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

BMC Pharmacology and Toxicology volume 25, Article number: 47 (2024) Cite this article

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, gastrointestinal effects, interstitial lung disease, and thrombosis. These findings provide valuable insights for CDK4/6 inhibitor selection.

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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. Real-world 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 [6,7,8]. A meta-analysis [9,10,11] 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 inhibitors may reveal previously unrecognized or severe safety issues. Therefore, as the use of these drugs increases, there is an urgent need for real-world safety studies to evaluate the safety profile of CDK4/6 inhibitors to delineate differences in the risk of AEs among the various CDK4/6 inhibitors.

The US FDA’s Adverse Event Reporting System (FAERS) serves as a repository for spontaneously reported AEs, providing a wealth of diverse and publicly available data. Due to its big data and open accessibility, FAERS is often used in AE signal mining research [13]. In this study, the reports collected by the FAERS system were mined and screened to analyze and compare the AE risk signals associated with the three FDA-approved CDK4/6 inhibitors. The goal is to provide insight into clinical decision-making and safe use of CDK4/6 inhibitors.

Methods

Data source

A retrospective pharmacovigilance study was conducted using data from the FAERS database, covering the period from the first quarter of 2015 (the FDA approval of the CDK4/6 inhibitor perphenazine) to the fourth quarter of 2022.

Data processing

AEs were coded using the Medical Dictionary for Regulatory Activities version 25.0. System organ classification (SOC) and preferred terms were analyzed in this study [14]. To evaluate drug-induced hepatic disorders, we used the Standardized Medical Dictionary for Regulatory Activities Queries (SMQ) classification. The FAERS database was deidentified and publicly available [15]. It consisted of seven databases, including demographic and administrative information, adverse drug reaction details, drug information, drug therapy start and end dates, report source information, and indications for use/diagnosis. The raw data were deduplicated. Target drugs were selected based on the names ‘PALBOCICLIB’, ‘RIBOCICLIB’, ‘ABEMACICLIB’, ‘IBRANCE’, ‘KISQALI’, and ‘VERZENIO’, and only AEs in which the target drug was listed as the primary suspect drug were selected. In addition, AEs reported as product issues, surgical and medical procedures, were excluded from further analysis.

Study design

The study flowchart is shown in Fig. 1. This study design employed a case/non-case approach, similar to a case-control study [16, 17]. Specifically, cases included reports with records related to CDK4/6 inhibitors, while non-cases included AEs recorded for all other drugs available in the FAERS database. Disproportionality analysis was used as a basic analytical tool, extensively utilized in pharmacovigilance research [18]. This method facilitated the identification of drug-associated AEs as signals by comparing the proportion of AEs associated with a specific drug with the proportion recorded for all other drugs (Table 1) [19]. Essentially, if the proportion of the target AEs was found to be higher in patients exposed to the drug of interest (cases) than in those not exposed (non-cases), a plausible association between the drug and the AEs could be hypothesized and considered a disproportionality or safety signal [20]. The sales number of three CDK4/6 inhibitors were obtained from IQVIA (IMS health) database.

Fig. 1
figure 1

Study flow chart

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Table 1 The 2 × 2 contingency table for signal detection
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Statistical analysis

Four disproportionality analysis methods were used (Table 2) [19]: reporting odds ratio (ROR), proportional reporting ratio (PRR), multi-item gamma-Poisson shrinker (MGPS) utilizing empirical Bayesian geometric mean (EBGM) as the signal index, and Bayesian confidence propagation neural network (BCPNN) analyses with information component (IC) as the signal index, to investigate the association between target drugs and AEs. A significant safety signal was identified when the lower limit of ROR 95%CI > 1, PRR ≥ 2, χ2 ≥ 4, IC025 > 0, and EBGM05 > 2.

Table 2 Calculation formulas of disproportionality analysis
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Venn analysis was used to compare and select common and specific AEs of CDK4/6 inhibitors. Data cleaning, deduplication processing, and statistical analyses were conducted using SAS v.9.4 in this study. GraphPad Prism v.8.0.2 and RAWGraphs v.2.0 were used for graph preparation.

Results

Cases’ characteristics

The characteristics of the cases were examined, and FAERS data were collected from January 2015 to December 2022. In total, 73,042 cases of palbociclib, 25,142 cases of ribociclib, and 7563 cases of abemaciclib were reported for CDK4/6 inhibitors. The clinical characteristics of the reported data for CDK4/6 inhibitors are shown in Table 3. The majority of cases for the three drugs were female (97.58, 97.99, and 98.13%, respectively). Cases older than 65 years old accounted for 54.02% of palbociclib, 41.36% of ribociclib, and 49.10% of abemaciclib reports. The majority of palbociclib and abemaciclib reports originated from the United States (78.76 and 77.79%, respectively), while the majority of ribociclib reports came from Germany. Patients represented a large proportion of the reporters. From 2015 to 2022, there was a gradual increase in the number of AE reports associated with CDK4/6 inhibitors, which coincided with the increased sales of the three CDK4/6 inhibitors (Supplementary Fig. 1).

Table 3 Clinical characteristics of CDK4/6 inhibitor reports (2015–2022)
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Disproportionality analysis of AEs based on system organ classification

Disproportionality analysis of AEs based on system organ classification was performed. AEs induced by CDK4/6 inhibitors and classified by system organ classifications (SOCs) are shown in Table 4. High signals were observed for all three CDK4/6 inhibitors in gastrointestinal disorders, investigations, neoplasms benign, malignant and unspecified, respiratory, thoracic and mediastinal disorders, blood and lymphatic system disorders, and metabolism and nutrition disorders. Hepatobiliary disorders showed a high signal in ribociclib and abemaciclib. Meanwhile, drug-induced hepatic disorders also showed high signals in ribociclib and abemaciclib (Supplementary Table 1). A specific signal for skin and subcutaneous tissue disorders was observed in palbociclib, while musculoskeletal and connective tissue disorders showed a specific high signal in ribociclib.

Table 4 Signal strength reported by CDK46 inhibitors at the system organ class (SOC) level
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Common safety signals of AEs in three CDK4/6 inhibitors

In this study, a total of 223 signals were detected for palbociclib, 437 signals for ribociclib, and 124 signals for abemaciclib. Through the application of Venn analysis (Fig. 2a), 27 common signals were identified among the three drugs. Figure 2b shows the number of reports and the ROR for AEs, excluding product issues or cancer-related symptoms. Hematologic toxicities exhibited the highest ROR for palbociclib, while ribociclib showed the highest ROR for macrocytosis, nail disorder, and hepatic lesions. Abemaciclib displayed the highest ROR for mucosal toxicity.

Fig. 2
figure 2

(a) Venn analysis of safety signals in three CDK4/6 inhibitors; (b) Common AE safety signals in CDK4/6 inhibitors

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Figure 3 illustrates the common AEs observed for two drugs. Hematologic toxicities, decreased immune responsiveness, and aphthous ulcer were identified as common signals for both palbociclib and ribociclib. Similarly, myelosuppression, oral pain, lung opacity, and pseudocirrhosis were identified as common signals for palbociclib and abemaciclib. Additionally, anaemia, hepatotoxicity, and pneumonitis were observed as common signals for ribociclib and abemaciclib.

Fig. 3
figure 3

Common safety signals of two drugs. (a) Common safety signals of palbociclib and ribociclib; (b) Common safety signals of palbociclib and abemaciclib; (c) Common safety signals of ribociclib and abemaciclib. *, This AE safety signal didn’t reach the top 20 in this drug

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Specific safety signals of AEs in three CDK4/6 inhibitors

Specific high signals of AEs were observed for each inhibitor (Fig. 4). The top 5 specific AEs associated with palbociclib included fatigue, alopecia, stomatitis, hot flush, and epistaxis. For ribociclib, the top 5 specific AEs were electrocardiogram QT prolongation, thrombocytopenia, decreased haemoglobin, polyneuropathy, and spinal pain. The top 5 specific AEs linked to abemaciclib were diarrhoea, vomiting, decreased appetite, dehydration, and interstitial lung disease.

Fig. 4
figure 4

Top 20 specific AE safety signals of CDK4/6 inhibitor. (a) palbociclib; (b) ribociclib; (c) abemaciclib

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Discussion

As a result of the widespread use of CDK4/6 inhibitors and increasing awareness among healthcare providers, the number of AEs reported has escalated over the years. As a result, there is an ongoing need for epidemiologic surveillance. Currently, there is a lack of head-to-head studies comparing the three different CDK4/6 inhibitors. Therefore, this study serves as the first comprehensive comparison of real-world AE reports for CDK4/6 inhibitors and provides a valuable reference point. Based on real-world data, healthcare professionals should be aware of the following aspects:

This study describes the most common AEs associated with each CDK4/6 inhibitor were coincidence with the information provided in the FDA labeling. The most frequently reported adverse reactions associated with palbociclib include neutropenia, infections, leukopenia, fatigue, and nausea [21]. The most common adverse reactions attributed to ribociclib, including laboratory abnormalities, are myelosuppression and abnormal liver function [22]. Similarly, the most common adverse reactions associated with abemaciclib include diarrhea, neutropenia, nausea, abdominal pain, and infection [23]. A comparative analysis and discussion of the AEs of these three CDK4/6 inhibitors are presented, categorized according to the main organ systems affected.

The main AEs associated with CDK4/6 inhibitors primarily involve hematologic toxicity, leading to a decrease in blood cell counts across different lineages. Notably, the RORs for palbociclib and ribociclib were higher than those for abemaciclib, and serious systemic infections were infrequent, which aligns with prior literature [24]. Hematologic toxicity, the most common AE of CDK4/6 inhibitors, is mainly associated with their ability to inhibit CDK6, a crucial regulator of hematopoietic precursor proliferation [25, 26]. Palbociclib exhibits comparable potency for both CDK4 and CDK6, whereas abemaciclib demonstrates a higher affinity for CDK4 [25, 27], resulting in relatively lower hematologic toxicity. Furthermore, the neutropenia induced by CDK4/6 inhibitors is mostly associated with their inhibitory influence on the cell cycle, differing from chemotherapy-induced DNA damage and subsequent induction of apoptosis in hematopoietic cells [28], thereby reducing the likelihood of severe infections. Notable disparities in hematologic toxicity exist among the three drugs. Therefore, physicians should administer palbociclib and ribociclib for three weeks, followed by a one-week break to promote the restoration of hematopoietic progenitor cells, while they can prescribe abemaciclib continuously. Although uncommon, severe infections are possible. The research uncovered 21 instances of serious infections, such as bacteremia and sepsis, in patients taking abemaciclib compared to only 3 cases in those who received ribociclib. Therefore, it is imperative to conduct regular monitoring of routine blood parameters when using CDK4/6 inhibitors and to provide prompt intervention in cases of severe neutropenia.

The risk signal intensity for gastrointestinal diseases associated with abemaciclib appears to be higher in comparison to ribociclib and palbociclib in gastrointestinal disorders. This difference may be attributed to the inhibition of the glycogen synthase kinase 3-mediated cascade [29]. Although the majority of these adverse effects are mild, they can have a significant impact on the quality of life of patients. Therefore, it is imperative to provide comprehensive medication education before administration, especially for abemaciclib, and to recommend initiating loperamide treatment once loose stools occur [30, 31].

Regarding liver and renal damage, both ribociclib and abemaciclib have reported seven AE signals related to liver function as well as renal damage, including elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase, and blood bilirubin, among others. The disproportionation analysis according to ‘Drug-related hepatic disorders’ criteria in Standardized MedDRA Queries (SMQ) also showed the same results (Supplementary Table 1). The ROR value and the number of cases for ribociclib were generally higher than those for abemaciclib, which is in line with existing literature [32,33,34]. The differences in liver-associated side effects among the three CDK4/6 inhibitors can be attributed to the fact that ribociclib and abemaciclib are mainly metabolized by the liver enzyme CYP3A4, while palbociclib goes through metabolism by CYP3A4 and Sulfotransferase Family 2 A Member 1 (SULT2A1) enzymes [35]. Most oral endocrine therapy drugs, typically used in conjunction with CDK4/6 inhibitors for patients suffering from advanced breast cancer with HR(+)/HER2(−) markers, are primarily metabolized by the liver and may cause liver toxicity. Additionally, instances of life-threatening AEs linked to liver failure have been documented for both ribociclib and abemaciclib. Therefore, patients with pre-existing liver conditions or those at risk of liver toxicity should avoid using CDK4/6 inhibitors. Alternatively, they can prioritize the use of palbociclib. Furthermore, it is essential to monitor liver function regularly in such cases. According to the literature, abemaciclib inhibits the secretion of tubular transporters but does not affect glomerular function [28]. However, our study found that ribociclib was associated with decreased glomerular filtration rates. As a precautionary measure, patients with renal insufficiency should avoid using ribociclib and exercise caution with abemaciclib.

For the cardiovascular system, among the AE risk signals associated solely with ribociclib, the most commonly reported in relation to the cardiovascular system was QT prolongation (n = 593, ROR = 13.04). Ribociclib has previously been linked to a reversible, concentration-dependent prolongation of the Qt interval [28]. Furthermore, our study uncovered cases of AEs related to the cardiovascular system, including hypertensive crisis and abnormal electrocardiogram findings. These findings emphasize the need for caution when administering ribociclib to patients with pre-existing cardiovascular diseases, or electrolytes abnormality [31]. These patients should also refrain from using drugs known to cause QT interval prolongation. In our study, abemaciclib demonstrated a higher number of risk signals associated with venous thrombosis, and the ROR was also elevated. Additionally, risk signals for vena cava thrombosis were observed with ribociclib as well. Notably, a meta-analysis indicated that among the three CDK4/6 inhibitors, only abemaciclib exhibited an increased risk of arterial thrombosis, while ribociclib did not show a statistically significant increase, although 10 cases were reported [36]. This discrepancy may be attributed to the limited sample size of randomized controlled trials included in the meta-analysis, which might not provide sufficient evidence to support a significant difference in risk between the ribociclib intervention group and the control group. Nevertheless, several studies have highlighted cardiovascular toxicities, such as myocardial infarction, associated with CDK4/6 inhibitors such as ribociclib [37]. Breast cancer patients undergoing endocrine therapy and chemotherapy already carry a high risk of thrombosis, and the addition of CDK4/6 inhibitors may further elevate this risk. Therefore, the potential risk of arterial thrombosis should not be overlooked when considering the use of ribociclib.

The FDA has issued a warning regarding rare but serious cases of pneumonia associated with all three CDK4/6 inhibitors. Reports have indicated a risk of interstitial lung disease with the use of these inhibitors, particularly abemaciclib [8, 23, 38]. Our study further supports this finding, demonstrating a significantly higher risk of interstitial lung disease, as well as the occurrence of emphysema and pulmonary ground glass opacity specifically with abemaciclib. Patients with interstitial lung disease often present with prodromal symptoms such as shortness of breath, dry cough, fatigue, and chest discomfort. Failure to promptly diagnose and treat interstitial lung disease can lead to severe and potentially life-threatening consequences [39]. A study based on the Japanese Adverse Drug Event Report and FAERS also identified a risk of interstitial lung disease with both abemaciclib and palbociclib [38]. Therefore, caution should be exercised when using any CDK4/6 inhibitor in patients with pre-existing pulmonary diseases or poor pulmonary function. Abemaciclib should be avoided in these patients, and other CDK4/6 inhibitors should be administered with careful consideration. Additionally, healthcare professionals must remain vigilant regarding the potential risks of interstitial lung disease during CDK4/6 inhibitor therapy. Regular monitoring of pulmonary symptoms is crucial, and if such symptoms arise, prompt diagnostic evaluation and discontinuation of the drug should be considered.

In conclusion, each CDK4/6 inhibitor exhibited distinct safety profiles. Palbociclib was associated with higher risks of hematologic toxicity and interstitial lung disease. Ribociclib showed associations with hematologic toxicity, hepatotoxicity, nephrotoxicity, and QT prolongation. Abemaciclib demonstrated associations with hepatotoxicity, gastrointestinal effects, interstitial lung disease, nephrotoxicity, and thrombosis. Therefore, when considering the use of CDK4/6 inhibitors, it is imperative to thoroughly assess the patient’s overall condition and choose drugs with relatively lower risks. This approach will enhance medication safety and improve the quality of life for patients.

Although this study has the advantages of realistic large-sample research and data mining techniques, there are still some limitations. First, it is important to note that FAERS is a spontaneous reporting system and lacks the rigorous design and data entry procedures seen in clinical trials. As a result, there may be missing data and biases. In this study, consumer reports accounted for over 39.29% of the total reports, which could introduce bias into the data analysis. Controlling for confounding factors that may impact AEs, such as differences in drug approval timing, market penetration, public awareness of specific reactions, and incomplete collection of serious AE reports, poses challenges that may affect the study’s overall quality. Second, it is important to acknowledge that not all AEs are reported to FAERS, and reporting rates may vary across different drugs included in the study. Although global sales figures from the IQVIA database were utilized, it is important to note that not all patients are represented in FAERS for AE reporting. Therefore, direct calculations of AE incidence are limited. Third, the algorithm used in this study evaluated only signal intensity and statistical significance, without considering the causal relationship between CDK4/6 inhibitors and AEs. Additionally, the algorithm has not been clinically validated. Therefore, further large-scale prospective studies are necessary to validate and evaluate these findings. Fourth, extracting all relevant anticancer drugs from the FAERS database and establishing proper comparators for disproportionality analysis can be challenging due to the wide variety of available drugs. This challenge may introduce bias and potentially lead to false positive associations. Fifth, it should be noted that the designation of a case as ‘primary suspect’ or ‘suspect’ in FAERS is subjective, which means that the influence of other drugs or factors cannot be completely ruled out. Moreover, the narrative texts that accompany case reports in FAERS, which may provide additional information from reporters or manufacturers about specific AE cases, were not included in the FDA-provided FAERS data and were therefore not reviewed. Despite these limitations, the results of our study may provide a valuable reference for medical personnel to closely monitor and promptly manage AEs associated with different CDK4/6 inhibitors and to individualize the selection of CDK4/6 inhibitors for patients with underlying diseases.

Conclusion

This pharmacovigilance analysis comprehensively compared the differences in AE reports of different CDK4/6 inhibitors under real-world data. Specifically, palbociclib has a high-risk signal of blood toxicity, ribociclib has a prominent risk signal in liver toxicity, and abemaciclib has a significant risk signal in diarrhea, interstitial lung disease, and thrombosis. In addition, the prolongation of QT on electrocardiogram and the decrease in glomerular filtration rate with ribociclib are also noteworthy. Therefore, this long-term post marketing safety evaluation can provide a broader understanding of the safety of CDK4/6 inhibitors to ensure the rational use of CDK4/6 inhibitors by individualized drug selection and targeted drug monitoring according to the situation of breast cancer patients.

Data availability

The data are openly available in the FDA Adverse Event Reporting System Public Dashboard at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. Or you can download the dataset directly from the online cloud storage at https://pan.baidu.com/s/1av43qbSqnEdI1OSguC1Fjw?pwd=1234.

Abbreviations

AE:

Adverse event

BCPNN:

Bayesian confidence propagation neural network

CDK4/6:

Cyclin-dependent kinase 4/6

EBGM:

Empirical Bayesian geometric mean

FAERS:

FDA adverse event reporting system

HR:

Hormone receptor

HER2:

Human epidermal growth factor receptor 2

IC:

Information component

MGPS:

Multi-item gamma-Poisson shrinker

PRR:

Proportional reporting ratio

ROR:

Reporting odds ratio

SOC:

System organ classification

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA-Cancer J Clin. 2021;71(3):209–49.

    Article  PubMed  Google Scholar 

  2. Waks AG, Winer EP. Breast cancer treatment: a review. JAMA-J Am Med Assoc. 2019;321(3):288–300.

    Article  CAS  Google Scholar 

  3. Gradishar WJ, Moran MS, Abraham J, Aft R, Agnese D, Allison KH, Anderson B, Burstein HJ, Chew H, Dang C, et al. Breast cancer, version 3.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Ne. 2022;20(6):691–722.

    Article  Google Scholar 

  4. Samuel EA, Varella L, Lynn KM, Jia X, Moore H, Thomas BG, Abraham J, Montero AJ. Real-world outcomes of cyclin-dependent kinase inhibitors continued beyond first disease progression in hormone receptor-positive metastatic breast cancer. Clin Breast Cancer. 2021;21(3):205–9.

    Article  Google Scholar 

  5. Wilcock P, Webster RM. The breast cancer drug market. Nat Rev Drug Discov. 2021;20(5):339–40.

    Article  PubMed  CAS  Google Scholar 

  6. Raschi E, Fusaroli M, Ardizzoni A, Poluzzi E, De Ponti F. Thromboembolic events with cyclin-dependent kinase 4/6 inhibitors in the FDA adverse event reporting system. Cancers. 2021;13(8).

  7. Silvestri M, Cristaudo A, Morrone A, Messina C, Bennardo L, Nistico SP, Mariano M, Cameli N. Emerging skin toxicities in patients with breast cancer treated with new cyclin-dependent kinase 4/6 inhibitors: a systematic review. Drug Saf. 2021;44(7):725–32.

    Article  PubMed  CAS  Google Scholar 

  8. Raschi E, Fusaroli M, Ardizzoni A, Poluzzi E, De Ponti F. Cyclin-dependent kinase 4/6 inhibitors and interstitial lung disease in the FDA adverse event reporting system: a pharmacovigilance assessment. Breast Cancer Res Tr. 2021;186(1):219–27.

    Article  CAS  Google Scholar 

  9. Li Y, Li L, Du Q, Li Y, Yang H, Li Q. Efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy in HR+/HER-2- ABC patients: a systematic review and meta-analysis. Cancer Invest. 2021;39(5):369–78.

    Article  PubMed  Google Scholar 

  10. Piezzo M, Chiodini P, Riemma M, Cocco S, Caputo R, Cianniello D, Di Gioia G, Di Lauro V, Rella FD, Fusco G, et al. Progression-free survival and overall survival of CDK 4/6 inhibitors plus endocrine therapy in metastatic breast cancer: a systematic review and meta-analysis. Int J Mol Sci. 2020;21(17).

  11. Li J, Huo X, Zhao F, Ren D, Ahmad R, Yuan X, Du F, Zhao J. Association of cyclin-dependent kinases 4 and 6 inhibitors with survival in patients with hormone receptor-positive metastatic breast cancer: a systematic review and Meta-analysis. JAMA Netw Open. 2020;3(10):e2020312.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Thill M, Schmidt M. Management of adverse events during cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-based treatment in breast cancer. Ther Adv Med Oncol. 2018;10:433558930.

    Article  Google Scholar 

  13. Lin X, Yang J, Weng L, Lin W. Differences in hypersensitivity reactions to iodinated contrast media: analysis of the US food and drug administration adverse event reporting system database. J Aller Cl Imm-Pract. 2023;11(5):1494–502.

    Article  CAS  Google Scholar 

  14. Mascolo A, Scavone C, Ferrajolo C, Rafaniello C, Danesi R, Del RM, Russo A, Coscioni E, Rossi F, Alfano R, et al. Immune checkpoint inhibitors and cardiotoxicity: an analysis of spontaneous reports in Eudravigilance. Drug Saf. 2021;44(9):957–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. FDA. FDA Adverse Event Reporting System Public Dashboard. 2023.

  16. Sakaeda T, Tamon A, Kadoyama K, Okuno Y. Data mining of the public version of the FDA adverse event reporting system. Int J Med Sci. 2013;10(7):796–803.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Brown EG. Methods and pitfalls in searching drug safety databases utilising the medical dictionary for regulatory activities (MedDRA). Drug Saf. 2003;26(3):145–58.

    Article  PubMed  Google Scholar 

  18. Duggirala HJ, Tonning JM, Smith E, Bright RA, Baker JD, Ball R, Bell C, Bright-Ponte SJ, Botsis T, Bouri K, et al. Use of data mining at the food and drug administration. J Am Med Inf Assn. 2016;23(2):428–34.

    Article  Google Scholar 

  19. Noguchi Y, Tachi T, Teramachi H. Detection algorithms and attentive points of safety signal using spontaneous reporting systems as a clinical data source. Brief Bioinform. 2021;22(6).

  20. Pace ND, Multani JK. On the reporting of odds ratios and risk ratios. Nutrients. 2018;10(10).

  21. FDA. IBRANCE® (palbociclib) capsules label. Revised Apr 2019.

  22. FDA. KISQALI® (ribociclib) tablets label. Revised Oct 2022.

  23. FDA. VERZENIO® (abemaciclib) tablets label. Revised Oct 2021.

  24. Onesti CE, Jerusalem G. CDK4/6 inhibitors in breast cancer: differences in toxicity profiles and impact on agent choice. A systematic review and meta-analysis. Expert Rev Anticanc. 2021;21(3):283–98.

    Article  CAS  Google Scholar 

  25. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015;14(2):130–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Laurenti E, Frelin C, Xie S, Ferrari R, Dunant CF, Zandi S, Neumann A, Plumb I, Doulatov S, Chen J, et al. CDK6 levels regulate quiescence exit in human hematopoietic stem cells. Cell Stem Cell. 2015;16(3):302–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Chen P, Lee NV, Hu W, Xu M, Ferre RA, Lam H, Bergqvist S, Solowiej J, Diehl W, He YA, et al. Spectrum and degree of CDK drug interactions predicts clinical performance. Mol Cancer Ther. 2016;15(10):2273–81.

    Article  PubMed  Google Scholar 

  28. Spring LM, Wander SA, Andre F, Moy B, Turner NC, Bardia A. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet. 2020;395(10226):817–27.

    Article  PubMed  CAS  Google Scholar 

  29. Thibault S, Hu W, Hirakawa B, Kalabat D, Franks T, Sung T, Khoh-Reiter S, Lu S, Finkelstein M, Jessen B, et al. Intestinal toxicity in rats following administration of CDK4/6 inhibitors is independent of primary pharmacology. Mol Cancer Ther. 2019;18(2):257–66.

    Article  PubMed  CAS  Google Scholar 

  30. Shaw C, Taylor L. Treatment-related diarrhea in patients with cancer. Clin J Oncol Nurs. 2012;16(4):413–7.

    Article  PubMed  Google Scholar 

  31. Ettl J. Management of adverse events due to cyclin-dependent kinase 4/6 inhibitors. Breast Care. 2019;14(2):86–92.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martin M, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. New Engl J Med. 2020;382(6):514–24.

    Article  PubMed  CAS  Google Scholar 

  33. Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martin M, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465–72.

    Article  PubMed  CAS  Google Scholar 

  34. Johnston S, Toi M, O’Shaughnessy J, Rastogi P, Campone M, Neven P, Huang CS, Huober J, Jaliffe GG, Cicin I, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):77–90.

    Article  PubMed  CAS  Google Scholar 

  35. Yu Y, Loi CM, Hoffman J, Wang D. Physiologically based pharmacokinetic modeling of palbociclib. J Clin Pharmacol. 2017;57(2):173–84.

    Article  PubMed  CAS  Google Scholar 

  36. Gao S, Li Y, He Z, Zhu J, Liang D, Yang S, Mo J, Lam K, Yu X, Huang M, et al. Thromboembolism profiles associated with cyclin-dependent kinase 4/6 inhibitors: a real-world pharmacovigilance study and a systematic review. Expert Opin Drug Saf. 2023:1–11.

  37. Master SR. Cardiac complications of CDK4/6 inhibitors for breast cancer. In: 2020 ASCO annual meeting. 2020.

  38. Nawa H, Niimura T, Yagi K, Goda M, Zamami Y, Ishizawa K. Evaluation of potential complication of interstitial lung disease with abemaciclib and palbociclib treatments. Cancer Rep-US. 2022;5(1):e1402.

    Article  CAS  Google Scholar 

  39. Antoniou KM, Margaritopoulos GA, Tomassetti S, Bonella F, Costabel U, Poletti V. Interstitial lung disease. Eur Respir Rev. 2014;23(131):40–54.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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Funding

This work was supported by the National Natural Science Foundation of China [grant number 82304629], the Natural Science Foundation of Xiamen, China [grant number 3502Z202371048].

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Authors and Affiliations

  1. Department of Pharmacy, Women and Children’s Hospital, School of Medicine, Xiamen University, 10# Zhenhai Road, Xiamen, China

    Wanlong Lin, Yanbin Zeng, Lizhu Weng, Jianhui Yang & Wei Zhuang

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  1. Wanlong Lin
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  2. Yanbin Zeng
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  3. Lizhu Weng
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Contributions

W.L. performed the main data mining and manuscript writing, Y.Z. participated data cleaning and revised this manuscript, L.W. and J.Y. participated data progression, W.Z. designed and supported this study, and revised this manuscript.

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Correspondence to Wei Zhuang.

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Not applicable. This study was used a public, de-identified database of spontaneous reports. This study was deemed non‑human subject related research.

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Lin, W., Zeng, Y., Weng, L. et al. Comparative analysis of adverse events associated with CDK4/6 inhibitors based on FDA’s adverse event reporting system: a case control pharmacovigilance study. BMC Pharmacol Toxicol 25, 47 (2024). https://doi.org/10.1186/s40360-024-00770-6

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  • DOI: https://doi.org/10.1186/s40360-024-00770-6

Keywords

BMC Pharmacology and Toxicology

ISSN: 2050-6511

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