背景:一些接受奥希替尼治疗的患者出现进行性疾病。目的是阐明奥希替尼耐药的潜在机制。
方法:ELUCIDATOR:多中心,prospective,观察性研究包括接受奥希替尼治疗的未接受化疗的晚期非小细胞肺癌患者.癌症相关基因的突变,通过循环肿瘤脱氧核糖核酸样品的超灵敏下一代测序检测,在基线和进行性疾病检测后收集。比较这些配对的血浆样品。
结果:纳入188例患者(2019年5月至2021年1月),178(119名女性[67%])中位年龄74岁,包括在内。患者,n=95(53%)存在表皮生长因子受体外显子19缺失突变。在115名进行性疾病患者中,分析了85例患者的循环肿瘤脱氧核糖核酸水平。MET扩增(n=4),TP53突变(n=4),PIK3CA突变(n=3),BRINP3突变(n=2),BRAF突变(n=2),APC突变(n=1),RET突变(n=1)和表皮生长因子受体(EGFR)耐药突变,检测到C797S(n=1)。基线TP53突变的患者,MET或EGFR扩增的无进展生存期(PFS)和总生存期较短.PIK3CA突变患者PFS较短。
结论:MET扩增和PIK3CA突变机制在患者中对奥希替尼耐药不足。基线时共存突变或扩增的患者PFS和总生存期较短。
BACKGROUND: Several patients treated with osimertinib experience progressive disease. The aim was to clarify the mechanisms underlying resistance to osimertinib.
METHODS: ELUCIDATOR: A multi-centre, prospective, observational study involved chemotherapy-naive patients with advanced non-small cell lung cancer receiving osimertinib. Mutations in cancer-associated genes, detected via ultrasensitive next-generation sequencing of circulating tumour deoxyribonucleic acid samples, were collected at baseline and after progressive disease detection. These paired plasma samples were compared.
RESULTS: Of 188 patients enrolled (May 2019-January 2021), 178 (119 females [67 %]) median age 74 years, were included. Patients, n = 95 (53 %) had epidermal growth factor receptor exon 19 deletion mutations. Among 115 patients with progressive disease, circulating tumour deoxyribonucleic acid levels of 85 patients were analysed. MET amplification (n = 4), TP53 mutations (n = 4), PIK3CA mutations (n = 3), BRINP3 mutation (n = 2), BRAF mutation (n = 2), APC mutation (n = 1), RET mutation (n = 1) and epidermal growth factor receptor (EGFR) resistance mutation, and C797S (n = 1) were detected. Patients with baseline TP53 mutations, with MET or EGFR amplification had shorter progression-free (PFS) and overall survival. Patients with PIK3CA mutations tended to shorter PFS.
CONCLUSIONS: MET amplification and PIK3CA mutation mechanisms underly resistance to osimertinib in patients. Patients with coexisting mutations or amplifications at baseline had shorter PFS and overall survival.