Management of Immune Checkpoint Inhibition-related Hepatitis Using Low-dose Corticosteroids

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but are associated with immune-related adverse events (irAEs), including immune-related hepatitis, a potentially serious complication that affects up to 30% of patients undergoing ICI combination therapy. Current management guidelines recommend corticosteroids as the first-line treatment for moderate to severe irAEs. However, high doses of corticosteroids are associated with increased risks of infections, metabolic and psychiatric side effects, and potentially impaired anti-tumor efficacy. Retrospective data suggest that lower doses may be equally effective while reducing toxicity and preserving treatment efficacy.

This prospective, registry-based cohort study aims to evaluate the clinical performance and outcomes of low-dose corticosteroid treatment for managing grade 2 or 3 IR-hepatitis. The hypothesis is that a corticosteroid "test dose" approach (0.5-1 mg/kg prednisolone) followed by early evaluation of clinical response can identify patients who benefit from reduced immunosuppression, thus minimizing side effects without compromising the effectiveness of ICI therapy.

Patients will be recruited from participating oncology centers where standardized management of IR-hepatitis has been implemented. Eligible participants are adult cancer patients who develop grade 2 or 3 IR-hepatitis during ICI therapy, excluding those with prior high-dose corticosteroid use, concurrent neurological or cardiac irAEs requiring high-dose corticosteroids, or underlying chronic liver diseases.

The primary endpoint is resolution of IR-hepatitis (defined as return to baseline or grade 1 liver function tests) within 8 weeks without corticosteroid dose escalation, additional immunosuppressive therapy, and with tapering to ≤10 mg/day prednisolone. Secondary endpoints include the proportion of patients requiring dose escalation, time to hepatitis resolution, cumulative corticosteroid exposure, relapse rates, occurrence of additional irAEs, progression-free survival (PFS), overall survival (OS), and identification of predictors of steroid-refractory hepatitis.

Patients will be followed for six months after the onset of IR-hepatitis. Follow-up assessments will align with standard clinical care, with no additional study-specific visits. Liver function tests, immunotherapy status, corticosteroid and immunosuppressive use, and occurrence of new irAEs will be recorded. A liver biopsy is recommended in refractory or ambiguous cases. Data will be collected via the REDCap system, ensuring standardized electronic data capture.

The study is powered to detect a successful resolution rate of at least 80% in patients with grade 3 IR-hepatitis treated with low-dose corticosteroids, assuming a null hypothesis threshold of 65%. Descriptive and exploratory statistical methods will be used to analyze the data, including Kaplan-Meier estimates for time-to-event outcomes and logistic regression for exploratory subgroup analyses.

This study addresses a critical gap in prospective evidence on the management of IR-hepatitis. By evaluating the efficacy and safety of a pragmatic, low-cost, low-toxicity intervention, it may inform future guidelines and serve as a foundation for a randomized non-inferiority trial. The study's design allows for real-world applicability while ensuring scientific rigor through harmonized protocols and data collection.

• Proportion of patients with resolution of their IR hepatitis CTCAE grade 2 or 3 within 8 weeks of onset [Time frame: 8 weeks]
• Proportion of patients requiring dose escalation of corticosteroids [Time frame: Outcome assessed at each visit until end of follow-up (6 months).]
• Time to resolution of IR hepatitis [Time frame: Outcome assessed at each visit until end of follow-up (6 months).]
• Peak dose of corticosteroids [Time frame: Outcome assessed at each visit until end of follow-up (6 months).]
• Cumulative dose of corticosteroids [Time frame: Outcome assessed at each visit until end of follow-up (6 months).]
• Proportion of patients with relapse of their IR hepatitis to grade 2 or higher [Time frame: Outcome assessed at each visit until end of follow-up (6 months).]
• Proportion of patients with incidence of irAE other than IR hepatitis [Time frame: Outcome assessed at each visit until end of follow-up (6 months).]
• Progression-free survival [Time frame: Up to 6 months]
• Overall survival [Time frame: Up to 6 months]
• Association of patient, disease and treatment characteristics and occurrence of corticosteroid refractory IR hepatitis [Time frame: Patient, disease and treatment characteristics at baseline]