Toxicity profiles of cyclin-dependent kinase 4/6 inhibitors: safety analysis from clinical trials and the FDA adverse event reporting system

Aims: This study aimed to evaluate the comprehensive safety profile of CDK4/6 inhibitors in breast cancer treatment by analyzing real-world adverse event (AE) data and systematically reviewing clinical trial findings to provide evidence-based safety guidance. Methods: A disproportionality analysis based on real-world data from the FDA adverse event reporting system (FAERS) was combined with a systematic review to evaluate adverse events (AEs) associated with CDK4/6 inhibitors. A total of 16 studies involving 6,722 patients with advanced breast cancer were included to analyze the toxicity risks of CDK4/6 inhibitor combination therapies. Temporal patterns of AEs were assessed using FAERS data, and signal strengths were determined using the reporting odds ratio (ROR). Results: Combination therapy with CDK4/6 inhibitors significantly increased the risk of grade 3-5 AEs. FAERS analysis revealed that most AEs occurred within the first month of treatment, with the lowest incidence between the second and sixth months, followed by a significant rise thereafter. All CDK4/6 inhibitors were associated with myelosuppression, gastrointestinal toxicity, interstitial lung disease (ILD), and QT prolongation. Disproportionality analysis for "Torsade de pointes/QT prolongation" identified Ribociclib as the only agent with a strong positive signal (ROR 6.16, 95% CI 5.54-6.84). Additionally, unexpected AEs such as peripheral neuropathy, taste disorders, and epistaxis were detected. Conclusion: Clinicians should prioritize monitoring for myelosuppression, gastrointestinal toxicity, and QT prolongation (particularly with Ribociclib) during the first month of CDK4/6 inhibitor therapy. Long-term surveillance beyond 6 months is crucial to detect delayed-onset AEs.