Abstract：
BACKGROUND: Stereotactic body radiotherapy (SBRT) is safe and effective for treatment of extracranial metastatic disease, but its safety when combined with immune checkpoint inhibitors (ICI) has not yet been comprehensively reported. Here we report adverse events (AEs) associated with combined SBRT and ICI using prospectively-collected data on patients in three trials investigating multi-site SBRT combined with ICI.
METHODS: Patients were included from three prospective trials of ICI (pembrolizumab; nivolumab/urelumab or nivolumab/cabiralizumab; nivolumab/ipilimumab) with SBRT to 1-4 sites. AEs were recorded prospectively using the CTCAE v4.0. Survival was analyzed using Kaplan-Meier method with a 90-day landmark. Association of patient characteristics with cumulative incidence of AEs was assessed using Fine-Gray regression.
RESULTS: 213 patients were included, with a median follow-up of 10 months. Over the follow-up period, 50 % and 27 % of patients experienced at least one grade ≥ 2 or grade ≥ 3 AE, respectively. Cumulative incidences of grade ≥ 2 and grade ≥ 3 AEs at 6 months were 47 % and 23 %, respectively. Three grade 5 AEs rated \"possibly\" related to treatment occurred outside the 90-day dose-limiting toxicity window. Landmarked survival analysis of patients with or without grade ≥ 3 AEs showed no significant difference in progression-free or overall survival. Dual-agent ICI was significantly associated with grade ≥ 3 AE.
CONCLUSIONS: This analysis features the largest prospectively evaluated cohort of patients treated with combination ablative SBRT and ICI to date and provides context for future trial design. We conclude that multi-site SBRT and ICI can be safely co-administered when SBRT is delivered with prioritization of normal tissue constraints.
METHODS: Patients were included from three prospective trials of ICI (pembrolizumab; nivolumab/urelumab or nivolumab/cabiralizumab; nivolumab/ipilimumab) with SBRT to 1-4 sites. AEs were recorded prospectively using the CTCAE v4.0. Survival was analyzed using Kaplan-Meier method with a 90-day landmark. Association of patient characteristics with cumulative incidence of AEs was assessed using Fine-Gray regression.
RESULTS: 213 patients were included, with a median follow-up of 10 months. Over the follow-up period, 50 % and 27 % of patients experienced at least one grade ≥ 2 or grade ≥ 3 AE, respectively. Cumulative incidences of grade ≥ 2 and grade ≥ 3 AEs at 6 months were 47 % and 23 %, respectively. Three grade 5 AEs rated \"possibly\" related to treatment occurred outside the 90-day dose-limiting toxicity window. Landmarked survival analysis of patients with or without grade ≥ 3 AEs showed no significant difference in progression-free or overall survival. Dual-agent ICI was significantly associated with grade ≥ 3 AE.
CONCLUSIONS: This analysis features the largest prospectively evaluated cohort of patients treated with combination ablative SBRT and ICI to date and provides context for future trial design. We conclude that multi-site SBRT and ICI can be safely co-administered when SBRT is delivered with prioritization of normal tissue constraints.
摘要：
背景：立体定向放射治疗（SBRT）对于颅外转移性疾病的治疗是安全有效的，但其与免疫检查点抑制剂（ICI）联合使用时的安全性尚未得到全面报道。在这里，我们报告了与SBRT和ICI联合相关的不良事件（AE），使用三个研究多位点SBRT联合ICI的前瞻性收集的患者数据。
方法：患者纳入了3项ICI前瞻性试验（pembrolizumab;nivolumab/urelumab或nivolumab/cabiralizumab;nivolumab/ipilimumab），SBRT至1-4个位点。使用CTCAEv4.0前瞻性记录AE。使用具有90天标志的Kaplan-Meier方法分析存活。使用Fine-Gray回归评估患者特征与AE累积发生率的关联。
结果：纳入213例患者，中位随访时间为10个月。在随访期间，50%和27%的患者经历至少一个≥2级或≥3级AE，分别。6个月≥2级和≥3级不良事件的累积发生率分别为47%和23%，分别。在90天剂量限制性毒性窗口之外发生了与治疗相关的“可能”等级5级AE。有或没有≥3级AEs的患者的标志生存分析显示，无进展生存或总生存没有显着差异。双药ICI与≥3级AE显著相关。
结论：本分析的特点是迄今为止最大的前瞻性评估队列患者接受消融性SBRT和ICI联合治疗，并为未来的试验设计提供了背景。我们得出的结论是，在优先考虑正常组织约束的情况下交付SBRT时，可以安全地共同施用多位点SBRT和ICI。
方法：患者纳入了3项ICI前瞻性试验（pembrolizumab;nivolumab/urelumab或nivolumab/cabiralizumab;nivolumab/ipilimumab），SBRT至1-4个位点。使用CTCAEv4.0前瞻性记录AE。使用具有90天标志的Kaplan-Meier方法分析存活。使用Fine-Gray回归评估患者特征与AE累积发生率的关联。
结果：纳入213例患者，中位随访时间为10个月。在随访期间，50%和27%的患者经历至少一个≥2级或≥3级AE，分别。6个月≥2级和≥3级不良事件的累积发生率分别为47%和23%，分别。在90天剂量限制性毒性窗口之外发生了与治疗相关的“可能”等级5级AE。有或没有≥3级AEs的患者的标志生存分析显示，无进展生存或总生存没有显着差异。双药ICI与≥3级AE显著相关。
结论：本分析的特点是迄今为止最大的前瞻性评估队列患者接受消融性SBRT和ICI联合治疗，并为未来的试验设计提供了背景。我们得出的结论是，在优先考虑正常组织约束的情况下交付SBRT时，可以安全地共同施用多位点SBRT和ICI。
