Yang Ching-Yao, Liao Wei-Yu, Ho Chao-Chi, Chen Kuan-Yu, Tsai Tzu-Hsiu, Hsu Chia-Lin, Su Kang-Yi, Chang Yih-Leong, Wu Chen-Tu, Hsu Chia-Chi, Liu Yi-Nan, Peng Guan-Ru, Kangartaputra Almanzo Aeterna, Yu Shu-Han, Liao Bin-Chi, Hsu Wei-Hsun, Lee Jih-Hsiang, Lin Chia-Chi, Shih Jin-Yuan, Chih-Hsin Yang James, Yu Chong-Jen
Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan.
J Formos Med Assoc. 2024 Dec 17. doi: 10.1016/j.jfma.2024.12.020.
PD-L1 is associated with poor efficacy of first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in untreated EGFR-mutant non-small-cell lung cancer (NSCLC). Whether PD-L1 is also predictive of osimertinib efficacy in pre-treated patients with an acquired EGFR T790 M mutation is unclear.
PD-L1 expression and tumor microenvironments were evaluated in tumors from EGFR-mutant T790 M + NSCLC patients treated with osimertinib. In vitro and in vivo experiments were also performed to examine the effect of PD-L1 overexpression on osimertinib susceptibility in EGFR T790 M + cells.
A total of 134 pre-treated EGFR T790 M + patients were enrolled, of whom 72 had del19, 58 had L858R, and 4 had G719X as initial EGFR mutation subtype. Positive PD-L1 expression (TC ≥ 1%) was found in 21 of 134 (15.7%) patients. PD-L1 expression did not differ across different biopsied sites and among different EGFR mutation subgroups. Kaplan-Meier estimate revealed no significant difference in progression-free survival (PFS) in PD-L1-positive versus PD-L1-negative patients. Multivariate analysis using the Cox proportional hazard model found that older age and L858R mutation were independent predictive factors. Multiplex IHC showed that immune cell infiltration was not associated with PD-L1 expression or osimertinib treatment response. By overexpressing PD-L1 in EGFR T790 M + cells, we found that PD-L1 did not result in osimertinib resistance in in vitro and xenograft models.
PD-L1 expression in pre-treated EGFR T790 M + lung adenocarcinoma is not predictive of osimertinib efficacy, as demonstrated by in vitro, xenograft, and clinical case studies.
在未经治疗的表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）中，程序性死亡受体配体1（PD-L1）与第一代或第二代EGFR酪氨酸激酶抑制剂（TKIs）疗效不佳相关。目前尚不清楚PD-L1是否也能预测奥希替尼对既往接受过治疗且获得性EGFR T790M突变患者的疗效。
对接受奥希替尼治疗的EGFR突变T790M+NSCLC患者的肿瘤组织进行PD-L1表达及肿瘤微环境评估。同时进行体外和体内实验，以检测PD-L1过表达对EGFR T790M+细胞奥希替尼敏感性的影响。
共纳入134例既往接受过治疗的EGFR T790M+患者，其中72例初始EGFR突变亚型为del19，58例为L858R，4例为G719X。134例患者中有21例（15.7%）PD-L1表达阳性（肿瘤细胞比例[TC]≥1%）。不同活检部位及不同EGFR突变亚组间的PD-L1表达无差异。Kaplan-Meier估计显示，PD-L1阳性与阴性患者的无进展生存期（PFS）无显著差异。使用Cox比例风险模型进行多因素分析发现，年龄较大和L858R突变是独立的预测因素。多重免疫组化显示，免疫细胞浸润与PD-L1表达或奥希替尼治疗反应无关。通过在EGFR T790M+细胞中过表达PD-L1，我们发现在体外和异种移植模型中，PD-L1并未导致奥希替尼耐药。
体外、异种移植及临床病例研究表明，既往接受过治疗的EGFR T790M+肺腺癌中PD-L1表达不能预测奥希替尼疗效。
