Characteristics and outcomes of immunotherapy-related liver injury in patients with hepatocellular carcinoma versus other advanced solid tumours

Background&aims: Immune-related liver injury(irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors(ICIs). We aimed to compare incidence, clinical characteristics and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma(HCC) versus other solid tumours. Methods: Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line Atezolizumab+Bevacizumab from AB-real study and a non-HCC cohort, including 459 patients treated with first-line ICI therapy from INVIDIa-2 multicentre study. IrLI was defined as treatment-related increase of transaminases levels after exclusion of alternative aetiologies of liver injury. Incidence of irLI was adjusted for the duration of treatment exposure. Results: In HCC patients, incidence of any-grade irLI was 11.4% over a median treatment exposure of 4.4 months(95%CI 3.7-5.2), compared to 2.6% in INVIDIa-2 cohort over a median treatment exposure of 12.4 months(95%CI 11.1-14.0). Exposure-adjusted-incidence of any-grade irLI was 22.1 per 100-Patient-years(PY) in HCC patients and 2.1 per 100-PY in non-HCC patients(p<0.001), with median time to irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of HCC and 75.0% of non-HCC patients(p<0.001) and irLI resolution was observed in 72.1% and 58.3%, respectively(p=0.362). In HCC patients, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival in HCC patients only(HR 0.53, 95%CI 0.29-0.96). Conclusions: Despite higher incidence and earlier onset in patients with HCC, IrLI is characterised by high rates of remission, low requirement for corticosteroid therapy and low risk of decompensation compared to other solid tumours. Hepatotoxicity leads to discontinuation in 7% of patients with HCC and does not negatively affect oncological outcomes. Impact and implications: Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICI), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement of corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival.