Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
Clin Cancer Res. 2021 Nov 1;27(21):5993-6000. doi: 10.1158/1078-0432.CCR-21-1283. Epub 2021 Aug 10.
Programmed cell death receptor-1 (PD-1) inhibitors are frontline therapy in advanced melanoma. Severe immune-related adverse effects (irAEs) often require immunosuppressive treatment with glucocorticoids (GCCs), but GCC use and its correlation with patient survival outcomes during anti-PD-1 monotherapy remains unclear.
In this multicenter retrospective analysis, patients treated with anti-PD-1 monotherapy between 2009 and 2019 and detailed GCC use, data were identified from five independent cohorts, with median follow-up time of 206 weeks. IrAEs were tracked from the initiation of anti-PD-1 until disease progression, initiation of a new therapy, or last follow-up. Correlations between irAEs, GCC use, and survival outcomes were analyzed.
Of the entire cohort of 947 patients, 509 (54%) developed irAEs. In the MGH cohort [irAE(+) = 90], early-onset irAE (within 8 weeks of anti-PD-1 initiation) with high-dose GCC use (≥60-mg prednisone equivalent once a day) was independently associated with poorer post-irAE PFS/OS (progression-free survival/overall survival) [post-irAE PFS: HR, 5.37; 95% confidence interval (CI), 2.10-13.70; < 0.001; post-irAE OS: HR, 5.95; 95% CI, 2.20-16.09; < 0.001] compared with irAEs without early high-dose GCC use. These findings were validated in the combined validation cohort [irAE(+) = 419, post-irAE PFS: HR, 1.69; 95% CI, 1.04-2.76; = 0.04; post-irAE OS: HR, 1.97; 95% CI, 1.15-3.39; = 0.01]. Similar findings were also observed in the 26-week landmark analysis for post-irAE-PFS but not for post-irAE-OS. A sensitivity analysis using accumulated GCC exposure as the measurement achieved similar results.
Early high-dose GCC use was associated with poorer PFS and OS after irAE onset. Judicious use of GCC early during anti-PD-1 monotherapy should be considered. Further prospective randomized control clinical trials designed to explore alternative irAE management options are warranted.
程序性死亡受体-1（PD-1）抑制剂是晚期黑色素瘤的一线治疗药物。严重的免疫相关不良事件（irAEs）通常需要使用糖皮质激素（GCCs）进行免疫抑制治疗，但在抗 PD-1 单药治疗期间，GCC 的使用及其与患者生存结局的相关性尚不清楚。
在这项多中心回顾性分析中，从五个独立队列中确定了 2009 年至 2019 年间接受抗 PD-1 单药治疗且详细记录了 GCC 使用情况的患者，中位随访时间为 206 周。irAEs 从抗 PD-1 开始至疾病进展、开始新治疗或最后一次随访进行跟踪。分析了 irAEs、GCC 使用与生存结局之间的相关性。
在整个 947 例患者队列中，有 509 例（54%）发生了 irAEs。在 MGH 队列[irAE（+）= 90]中，早期（抗 PD-1 起始后 8 周内）发生的 irAE 与高剂量 GCC （≥60mg 泼尼松当量，每天一次）的使用与较差的 post-irAE PFS/OS（无进展生存期/总生存期）相关（post-irAE PFS：HR，5.37；95%CI，2.10-13.70；<0.001；post-irAE OS：HR，5.95；95%CI，2.20-16.09；<0.001），与未使用早期高剂量 GCC 的 irAEs 相比。这些发现在联合验证队列中得到了验证[irAE（+）= 419，post-irAE PFS：HR，1.69；95%CI，1.04-2.76；= 0.04；post-irAE OS：HR，1.97；95%CI，1.15-3.39；= 0.01]。在 26 周的 post-irAE-PFS 里程碑分析中也观察到了类似的结果，但在 post-irAE-OS 中没有观察到。使用累积 GCC 暴露作为测量方法的敏感性分析得出了类似的结果。
早期高剂量 GCC 的使用与 irAE 发生后的 PFS 和 OS 较差相关。在抗 PD-1 单药治疗期间，应谨慎使用早期的 GCC。需要进一步设计前瞻性随机对照临床试验，以探索替代 irAE 管理方案。
