Multi-Institutional Phase II Study of Selumetinib in Patients With Metastatic Biliary Cancers
Multi-Institutional Phase II Study of Selumetinib in Patients With Metastatic Biliary Cancers
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DOI：
10.1200/jco.2010.33.9473
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发表时间：
2011-06-10
影响因子：
45.3
通讯作者：
Villalona-Calero, Miguel A.
中科院分区：
文献类型：
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作者：
Bekaii-Saab, Tanios;Phelps, Mitch A.;Villalona-Calero, Miguel A.
目的胆道癌（BC）预后较差，但靶向RAS/RAF/丝裂原激活蛋白激酶激酶（MEK）/细胞外信号相关激酶（ERK）通路具有重要意义。 Selumetinib 是 MEK1/2 的抑制剂，因此本试验旨在确定 Selumetinib 在 BC 中的安全性和有效性。患者和方法这是一项多机构 II 期研究，对晚期 BC 患者每天口服两次 100 mg 的 Selumetinib。主要终点是缓解率。所有患者在入组前都必须提供组织。通过免疫组织化学评估磷酸化 ERK (pERK) 和 AKT (pAKT) 的水平。对肿瘤进行基因分型以确定是否存在 BRAF 和/或 RAS 激活突变。结果 纳入了 28 名中位年龄为 55.6 岁的符合条件的患者。百分之三十九的患者之前接受过一种全身治疗。三名患者 (12%) 获得了确认的客观缓解。另外 17 名患者 (68%) 经历了疾病稳定 (SD)，其中 14 名 (56%) 经历了长期 SD（> 16 周）。患者非液体体重平均增加 8.6 磅。中位无进展生存期为 3.7 个月（95% CI，3.5 至 4.9），中位总生存期为 9.8 个月（95% CI，5.97 至不可用）。毒性较轻微，最常见的是皮疹（90%）和口干症（54%）。只有一名患者出现 4 级毒性（疲劳）。所有患者都有可供分析的组织。未发现 BRAF V600E 突变。两名短命 SD 患者存在 KRAS 突变。 pERK 染色缺失与缺乏反应相关。结论司美替尼在转移性 BC 患者中显示出有趣的活性和可接受的耐受性。我们的结果值得进一步评估司美替尼治疗转移性 BC 患者的效果。 J 临床肿瘤杂志 29：2357-2363。 (C) 2011 年美国临床肿瘤学会
PurposeBiliary cancers (BCs) carry a poor prognosis, but targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is of significance. Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC.Patients and MethodsThis was a multi-institutional phase II study of selumetinib at 100 mg given orally twice per day to patients with advanced BC. The primary end point was response rate. All patients were required to provide tissue before enrolling. The levels of phosphorylated ERK (pERK) and AKT (pAKT) were assessed by immunohistochemistry. Tumors were genotyped for the presence of BRAF- and/or RAS-activating mutations.ResultsTwenty-eight eligible patients with a median age of 55.6 years were enrolled. Thirty-nine percent of patients had received one prior systemic therapy. Three patients (12%) had a confirmed objective response. Another 17 patients (68%) experienced stable disease (SD), 14 of whom (56%) experienced prolonged SD (> 16 weeks). Patients gained an average nonfluid weight of 8.6 pounds. Median progression-free survival was 3.7 months (95% CI, 3.5 to 4.9) and median overall survival was 9.8 months (95% CI, 5.97 to not available). Toxicities were mild, with rash (90%) and xerostomia (54%) being most frequent. Only one patient experienced grade 4 toxicity (fatigue). All patients had tissue available for analysis. No BRAF V600E mutations were found. Two patients with short-lived SD had KRAS mutations. Absence of pERK staining was associated with lack of response.ConclusionSelumetinib displays interesting activity and acceptable tolerability in patients with metastatic BC. Our results warrant further evaluation of selumetinib in patients with metastatic BC. J Clin Oncol 29:2357-2363. (C) 2011 by American Society of Clinical Oncology