免疫检查点抑制剂(ICI)通过利用免疫系统彻底改变了癌症治疗,但ICI可以诱导危及生命的免疫相关不良事件(irAE),影响每个器官。
■我们从VigiBase中提取了irAE,国际药物警戒数据库,首次报告于2008年,直到2023年1月1日,以描述IRAE报告趋势,临床特征,风险因素和结果。
■我们区分了25种类型的irAE(n=50,347例,单IRAE/例84.9%)。病例主要涉及抗PD1(程序性死亡-1)单药治疗(62.4%),男性(61.7%),年龄为64.3±12.6岁。2020年后vs.在2016年之前,抗CTLA4(细胞毒性T淋巴细胞抗原-4)单一疗法处方的比例几乎消失(1.6%vs.47%,分别)与增加使用抗PDL1(PD1-配体)单一疗法(18%vs.0.9%)和抗CTLA4+抗PD(L)1组合(20%vs.8.9%)。在所研究的时间范围内,抗LAG3(淋巴细胞活化基因-3)处方是有限的(<1%)。2020年后,超过14种不同类型的癌症接受了治疗,而不是在2016年之前几乎完全是黑色素瘤和肺癌。总的来说,报告最多的是皮肤反应(22.9%),肺炎(18.5%),小肠结肠炎(14.4%)和甲状腺炎(12.1%)。ICI-肌毒性(6.6%)包括肌炎,心肌炎和重症肌无力样综合征,是最重叠的irAE(高达30%重叠,vs.对于其他IRAE间重叠,一般<3%)。与特异性irAE(比值比>5)相关的主要因素是ICI肌毒性或肝炎的胸腺癌的存在;白癜风的黑色素瘤的存在,葡萄膜炎或结节病;ICI方案的特定类型(抗LAG3用于脑膜炎,抗CTLA4用于垂体炎);和特定报告区域(东亚用于胆管炎)。中位发病时间为31至273天,肌毒性最短,皮肤大疱性自身免疫反应最延迟。心肌炎的总死亡率最高=27.6%,肌无力=23.1%,严重皮肤不良反应(SCAR)=22.1%,肌炎=21.9%,肺炎=21%,脑脊髓炎=18%;除肌无力和SCAR外,2020年后总体下降。报告时,再攻击后irAE复发率为28.9%(n=275/951)。
■这项最新的全球综合药物警戒研究定义了光谱,特点,以及IRAE报告的演变,总结了十多年的使用情况。特定irAE的多种危险因素和临床特点已被确定为指导临床实践和未来研究的信号。
■PaulGougis获得了学术课程的支持:“ContratsED:ProgrammeblancInstituteCuriePSL”,以进行博士学位。BaptisteAbbar得到了“ARCPourleRechhercherSurleCancer基金会”的支持。RT2L研究小组(InstitutCurie)得到了学术计划“SHSINCa”的支持,赛诺菲iTech奖,和Monoprix*。
UNASSIGNED: Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment by harnessing the immune system but ICI can induce life-threatening immune-related adverse events (irAE) affecting every organ.
UNASSIGNED: We extracted irAE from VigiBase, the international pharmacovigilance database, first reported in 2008 until 01/2023 to characterize irAE reporting trends, clinical features, risk factors and outcomes.
UNASSIGNED: We distinguished 25 types of irAE (n = 50,347cases, single irAE/case in 84.9%). Cases mainly involved anti-PD1 (programmed-death-1) monotherapy (62.4%) in male (61.7%) aged 64.3 ± 12.6 years. After 2020 vs. prior to 2016, proportion of anti-CTLA4 (Cytotoxic-T-Lymphocyte-Antigen-4) monotherapy prescription almost vanished (1.6% vs. 47%, respectively) contrasting with increased use of anti-PDL1 (PD1-ligand) monotherapy (18% vs. 0.9%) and anti-CTLA4+anti-PD(L)1 combination (20% vs. 8.9%). Anti-LAG3 (Lymphocyte-Activation-Gene-3) prescription was limited (<1%) in the studied timeframe. After 2020, over 14 different cancer types were treated vs. almost exclusively melanoma and lung cancers before 2016. Overall, the most reported irAE were skin reactions (22.9%), pneumonitis (18.5%), enterocolitis (14.4%) and thyroiditis (12.1%). ICI-myotoxicities (6.6%) included myositis, myocarditis and myasthenia-gravis like syndrome and were the most overlapping irAE (up to 30% overlap, vs. <3% in general for other inter-irAE overlap). The top factors associated with specific irAE (odds-ratio>5) were presence of thymic cancer for ICI-myotoxicities or hepatitis; presence of melanoma for vitiligo, uveitis or sarcoidosis; specific types of ICI regimen (anti-LAG3 for meningitis, anti-CTLA4 for hypophysitis); and specific reporting regions (eastern Asia for cholangitis). Median time-to-onset ranged from 31 to 273 days, being shortest for myotoxicities and most delayed for skin-bullous auto-immune reactions. Overall fatality was highest for myocarditis = 27.6%, myasthenia = 23.1%, severe cutaneous adverse reactions (SCAR) = 22.1%, myositis = 21.9%, pneumonitis = 21%, and encephalomyelitis = 18%; generally decreasing after 2020, except for myasthenia and SCAR. When reported, irAE recurrence rate after rechallenge was 28.9% (n = 275/951).
UNASSIGNED: This up-to-date comprehensive worldwide pharmacovigilance study defines the spectrum, characteristics, and evolution of irAE reporting summarizing over a decade of use. Multiple risk factors and clinical peculiarities for specific irAE have been identified as signals to guide clinical practice and future research.
UNASSIGNED: Paul Gougis was supported by the academic program: \"Contrats ED: Programme blanc Institut Curie PSL\" for the conduct of his PhD. Baptiste Abbar was supported by \"the Fondation ARC Pour le Rechercher Sur le Cancer\". The RT2L research group (Institut Curie) was supported by the academic program \"SHS INCa\", Sanofi iTech award, and by Monoprix∗.