Sarah Cannon Research Institute, Nashville, TN 37203, USA.
J Thorac Oncol. 2010 Oct;5(10):1630-6. doi: 10.1097/JTO.0b013e3181e8b3a3.
AZD6244 (ARRY-142886) is a potent, selective MEK inhibitor. This study aimed to evaluate the efficacy and safety of AZD6244 versus pemetrexed as second- or third-line treatment in patients with advanced non-small cell lung cancer (NSCLC).
In this randomized phase II study, patients received either 100 mg oral AZD6244 free-base suspension twice daily or 500 mg/m(2) intravenous pemetrexed once every 3 weeks after pretreatment with a corticosteroid, folic acid, and vitamin B12. The primary end point of the study was the disease progression event count.
Eighty-four patients were randomized. Disease progression events were experienced by 28 (70%) and 26 (59%) patients in the AZD6244 and pemetrexed groups, respectively. Median progression-free survival was not statistically significantly different between the AZD6244 and pemetrexed groups (67 versus 90 days, respectively; hazard ratio 1.08, two-sided 80% confidence interval = 0.75-1.54; p = 0.79). Two patients in the AZD6244 group had a best response to treatment of partial response. In the pemetrexed group, one patient achieved a complete response and one patient a partial response. Dermatitis acneiform, diarrhea, nausea, and vomiting were the most frequently reported adverse events with AZD6244, compared with fatigue, anemia, nausea, anorexia, and dermatitis acneiform with pemetrexed.
Oral AZD6244 showed clinical activity as second- or third-line therapy for patients with advanced NSCLC. In an unselected NSCLC population, there is no suggestion that AZD6244 monotherapy offers any advantage over standard treatment with pemetrexed. Based on preclinical data and recent clinical observations, further development of AZD6244 in NSCLC should focus on BRAF or RAS mutation-positive patients and/or AZD6244-based combination regimens.
AZD6244（ARRY-142886）是一种有效的、选择性的 MEK 抑制剂。本研究旨在评估 AZD6244 对比培美曲塞二线或三线治疗晚期非小细胞肺癌（NSCLC）患者的疗效和安全性。
在这项随机 II 期研究中，患者在接受皮质类固醇、叶酸和维生素 B12 预处理后，每日两次口服 100mg AZD6244 游离碱混悬液或每 3 周静脉注射 500mg/m2培美曲塞。该研究的主要终点为疾病进展事件计数。
共 84 例患者随机分组。AZD6244 和培美曲塞组分别有 28（70%）和 26（59%）例患者出现疾病进展事件。AZD6244 和培美曲塞组中位无进展生存期无统计学显著差异（分别为 67 天和 90 天；风险比 1.08，双侧 80%置信区间为 0.75-1.54；p=0.79）。AZD6244 组有 2 例患者的治疗最佳反应为部分缓解。培美曲塞组中，1 例患者完全缓解，1 例患者部分缓解。与培美曲塞相比，AZD6244 组最常报告的不良反应为痤疮样皮炎、腹泻、恶心和呕吐，而培美曲塞组为疲劳、贫血、恶心、厌食和痤疮样皮炎。
口服 AZD6244 作为晚期 NSCLC 二线或三线治疗具有临床活性。在未选择的 NSCLC 人群中，AZD6244 单药治疗与培美曲塞标准治疗相比没有优势。基于临床前数据和最近的临床观察，AZD6244 在 NSCLC 中的进一步开发应集中在 BRAF 或 RAS 突变阳性患者和/或基于 AZD6244 的联合治疗方案上。
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