基于FAERS数据库的PD-1/PD-L1抑制剂免疫相关不良事件信号分析 ★

Analysis of immune-related adverse events induced by PD-1/PD-L1 inhibitors based on FAERS ★

摘要:

目的 基于美国FAERS数据库挖掘帕博利珠单抗、纳武利尤单抗、阿替利珠单抗、度伐利尤单抗的免疫相关不良事件（irAE）信号，为降低临床用药风险和药品上市后安全性监测提供导向和参考。 方法 提取美国FAERS数据库2012年第四季度至2022年第一季度的不良事件报告，采用报告比值比法、MHRA综合标准法、贝叶斯置信递进神经网络法（BCPNN）展开信号检测，应用标准MedDRA分析查询（Standardized MedDRA Queries，SMQ）在特定“免疫介导/自身免疫性疾病”中广义检索irAEs信号，分析四种PD-1/PD-L1抑制剂导致irAEs的共有特征。 结果 统计分析结果显示，纳武利尤单抗不良事件报告数最多且逐年增幅最大，不良事件患者中男性群体和老年群体占比较高，且主要临床结局为其他严重的重要医疗事件、住院和死亡。信号检测结果显示，四种PD-1/PD-L1抑制剂共检出23个irAEs信号，包括脑炎、重症肌无力、甲状腺疾病、类天疱疮、结肠炎、肌炎、肝炎、暴发性1型糖尿病等，累及11个系统器官分类（SOC）；其中年龄差异性信号较多，主要表现为免疫性血小板减少症、肌炎、心肌炎在老年群体中高发。 结论 PD-1/PD-L1抑制剂irAEs信号累及SOC范围较广泛，建议临床用药前详细询问患者既往病史，尤其需要关注老年群体的用药风险，加强免疫相关不良事件的早期管理和迅速评估；注重中国用药群体免疫相关不良事件数据的收集和分析，挖掘其不良反应特征，不断完善药品说明书，促进我国临床安全、合理使用PD-1/PD-L1抑制剂。

Abstract:

Objectives To mine the immune-related adverse event (irAE) signals of pembrolizumab, nivolumab, atezolizumab and durvalumab based on the FDA Adverse Event Reporting System (FAERS), so as to provide guidance and reference for reducing clinical risks and post-marketing safety monitoring. Methods Adverse event reports were extracted from the fourth quarter of 2012 to the first quarter of 2022 in FAERS. The reporting odds ratio (ROR), comprehensive standard method (MHRA) and Bayesian confidence propagation neural network (BCPNN) were used to conduct signal detection. Standardized MedDRA Queries (SMQ) was applied to broadly retrieve signals about irAEs in immune-mediated/autoimmune diseases, which aimed to analyze the common characteristics of irAEs caused by the four PD-1/PD-L1 inhibitors. Results Statistical analysis results revealed that the number of adverse events reported for nivolumab was the highest and increased the most year by year. Male and elderly patients constituted a larger proportion of those experiencing adverse events, and the main clinical outcomes were other serious important medical events, hospitalization and death. Signal detection results identified a total of 23 signals for irAEs across the four PD-1/PD-L1 inhibitors, including encephalitis, myasthenia gravis, thyroid disorders, pemphigoid, colitis, myositis, hepatitis, and fulminant type 1 diabetes and so on, affecting 11 system organ classes (SOC). Age-specific signals were more prevalent and predominantly manifested as immune thrombocytopenia in addition to myositis and myocarditis among the elderly population. Conclusion Signals about irAEs induced by PD-1/PD-L1 inhibitors affect a wide range of SOC. Therefore, it is recommended that clinicians obtain a detailed history of the patient's previous illnesses before administering the drug. Special attention should be paid to the risk of drug use in the elderly population. Early management and prompt assessment of irAEs should be strengthened. Emphasis should be placed on collecting and analyzing immune-related adverse event data in the Chinese drug-using population to identify its adverse reaction characteristics and continuously improve the drug's package insert. This approach will promote the safe and rational use of PD-1/PD-L1 inhibitors in clinical practice in China.