Feldt Susan L, Bestvina Christine M
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Cancers (Basel). 2023 May 31;15(11):2998. doi: 10.3390/cancers15112998.
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 -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 oncogenic pathway have been implicated as common alterations after progression, with 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 -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.
针对激活突变使用靶向治疗为晚期非小细胞肺癌（NSCLC）患者开启了治疗模式的新时代。对于携带 - 突变癌症的患者，包括第三代酪氨酸激酶抑制剂（TKI）奥希替尼在内的表皮生长因子受体（EGFR）抑制剂可显著延长无进展生存期和总生存期，是目前的标准治疗方法。然而，EGFR抑制后进展仍不可避免地发生，进一步研究有助于阐明耐药机制。致癌途径异常被认为是进展后的常见改变，其中 扩增是最常见的机制之一。多种对MET具有抑制活性的药物，包括TKI、抗体和抗体 - 药物偶联物，已在晚期NSCLC中研发并进行研究。对于发现具有 - 驱动耐药机制的患者，联合使用MET和EGFR是一种有前景的治疗策略。联合TKI治疗和EGFR - MET双特异性抗体在早期临床试验中已显示出有前景的抗肿瘤活性。未来的研究，包括正在进行的EGFR - MET联合抑制的大规模试验，将有助于明确针对EGFR耐药背后的这一机制是否会对晚期EGFR突变NSCLC患者产生有意义的临床益处。
