Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands.
J Clin Oncol. 2024 Nov;42(31):3713-3724. doi: 10.1200/JCO.24.00191. Epub 2024 Aug 7.
Retrospective studies suggest that immunosuppressive treatment of immune-related adverse events (irAEs) impairs survival in patients with melanoma who received immune checkpoint inhibitors. Here, we study this association across tumor types using data from six international phase II/III registrational trials.
A post hoc analysis was performed on individual patient data from the anti-programmed cell death-1 (anti-PD-1) + anti-cytotoxic T lymphocyte-associated protein-4 (anti-CTLA-4) treatment arms of six clinical trials (CheckMate-067, -142, -214, -648, -743, and -9LA). Among patients who received systemic immunosuppression for treatment-related adverse events (trAEs), associations of peak and cumulative corticosteroid dose, and use of second-line immunosuppression with overall survival (OS) and progression-free survival (PFS) were assessed using multilevel Cox regression with adjustment for age and sex.
Of the 1,959 patients who received anti-PD-1 + anti-CTLA-4 therapy, 834 patients who were treated with immunosuppression for trAEs were included. Eight hundred and thirty-two patients (100%) received corticosteroids and 81 patients (10%) received second-line immunosuppressants. High corticosteroid peak dose was associated with worse PFS: adjusted hazard ratio (HR), 1.15 (95% CI, 1.02 to 1.29) for 1 versus 0.5 mg/kg prednisolone and HR, 1.43 (95% CI, 1.05 to 1.96) for 2 versus 0.5 mg/kg. Similar effects were observed for OS: HR, 1.21 (95% CI, 1.06 to 1.39) and HR, 1.66 (95% CI, 1.17 to 2.37) for 1 and 2 versus 0.5 mg/kg, respectively. Cumulative corticosteroid dose was not associated with survival. HR of use of second-line immunosuppression was 1.23 (95% CI, 0.90 to 1.68) for PFS and 1.25 (95% CI, 0.88 to 1.77) for OS.
Higher corticosteroid peak dose for trAEs is associated with worse survival across tumor types, while cumulative dose is not. Too few patients received second-line immunosuppressants to confirm or reject an association with survival. These data argue for a reconsideration of irAE management approaches, starting with lower corticosteroid dose whenever feasible.
回顾性研究表明，免疫抑制治疗免疫相关不良事件（irAEs）会损害接受免疫检查点抑制剂治疗的黑色素瘤患者的生存。在这里，我们使用来自六项国际 II/III 期注册试验的数据研究了这种关联在肿瘤类型中的作用。
对六项临床试验（CheckMate-067、-142、-214、-648、-743 和 -9LA）中抗程序性死亡-1（抗 PD-1）+抗细胞毒性 T 淋巴细胞相关蛋白 4（抗 CTLA-4）治疗组的个别患者数据进行了事后分析。在因治疗相关不良反应（trAEs）而接受全身免疫抑制治疗的患者中，使用多水平 Cox 回归模型，根据年龄和性别进行调整，评估了峰剂量和累积皮质类固醇剂量以及二线免疫抑制剂的使用与总生存期（OS）和无进展生存期（PFS）的相关性。
在接受抗 PD-1+抗 CTLA-4 治疗的 1959 名患者中，有 834 名患者因 trAEs 接受了免疫抑制治疗。832 名患者（100%）接受皮质类固醇治疗，81 名患者（10%）接受二线免疫抑制剂治疗。高皮质类固醇峰剂量与较差的 PFS 相关：调整后的风险比（HR），1.15（95%CI，1.02 至 1.29），1 比 0.5mg/kg 泼尼松龙，HR，1.43（95%CI，1.05 至 1.96），2 比 0.5mg/kg。OS 也观察到类似的效果：HR，1.21（95%CI，1.06 至 1.39）和 HR，1.66（95%CI，1.17 至 2.37），1 和 2 比 0.5mg/kg，分别。累积皮质类固醇剂量与生存无关。二线免疫抑制剂使用的 HR 为 PFS 时为 1.23（95%CI，0.90 至 1.68），OS 时为 1.25（95%CI，0.88 至 1.77）。
治疗 trAEs 的皮质类固醇峰剂量较高与多种肿瘤类型的生存较差相关，而累积剂量则不然。接受二线免疫抑制剂治疗的患者太少，无法确认或拒绝其与生存相关。这些数据表明需要重新考虑 irAE 管理方法，只要有可能，就应使用较低的皮质类固醇剂量。
