Hepatotoxicity of immune checkpoint inhibitors: An evolving picture of risk associated with a vital class of immunotherapy agents

<jats:title>Abstract</jats:title><jats:p>Immune checkpoint inhibitors (<jats:styled-content style="fixed-case">ICI</jats:styled-content>s) block <jats:styled-content style="fixed-case">CTLA</jats:styled-content>‐4, <jats:styled-content style="fixed-case">PD</jats:styled-content>‐1 and <jats:styled-content style="fixed-case">PD</jats:styled-content>‐L1, or other molecules that control antitumour activities of lymphocytes. These products are associated with a broad array of immune‐related toxicities affecting a variety of organs, including the liver. <jats:styled-content style="fixed-case">ICI</jats:styled-content>‐associated immune‐mediated hepatitis (<jats:styled-content style="fixed-case">IMH</jats:styled-content>) ranges in severity between mild and life‐threatening and is marked by findings that bear both similarities as well as differences with idiopathic autoimmune hepatitis. Hepatotoxic events are often detected in clinical trials of <jats:styled-content style="fixed-case">ICI</jats:styled-content>s that are powered for efficacy. Risk levels for <jats:styled-content style="fixed-case">ICI</jats:styled-content>‐induced liver injury may be impacted by the specific checkpoint molecule targeted for treatment, the <jats:styled-content style="fixed-case">ICI</jats:styled-content> dose levels, and the presence of a pre‐existing autoimmune diathesis, chronic infection or tumour cells which infiltrate the liver parenchyma. When patients develop liver injury during <jats:styled-content style="fixed-case">ICI</jats:styled-content> treatment, a prompt assessment of the cause of injury, in conjunction with the application of measures to optimally manage the adverse event, should be made. Strategies to manage the risk of IMH include the performance of pretreatment liver tests with regular monitoring during and after <jats:styled-content style="fixed-case">ICI</jats:styled-content> treatment and patient education. Using Common Terminology Criteria for Adverse Events developed at the National Cancer Institute to measure the severity level of liver injury, recommended actions may include continued <jats:styled-content style="fixed-case">ICI</jats:styled-content> treatment with close patient monitoring, <jats:styled-content style="fixed-case">ICI</jats:styled-content> treatment suspension or discontinuation and/or administration of corticosteroids or, when necessary, a non‐steroidal immunosuppressive agent. The elucidation of reliable predictors of tumour‐specific <jats:styled-content style="fixed-case">ICI</jats:styled-content> treatment responses, as well as an increased susceptibility for clinically serious immune‐related adverse events, would help optimize treatment decisions for individual patients.</jats:p>