Clinical features and management for CDK4/6 inhibitor-DILI.

BACKGROUND & AIMS: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) -ribociclib, abemaciclib, palbociclib- are the standard-of-care for metastatic breast cancer. Although hepatotoxicity is a frequent adverse event, data on CDK4/6i drug-induced liver injury (DILI) remains scarce. We aimed to define the incidence, clinical presentation, severity, management and relapse of CDK4/6i-related DILI in a large real-world cohort. METHODS: Retrospective multicentre study including all patients who developed ≥ grade-2 DILI (ALT/AST >3x ULN) while receiving CDK4/6i between January/2018 and December/2022. Severity was assessed according to CTCAEv5 and DILI-IEWG criteria. RESULTS: Among 2,222 CDK4/6i-treated patients, 100 (4.5%, 95% CI 3.7%-5.4%) developed DILI. Incidence was significantly higher for ribociclib (8.3%, 95% CI 6.3%-10.7%) and abemaciclib (6.7%, 95% CI 4.6%-9.3%) than for palbociclib (1.4%, 95% CI 0.8%-2.2%) (Difference, p2x ULN, n=12) occurred with all three CDK4/6i. The most frequent pattern was hepatocellular, while cholestatic was mainly observed with abemaciclib. Liver biopsy findings (n=11) were heterogeneous and, together with biochemical results, did not support an immune-mediated mechanism as the primary driver. Corticosteroids (n=20) did not impact time to grade-1 or ALT normalization. DILI recurred in 28.2% of CDK4/6i rechallenges (n=85). Among ribociclib-treated patients, rechallenge with an alternative CDK4/6i was associated with lower risk of recurrence (p=0.010). CONCLUSIONS: DILI due to ribociclib and abemaciclib are more common that with palbociclib. The absence of immune-mediated features and the limited benefit of corticosteroids question their routine use. After CDK4/6i reintroduction, DILI recurrence rate was 28%. Standardized management is needed, particularly following the approval of ribociclib and abemaciclib as adjuvant therapy. IMPACT AND IMPLICATIONS: ● Although hepatotoxicity is a frequent adverse event, real-world data on CDK4/6i drug-induced liver injury (DILI) remains scarce.● DILI associated with ribociclib and abemaciclib is more common than for palbociclib, though moderate DILI (bilirubin >2x normality) was observed with the three drugs.● The absence of immune-mediated features and the limited benefit of corticosteroids question their routine use in CDK4/6i drug-induced liver injury.● Relapse of DILI after rechallenge with a CDK4/6i was 28%, with all cases presenting as mild.● The increasing use of CDK4/6i (metastatic breast cancer and ribociclib and abemaciclib as adjuvant therapy) highlights the need of standardizing the management of CDK4/6i drug-induced liver injury.