Li Hong-Shuai, Yang Guang-Jian, Wang Yan
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Oncol. 2021 Apr 15;11:649843. doi: 10.3389/fonc.2021.649843. eCollection 2021.
The acquired C797X mutation has been identified as the most notable resistance to osimertinib, and novel secondary mutations of L718 and L792 residues have also been demonstrated to confer osimertinib resistance, making the choice of medication after osimertinib treatment a quandary. Dacomitinib has been reported to have potential impact on patients acquiring rare compound mutations after osimertinib resistance; however, little evidence is available to date. In five lung adenocarcinoma patients resistant to later-line osimertinib, recurrent mutations at L792 and/or L718 were identified using targeted next-generation sequencing of tissue or cell-free DNA from plasma or pleural effusion. Dacomitinib was initiated after osimertinib resistance; however, all patients progressed within 2 months. Molecular structural simulation revealed that L792H + T790M and L718Q mutations could interfere with the binding of dacomitinib to EGFR and potentially cause primary drug resistance. Our case series study, to our knowledge, is the first to report the clinical efficacy of dacomitinib in patients harboring rare complex mutations after later-line osimertinib resistance.
获得性C797X突变已被确定为对奥希替尼最显著的耐药性，并且L718和L792残基的新型继发性突变也已被证明可导致奥希替尼耐药，这使得奥希替尼治疗后的用药选择成为一个难题。据报道，达可替尼对奥希替尼耐药后获得罕见复合突变的患者有潜在影响；然而，迄今为止几乎没有证据。在5例对后线奥希替尼耐药的肺腺癌患者中，通过对来自血浆或胸腔积液的组织或游离DNA进行靶向二代测序，发现了L792和/或L718的复发性突变。在奥希替尼耐药后开始使用达可替尼；然而，所有患者均在2个月内病情进展。分子结构模拟显示，L792H + T790M和L718Q突变可能会干扰达可替尼与EGFR的结合，并可能导致原发性耐药。据我们所知，我们的病例系列研究是首个报道达可替尼在奥希替尼后线耐药且携带罕见复合突变患者中的临床疗效的研究。
