背景:程序性细胞死亡配体-1(PD-L1)表达是晚期非小细胞肺癌(NSCLC)中抗程序性细胞死亡受体-1/PD-L1抗体功效的预测性生物标志物。尽管已经批准了几种用于评估PD-L1表达状态的方法,已观察到一些测定之间的测定间不一致。这些差异的临床意义尚不清楚。
方法:我们回顾性回顾了使用22C3和SP142测定评估PD-L1表达的未治疗NSCLC患者。其中,对PD-L1肿瘤比例评分(TPS)≥50%(22C3)的患者进行疗效分析,曾接受过一线pembrolizumab单药治疗的患者.此外,在TPS≥50%的可用肿瘤中进行转录组分析,以研究伴随分析间不一致的不同免疫谱。
结果:总计,611名患者符合条件。在198例TPS≥50%的患者中,91(46%)的肿瘤细胞评分≤1(SP142,即测定间差异)。在接受一线派姆单抗单药治疗的52例患者中,差异患者的治疗效果明显低于无差异患者(客观缓解率:18%vs.83%,p<0.001;中位无进展生存期[月]:3.2vs.8.3,p<0.001)。转录组分析显示,在具有测定间差异的肿瘤中,具有异常3'末端序列的CD274剪接变体明显多于没有测定差异的肿瘤。
结论:22C3和SP142测定之间肿瘤细胞PD-L1状态的测定间差异,反映了CD274剪接变体的不平衡,可能是高表达PD-L1的NSCLC中针对派姆单抗单药治疗的主要耐药性的生物标志物。
BACKGROUND: Programmed cell death ligand-1 (PD-L1) expression is a predictive biomarker for the efficacy of anti-programmed cell death receptor-1/PD-L1 antibodies in advanced non-small cell lung cancer (NSCLC). Although several assays have been approved for evaluating PD-L1 expression status, inter-assay discordance has been observed between some assays. The clinical significance of these discrepancies is still unclear.
METHODS: We retrospectively reviewed treatment-naïve NSCLC patients whose PD-L1 expression was evaluated using both 22C3 and SP142 assays. Among those, efficacy analysis was performed for patients with PD-L1 tumor proportion score (TPS) ≥ 50 % (22C3), who had received first-line pembrolizumab monotherapy. Additionally, transcriptome analysis was conducted in the available tumors with TPS ≥ 50 % to investigate the distinct immune profiles that accompany inter-assay discordance.
RESULTS: In total, 611 patients were eligible. Among 198 patients with TPS ≥ 50 %, 91 (46 %) had tumor cell score ≤ 1 (SP142, i.e., inter-assay discrepancy). In the 52 patients who received first-line pembrolizumab monotherapy, treatment efficacy was significantly lower in patients with the discrepancy than that in those without (objective response rate: 18 % vs. 83 %, p < 0.001; median progression-free survival [months]: 3.2 vs. 8.3, p < 0.001). Transcriptome analysis revealed significantly more CD274 splice variants with aberrant 3\'-terminal sequences in tumors with the inter-assay discrepancy than in those without.
CONCLUSIONS: The inter-assay discrepancy in the PD-L1 status of tumor cells between the 22C3 and SP142 assays, reflecting an imbalance in the CD274 splice variants, could be a biomarker for primary resistance against pembrolizumab monotherapy in high PD-L1-expressing NSCLCs.