黑色素瘤中基于抗PD-1免疫疗法的延迟性免疫相关不良事件。
Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma.
作者信息
Owen C N, Bai X, Quah T, Lo S N, Allayous C, Callaghan S, Martínez-Vila C, Wallace R, Bhave P, Reijers I L M, Thompson N, Vanella V, Gerard C L, Aspeslagh S, Labianca A, Khattak A, Mandala M, Xu W, Neyns B, Michielin O, Blank C U, Welsh S J, Haydon A, Sandhu S, Mangana J, McQuade J L, Ascierto P A, Zimmer L, Johnson D B, Arance A, Lorigan P, Lebbé C, Carlino M S, Sullivan R J, Long G V, Menzies A M
机构信息
Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Massachusetts General Hospital, Boston, USA; Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma, Peking University Cancer Hospital & Institute, Beijing, China.
出版信息
Ann Oncol. 2021 Jul;32(7):917-925. doi: 10.1016/j.annonc.2021.03.204. Epub 2021 Mar 30.
BACKGROUND
Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy.
PATIENTS AND METHODS
Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined.
RESULTS
One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%).
CONCLUSIONS
Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.
背景
免疫相关不良事件（irAEs）通常在开始基于抗程序性细胞死亡蛋白1（PD-1）的治疗[抗PD-1±抗细胞毒性T淋巴细胞相关蛋白4（CTLA4）]后的4个月内发生，但也可能出现延迟性irAEs（开始治疗>12个月后发病）。本研究描述了接受基于抗PD-1免疫治疗的患者中延迟性irAEs的发生率、性质及管理。
患者与方法
对来自20个中心的发生延迟性irAEs的患者进行研究。延迟性irAEs的发生率以接受基于抗PD-1治疗且存活>1年的黑色素瘤患者的比例来估计。检查irAEs的发病时间、临床特征、管理及结局。
结果
118例患者共发生140例延迟性irAEs（20例在最初联合抗CTLA4治疗后发生），估计发生率为5.3%（95%置信区间4.0 - 6.9，有可用数据的研究点999例患者中的53例）。延迟性irAE的中位发病时间为16个月（范围12 - 53个月）。87例患者（74%）在irAE发病时正在接受抗PD-1治疗，15例患者（12%）距最后一剂抗PD-1治疗<3个月，16例患者（14%）距最后一剂抗PD-1治疗>3个月。最常见的延迟性irAEs为结肠炎、皮疹和肺炎；所有irAEs中55例（39%）为≥3级。80例患者（68%）需要使用类固醇，27例患者（23%）还需要额外使用一种免疫抑制剂。有2例与irAE相关的死亡：1例在抗PD-1治疗期间发生的脑炎，1例在停止抗PD-1治疗11个月后发生的多器官irAE。69例患者（58%）也发生了早期irAEs（<12个月），其中59例患者（86%）的早期irAEs累及的器官与延迟性irAE不同。
结论
延迟性irAEs发生在一小部分但相关的患者亚组中。延迟性irAEs通常与既往irAEs不同，可能为高级别且可导致死亡。它们大多发生在仍在接受抗PD-1治疗的患者中。在决定反应性患者的治疗持续时间时应考虑延迟性irAE的风险。然而，停止治疗的患者也可能很少发生延迟性irAE。
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