Endocrine toxicity of immune checkpoint inhibitors: a real-world study leveraging US Food and Drug Administration adverse events reporting system
Endocrine toxicity of immune checkpoint inhibitors: a real-world study leveraging US Food and Drug Administration adverse events reporting system
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免疫检查点抑制剂的内分泌毒性：利用美国食品和药物管理局不良事件报告系统进行的真实世界研究
DOI：
10.1186/s40425-019-0754-2
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发表时间：
2019-11-06
影响因子：
10.9
通讯作者：
He, Jia
中科院分区：
文献类型：
--
作者：
Zhai, Yinghong;Ye, Xiaofei;He, Jia
背景免疫检查点抑制剂（Immune-checkpoint inhibitors，ICI）是近年来出现的一类新型抗肿瘤药物。ICI可以产生持久的抗肿瘤反应，但它们也与免疫相关不良事件（irAE）相关。内分泌疾病已报告为ICIS.MethodsThis研究的最常见的irAE之一，旨在量化内分泌不良事件（AE）和ICI治疗的关联，并从现实世界的实践中ICI相关的内分泌并发症的特征。收集了FDA不良事件报告系统（FAERS）数据库中2014年第一季度至2019年第一季度的数据，以进行重复性分析。内分泌AE的定义依赖于国际医学用语词典（MedDRA）提供的首选术语（PT）。基于统计收缩变换的两个信号指标，报告比值比（ROR）和信息成分（IC），用于评估ICI和内分泌事件之间的相关性。对于ROR，如果95%置信区间（ROR 025）的下限大于1，则定义为信号，至少有3例病例。结果共纳入29，294，336条记录，其中6260条记录与ICIs治疗后的内分泌AE有关。一般而言，男性的ICIs相关内分泌疾病报告频率略低于女性，但不显著（ROR = 0.98 95%CI：0.93-1.04），且几种常见内分泌AE的差异各不相同。值得注意的是，一般而言，ICI药物与内分泌并发症的过度报告频率显著相关，对应于IC 025 = 2.49和ROR 025 = 5.99。对于单药治疗，三种策略（抗PD-1、抗PD-L1和抗CTLA-4）均与内分泌事件显著增加相关。当抗CTLA-4治疗与抗PD-1/PD-L1药物治疗内分泌毒性比较时，出现不同的报告频率，分别对应于ROR = 1.68（95%CI 1.55-1.83），ROR = 2.54（95%CI 2.20-2.93）。与单药治疗相比，联合治疗与内分泌疾病的高风险相关（ROR = 2.00，95%CI 1.89-2.11）。当进一步分析时，免疫治疗方案的内分泌AE谱不同。甲减（N= 885，14.14%），肾上腺功能不全（N= 730，11.66%），垂体炎（N= 688，10.99%）（N= 472，（7.54%）ICI治疗后的前4位内分泌事件，其报告频率在ICI免疫治疗中也不同。结论我们的药物警戒分析显示ICI引起的内分泌AE报告频率较高单药治疗（尤其是抗CTLA-4治疗）并通过联合治疗进一步加强。此外，用不同的ICI免疫疗法治疗可能导致内分泌病的独特和不同的特征。早期识别和管理ICI相关的内分泌irAE在临床实践中至关重要。
BackgroundImmune-checkpoint inhibitors (ICIs) emerged as a novel class of drugs for the treatment of a broad spectrum of malignancies. ICIs can produce durable antitumor responses but they are also associated with immune-related adverse events (irAEs). Endocrinopathies have reported as one of the most common irAEs of ICIs.MethodsThis study aimed to quantify association of endocrine adverse events (AEs) and ICI therapy and also to characterize the profiles of ICI-related endocrine complications from real-world practice. Data from the first quarter of 2014 to first quarter of 2019 in FDA Adverse Event Reporting System (FAERS) database were gathered to conduct disproportionality analysis. The definition of endocrine AEs relied on the preferred terms (PTs) provided by the Medical Dictionary for Regulatory Activities (MedDRA). Two signal indices based on statistical shrinkage transformation, reporting odds ratios (ROR) and information component (IC), were used to evaluate correlations between ICIs and endocrine events. For ROR, it was defined a signal if the lower limit of the 95% confidence interval (ROR025) more than one, with at least 3 cases. For IC, lower end of the 95% confidence interval of IC (IC025) exceeding zero was deemed statistically significant.ResultsA total of 29,294,336 records were involved, among these 6260 records related to endocrine AEs after ICIs treatment were identified. In general, male had a slightly lower reporting frequencies for ICIs-related endocrinopathies compared with female but not significant (ROR = 0.98 95%CI: 0.93–1.04) and the difference varied in several common endocrine AEs. Notably, in general, ICI drugs were significantly associated with over-reporting frequencies of endocrine complications, corresponding to IC025= 2.49 and ROR025= 5.99. For monotherapy, three strategies (anti-PD-1, anti-PD-L1 and anti-CTLA-4) were all associated with significant increasing endocrine events. Different reporting frequencies emerged when anti-CTLA-4 therapy was compared with anti-PD-1/PD-L1 medications for endocrine toxicities, corresponding to ROR = 1.68 (95%CI 1.55–1.83), ROR = 2.54 (95%CI 2.20–2.93), respectively. Combination therapy was associated with higher risk of endocrinopathies compared with monotherapy (ROR = 2.00, 95%CI 1.89–2.11). When further analysis, the spectrum of endocrine AEs differed in immunotherapy regimens. Hypothyroidism (N= 885,14.14%), adrenal insufficiency(N= 730,11.66%), hypophysitis (N= 688,10.99%) and hyperthyroidism (N= 472,7.54%) were top 4 ranked endocrine events after ICI therapy and their reporting frequency also differed in ICI immunotherapies.ConclusionOur pharmacovigilance analysis shows a high reporting frequency of endocrine AEs provoked by ICI monotherapy (especially anti-CTLA-4 therapy) and further reinforced by combination therapy. In addition, treatment with different ICI immunotherapies may result in a unique and distinct profile of endocrinopathies. Early recognition and management of ICI-related endocrine irAEs is of vital importance in clinical practice.