Hepatotoxicity of immune checkpoint inhibitors: What is Currently Known

Abstract

Background: This systematic review and network meta-analysis aimed to provide a complete hepatotoxicity profile, hepatotoxicity spectrum, and safety ranking of immune checkpoint inhibitor drugs for cancer treatment. Methods: PubMed, Embase, Scopus, CINAHL, Web of Science, psycINFO, Cochrane Library, and ClinicalTrials.gov. websites were searched, and a manual search of relevant reviews and trials up to January 1, 2022, was undertaken. Head-to-head III randomized controlled trials comparing any 2 or 3 of the following treatments or different doses of the same immune checkpoint inhibitor drug were included: programmed death 1 (PD-1), programmed death ligand 1, and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitors and conventional therapy. We included 106 randomized trials (n=164,782) containing 17 treatment arms. Results: The overall incidence of hepatotoxicity was 4.06%. The rate of fatal liver adverse events was 0.07%. The programmed death ligand 1 inhibitor+targeted therapy drug+chemotherapy group had the highest risk of treatment-related increases in all-grade alanine aminotransferase and aspartate aminotransferase levels, and the differences were significant. For immune-related hepatotoxicity, no significant difference was found between PD-1 and CTLA-4 inhibitors for all-grade hepatotoxicity; however, CTLA-4 inhibitors were associated with a higher risk of grade 3–5 hepatotoxicity than PD-1 inhibitors. Conclusions: The highest incidence of hepatotoxicity and fatality was observed with triple therapy. The overall incidence of hepatotoxicity was similar between different dual regimens. For immune checkpoint inhibitor monotherapy, the overall risk of immune-mediated hepatotoxicity related to CTLA-4 inhibitors did not differ significantly from that of PD-1 inhibitors. There was no direct relationship between the risk of liver injury and drug dose, whether monotherapy or combination therapy was used.

The Epidemiology of Newly Recognized Causes of Drug-Induced Liver Injury: An Update

“…Patients receiving combination regimens have constantly been found to have a greater risk than those treated with monotherapy [ 29 , 30 , 31 , 32 , 33 , 34 ]. Previous studies have also shown that melanoma patients have a greater risk of hepatotoxicity as they often receive combination therapy in their treatment regimens.…”

“…Previous studies have also shown that melanoma patients have a greater risk of hepatotoxicity as they often receive combination therapy in their treatment regimens. Several studies have found that CTLA-4 inhibitors have a higher risk of liver injury than anti-PD1 agents [ 29 , 30 , 31 , 32 , 33 , 34 ]. However, in a recent systematic review and network meta-analysis focused on monotherapy with CPIs, the overall risk of immune-mediated hepatotoxicity related to CTLA-4 inhibitors did not differ significantly from that of PD-1 inhibitors [ 34 ].…”

“…Several studies have found that CTLA-4 inhibitors have a higher risk of liver injury than anti-PD1 agents [ 29 , 30 , 31 , 32 , 33 , 34 ]. However, in a recent systematic review and network meta-analysis focused on monotherapy with CPIs, the overall risk of immune-mediated hepatotoxicity related to CTLA-4 inhibitors did not differ significantly from that of PD-1 inhibitors [ 34 ]. The overall incidence of hepatotoxicity was 4.1% [ 34 ].…”

“…However, in a recent systematic review and network meta-analysis focused on monotherapy with CPIs, the overall risk of immune-mediated hepatotoxicity related to CTLA-4 inhibitors did not differ significantly from that of PD-1 inhibitors [ 34 ]. The overall incidence of hepatotoxicity was 4.1% [ 34 ]. The highest incidence of hepatotoxicity was observed with triple therapy, and the overall incidence of hepatotoxicity was similar between different dual regimens [ 34 ].…”

“…The overall incidence of hepatotoxicity was 4.1% [ 34 ]. The highest incidence of hepatotoxicity was observed with triple therapy, and the overall incidence of hepatotoxicity was similar between different dual regimens [ 34 ]. Interestingly, no direct relationship was found between the risk of liver injury and drug dose, whether monotherapy or combination therapy was used [ 34 ].…”