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

Area of Science:

• Oncology
• Hepatology
• Pharmacovigilance

Background:

• Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are standard treatments for metastatic breast cancer.
• Hepatotoxicity is a known adverse event, but real-world data on drug-induced liver injury (DILI) from CDK4/6i is limited.

Purpose of the Study:

• To determine the incidence, clinical presentation, severity, management, and relapse rates of DILI in patients treated with CDK4/6i.
• To compare DILI occurrence among ribociclib, abemaciclib, and palbociclib.

Main Methods:

• A retrospective, multicenter study of 2,222 patients treated with CDK4/6i from January 2018 to December 2022.
• Inclusion criteria: development of ≥ grade-2 DILI (ALT/AST >3x ULN).
• Severity assessed using CTCAEv5 and DILI-IEWG criteria.

Main Results:

• 100 patients (4.5%) developed DILI, with significantly higher incidence for ribociclib (8.3%) and abemaciclib (6.7%) versus palbociclib (1.4%).
• Most DILI cases were mild to moderate; 12 cases of moderate DILI (bilirubin >2x ULN) occurred across all three drugs.
• Hepatocellular injury was most common; cholestatic injury was mainly seen with abemaciclib. Liver biopsies did not suggest an immune-mediated mechanism. Corticosteroids showed limited benefit. DILI recurred in 28.2% of rechallenges.

Conclusions:

• Ribociclib and abemaciclib are associated with a higher incidence of DILI compared to palbociclib.
• The lack of immune features and limited efficacy of corticosteroids suggest caution regarding their routine use.
• The 28% recurrence rate after CDK4/6i reintroduction underscores the need for standardized DILI management, especially with expanding indications for these drugs.