Hepatotoxicity in Patients with Hepatocellular Carcinoma on Treatment with Immune Checkpoint Inhibitors

SIMPLE SUMMARY: Hepatitis is a relatively frequent immune-related adverse event in patients with hepatocellular carcinoma receiving immunotherapy, but risk factors and clinical course are unclear. Herein, we show that the development of high-grade hepatitis is associated with increased baseline ALT levels and infectious etiology of hepatocellular carcinoma (related to prior hepatitis B or C virus exposure). In addition, when resolved, high-grade hepatitis does not preclude treatment resumption and does not affect subsequent time to treatment failure. Analysis of baseline tumor specimens, at a preliminary level, suggests that biological features reminiscent of the hepatocellular carcinoma “immune class” could protect against high-grade hepatitis development, thereby warranting further investigation. ABSTRACT: Risk factors for hepatic immune-related adverse events (HIRAEs) in patients with advanced/unresectable hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs) are unclear. We investigated: (i) clinical and morpho-pathological predictors of HIRAEs in 27 pretreatment tumor specimens, including surrogate biomarkers of the HCC immune class (based on intratumoral tertiary lymphoid structures, and glutamine synthase, CD3, and CD79 expression); and (ii) the relationship between HIRAE onset and subsequent treatment outcomes. Fifty-eight patients were included—20 (34%) received ICIs alone, and 38 (66%) received ICIs plus targeted agents as first- or further-line treatment. After a median time of 0.9 months (range, 0.4–2.7), nine patients (15.5%) developed grade ≥ 3 hepatitis, which was significantly associated with higher baseline ALT levels (p = 0.037), and an infectious HCC etiology (p = 0.023). ICIs were safely resumed in six out of nine patients. Time to treatment failure (TTF) was not significantly different in patients developing grade ≥ 3 hepatitis vs. lower grades (3.25 vs. 3.91 months, respectively; p = 0.81). Biomarker surrogates for the HCC immune class were not detected in patients developing grade ≥ 3 hepatitis. Grade ≥ 3 hepatitis has a benign course that does not preclude safe ICI reintroduction, without any detrimental effect on TTF.