Gastrointestinal toxicity associated with cyclin-dependent kinase 4/6 inhibitors in breast cancer patients: insights from a real-world pharmacovigilance analysis.

Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors play an important role in the treatment of breast cancer and show therapeutic potential for gastrointestinal (GI) tumors. However, their real-world GI safety profile remains incompletely characterized. Methods: Disproportionate reporting signals of GI adverse events (AEs) were assessed using the ROR, PRR and BCPNN algorithms, based on data from the FDA Adverse Event Reporting System database (2004-Q1 2025). Time-to-onset was analyzed using Weibull distribution, and serious vs. non-serious AE comparisons used non-parametric tests. Results: A total of 63,722 reports were associated with CDK4/6 inhibitors in breast cancer patients, among which 18,589 involved GI AEs. The three agents showed heterogeneous GI reporting patterns, with abdominal discomfort being the sole identified class-wide effect. Palbociclib accounted for the largest proportion of CDK4/6 inhibitor-related GI AE reports among the three agents, and its disproportionate reporting signals primarily involved oropharyngeal and upper GI events, with lip exfoliation and tongue blistering identified as its strongest signals. Ribociclib had the highest proportion of serious GI reports among the three drugs (82.38%), with 14.25% of its reports having a fatal outcome, and showed significant disproportionality signals for reflux gastritis and dysbiosis. For abemaciclib, gastrointestinal disorders was the most frequently reported System Organ Class, and diarrhea was its strongest disproportionate reporting signal. Notably, over 80% of positive GI pharmacovigilance signals detected in this study were absent from current prescribing information. All agents exhibited an early failure-type time-to-onset profile (β < 1), with a statistically significant difference in median onset time across agents: 15 days for abemaciclib, 27 days for ribociclib, and 49 days for palbociclib ( Conclusion: This study revealed heterogeneous disproportionate reporting patterns for GI AEs among CDK4/6 inhibitors and identified unlabeled pharmacovigilance signals. These findings are exclusively hypothesis-generating pharmacovigilance observations, not evidence of incidence, causal associations, or clinically confirmed inter-drug risk differences. The results might help prioritize drug-event pairs for further research and require validation in well-designed observational or prospective studies.