Comparative analysis of adverse events associated with CDK4/6 inhibitors based on FDA’s adverse event reporting system: a case control pharmacovigilance study

Lin et al. BMC Pharmacology and Toxicology https://doi.org/10.1186/s40360-024-00770-6 (2024) 25:47 BMC Pharmacology and Toxicology Open Access RESEARCH Comparative analysis of adverse events associated with CDK4/6 inhibitors based on FDA’s adverse event reporting system: a case control pharmacovigilance study Wanlong Lin1, Yanbin Zeng1, Lizhu Weng1, Jianhui Yang1 and Wei Zhuang1* Abstract Background Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors marked a milestone in the breast cancer treatment. Due to the potential impact of adverse effects on treatment decisions and patient outcomes, careful consideration of the varying toxicities of CDK4/6 inhibitors is crucial, as three inhibitors—palbociclib, abemaciclib, and ribociclib— have been approved with differences in adverse event profiles. However, limitations in clinical trials call for urgent real-world safety studies to evaluate and compare the risk of adverse events (AEs) among these CDK4/6 inhibitors. Therefore, this study aimed to analyze AEs of CDK4/6 inhibitors and provide insights for clinical drug selection, using real world database. Methods The AEs of CDK4/6 inhibitors in the FDA Adverse Event Reporting System (2015–2022) were analyzed. Four disproportionality methods were used to detect safety signals: reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Neural Network Propagation, and Multi-Item Gamma Poisson Shrinker. Venn analysis was used to compare and select common and specific AEs. Results This study included 73,042 patients treated with palbociclib, 25,142 with ribociclib, and 7563 with abemaciclib. All three inhibitors had 27 common AEs. Palbociclib exhibited the highest ROR for hematologic toxicities, while ribociclib showed the highest ROR for macrocytosis, nail disorders, and hepatic lesions. Abemaciclib displayed the highest ROR for mucosal toxicity. Common signals for both palbociclib and ribociclib included hematologic toxicities, decreased immune responsiveness, and aphthous ulcers. Myelosuppression, oral pain, and pseudocirrhosis were common signals for palbociclib and abemaciclib. Anemia, hepatotoxicity, and pneumonitis were observed as common signals for ribociclib and abemaciclib. Furthermore, specific AEs associated with palbociclib included fatigue, alopecia, and stomatitis. For ribociclib, specific AEs included electrocardiogram QT prolongation, thrombocytopenia, and decreased hemoglobin. Abemaciclib was specifically linked to diarrhea, vomiting, and interstitial lung disease. Conclusion Our analysis revealed that palbociclib showed a higher risk of hematologic toxicity. Ribociclib showed higher risks of hepatotoxicity, nephrotoxicity, and QT prolongation. Abemaciclib showed higher risks of hepatotoxicity, *Correspondence: Wei Zhuang ; Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it.The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/. Lin et al. BMC Pharmacology and Toxicology (2024) 25:47 Page 2 of 11 gastrointestinal effects, interstitial lung disease, and thrombosis. These findings provide valuable insights for CDK4/6 inhibitor selection. Keywords CDK4/6 inhibitor, Side effect, Palbociclib, Ribociclib, Abemaciclib, Hepatotoxicity, Nephrotoxicity, Interstitial lung disease, Hematologic toxicity, FAERS Introduction Breast cancer has overtaken lung cancer as the most common cancer worldwide [1]. Approximately 70% of breast cancer cases are classified as hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative subtypes [2]. The approval of the first cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, palbociclib, by the US FDA in 2015 was a major milestone. Subsequent clinical research and practice have shown that combining CDK4/6 inhibitors with endocrine therapy can significantly enhance the efficacy of endocrine therapy in HR(+)/HER2(−) advanced breast cancer [3]. CDK4/6 inhibitors play a critical role in inhibiting cell cycle progression from G1 phase to S phase, thereby halting cancer cell division and tumor proliferation. Realworld studies in the United States have shown a notable increase in the use of CDK4/6 inhibitors in combination with endocrine therapy as first-line treatment for HR+/ HER2− breast cancer, rising from 22 to 49% between 2015 and 2018 [4]. Notably, HER2-targeted drugs and CDK4/6 inhibitors accounted for 68% of breast cancer drug sales in 2019, underscoring the growing importance of these therapies [5]. Forecasts indicate a continued upward trend in the use of CDK4/6 inhibitors. As the use of CDK4/6 inhibitors escalates, reports of adverse drug events have also increased. In addition to commonly observed side effects such as myelosuppression and diarrhea, potential adverse effects such as venous thrombosis, skin toxicity, and interstitial lung disease must be considered [6–8]. A meta-analysis [9–11] has suggested that the benefits of CDK4/6 inhibitors are independent of age, menopausal status, progesterone receptor expression, site of metastasis, and the number and type of prior therapies. Given the potential impact of adverse effects on physician choice of medication, patient compliance, quality of life, and ultimately clinical outcomes, it is imperative that adverse effects of CDK4/6 inhibitors be carefully considered. The three CDK4/6 inhibitors approved by the FDA are palbociclib, abemaciclib, and ribociclib. Although they belong to the same drug class, there are variations in the type, frequency, and severity of toxicities, which may influence drug selection. Early clinical trials and case reports have shown that abemaciclib has the highest incidence of diarrhea, while neutropenia is the most common side effect associated with palbociclib and ribociclib [12]. However, the strict diagnostic and selection criteria in clinical trials resulted in relatively small sample sizes, limited follow-up periods, and limited ability to observe adverse events (AEs). In addition, prolonged use of CDK4/6 inhibito (...truncated)