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Abstract：
Utilizing targeted therapy against activating mutations has opened a new era of treatment paradigms for patients with advanced non-small cell lung cancer (NSCLC). For patients with epidermal growth factor (EGFR)-mutated cancers, EGFR inhibitors, including the third-generation tyrosine kinase inhibitor (TKI) osimertinib, significantly prolong progression-free survival and overall survival, and are the current standard of care. However, progression after EGFR inhibition invariably occurs, and further study has helped elucidate mechanisms of resistance. Abnormalities in the mesenchymal-epithelial transition (MET) oncogenic pathway have been implicated as common alterations after progression, with MET amplification as one of the most frequent mechanisms. Multiple drugs with inhibitory activity against MET, including TKIs, antibodies, and antibody-drug conjugates, have been developed and studied in advanced NSCLC. Combining MET and EGFR is a promising treatment strategy for patients found to have a MET-driven resistance mechanism. Combination TKI therapy and EGFR-MET bispecific antibodies have shown promising anti-tumor activity in early clinical trials. Future study including ongoing large-scale trials of combination EGFR-MET inhibition will help clarify if targeting this mechanism behind EGFR resistance will have meaningful clinical benefit for patients with advanced EGFR-mutated NSCLC.
摘要：
利用针对激活突变的靶向治疗为晚期非小细胞肺癌（NSCLC）患者开辟了治疗范式的新时代。对于表皮生长因子（EGFR）突变的癌症患者，EGFR抑制剂，包括第三代酪氨酸激酶抑制剂（TKI）奥希替尼，显著延长无进展生存期和总生存期，是目前的护理标准。然而,EGFR抑制后总是发生进展，进一步的研究有助于阐明抗性机制。间质上皮转化（MET）致癌途径的异常被认为是进展后的常见改变，MET扩增是最常见的机制之一。对MET具有抑制活性的多种药物，包括TKIs,抗体，和抗体-药物缀合物，已在晚期NSCLC中进行了开发和研究。对于发现具有MET驱动的耐药机制的患者，将MET和EGFR结合是一种有希望的治疗策略。TKI联合治疗和EGFR-MET双特异性抗体在早期临床试验中显示出有希望的抗肿瘤活性。未来的研究，包括正在进行的大规模EGFR-MET联合抑制试验，将有助于澄清针对EGFR耐药背后的这种机制是否对晚期EGFR突变的NSCLC患者具有有意义的临床益处。
