晚期EGFR阳性NSCLC患者PD-L1表达特点及其与EGFR-TKIs治疗疗效关系的真实世界研究

A Real-world Study on the Expression Characteristics of PD-L1 in Patients with Advanced EGFR Positive NSCLC and Its Relationship with the Therapeutic Efficacy of EGFR-TKIs

背景与目的晚期表皮生长因子受体(epidermal growth factor receptor,EGFR)阳性非小细胞肺癌(nonsmall cell lung cancer,NSCLC)患者的一线治疗首选EGFR酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitors,EGFR-TKIs)。晚期驱动基因阴性,程序性死亡配体1(programmed cell death ligand 1,PD-L1)阳性或高表达的NSCLC患者一线治疗推荐免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)单药治疗或ICIs联合化疗。所以不同PD-L1表达水平的EGFR阳性晚期NSCLC患者的一线治疗策略值得进一步探究。既往众多研究提示PD-L1的表达明显受EGFR突变情况的影响,PD-L1表达很有可能与EGFR-TKIs耐药机制相关。本研究旨在分析晚期EGFR阳性NSCLC患者PD-L1表达特点及其与EGFR-TKIs疗效的关系。方法以159例EGFR阳性初治晚期NSCLC患者(其中包含141例EGFR敏感突变患者)为研究对象,分析159例患者相关临床病理特征与PD-L1表达的关系及141例EGFR敏感突变患者EGFR-TKIs治疗疗效的的相关影响因素。结果所纳入159例患者PD-L1表达按肿瘤细胞阳性比例分数(tumor proportion score,TPS)分类:阴性(TPS<1%)占47.2%,低表达(1%≤TPS<50%)占32.1%,高表达(TPS≥50%)占20.7%。癌细胞病理形态学分类实体为主型患者更容易出现PD-L1高表达(高表达占比52.9%,组间差异P<0.0001)。PD-L1阴性表达、低表达、高表达患者一线接受一代EGFR-TKIs治疗的中位无进展生存期分别为12.4个月、10.5个月和3.7个月,三者间差异有明显统计学意义(P<0.0001);EGFR-TKIs治疗期间,有肺部病灶放疗史相对于无肺部病灶放疗史有更长的无进展生存期获益(中位无进展生存期:17.0个月vs 9.3个月,P<0.0001)。结论晚期EGFR阳性NSCLC患者PD-L1的表达水平与癌细胞病理形态学分类显著相关。PD-L1高表达NSCLC患者接受EGFR-TKIs疗效明显较差。靶向治疗期间联合肺部病灶放疗可以显著延长无进展生存期。

Background and objective Epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)is the first choice for first-line treatment of advanced patients with EGFR positive non-small cell lung cancer(NSCLC).For advanced NSCLC patients with negative drive gene and positive programmed cell death ligand 1(PD-L1)or highly expressed NSCLC patients,the first-line treatment recommends immune checkpoint inhibitors(ICIs)monotherapy or ICIs combined chemotherapy.Therefore,the first-line treatment strategy for advanced NSCLC patients with EGFR positive at different PD-L1 expression levels is worth further exploring.Many previous studies have suggested that the expression of PD-L1 is obviously affected by EGFR mutation,and the expression of PD-L1 is likely to be related to the mechanism of EGFR-TKIs resistance.The purpose of this study was to analyze the expression characteristics of PD-L1 in patients with advanced EGFR positive NSCLC and its relationship with the efficacy of EGFR-TKIs.Methods 159 patients with newly diagnosed advanced NSCLC with EGFR positive(including 141 patients with EGFR sensitive mutations)were enrolled to analyze the relationship between clinicopathological characteristics and PD-L1 expression.The factors affecting the therapeutic effect of EGFR-TKIs in 141 patients with EGFR sensitive mutations were also explored.Results The PD-L1 expression of the included patients was classified according to the tumor promotion score(TPS):negative(TPS<1%)accounted for 47.2%,low expression(1%≤TPS<50%)accounted for 32.1%,and high expression(TPS≥50%)accounted for 20.7%.Among them,patients with solid predominant cancer cell pathomorphology classification are more likely to have high expression of PD-L1,accounting for 52.9%(P<0.0001).The median progression-free survival(mPFS)of patients with PD-L1 negative expression,low expression and high expression who received first generation EGFR-TKIs treatment were 12.4 months,10.5 months and 3.7 months,respectively,with significant statistical difference(P<0.0001).During the EGFR-TKIs treatment,patients with a history of radiotherapy for lung lesions have a longer PFS benefit than those without a history of radiotherapy(mPFS:17.0 months vs 9.3 months,P<0.0001).Conclusion The expression level of PD-L1 in advanced EGFR positive NSCLC patients was significantly correlated with the pathomorphology classification of cancer cells.The efficacy of EGFR-TKIs in patients with PD-L1 overexpression NSCLC was significantly poor.PFS can be significantly prolonged during targeted therapy combined with radiotherapy of lung lesions.