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.

Graphical abstract

FIGURE 1

Network of included studies with available direct comparisons of hepatotoxicity. Abbreviations: Chemo, chemotherapy; CTLA-4, cytotoxic T-lymphocyte antigen 4 inhibitor; PD-1, programmed cell death 1 inhibitor; PD-L1, programmed cell death ligand 1 inhibitor; TTD, targeted therapy drug.

FIGURE 2

Incidence of liver adverse events. (A) Incidence of treatment-related hepatotoxicity according to the adverse event type. (B) Incidence of immune-mediated hepatotoxicity according to the adverse event type. (C) Incidence of treatment-related hepatotoxicity according to the treatment regimen. (D) Incidence of treatment-related all-grade hepatotoxicity according to the treatment regimen. (E), Incidence of treatment-related grade 3–5 hepatotoxicity according to the treatment regimen. (F) Immune-mediated all-grade hepatotoxicity according to the treatment regimen. (G) Immune-mediated grade 3–5 hepatotoxicity according to the treatment regimen. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Chemo, chemotherapy; CTLA-4, cytotoxic T-lymphocyte antigen 4 inhibitor; GGT, gamma-glutamyl transferase; ICIs, immune checkpoint inhibitors; PD-1, programmed cell death 1 inhibitor; PD-L1, programmed cell death ligand 1 inhibitor; TTD, targeted therapy drug.

FIGURE 3

Main network meta-analysis results of hepatotoxicity. (A) Distribution of treatment-related surface under the cumulative ranking (SUCRA) values for ALT elevation. (B) Distribution of immune-mediated SUCRA values for ALT elevation. (C) Network estimates of main treatment comparisons for treatment-related ALT elevation. (D) Network estimates of treatment comparisons for immune-mediated ALT elevation. Abbreviations: ALT, alanine aminotransferase; Chemo, chemotherapy; CTLA-4, cytotoxic T-lymphocyte antigen 4 inhibitor; ICIs, immune checkpoint inhibitors; PD-1, programmed cell death 1 inhibitor; PD-L1, programmed cell death ligand 1 inhibitor; TTD, targeted therapy drug.

FIGURE 4

Distribution of treatment-related ALT surface under the cumulative ranking values stratified by cancer type. (A) All-grade ALT. (B) Grade 3–5 ALT. Abbreviations: ALT, alanine aminotransferase; Chemo, chemotherapy; CTLA-4, cytotoxic T-lymphocyte antigen 4 inhibitor; PD-1, programmed cell death 1 inhibitor; PD-L1, programmed cell death ligand 1 inhibitor; TTD, targeted therapy.

FIGURE 5

Assessment of transitivity among all included trials. (A) Number of patients by treatment comparison. (B) Age by treatment comparison. (C) Male ratio by treatment comparison. (D) Number by tumor types. (E) Age by tumor type. (F) Male ratio by tumor type. Abbreviations: Chemo, chemotherapy; CTLA-4, cytotoxic T-lymphocyte antigen 4 inhibitor; PD-1, programmed cell death 1 inhibitor; PD-L1, programmed cell death ligand 1 inhibitor; TTD, targeted therapy.