Evaluation of adverse events of CDK4/6 inhibitors: a real-world study based on the FAERS database

Youjun SHE; Zihan GUO; Zhongwei ZHANG; Qiong DU

doi:10.19401/j.cnki.1007-3639.2023.10.003

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Evaluation of adverse events of CDK4/6 inhibitors: a real-world study based on the FAERS database

Article | 更新时间：2025-12-31

- Evaluation of adverse events of CDK4/6 inhibitors: a real-world study based on the FAERS database
- China Oncology Vol. 33, Issue 10, Pages: 908-919(2023)
- 作者机构：
  
  1. 复旦大学附属肿瘤医院药剂科，复旦大学上海医学院肿瘤学系，上海 200032
  2. 复旦大学附属肿瘤医院重症医学科，复旦大学上海医学院肿瘤学系，上海 200032
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2023.10.003
  CLC： R730.51
- Received：19 July 2023，
  
  Revised：2023-10-18，
  
  Published：30 October 2023
- 稿件说明：
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Youjun SHE, Zihan GUO, Zhongwei ZHANG, et al. Evaluation of adverse events of CDK4/6 inhibitors: a real-world study based on the FAERS database[J]. China Oncology, 2023, 33(10): 908-919.
DOI：

Youjun SHE, Zihan GUO, Zhongwei ZHANG, et al. Evaluation of adverse events of CDK4/6 inhibitors: a real-world study based on the FAERS database[J]. China Oncology, 2023, 33(10): 908-919. DOI： 10.19401/j.cnki.1007-3639.2023.10.003.

摘要

背景与目的：

细胞周期蛋白依赖性激酶4和6（cyclin-dependent kinase 4/6，CDK4/6）抑制剂的开发和批准是激素受

体阳性转移性乳腺癌治疗的一个重要里程碑。这类药物疗效相似，但不良事件（adverse events，AE）各有不同，直接影响临床用药选择。目前关于CDK4/6抑制剂的安全性在真实世界中的系统研究尚不全面。而本研究则通过对美国食品药品管理局（Food And Drug Administration，FDA）不良事件报告系统（FDA Adverse Event Reporting System，FAERS）进行信号挖掘，比较CDK4/6抑制剂AE的差异，发现未知AE信息，旨在为临床治疗方案的选择和AE监测提供参考依据。

方法：

提取FAERS数据库中2014年第一季度至2023年第一季度的所有数据，去除重复报告后，对将“palbociclib（哌柏西利）”、“abemaciclib（阿贝西利）”和“ribociclib（瑞波西利）”列为“首要怀疑”的报告，通过比例失衡测量法进行数据分析。本研究采用报告比值比（reporting odds ratio，ROR）法和MHRA法识别信号，阳性信号需要同时满足：报告数≥3、ROR的95%置信区间的下限

1、比例报告比值比（proportional reporting ratios，PRR）

2、

4的标准。

结果：

研究选出85 562条与CDK4/6抑制剂相关的AE报告。哌柏西利在血液学和淋巴系统AE中信号最强（白细胞减少症ROR = 20.01）。在胃肠道系统和肝肾系统中，哌柏西利的AE信号较其他药物低（腹泻ROR = 1.95，γ-谷氨酰转移酶升高ROR = 0.36，血肌酐升高ROR = 1.01）。阿贝西利在胃肠道系统信号最强（腹泻ROR = 13.54）；在肝肾系统也表现出较强的AE信号（γ-谷氨酰转移酶升高ROR = 2.58，血肌酐升高ROR = 7.74）；在血液和淋巴系统AE信号较其他药物低（白细胞减少ROR = 5.34）。瑞波西利在血液和淋巴系统中的AE信号强度低于哌柏西利（白细胞减少症ROR = 7.55）；但在肝肾系统AE中，瑞波西利的γ-谷氨酰转移酶升高信号强度最高（ROR = 4.05）。另外，在罕见严重的肝脏AE中，阿贝西利肝衰竭（ROR = 3.50）和药物诱导的肝损伤（ROR = 4.68）信号最强。研究还发现多形性红斑（ROR = 3.06）是阿贝西利新的AE信号。

结论：

CDK4/6抑制剂安全性的特点各不相同。对FAERS数据库的分析揭示哌柏西利和瑞波西利有血液和淋巴系统毒性、阿贝西利存在胃肠道毒性和肝毒性。研究同时发现阿贝西利严重AE为多形性红斑。结果提示，治疗期间医疗人员需要依据患者生理状态和药物AE的特点进行个体化用药选择和AE监测。

Abstract

Background and purpose:

The development and approval of inhibitors of cyclin-dependent kinase 4/6 (CDK4/6) is an essential milestone in treating hormone receptor-positive metastatic breast cancer. The efficacy of these drugs is similar

but the adverse events (AE) are different

directly affecting the physician's choice of drug. There is no systematic study on the safety of CDK4/6 inhibitors in the real world. In this study

we compared the differences in AE of CDK4/6 inhibitors through signal mining in the FDA Adverse Event Reporting System (FAERS) and identified unknown AE signals to provide a reference for the clinical choice of treatment and monitoring AE.

Methods:

All data in the FAERS database were extracted from

the first quarter of 2004 to the first quarter of 2023. After removing duplicates

data were analyzed by the disproportionality method for reports ranking palbociclib

abemaciclib

or ribociclib as the primary suspect. Signals were identified using the reporting odds ratio (ROR) and MHRA methods. Positive signals were required to meet the following criteria: the number of reports ≥3

the lower limit of the 95% confidence interval of the ROR

proportional reporting ratios (PRR)

and the

Results:

A total of 85 562 reports of AE associated with CDK4/6 inhibitors were identified. The highest signal intensity of palbociclib was observed in hematologic and lymphatic AE (leukopenia ROR = 20.01). Palbociclib had lower AE signals in the gastrointestinal

hepatic

and renal systems than the other drugs (diarrhea ROR = 1.95

gamma-glutamyltransferase increased ROR = 0.36

blood creatinine increased ROR = 1.01). Abemaciclib had the strongest signal in the gastrointestinal system (diarrhea ROR = 13.54); it also showed a strong AE signal in the hepatic and renal systems (gamma-glutamyltransferase increased ROR = 2.58

blood creatinine increased ROR = 7.74) and a lower AE signal than the other drugs in the blood and lymphatic systems (leukopenia ROR = 5.34). Ribociclib had a lower AE signal intensity in the blood and lymphatic system than palbociclib (leukopenia ROR = 7.55); however

among hepatic AE

ribociclib had the highest signal intensity of increased gamma-glutamyltransferase (ROR = 4.05). In rare severe hepatic systemic AE

abemaciclib had the strongest signal in hepatic failure (ROR = 3.50) and drug-induced liver injury (ROR = 4.68). Erythema multiforme was a newly identified signal in the abemaciclib reports (ROR = 3.06).

Conclusion:

The safety profile of CDK4/6 inhibitors varies. Analysis of the FAERS database revealed hematologic and lymphatic system toxicities for palbociclib and ribociclib and gastrointestinal and hepatorenal toxicities f

or abemaciclib. Erythema multiforme was found as a novel severe AE for abemaciclib. Individualized drug selection and monitoring of AE based on the patient’s physiological status and AE are needed during treatment.

关键词

Keywords

references

HUPPERT L A , GUMUSAY O , IDOSSA D , et al. Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer [J ] . CA Cancer J Clin , 2023 , 73 ( 5 ): 480 - 515 . DOI: 10.3322/caac.v73.5 http://doi.org/10.3322/caac.v73.5 https://acsjournals.onlinelibrary.wiley.com/toc/15424863/73/5 https://acsjournals.onlinelibrary.wiley.com/toc/15424863/73/5

WU Y M , ZHANG Y , PI H , et al. Current therapeutic progress of CDK4/6 inhibitors in breast cancer [J ] . Cancer Manag Res , 2020 , 12 : 3477 - 3487 . DOI: 10.2147/CMAR.S250632 http://doi.org/10.2147/CMAR.S250632

中华人民共和国国家卫生健康委员会 . 乳腺癌诊疗指南(2022年版) [J ] . 中国合理用药探索 , 2022 , 19 ( 10 ): 51 .

National Health Commission of the People's Republic of China . Guidelines for the diagnosis and treatment of breast cancer (2022 edition) [J ] . China Licens Pharm , 2022 , 19 ( 10 ): 51 .

GRADISHAR W J , MORAN M S , ABRAHAM J , et al. Breast cancer, version 3.2022, NCCN clinical practice guidelines in oncology [J ] . J Natl Compr Canc Netw , 2022 , 20 ( 6 ): 691 - 722 . DOI: 10.6004/jnccn.2022.0030 http://doi.org/10.6004/jnccn.2022.0030 https://jnccn.org/view/journals/jnccn/20/6/article-p691.xml https://jnccn.org/view/journals/jnccn/20/6/article-p691.xml

ONESTI C E , JERUSALEM G . CDK4/6 inhibitors in breast cancer: differences in toxicity profiles and impact on agent choice. A systematic review and meta-analysis [J ] . Expert Rev Anticancer Ther , 2021 , 21 ( 3 ): 283 - 298 . DOI: 10.1080/14737140.2021.1852934 http://doi.org/10.1080/14737140.2021.1852934 https://www.tandfonline.com/doi/full/10.1080/14737140.2021.1852934 https://www.tandfonline.com/doi/full/10.1080/14737140.2021.1852934

GRINSHPUN A , TOLANEY S M , BURSTEIN H J , et al. The dilemma of selecting a first line CDK4/6 inhibitor for hormone receptor-positive/HER2-negative metastatic breast cancer [J ] . NPJ Breast Cancer , 2023 , 9 ( 1 ): 15 . DOI: 10.1038/s41523-023-00520-7 http://doi.org/10.1038/s41523-023-00520-7

GAO J J , CHENG J , BLOOMQUIST E , et al. CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis [J ] . Lancet Oncol , 2020 , 21 ( 2 ): 250 - 260 . DOI: S1470-2045(19)30804-6 http://doi.org/S1470-2045(19)30804-6

SCHETTINI F , GIUDICI F , GIULIANO M , et al. Overall survival of CDK4/6-inhibitor-based treatments in clinically relevant subgroups of metastatic breast cancer: systematic review and meta-analysis [J ] . J Natl Cancer Inst , 2020 , 112 ( 11 ): 1089 - 1097 . DOI: 10.1093/jnci/djaa071 http://doi.org/10.1093/jnci/djaa071

THILL M , SCHMIDT M . Management of adverse events during cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-based treatment in breast cancer [J ] . Ther Adv Med Oncol , 2018 , 10 : 1758835918793326.

国家肿瘤质控中心乳腺癌专家委员会 , 中国抗癌协会肿瘤药物临床研究专业委员会 , 徐兵河 , 等 . CDK4/6抑制剂治疗激素受体阳性人表皮生长因子受体2阴性晚期乳腺癌的临床应用共识 [J ] . 中华肿瘤杂志 , 2021 , 43 ( 4 ): 405 - 413 .

Breast Cancer Expert Committee of National Cancer Quality Control Center, Cancer Drug Clinical Research Professional Committee of China Anti-Cancer Association , XU B H , et al. Consensus recommendations for the clinical application of CDK4/6 inhibitors in patients with hormone receptor positive, human epidermal growth factor receptor 2 negative advanced breast cancer [J ] . Chin J Oncol , 2021 , 43 ( 4 ): 405 - 413 .

DESNOYERS A , NADLER M B , KUMAR V , et al. Comparison of treatment-related adverse events of different cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer: a network meta-analysis [J ] . Cancer Treat Rev , 2020 , 90 : 102086 . DOI: 10.1016/j.ctrv.2020.102086 http://doi.org/10.1016/j.ctrv.2020.102086 https://linkinghub.elsevier.com/retrieve/pii/S0305737220301249 https://linkinghub.elsevier.com/retrieve/pii/S0305737220301249

RASCHI E , FUSAROLI M , ARDIZZONI A , et al. Cyclin-dependent kinase 4/6 inhibitors and interstitial lung disease in the FDA adverse event reporting system: a pharmacovigilance assessment [J ] . Breast Cancer Res Treat , 2021 , 186 ( 1 ): 219 - 227 . DOI: 10.1007/s10549-020-06001-w http://doi.org/10.1007/s10549-020-06001-w

RASCHI E , FUSAROLI M , LA PLACA M , et al. Skin toxicities with cyclin-dependent kinase 4/6 inhibitors in breast cancer: signals from disproportionality analysis of the FDA adverse event reporting system [J ] . Am J Clin Dermatol , 2022 , 23 ( 2 ): 247 - 255 . DOI: 10.1007/s40257-021-00645-0 http://doi.org/10.1007/s40257-021-00645-0

SAKAEDA T , TAMON A , KADOYAMA K , et al. Data mining of the public version of the FDA Adverse Event Reporting System [J ] . Int J Med Sci , 2013 , 10 ( 7 ): 796 - 803 . DOI: 10.7150/ijms.6048 http://doi.org/10.7150/ijms.6048

Administration USDO . FDA Adverse Event Reporting System (FAERS) quarterly data extract files [EB/OL ] ( 2023-04-27 )[ 2023-7-14 ] . https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.

CANDORE G , JUHLIN K , MANLIK K , et al. Comparison of statistical signal detection methods within and across spontaneous reporting databases [J ] . Drug Saf , 2015 , 38 ( 6 ): 577 - 587 . DOI: 10.1007/s40264-015-0289-5 http://doi.org/10.1007/s40264-015-0289-5 http://link.springer.com/10.1007/s40264-015-0289-5 http://link.springer.com/10.1007/s40264-015-0289-5

尚鹏辉 , 詹思延 . 数据挖掘在药品不良反应信号检出和分析中的应用(下): 药物流行病学研究新方法系列讲座(三) [J ] . 中国药物应用与监测 , 2009 , 6 ( 3 ): 187 - 190 .

HANG P H , ZHAN S Y . Application of data excavation in the signal detection and analysis of adverse drug reactions(third) [J ] . Chin J Drug Appl Monit , 2009 , 6 ( 3 ): 187 - 190 .

Agency EM . Designated Medical Event (DME) list [EB/OL ] ( 2020-06-15 )[ 2023-7-14 ] . https://www.ema.europa.eu/documents/other/designated-medical-event-dme-list_en.xls https://www.ema.europa.eu/documents/other/designated-medical-event-dme-list_en.xls https://www.ema.europa.eu/documents/other/designated-medical-event-dme-list_en.xls.

BRAAL C L , JONGBLOED E M , WILTING S M , et al. Inhibiting CDK4/6 in breast cancer with palbociclib, ribociclib, and abemaciclib: similarities and differences [J ] . Drugs , 2021 , 81 ( 3 ): 317 - 331 . DOI: 10.1007/s40265-020-01461-2 http://doi.org/10.1007/s40265-020-01461-2

WANDER S A , O'BRIEN N , LITCHFIELD L M , et al. Targeting CDK4 and 6 in cancer therapy: emerging preclinical insights related to abemaciclib [J ] . Oncologist , 2022 , 27 ( 10 ): 811 - 821 . DOI: 10.1093/oncolo/oyac138 http://doi.org/10.1093/oncolo/oyac138

LI J , FU F M , YU L W , et al. Cyclin-dependent kinase 4 and 6 inhibitors in hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer: a meta-analysis of randomized clinical trials [J ] . Breast Cancer Res Treat , 2020 , 180 ( 1 ): 21 - 32 . DOI: 10.1007/s10549-020-05528-2 http://doi.org/10.1007/s10549-020-05528-2

THIBAULT S , HU W Y , HIRAKAWA B , et al. Intestinal toxicity in rats following administration of CDK4/6 inhibitors is independent of primary pharmacology [J ] . Mol Cancer Ther , 2019 , 18 ( 2 ): 257 - 266 . DOI: 10.1158/1535-7163.MCT-18-0734 http://doi.org/10.1158/1535-7163.MCT-18-0734

CHAPPELL J C , TURNER P K , PAK Y A , et al. Abemaciclib inhibits renal tubular secretion without changing glomerular filtration rate [J ] . Clin Pharmacol Ther , 2019 , 105 ( 5 ): 1187 - 1195 . DOI: 10.1002/cpt.1296 http://doi.org/10.1002/cpt.1296

VRANA E , MYLONA S , BOBOS M , et al. Ribociclib and palbociclib-induced erythema multiforme: a case report [J ] . Oxf Med Case Reports , 2022 , 2022 ( 11 ): omac116 . DOI: 10.1093/omcr/omac116 http://doi.org/10.1093/omcr/omac116 https://academic.oup.com/omcr/article/doi/10.1093/omcr/omac116/6845485 https://academic.oup.com/omcr/article/doi/10.1093/omcr/omac116/6845485

ZHANG P , ZHANG Q Y , TONG Z S , et al. Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial [J ] . Lancet Oncol , 2023 , 24 ( 6 ): 646 - 657 . DOI: 10.1016/S1470-2045(23)00172-9 http://doi.org/10.1016/S1470-2045(23)00172-9 https://linkinghub.elsevier.com/retrieve/pii/S1470204523001729 https://linkinghub.elsevier.com/retrieve/pii/S1470204523001729

XU B H , ZHANG Q Y , ZHANG P , et al. Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial [J ] . Nat Med , 2021 , 27 ( 11 ): 1904 - 1909 . DOI: 10.1038/s41591-021-01562-9 http://doi.org/10.1038/s41591-021-01562-9

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