Immune-Mediated Hepatotoxicity Associated With Ribociclib: A Multipatient Case Series and Management Strategy.

Abstract

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), when combined with endocrine therapy, have significantly transformed the management of hormone receptor-positive, HER2-negative metastatic breast cancer. Ribociclib, abemaciclib and palbociclib improve progression-free survival and delay chemotherapy initiation, with ribociclib additionally demonstrating an overall survival advantage. The NATALEE trial has further expanded the role of CDK4/6 inhibition in early breast cancer, showing significant improvement in 4-year invasive disease-free survival with adjuvant ribociclib in HR+/HER2-negative disease. Despite their shared mechanisms of targeting the CDK4/6-p16-retinoblastoma pathway, these agents differ in pharmacokinetics, kinase selectivity and toxicity. Hepatoxicity is a recognised adverse event of ribociclib with all grade toxicity occurring in around 20% of patients and Grade 3-4 events in 11%-15%. This drug-induced liver injury (DILI) typically resolves with drug withdrawal.Immune-mediated or autoimmune-like presentations of ribociclib-associated hepatotoxicity have been reported, although detailed management strategies remain poorly described. We report a series of five patients who developed ribociclib-induced liver injury that failed to improve with cessation of therapy, and instead demonstrated features suggestive of an immune-mediated mechanism. Hepatotoxicity occurred predominantly within the first few treatment cycles, highlighting the importance of early monitoring. All patients experienced significant biochemical improvement with corticosteroids; however, three developed recurrent transaminase elevation during tapering. Two required tacrolimus as a steroid-sparing agent, allowing eventual withdrawal of immunosuppression without relapse. Rechallenge with ribociclib in one patient led to recurrent hepatotoxicity, again responsive to steroids. Three patients were subsequently treated with palbociclib without recurrence of hepatotoxicity, maintaining disease control for more than 2 years. Liver biopsy in four patients was consistent with DILI in three and revealed mixed DILI with underlying primary biliary cholangitis in one, illustrating the complexity of managing hepatotoxicity in individuals with comorbid liver disease. This series highlights a pattern suggestive of immune-mediated ribociclib-induced hepatotoxicity responsive to short course corticosteroids with or without additional immunosuppression. Palbociclib appears to be a safe alternative, enabling continuation of CDK4/6-targeted therapy without premature transition to chemotherapy.