BACKGROUND EGFR tyrosine kinase inhibitors (TKIs) have shifted the treatment paradigm in advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, patients who are treated with TKIs inevitably develop acquired resistance by mechanisms that are not fully understood. The purpose of this study was to investigate the mechanism of acquired resistance after treatment with third-generation EGFR TKIs. METHODS Advanced EGFR-mutant NSCLC patients treated with olmutinib or osimertinib who underwent a rebiopsy before treatment or after progression were analyzed retrospectively. Targeted sequencing was performed on 113 specimens (77 pretreatment and 36 posttreatment, including 15 paired samples) obtained via tissue biopsy. RESULTS A total of 98 patients were included, 53 (54%) of whom were treated with osimertinib and 45 (46%) of whom were treated with olmutinib. Of the 36 patients with posttreatment biopsies, EGFR-dependent mechanisms, including C797S and L718Q mutations, were observed in 10 (28%) patients: 29% (5/17) in the osimertinib group and 26% (5/19) in the olmutinib group. EGFR-independent mechanisms were detected in 21 patients (21/36, 58%): 65% (11/17) in the osimertinib group and 53% (10/19) in the olmutinib group. The disappearance of EGFR T790M was detected in 14 patients (39%); of these patients, 59% (10/17) were treated with osimertinib and 21% (4/19) were treated with olmutinib. Patients who lost the T790M mutation were more inclined to show EGFR-independent pathways as a secondary resistance mechanism. CONCLUSION Resistance acquired after third-generation EGFR TKIs is associated with diverse pathways; however, treatment with osimertinib is primarily associated with a loss of EGFR T790M and the subsequent emergence of EGFR-independent resistance mechanisms.

中文翻译：

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EGFR T790M突变型非小细胞肺癌中对第三代EGFR酪氨酸激酶抑制剂获得性耐药的基因组格局。

背景技术EGFR酪氨酸激酶抑制剂（TKIs）改变了晚期EGFR突变非小细胞肺癌（NSCLC）的治疗模式。但是，接受TKI治疗的患者不可避免地会通过尚未完全了解的机制产生获得性耐药。这项研究的目的是研究用第三代EGFR TKI治疗后获得性耐药的机制。方法回顾性分析接受olmutinib或osimertinib治疗的晚期EGFR突变NSCLC患者，这些患者在治疗前或进展后进行了活检。通过组织活检对113个标本（77个预处理和36个后处理，包括15个配对的样品）进行了靶向测序。结果共纳入98例患者，其中53例（54％）用奥西替尼治疗，其中45例（46％）用olmutinib治疗。在36名接受治疗后活检的患者中，在10名（28％）患者中观察到了EGFR依赖性机制，包括C797S和L718Q突变：在奥西替尼组中为29％（5/17），在奥西替尼组中为26％（5/19）。 olmutinib组。在21例患者中（21/36，58％）检测到了EGFR依赖性机制：osimertinib组为65％（11/17），olmutinib组为53％（10/19）。在14例患者中检测到EGFR T790M消失（39％）；这些患者中，有59％（10/17）用奥西替尼治疗，而21％（4/19）用olmutinib治疗。失去T790M突变的患者更倾向于显示EGFR非依赖性途径作为第二耐药机制。结论第三代EGFR TKIs后获得的耐药性与多种途径相关。但是，用奥西替尼治疗主要与EGFR T790M缺失以及随后出现的EGFR独立耐药机制有关。