A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer
A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer
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DOI：
10.1093/annonc/mdu550
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发表时间：
2015-02-01
影响因子：
50.5
通讯作者：
Schiller, J. H.
中科院分区：
文献类型：
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作者：
Chiappori, A. A.;Kolevska, T.;Schiller, J. H.
背景：晚期非小细胞肺癌（NSCLC）患者通常采用持续或“转换”维持治疗。在这里，我们评估了端粒酶抑制剂，imetelstat，开关维持治疗晚期NSCLC患者的疗效。患者和方法：这个开放标签，随机II期研究的主要终点是无进展生存期（PFS）。接受铂类药物双联（一线）化疗（联合或不联合贝伐珠单抗）、任何组织学、东部肿瘤协作组体能状态评分为0 - 1的非进展性晚期NSCLC患者符合入选条件。随机化比例为2：1，支持伊美司他，在21天周期的第1天和第8天以9.4 mg/kg给药或观察。采用定量PCR（qPCR）和端粒酶荧光原位杂交技术对肿瘤组织进行端粒长度（TL）生物标志物探索性分析。伊美司他组3/4级中性粒细胞减少症和血小板减少症更常见。伊美司他治疗组与对照组的中位PFS分别为2.8和2.6个月[风险比（HR）= 0.844; 95% CI 0.54 - 1.31; P = 0.446]。中位生存时间支持imetelstat（14.3 vs 11.5个月），但不显著（HR = 0.68; 95% CI 0.41 - 1.12; P = 0.129）。探索性分析显示了中位PFS延长的趋势（HR = 0.43; 95% CI 0.14 - 1.3; P = 0.124）和总生存期（OS; HR = 0.41; 95% CI 0.11 - 1.46; P = 0.155），但中位PFS和OS在长TL患者中无改善（HR = 0.86; 95%CI 0.39 - 1.88;和HR = 0.51; 95%CI 0.2 - 1.28; P = 0.145）结论：维持伊美司他未能改善对一线治疗有反应的晚期NSCLC患者的PFS。在短TL患者中，中位PFS和OS有改善的趋势。短TL作为预测性生物标志物，需要进一步研究伊美司他的临床开发。
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.