR 025 = 4.07, IC 025 = 1.90). The combination of nivolumab and ipilimumab showed stronger signals of hepatic failure compared with nivolumab or ipilimumab alone (nivolumab + ipilimumab vs. ipilimumab: ROR 025 = 1.40, IC 025 = 0.16; nivolumab + ipilimumab vs. nivolumab: ROR 025 = 1.24, IC 025 = 0.34). Considering the concomitant agents used with ICIs, the majority of these regimens showed stronger signals than ICI monotherapy, such as acetaminophen (ICIs + acetaminophen vs. ICIs: ROR 025 = 1.06, IC 025 = 0.32). Conclusions ICIs had possible strong signals associated with hepatic failure, and most cases of hepatic failure occurred within the first 3 months and had poor outcomes, which should attract clinical attention.