Randomized phase II trial of erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy.
Randomized phase II trial of erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy.
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在先前的化学疗法中进展的晚期非小细胞肺癌患者中，erlotinib的随机II期试验，有或没有恩替纳替替纳替替纳替尼。
DOI：
10.1200/jco.2011.38.9411
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发表时间：
2012-06-20
期刊：
影响因子：
--
通讯作者：
Hirsch FR
中科院分区：
文献类型：
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作者：
Witta SE;Jotte RM;Konduri K;Neubauer MA;Spira AI;Ruxer RL;Varella-Garcia M;Bunn PA Jr;Hirsch FR
组蛋白去乙酰化酶抑制剂（HDACis）已被证明可以克服对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的耐药性，这些抑制剂与表观遗传变化和上皮-间充质转化（EMT）状态有关。这项随机II期研究评估了厄洛替尼在联合和不联合亚型选择性HDACi恩替诺特的情况下的结果。既往接受过治疗的IIIB/IV期非小细胞肺癌、既往无EGFR-TKI且体能状态≤ 2的患者随机接受厄洛替尼150 mg（第1天至第28天）联合恩替司他10 mg（第1天和第15天）口服给药，每28天一次（EE）或厄洛替尼+安慰剂（EP）。主要终点是4个月无进展生存期（PFS）率，其他终点包括6个月PFS率、PFS和总生存期（OS）。探索性分析包括存档组织的EMT和EGFR相关生物标志物分析。入组了132例患者（EE，67例; EP，65例）。两组的4个月PFS率相当（EE，18% vs EP，20%; P = .7）。在E-钙粘蛋白水平高的患者亚组中，EE组的OS长于EP组（9.4 vs 5.4个月;风险比，0.35; 95% CI，0.13 - 0.92; P = 0.03），相应的PFS趋势增加。不良事件（AE）特征可接受，皮疹、疲乏、腹泻和恶心是两组中最常见的AE。与厄洛替尼单药治疗相比，厄洛替尼联合恩替司他未改善总体研究人群中患者的结局。诊断时的高E-钙粘蛋白表达水平表明对HDACi/EGFR-TKI抑制的敏感性增加，为生物标志物驱动的验证研究提供了基础。
Histone deacetylase inhibitors (HDACis) have been shown to overcome resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) linked to epigenetic changes and epithelial-mesenchymal transition (EMT) state. This randomized phase II study evaluated the outcome of erlotinib with and without the isoform selective HDACi, entinostat. Previously treated patients with stage IIIB/IV non–small-cell lung cancer, no prior EGFR-TKIs, and performance status ≤ 2 were randomly administered erlotinib 150 mg on days 1 through 28 plus entinostat 10 mg orally on days 1 and 15 every 28 days (EE) or erlotinib plus placebo (EP). The primary end point was 4-month progression-free survival (PFS) rate with additional end points including 6-month PFS rate, PFS, and overall survival (OS). Exploratory analyses included EMT- and EGFR-related biomarker analysis on archival tissue. One hundred thirty-two patients were enrolled (EE, 67; EP, 65). The 4-month PFS rate was comparable for both groups (EE, 18% v EP, 20%; P = .7). In the subset of patients with high E-cadherin levels, OS was longer in the EE group compared with the EP group (9.4 v 5.4 months; hazard ratio, 0.35; 95% CI, 0.13 to 0.92; P = .03) with a corresponding trend toward increased PFS. The adverse event (AE) profile was acceptable, with rash, fatigue, diarrhea, and nausea the most common AEs in both groups. Erlotinib combined with entinostat did not improve the outcomes of patients in the overall study population when compared with erlotinib monotherapy. High E-cadherin expression levels at time of diagnosis indicate an increased sensitivity to HDACi/EGFR-TKI inhibition providing the basis for a biomarker-driven validation study.