Hepatic Failure Associated with Immune Checkpoint Inhibitors: A Real-world Study from the Food and Drug Administration Adverse Event Reporting System (FAERS) Database

Abstract Background Although Immune checkpoint inhibitors (ICIs) associated liver damage usually presented as mild elevations of liver enzymes, hepatic failure induced by ICIs have 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 real-world 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 A total of 654 reports of ICI-associated hepatic failure were identified. The overall median time from ICIs initiation to hepatic failure onset was 38 days, and 72.3% of the adverse events occurred within the first 3 months. Death cases accounted for 68.65%. Generally, a strong signal was shown between ICIs and hepatic failure (ROR025 = 2.70, IC025 = 1.39). For three categories of ICIs, anti-PD-1s (ROR025 = 2.54, IC025 = 1.32) had a higher risk signal than anti-PD-L1s and anti-CTLA-4s. For monotherapy, atezolizumab showed the strongest risk signal (ROR025 = 4.07, IC025 = 1.90). The combination of nivolumab and ipilimumab showed stronger signals of hepatic failure compared with nivolumab or ipilimumab alone(nivolumab + ipilimumab vs. ipilimumab: ROR025 = 1.40, IC025 = 0.16; nivolumab + ipilimumab vs. nivolumab: ROR025 = 1.24, IC025 = 0.34). Considering the concomitant used agents with ICIs, the majority of these regimens showed stronger signals than ICI monotherapy, such as acetaminophen (ICIs + acetaminophen vs. ICIs: ROR025 = 1.06, IC025 = 0.32). Conclusion ICIs had possible strong signals associated with hepatic failure, and most cases of hepatic failure occurred within the first three months and had poor outcomes, which should attract clinical attention.