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Abstract：
OBJECTIVE: Patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) have proven benefit from anti-programmed cell death 1 (anti-PD-1) monotherapy. Here, we retrospectively analyze the association of plasma Epstein-Barr virus (EBV) DNA load and tumor viral lytic genome with clinical outcome from 2 registered phase I trials.
METHODS: Patients with RM-NPC from Checkmate 077 (nivolumab phase I trial in China) and Camrelizumab phase I trial between March 2016 and January 2018 were enrolled. Baseline EBV DNA titers were tested in 68 patients and EBV assessment was performed in 60 patients who had at least 3 post-baseline timepoints of EBV data and at least 1 post-baseline timepoint of radiographic assessment. We defined \"EBV response\" as 3 consecutive timepoints of load below 50% of baseline, and \"EBV progression\" as 3 consecutive timepoints of load above 150% of baseline. Whole-exome sequencing was performed in 60 patients with available tumor samples.
RESULTS: We found that the baseline EBV DNA load was positively correlated with tumor size (spearman p < 0.001). Both partial response (PR) and stable disease (SD) patients had significantly lower EBV load than progression disease (PD) patients. EBV assessment was highly consistent with radiographic evaluation. Patients with EBV response had significantly improved overall survival (OS) than patients with EBV progression (log-rank p = 0.004, HR = 0.351 [95% CI: 0.171-0.720], median 22.5 vs. 11.9 months). The median time to initial EBV response and progression were 25 and 36 days prior to initial radiographic response and progression, respectively. Patients with high levels of EBV lytic genomes at baseline, including BKRF2, BKRF3 and BKRF4, had better progression-free survival (PFS) and OS.
CONCLUSIONS: In summary, early clearance of plasma EBV DNA load and high levels of lytic EBV genes were associated with better clinical outcome in patients with RM-NPC receiving anti-PD-1 monotherapy.
METHODS: Patients with RM-NPC from Checkmate 077 (nivolumab phase I trial in China) and Camrelizumab phase I trial between March 2016 and January 2018 were enrolled. Baseline EBV DNA titers were tested in 68 patients and EBV assessment was performed in 60 patients who had at least 3 post-baseline timepoints of EBV data and at least 1 post-baseline timepoint of radiographic assessment. We defined \"EBV response\" as 3 consecutive timepoints of load below 50% of baseline, and \"EBV progression\" as 3 consecutive timepoints of load above 150% of baseline. Whole-exome sequencing was performed in 60 patients with available tumor samples.
RESULTS: We found that the baseline EBV DNA load was positively correlated with tumor size (spearman p < 0.001). Both partial response (PR) and stable disease (SD) patients had significantly lower EBV load than progression disease (PD) patients. EBV assessment was highly consistent with radiographic evaluation. Patients with EBV response had significantly improved overall survival (OS) than patients with EBV progression (log-rank p = 0.004, HR = 0.351 [95% CI: 0.171-0.720], median 22.5 vs. 11.9 months). The median time to initial EBV response and progression were 25 and 36 days prior to initial radiographic response and progression, respectively. Patients with high levels of EBV lytic genomes at baseline, including BKRF2, BKRF3 and BKRF4, had better progression-free survival (PFS) and OS.
CONCLUSIONS: In summary, early clearance of plasma EBV DNA load and high levels of lytic EBV genes were associated with better clinical outcome in patients with RM-NPC receiving anti-PD-1 monotherapy.
摘要：
目的：已证明复发或转移性鼻咽癌（RM-NPC）患者从抗程序性细胞死亡1（抗PD-1）单药治疗中获益。这里,我们回顾性分析了血浆爱泼斯坦-巴尔病毒(EBV)DNA载量和肿瘤病毒裂解基因组与2项已注册的I期试验的临床结局的相关性.
方法：纳入2016年3月至2018年1月Checkmate077（中国nivolumabI期试验）和CamrelizumabI期试验的RM-NPC患者。在68例患者中测试了基线EBVDNA滴度，并在60例患者中进行了EBV评估，这些患者具有至少3个基线后时间点的EBV数据和至少1个基线后时间点的放射学评估。我们将“EBV反应”定义为连续3个时间点的负荷低于基线的50%，和“EBV进展”作为超过基线150%的3个连续负荷时间点。在60名具有可用肿瘤样品的患者中进行全外显子组测序。
结果：我们发现基线EBVDNA载量与肿瘤大小呈正相关（spearmanp<0.001）。部分反应（PR）和疾病稳定（SD）患者的EBV负荷均明显低于疾病进展（PD）患者。EBV评估与影像学评估高度一致。与EBV进展患者相比，EBV反应患者的总生存期（OS）显着提高（log-rankp=0.004，HR=0.351[95％CI：0.171-0.720]，中位数22.5vs.11.9个月）。初始EBV反应和进展的中位时间为初始影像学反应和进展前25天和36天，分别。基线时EBV裂解基因组水平高的患者，包括BKRF2，BKRF3和BKRF4，具有更好的无进展生存期（PFS）和OS。
结论：总之，在接受抗PD-1单药治疗的RM-NPC患者中,血浆EBVDNA负荷的早期清除和高水平的裂解性EBV基因与更好的临床结局相关.
方法：纳入2016年3月至2018年1月Checkmate077（中国nivolumabI期试验）和CamrelizumabI期试验的RM-NPC患者。在68例患者中测试了基线EBVDNA滴度，并在60例患者中进行了EBV评估，这些患者具有至少3个基线后时间点的EBV数据和至少1个基线后时间点的放射学评估。我们将“EBV反应”定义为连续3个时间点的负荷低于基线的50%，和“EBV进展”作为超过基线150%的3个连续负荷时间点。在60名具有可用肿瘤样品的患者中进行全外显子组测序。
结果：我们发现基线EBVDNA载量与肿瘤大小呈正相关（spearmanp<0.001）。部分反应（PR）和疾病稳定（SD）患者的EBV负荷均明显低于疾病进展（PD）患者。EBV评估与影像学评估高度一致。与EBV进展患者相比，EBV反应患者的总生存期（OS）显着提高（log-rankp=0.004，HR=0.351[95％CI：0.171-0.720]，中位数22.5vs.11.9个月）。初始EBV反应和进展的中位时间为初始影像学反应和进展前25天和36天，分别。基线时EBV裂解基因组水平高的患者，包括BKRF2，BKRF3和BKRF4，具有更好的无进展生存期（PFS）和OS。
结论：总之，在接受抗PD-1单药治疗的RM-NPC患者中,血浆EBVDNA负荷的早期清除和高水平的裂解性EBV基因与更好的临床结局相关.
