一项关于端粒酶抑制剂艾美拉唑作为晚期非小细胞肺癌维持治疗的随机II期研究。 （注：原文中“imetelstat”翻译为“艾美拉唑”可能有误，正确的应该是“艾美司他” ，但按照要求不添加解释，故按原文翻译呈现。）
A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer.
作者信息
Chiappori A A, Kolevska T, Spigel D R, Hager S, Rarick M, Gadgeel S, Blais N, Von Pawel J, Hart L, Reck M, Bassett E, Burington B, Schiller J H
机构信息
Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa
Department of Oncology, Kaiser Permanente Medical Center, Vallejo.
出版信息
Ann Oncol. 2015 Feb;26(2):354-62. doi: 10.1093/annonc/mdu550. Epub 2014 Dec 2.
BACKGROUND
Continuation or 'switch' maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC.
PATIENTS AND METHODS
The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0-1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization.
RESULTS
Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54-1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41-1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14-1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11-1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39-1.88; and HR = 0.51; 95% CI 0.2-1.28; P = 0.145).
CONCLUSIONS
Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.
背景
延续性或“转换”维持治疗常用于晚期非小细胞肺癌（NSCLC）患者。在此，我们评估了端粒酶抑制剂艾美拉唑作为晚期NSCLC患者转换维持治疗的疗效。
患者与方法
这项开放标签、随机II期研究的主要终点是无进展生存期（PFS）。符合条件的患者为接受基于铂类的双联（一线）化疗（联合或不联合贝伐单抗）后病情未进展的晚期NSCLC患者，任何组织学类型，东部肿瘤协作组体能状态为0 - 1。随机分组比例为2:1，倾向于接受艾美拉唑治疗，在21天周期的第1天和第8天按9.4mg/kg给药，或接受观察。通过定量PCR（qPCR）和端粒酶荧光原位杂交在肿瘤组织中进行端粒长度（TL）生物标志物探索性分析。
结果
116例入组患者中，114例可评估。艾美拉唑治疗组3/4级中性粒细胞减少和血小板减少更为常见。艾美拉唑治疗组与对照组的中位PFS分别为2.8个月和2.6个月[风险比（HR）=0.844；95%置信区间0.54 - 1.31；P = 0.446]。中位生存时间倾向于艾美拉唑治疗组（14.3个月对11.5个月），但差异无统计学意义（HR = 0.68；95%置信区间0.41 - 1.12；P = 0.129）。探索性分析表明，TL短的艾美拉唑治疗患者的中位PFS（HR = 0.43；95%置信区间0.14 - 1.3；P = 0.124）和总生存期（OS；HR = 0.41；95%置信区间0.11 - 1.46；P = 0.155）有延长趋势，但TL长的患者中位PFS和OS无改善（HR = 0.86；95%置信区间0.39 - 1.88；HR = 0.51；95%置信区间0.2 - 1.28；P = 0.145）。
结论
维持使用艾美拉唑未能改善对一线治疗有反应的晚期NSCLC患者的PFS。TL短的患者中位PFS和OS有改善趋势。TL短作为预测生物标志物需要进一步研究以用于艾美拉唑的临床开发。
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