Proto Claudia, Lo Russo Giuseppe, Corrao Giulia, Ganzinelli Monica, Facchinetti Francesco, Minari Roberta, Tiseo Marcello, Garassino Marina Chiara
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan - Italy.
Thoracic Oncology Unit, Medical Oncology Unit, University Hospital of Parma, Parma - Italy.
Tumori. 2017 Jul 31;103(4):325-337. doi: 10.5301/tj.5000663. Epub 2017 Jul 1.
In non-small cell lung cancer (NSCLC), the identification of epidermal growth factor receptor (EGFR) mutations and the parallel development of EGFR tyrosine kinase inhibitors (TKIs) have radically changed the therapeutic management strategies. Currently, erlotinib, gefitinib, and afatinib are all approved as standard first-line treatment in EGFR-mutated NSCLC. However, despite the proven efficacy, some EGFR-mutated NSCLCs do not respond to EGFR TKIs, while some patients, after a favorable and prolonged response to EGFR TKIs, inevitably progress within about 10-14 months. Epidermal growth factor receptor-dependent mechanisms, activation of alternative pathways, or phenotypic transformation can cause the resistance to EGFR TKIs. The exon 20 p.Thr790Met point mutation (T790M) is responsible for about 60% of cases of resistance when progression occurs. A third-generation TKI, osimertinib, improved outcome in patients harboring T790M after first- and second-generation TKI treatment. However, resistance develops even after treatment with third-generation drugs. To date, the Cys797Ser (C797S) mutation in exon 20 of EGFR is the most well-known resistance mutation after osimertinib. Fourth-generation TKIs are already under development. Nevertheless, additional information is needed to better understand and effectively overcome resistance. The aim of this review is to report recent advances and future perspectives in the treatment of EGFR-mutated NSCLC, highlighting the resistance mechanisms that underlie disease progression.
在非小细胞肺癌（NSCLC）中，表皮生长因子受体（EGFR）突变的鉴定以及EGFR酪氨酸激酶抑制剂（TKIs）的同步研发从根本上改变了治疗管理策略。目前，厄洛替尼、吉非替尼和阿法替尼均被批准作为EGFR突变型NSCLC的标准一线治疗药物。然而，尽管已证实其疗效，但一些EGFR突变的NSCLC对EGFR TKIs无反应，而一些患者在对EGFR TKIs产生良好且持久的反应后，仍不可避免地在约10 - 14个月内出现病情进展。依赖EGFR的机制、替代途径的激活或表型转化可导致对EGFR TKIs产生耐药性。外显子20的p.Thr790Met点突变（T790M）在病情进展时约占60%的耐药病例。第三代TKI奥希替尼改善了第一代和第二代TKI治疗后携带T790M患者的预后。然而，即使在使用第三代药物治疗后仍会产生耐药性。迄今为止，EGFR外显子20中的Cys797Ser（C797S）突变是奥希替尼治疗后最广为人知的耐药突变。第四代TKIs已在研发中。尽管如此，仍需要更多信息以更好地理解并有效克服耐药性。本综述的目的是报告EGFR突变型NSCLC治疗的最新进展和未来前景，强调疾病进展背后的耐药机制。
