Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
Burning Rock Biotech, Guangzhou, People's Republic of China.
J Thorac Oncol. 2017 Nov;12(11):1723-1727. doi: 10.1016/j.jtho.2017.06.017. Epub 2017 Jun 27.
The efficacy of osimertinib was compromised by the development of resistance mechanisms, such as EGFR C797S. In vitro study proved that cells harboring EGFR C797S in trans with T790M are sensitive to a combination of first- and third-generation EGFR tyrosine kinase inhibitors. However, this has not been reported clinically.
We performed capture-based sequencing on longitudinal plasma samples obtained at various treatment milestones from a patient with advanced lung adenocarcinoma who was undergoing targeted therapy.
At the development of resistance to osimertinib, the patient's plasma sample revealed EGFR C797S located in trans with T790M. He achieved partial response accompanied by undetectable C797S after commencement of a combinatorial treatment consisting of erlotinib and osimertinib. After 3 months of progression-free survival, he experienced progressive disease with emergence of EGFR C797S located in cis to T790M.
We report the first clinical evidence of efficacy generated by combination therapy consisting of first- and third-generation EGFR tyrosine kinase inhibitors targeting concomitant EGFR T790M and C797S in trans. We also reveal that the clonal progression of C797S from in trans to in cis at disease progression may serve as a potential resistance mechanism.
奥希替尼的疗效受到耐药机制的影响，如 EGFR C797S。体外研究证明，同时携带 EGFR T790M 和 EGFR C797S 的细胞对第一代和第三代 EGFR 酪氨酸激酶抑制剂的联合治疗敏感。然而，这尚未在临床上得到报道。
我们对一名接受靶向治疗的晚期肺腺癌患者在不同治疗里程碑获得的纵向血浆样本进行了基于捕获的测序。
在对奥希替尼产生耐药性时，患者的血浆样本显示 EGFR C797S 与 T790M 处于反式位置。他在开始联合使用厄洛替尼和奥希替尼的治疗后，出现部分缓解，同时 C797S 无法检测到。在无进展生存期 3 个月后，他出现疾病进展，出现 EGFR C797S 与 T790M 处于顺式位置。
我们报告了首例临床证据，证明联合使用第一代和第三代 EGFR 酪氨酸激酶抑制剂针对同时存在的 EGFR T790M 和 C797S 反式突变可产生疗效。我们还揭示了疾病进展时 C797S 从反式到顺式的克隆进展可能是一种潜在的耐药机制。
