Zhou Qing, Yang Jin-Ji, Chen Zhi-Hong, Zhang Xu-Chao, Yan Hong-Hong, Xu Chong-Rui, Su Jian, Chen Hua-Jun, Tu Hai-Yan, Zhong Wen-Zhao, Yang Xue-Ning, Wu Yi-Long
Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, 106 Zhongshan Er Road, Guangzhou, 510080, China.
J Hematol Oncol. 2016 Sep 13;9(1):86. doi: 10.1186/s13045-016-0316-8.
Detecting epidermal growth factor receptor (EGFR) activating mutations in plasma could guide EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment for advanced non-small cell lung cancer (NSCLC). However, dynamic quantitative changes of plasma EGFR mutations during the whole course of EGFR-TKI treatment and its correlation with clinical outcomes were not determined. The aim of this study was to measure changes of plasma EGFR L858R mutation during EGFR-TKI treatment and to determine its correlation with the response and resistance to EGFR-TKI.
This study was a pre-planned exploratory analysis of a randomized phase III trial conducted from 2009 to 2014 comparing erlotinib with gefitinib in advanced NSCLC harboring EGFR mutations in tumor (CTONG0901). Totally, 256 patients were enrolled in CTONG0901 and randomized to receive erlotinib or gefitinib. One hundred and eight patients harbored L858R mutation in their tumors and 80 patients provided serial blood samples as pre-planned scheduled. Serial plasma L858R was detected using quantitative polymerase chain reaction. Dynamic types of plasma L858R were analyzed using Ward's hierarchical clustering method. Progression-free survival (PFS) and overall survival (OS) were compared between different types.
As a whole, the quantity of L858R decreased and reached the lowest level at the time of best response to EGFR-TKI. After the analysis of Ward's hierarchical clustering method, two dynamic types were found. In 61 patients, L858R increased to its highest level when disease progressed (ascend type), while in 19 patients, L858R maintained a stable level when disease progressed (stable type). Median PFS was 11.1 months (95 % CI, 6.6-15.6) and 7.5 months (95 % CI, 1.4-13.6) in patients with ascend and stable types, respectively (P = 0.023). Median OS was 19.7 months (95 % CI, 16.5-22.9) and 16.0 months (95 % CI, 13.4-18.5), respectively (P = 0.050).
This is the first report finding two different dynamic types of plasma L858R mutation during EGFR-TKI treatment based on a prospective randomized study. Different dynamic types were correlated with benefits from EGFR-TKI. The impact of plasma L858R levels at disease progression on subsequent treatment strategy needs further exploration.
ClinicalTrials.gov, NCT01024413.
检测血浆中表皮生长因子受体（EGFR）激活突变可指导晚期非小细胞肺癌（NSCLC）的EGFR酪氨酸激酶抑制剂（EGFR-TKI）治疗。然而，EGFR-TKI治疗全程中血浆EGFR突变的动态定量变化及其与临床结局的相关性尚未明确。本研究旨在测量EGFR-TKI治疗期间血浆EGFR L858R突变的变化，并确定其与EGFR-TKI反应和耐药性的相关性。
本研究是对2009年至2014年进行的一项随机III期试验的预先计划的探索性分析，该试验比较了厄洛替尼与吉非替尼在肿瘤中携带EGFR突变的晚期NSCLC患者中的疗效（CTONG0901）。共有256例患者纳入CTONG0901并随机接受厄洛替尼或吉非替尼治疗。108例患者肿瘤中存在L858R突变，80例患者按预先计划提供了系列血样。使用定量聚合酶链反应检测系列血浆L858R。使用沃德分层聚类方法分析血浆L858R的动态类型。比较不同类型之间的无进展生存期（PFS）和总生存期（OS）。
总体而言，L858R的数量减少，并在对EGFR-TKI的最佳反应时达到最低水平。经过沃德分层聚类方法分析，发现了两种动态类型。在61例患者中，疾病进展时L858R增加到最高水平（上升型），而在19例患者中，疾病进展时L858R保持稳定水平（稳定型）。上升型和稳定型患者的中位PFS分别为11.1个月（95%CI，6.6-15.6）和7.5个月（95%CI，1.4-13.6）（P = 0.023）。中位OS分别为19.7个月（95%CI，16.5-22.9）和16.0个月（95%CI，13.4-18.5）（P = 0.050）。
这是第一份基于前瞻性随机研究发现EGFR-TKI治疗期间血浆L858R突变存在两种不同动态类型的报告。不同的动态类型与EGFR-TKI的获益相关。疾病进展时血浆L858R水平对后续治疗策略的影响需要进一步探索。
ClinicalTrials.gov，NCT01024413。
