Hepatotoxicity across CDK 4/6 inhibitors: a Narrative Review

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have become key agents in the treatment of hormone receptor positive (HR +), human epidermal factor receptor 2 negative (HER2-) metastatic breast cancer (MBC). In combination with endocrine therapy, CDK4/6 inhibitors are currently considered first-line treatment for HR + /HER2- MBC. There are three CDK4/6 inhibitors currently available: palbociclib, ribociclib and abemaciclib. The toxicity profiles of the CDK4/6 inhibitors are well-detailed in the respective clinical trials and post-marketing reports. This review will detail the hepatotoxic effects of CDK 4/6 inhibitors and how the incidence rate compares among agents.

This narrative review will fulfill the following objectives: 1. Record and analyze the rates of palbociclib, ribociclib and abemaciclib induced hepatotoxicity in HR + /HER2- breast cancer patients in the literature. 2. Compare the incidences of hepatotoxicity between ribociclib, abemaciclib and palbociclib. 3. Summarize findings and outline future directions in research.

Databases (PubMed, Embase) were searched on January 24, 2024.

Evaluating the systematic reviews and meta-analyses included in the narrative review, ribociclib showed the highest risk for all-grade (AG) and grade ≥ 3 (G3 +) alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) elevation. Additionally, ribociclib showed the highest incidence rate of AG and G3 + ALAT/ASAT elevation across its respective randomized clinical trials (RCTs) and pooled safety analysis. Palbociclib showed the highest incidence rate of AG ALAT/ASAT elevation in its respective RCTs and pooled safety analysis. However, palbociclib showed the lowest risk for both AG and G3 + ALAT/ASAT elevation.

Twenty-five systematic reviews and meta-analyses, RCTs, pooled safety analysis and observational studies were included in this narrative review to evaluate the incidence rate of palbociclib, ribociclib and abemaciclib induced hepatoxicity. Ribociclib seems to be associated with the highest risk of drug-induced hepatotoxicity. More studies need to be done to confirm and quantify this finding.