几名接受奥西替尼治疗的患者出现疾病进展。目的是阐明奥希替尼耐药的潜在机制。阐明者：一项多中心、前瞻性、观察性研究涉及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。通过循环肿瘤脱氧核糖核酸样本的超灵敏下一代测序检测到癌症相关基因的突变，在基线时和进展性疾病检测后收集。对这些配对的血浆样本进行了比较。在 2019 年 5 月至 2021 年 1 月入组的 188 名患者中，包括 178 名患者（119 名女性 [67%]），中位年龄为 74 岁。患者 n = 95 (53%) 患有表皮生长因子受体外显子 19 缺失突变。在 115 名病情进展的患者中，分析了 85 名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 突变检测到（n = 1）和表皮生长因子受体（EGFR）耐药突变，以及C797S（n = 1）。基线 TP53 突变、MET 或 EGFR 扩增的患者无进展生存期 (PFS) 和总生存期较短。 PIK3CA 突变患者的 PFS 往往较短。MET 扩增和 PIK3CA 突变机制是患者对奥希替尼产生耐药性的原因。基线时共存突变或扩增的患者的 PFS 和总生存期较短。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Several patients treated with osimertinib experience progressive disease. The aim was to clarify the mechanisms underlying resistance to osimertinib.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.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.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.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.