Clinical features and treatment response in patients with immune checkpoint inhibitor associated cholangiopathy

Abstract

Background: Immune mediated biliary injury (ICI-cholangiopathy) is a rare toxicity in patients treated with immune checkpoint inhibitors (ICI) and clinical characteristics, treatment responses and optimal management remain poorly characterised. This study aimed to characterize clinical profiles and treatment response in ICI-cholangiopathy.
Methods: Patients treated with anti-PD-1, PDL-1 or CTLA-4 therapy between January 2010 and December 2025 were included in this retrospective study. Patients with ICI-cholangiopathy were identified from patients with significant elevation in cholestatic liver enzymes (R value <2) within 12 months of ICI exposure and clinical records were reviewed.
Results: Of 5103 patients treated with ICI during the study period, 14 patients developed ICI-cholangiopathy (0.3%). Median age was 71 years and most (64%) were male. Most common primary malignancy was lung cancer (57%) and most were treated with pembrolizumab (71%). Most patients (8, 57%) had abnormal biliary imaging, with the majority reporting intra- and extra-hepatic biliary wall thickening and dilatation. All patients were treated with immunosuppression. ALP normalised over 3-6 months in 10 patients (71%; termed acute ICI-c) and improved but remained elevated < 2.5 x ULN in 4 (29%, chronic ICI-c). There were no significant differences in age, sex, primary cancer type, presence of liver metastases, duration of ICI therapy, or extent of ALP or ALT elevation at ICI-c diagnosis between patients with acute or chronic ICI-c. Patients with acute ICI-c improved faster than patients with chronic ICI-c (median time to ALP < 2.5 x ULN 16.5 vs 270 days, p = 0.007). Percent ALP reduction at 7 days distinguished patients with acute and chronic ICI-c (area under the receiver operating characteristic curve (AUROC) 0.92 (95% CI 0.63 - 0.99, p < 0.0001)). An optimal cut-off of <=20% ALP reduction at treatment day 7 was identified.
Conclusion: ICI-cholangiopathy, defined using biochemical criteria, is an uncommon complication of ICI treatment. Most patients (71%) respond to immunosuppression and normalise ALP over time. ALP reduction <=20% at treatment day 7 may identify patients who will respond poorly to treatment, allowing management to be tailored accordingly, and this approach should be evaluated in future prospective studies.