https://scholars.lib.ntu.edu.tw/handle/123456789/494938
標題: | Modulation of Biomarker Expression by Osimertinib: Results of the Paired Tumor Biopsy Cohorts of the AURA Phase I Trial | 作者: | Thress K.S Jacobs V Angell H.K CHIH-HSIN YANG Sequist L.V Blackhall F Su W.-C Schuler M Wolf J Gold K.A Cantarini M Barrett J.C Jänne P.A. |
關鍵字: | Biomarker; EGFR; NSCLC; Osimertinib; T790M | 公開日期: | 2017 | 出版社: | Elsevier Inc | 卷: | 12 | 期: | 10 | 起(迄)頁: | 1588-1594 | 來源出版物: | Journal of Thoracic Oncology | 摘要: | Introduction Osimertinib is an oral, potent, irreversible EGFR tyrosine kinase inhibitor (TKI) selective for EGFR TKI and T790M resistance mutations. To enhance understanding of osimertinib's mechanism of action, we aimed to evaluate the modulation of key molecular biomarkers after osimertinib treatment in paired clinical samples from the phase I AURA trial. Methods Paired tumor biopsy samples were collected before the study and after 15 plus or minus 7 days of osimertinib treatment (80 or 160 mg daily). Clinical efficacy outcomes were assessed according to whether viable paired biopsy samples could be collected; safety was also assessed. Immunohistochemical analyses assessed key pathway and tumor/immune-relevant markers (phospho-EGFR, phospho-S6, phospho-AKT, programmed death ligand 1, and CD8), with samples scored by image analysis or a pathologist blinded to treatment allocation. Results Predose tumor biopsy samples were collected from 61 patients with EGFR T790M tumors; 29 patients had no viable postdose biopsy sample because of tumor regression or insufficient tumor sample. Evaluable predose and postdose tumor biopsy samples were collected from 24 patients. Objective response rate (ORR) and median progression-free survival (mPFS) were improved in patients from whom a postdose biopsy sample could not be collected (ORR 62% and mPFS 9.7 months [p = 0.027]) compared with those from whom paired samples were collected (ORR 29% and mPFS 6.6 months). Osimertinib modulated key EGFR signaling pathways and led to increased immune cell infiltration. Conclusions Collection of paired biopsy samples was challenging because of rapid tumor regression after osimertinib treatment, highlighting the difficulties of performing on-study biopsies in patients treated with highly active drugs. ? 2017 International Association for the Study of Lung Cancer |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85027704013&doi=10.1016%2fj.jtho.2017.07.011&partnerID=40&md5=6def4ee8d5f23c26dcb1f538d8a50ae6 https://scholars.lib.ntu.edu.tw/handle/123456789/494938 |
ISSN: | 1556-0864 | DOI: | 10.1016/j.jtho.2017.07.011 | SDG/關鍵字: | CD8 antigen; epidermal growth factor receptor; methionine; osimertinib; programmed death 1 ligand 1; protein kinase B; protein S6; threonine; tumor marker; antineoplastic agent; osimertinib; piperazine derivative; tumor marker; Article; cancer survival; cell infiltration; clinical effectiveness; clinical outcome; cohort analysis; drug efficacy; drug mechanism; drug safety; EGFR gene; EGFR signaling; enzyme phosphorylation; human; human cell; immunocompetent cell; immunohistochemistry; major clinical study; malignant neoplasm; multicenter study; open study; outcome assessment; phase 1 clinical trial; priority journal; progression free survival; protein expression; protein phosphorylation; side effect; signal transduction; survival rate; survival time; treatment duration; treatment response; tumor biopsy; tumor regression; biopsy; clinical trial; disease free survival; metabolism; procedures; Antineoplastic Agents; Biomarkers, Tumor; Biopsy; Cohort Studies; Disease-Free Survival; Humans; Piperazines |
顯示於: | 腫瘤醫學研究所 |
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