Drug-Induced Liver Injury Associated With Emerging Cancer Therapies

Abstract

Targeted therapies and immunotherapies have shown great promise as best-in-class treatments for several cancers with respect to efficacy and safety. While liver test abnormalities are rather common in patients treated with kinase inhibitors or immunotherapy, events of severe hepatotoxicity in these patients are rare in comparison with those associated with chemotherapeutics. The underlying mechanisms and risk factors for severe hepatotoxicity with novel oncology therapies are not well understood, complicating the drug-induced liver injury (DILI) risk assessment in the preclinical and clinical phases of drug development. The epidemiological and clinical characteristics, as well as mechanisms of liver toxicity, are described here to the current state of knowledge. Tools to study and assess the risk of DILI during drug development are concisely summarised, focusing on caveats thereof for novel oncology treatments. Emerging tools to optimise safety assessments and gather additional mechanistic insights into DILI are introduced. Particularly in oncology, where standard liver signals during drug development are tolerated to a marginally higher degree than in other indications due to the life-saving, life-extending and quality-of-life improvements for patients with severe or advanced cancers versus previous standard-of-care therapeutics, safety assessments must be tailored to the drug and indication. Trends in patient safety-centred drug development programmes and regulatory approval processes must continually be revisited and streamlined via obtaining an overall greater understanding of DILI and the tools available to assess mechanisms of injury, frequency, severity and prognosis.