针对癌基因突变的靶向治疗的出现已经导致了非小细胞肺癌 (NSCLC) 管理中的一个重大范式转变。分子靶点，如表皮生长因子受体 (EGFR) 在18至21号外显子区域的活化突变，是NSCLC中最常见的致癌驱动基因。典型的活化突变，如19号外显子的框内缺失和21号外显子的点突变 (L858R)，对已批准的EGFR酪氨酸激酶抑制剂 (EGFR-TKI) 的良好临床反应具有很强的预测能力。然而，在20号外显子发生的低频突变 (ex20ins) 对一/二代EGFR-TKI的反应较差。此外，携带EGFR ex20ins的NSCLC患者的预后差于携带其他EGFR-TKI敏感突变的患者，从而导致对新型特异性治疗选择的未满足临床需求。快速变化的分子诊断技术对特定病因的识别加快了诊断建议在临床实践中的应用。针对EGFR ex20ins的治疗策略的出现，例如具有增加特异性的新型EGFR-TKI和使用双特异性单克隆抗体的新方法，可能在不久的将来提供有希望的治疗选择。在本综述中，我们将描述EGFR ex20ins突变的结构、分子特性和检测策略，并总结针对携带EGFR ex20ins突变的NSCLC患者的已批准治疗和新兴治疗的最新临床数据。此外，我们还将讨论ex20ins突变对新药物的反应异质性以及获得性药物抵抗机制。版权所有© 2023年，由Elsevier Ltd出版。

The advent of targeted therapies for oncogenic mutations has led to a major paradigm shift in the management of non-small cell lung cancer (NSCLC). Molecular targets, such as epidermal growth factor receptor (EGFR)-activating mutations in the region of exons 18 through 21 are the most common oncogenic driver in NSCLC. Classical activating mutations, such as in-frame deletions in exon 19 and point mutations in exon 21 (L858R), are strong predictors for good clinical response to the approved EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, low frequency mutations occurring within exon 20 (ex20ins) have poorer responses to first/second generation EGFR-TKIs. Moreover, patients with NSCLC harboring EGFR ex20ins are known to have poorer prognosis than those with other EGFR-TKI sensitive mutations, leading to unmet clinical need of novel specific therapeutic options. Rapid changes in molecular diagnostics identifying specific causes have hastened the translation of diagnostic recommendations into clinical practice. Emergence of treatment strategies targeting EGFR ex20ins, such as newer EGFR-TKIs with increased specificity and novel approaches using bispecific monoclonal antibodies, may hold promising therapeutic options in the near future. In this review, we describe the structural, molecular characteristics, and detection strategies of EGFR ex20ins mutations and summarize the latest clinical data on approved treatments and emerging therapies for patients with NSCLC harboring EGFR ex20ins mutations. Further, we will discuss the response heterogeneity of ex20ins mutations to new drugs and acquired drug resistance mechanisms.Copyright © 2023. Published by Elsevier Ltd.