Zeng Yue, Yu Danlei, Tian Wentao, Wu Fang
Department of Oncology, The Second Xiangya Hospital, Central South University.
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu.
Curr Opin Oncol. 2022 Jan 1;34(1):54-65. doi: 10.1097/CCO.0000000000000805.
This review aims to introduce the resistance mechanisms to osimertinib, discuss the therapeutic strategies, and make clinical updates in overcoming resistance to osimertinib.
Osimertinib has shown favorable efficacy on second-line and first-line treatments in EGFR-mutant advanced nonsmall cell lung cancer (NSCLC). However, the presence of primary and acquired resistance to osimertinib restricts its clinical benefits. The primary resistance mainly consists of BIM deletion polymorphism and EGFR exon 20 insertions. Meanwhile, the heterogeneous mechanisms of acquired resistance include EGFR-dependent (on-target) and EGFR-independent (off-target) mechanisms. EGFR C797S mutation, MET amplification, HER2 amplification, and small cell lung cancer transformation were identified as frequent resistance mechanisms. Recently, more novel mechanisms, including rare EGFR point mutations and oncogenic fusions, were reported. With the results of completed and on-going clinical trials, the emerging therapeutic strategies of postosimertinib progression are summarized.
The resistance mechanisms to osimertinib are heterogeneous and gradually perfected. The combination of osimertinib with bypass targeted therapy and other therapeutic approaches emerge as promising strategies.
本综述旨在介绍奥希替尼的耐药机制，讨论治疗策略，并更新克服奥希替尼耐药的临床进展。
奥希替尼在表皮生长因子受体（EGFR）突变的晚期非小细胞肺癌（NSCLC）二线及一线治疗中显示出良好疗效。然而，奥希替尼原发性和获得性耐药的存在限制了其临床获益。原发性耐药主要包括BIM缺失多态性和EGFR外显子20插入。同时，获得性耐药的异质性机制包括EGFR依赖性（靶向）和EGFR非依赖性（非靶向）机制。EGFR C797S突变、MET扩增、HER2扩增和小细胞肺癌转化被确定为常见耐药机制。最近，有报道称出现了更多新机制，包括罕见的EGFR点突变和致癌融合。根据已完成和正在进行的临床试验结果，总结了奥希替尼进展后的新兴治疗策略。
奥希替尼的耐药机制具有异质性且逐渐完善。奥希替尼与旁路靶向治疗及其他治疗方法联合使用是有前景的策略。
