奥西默替尼
T790米
吉非替尼
肺癌
医学
临床终点
肿瘤科
内科学
养生
表皮生长因子受体
抗性突变
无进展生存期
临床研究阶段
临床试验
癌症研究
癌症
化疗
生物
埃罗替尼
遗传学
基因
逆转录酶
核糖核酸
作者
Lavinia Tan,Chris Brown,Antony Mersiades,Chee Khoon Lee,Thomas John,Steven Kao,Genni M Newnham,Kenneth J. O’Byrne,Sagun Parakh,Victoria Bray,Kevin Jasas,Sonia Yip,Stephen Q. Wong,Sarah Ftouni,Jerick Guinto,Sushma Chandrashekar,Stephen Clarke,Nick Pavlakis,Martin R. Stockler,Sarah-Jane Dawson,Benjamin Solomon
标识
DOI:10.1038/s41467-024-46008-1
摘要
Abstract In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor ( EGFR) T790M mutation ( n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5–55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR -T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.
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