First- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, erlotinib, afatinib, and dacomitinib, are effective as first-line treatment for advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations (e.g. deletions in exon 19 and the exon 21 L858R mutation).^1–7 EGFR T790M mutation emerges following EGFR-TKI therapy, and accounts for 55% of mechanisms of acquired resistance to first- and second-generation EGFR-TKIs.^8–11 Osimertinib monotherapy is the currently recommended second-line treatment for EGFR T790M mutation-positive (T790M-pos) NSCLC.^12–14 Other secondary resistance mutations in EGFR, such as D761Y, T854A, and L747S, are rare, and the irreversible EGFR-TKIs, afatinib and osimertinib, have been shown to inhibit EGFR phosphorylation in cells harboring these secondary mutations.^15–18 For patients with EGFR T790M mutation-negative (T790M-neg) NSCLC, platinum-based chemotherapy is the currently recommended second-line treatment.^19–21 In addition to the T790M resistance mutation, the molecular alternations identified as resistance mechanisms include bypass pathway activation [e.g. MET amplification [MET-amp] and HER2 amplification (HER2-amp)] and downstream signaling pathways (e.g. PI3K and BRAF mutations). Histological transformations [e.g. small cell and epithelial–mesenchymal transition (EMT)] are also mechanisms of resistance. T790M-neg NSCLC comprises these mechanisms plus other unknown mechanisms and is seen in a heterogeneous group of patients. In the era of molecular targeted therapy, immunotherapy, next-generation sequencing (NGS), and liquid biopsy, exploratory strategies are under development to identify patients suitable for molecular targeted therapy to overcome resistance mechanisms.

中文翻译：

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EGFR T790M阴性非小细胞肺癌患者的二线治疗

第一代和第二代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs），包括吉非替尼，厄洛替尼，阿法替尼和达可替尼，对于作为具有活化EGFR的晚期非小细胞肺癌（NSCLC）的一线治疗是有效的突变（例如外显子19的缺失和外显子21 L858R突变）。EGFR-TKI治疗后出现^1–7个 EGFR T790M突变，占第一代和第二代EGFR-TKIs获得性耐药机制的55％。^8-11奥西替尼单一疗法是目前推荐的EGFR T790M突变阳性（T790M-pos）NSCLC的二线治疗。^12-14 EGFR中的其他继发性耐药突变，例如D761Y，T854A和L747S，是罕见的，不可逆的EGFR-TKIs，阿法替尼和奥西替尼已经显示出在具有这些次级突变的细胞中抑制EGFR磷酸化。^15–18对于EGFR T790M突变阴性（T790M-neg）NSCLC患者，目前推荐的铂类化疗是二线治疗。^19–21除了T790M抗性突变外，被鉴定为抗性机制的分子替代还包括旁路途径激活（例如MET扩增[ MET -amp]和HER2扩增（HER2- amp））和下游信号传导途径（例如PI3K和BRAF突变）。组织学转化（例如小细胞和上皮-间质转化（EMT））也是抗药性的机制。T790M-neg NSCLC包括这些机制以及其他未知机制，在异类患者中可见。在分子靶向治疗，免疫治疗，下一代测序（NGS）和液体活检时代，正在开发探索性策略，以鉴定适合分子靶向治疗以克服耐药机制的患者。