Adverse Event Profiles of CDK4/6 inhibitors: A pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database

Abstract

Abstract Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6 inhibitors) have changed the therapeutic landscape of HR+ and HER2− advanced breast cancer. The safety profile of CDK4/6 inhibitors has not yet been systemically analysed in the real world. This study aimed to provide a comprehensive understanding of AEs associated with CDK4/6 inhibitors andthe factors that influence them using the FAERS database. Methods: FAERS data (2014Q1 to 2022Q4) were searched for reports of all FDA-approved CDK4/6 inhibitors across all indications. We used the standardized MedDRA query (SMQ) generalized search AEs on the preferred term (PT) level based on case reports. After filtering duplicate reports, disproportionality analysis was used to detect safety signals by calculating reporting odds ratios (RORs). Reports were considered statistically significant if the 95% confidence interval did not contain the null value. Results: Within the standardized MedDRA queries, significant safety signals were found, including those for palbociclib [haematopoietic leukopenia (ROR=14.93), erythropenia (ROR=11.12)], ribociclib [haematopoietic leukopenia (ROR=10.81), conduction defects (ROR=8.40)], and abemaciclib [eosinophilic pneumonia (ROR=7.86), dehydration (ROR=5.88)]. For AEs at the PT level, we found several significant blood and lymphatic system disorders for both palbociclib and ribociclib, such as abnormal full blood count (ROR=46.45) and decreased white blood cell count (ROR=33.13) for palbociclib and anisocytosis (ROR=54.84), neutropenia (ROR=14.88) for ribociclib. Palbociclib also had high RORs for pseudocirrhosis, stomatitis, oral pain, and alopecia, while ribociclib had high RORs for electrocardiogram PR shortened, sinus arrhythmia, and blood bilirubin abnormal. However, the RORs were significant for abemaciclib in terms of diarrhoea (ROR=15.06), vena cava thrombosis (ROR=10.45), thrombophlebitis migrans (ROR=27.08) and pneumonitis (ROR=10.05). Conclusion: CDK4/6 inhibitors differed in their safety profile reports; for example, neutropenia mainly occurs with palbociclib and ribociclib, diarrhoea and venous thromboembolism mainly occur with abemaciclib, and QTc prolongation mainly occurs with ribociclib. Individualized drug administration according to patients' conditions is needed in clinical practice.