High Grade Hepatotoxicity From Dual Checkpoint Inhibitors Is More Common in Hepatocellular Carcinoma Than Other Cancers.

Background & aims: Immune checkpoint inhibitors (ICIs) are therapy for many malignancies including hepatocellular carcinoma (HCC), yet the impact of HCC on immune-mediated liver injury from checkpoint inhibitors (ILICI) remains poorly understood and no direct comparison exists for hepatotoxicity rates between ICI and sorafenib in HCC.

Methods: In this retrospective cohort study, we extracted data on adult patients treated with five ICI regimens for HCC or non-HCC cancers, and HCC patients who received sorafenib between 2010 and 2020. The primary outcome was grade ≥ 3 ILICI or sorafenib (DILI). Logistic regression estimated adjusted odds ratios (OR) for liver injury.

Results: We identified 530 patients, 129 (24%) HCC-ICI, 256 (48%) non-HCC ICI, and 145 (27%) HCC-sorafenib. Compared to non-HCC ICI, HCC-ICI and HCC-sorafenib were more often male (57%, 82%, 77%), Hispanic (14%, 35%, 34%), and cirrhotic (1%, 85%, 88%). Twenty-three patients developed grade ≥ 3 ILICI. ILICI incidence was higher for HCC-ICI (11%, CI 6-18) versus non-HCC ICI (4%, CI 2-6, p = 0.006) and DILI in HCC-sorafenib (3%, CI 1-8, p = 0.02) with incidence highest for ipilimumab-nivolumab (HCC-ICI 42%, CI 15-72 versus non-HCC 10%, CI 3-24; p = 0.02). On multivariable regression, ILICI was associated with HCC (OR 4.5, CI 1.8-11.4, p = 0.002) and treatment with ipilimumab-nivolumab (OR 6.9, CI 2.6-18.3, p < 0.001). Incidence of liver injury in HCC remained elevated for ICI versus sorafenib (OR 3.5, CI 1.2-10.4, p = 0.02).

Conclusions: We identified an elevated risk of liver injury in HCC patients receiving ICIs compared to ICI-treated non-HCC cancers and sorafenib-treated HCC, with dual ipilimumab-nivolumab therapy carrying the highest risk.