一项将MEK1/MEK2抑制剂曲美替尼（GSK1120212）与多西他赛对比用于KRAS突变的晚期非小细胞肺癌（NSCLC）的随机II期研究†。
A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†.
作者信息
Blumenschein G R, Smit E F, Planchard D, Kim D-W, Cadranel J, De Pas T, Dunphy F, Udud K, Ahn M-J, Hanna N H, Kim J-H, Mazieres J, Kim S-W, Baas P, Rappold E, Redhu S, Puski A, Wu F S, Jänne P A
机构信息
MD Anderson Cancer Center, The University of Texas, Houston, USA.
Department of Pulmonary Diseases, Vrije Universiteit VU Medical Centre, Amsterdam, The Netherlands.
出版信息
Ann Oncol. 2015 May;26(5):894-901. doi: 10.1093/annonc/mdv072. Epub 2015 Feb 26.
BACKGROUND
KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC.
PATIENTS AND METHODS
Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m(2) i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary.
RESULTS
One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75-1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52-1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia.
CONCLUSION
Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC.
CLINICALTRIALSGOV REGISTRATION NUMBER
NCT01362296.
背景
在25%的非小细胞肺癌（NSCLC）中检测到KRAS突变，且尚无针对该亚群人群的靶向治疗药物获批。曲美替尼是一种MEK1/MEK2的选择性变构抑制剂，在KRAS突变型NSCLC中显示出临床前及临床活性。我们报告一项II期试验，比较曲美替尼与多西他赛在晚期KRAS突变型NSCLC患者中的疗效。
患者与方法
符合条件的组织学确诊KRAS突变型NSCLC患者，此前接受过一次含铂类化疗，按2:1的比例随机分配至曲美替尼组（口服2mg，每日一次）或多西他赛组（静脉注射75mg/m²，每3周一次）。疾病进展后允许交叉至另一组。主要终点为无进展生存期（PFS）。在对92例PFS事件进行中期分析后，该研究提前终止，结果显示曲美替尼与多西他赛在PFS方面的比较越过了无效边界。
结果
129例KRAS突变型NSCLC患者被随机分组；其中，86例患者接受曲美替尼治疗，43例接受多西他赛治疗。曲美替尼组的中位PFS为12周，多西他赛组为11周（风险比[HR]1.14；95%置信区间0.75 - 1.75；P = 0.5197）。中位总生存期方面，虽然数据尚不成熟，但曲美替尼组为8个月，多西他赛组未达到（HR 0.97；95%置信区间0.52 - 1.83；P = 0.934）。曲美替尼组有10例（12%）部分缓解（PR），多西他赛组有5例（12%）PR（P = 1.0000）。在≥20%的曲美替尼治疗患者中最常见的不良事件（AE）为皮疹、腹泻、恶心、呕吐和疲劳。曲美替尼组最常见的3级治疗相关AE为高血压、皮疹、腹泻和乏力。
结论
在既往接受治疗的KRAS突变阳性NSCLC患者中，曲美替尼显示出与多西他赛相似的PFS和缓解率。
临床试验注册编号
NCT01362296。
Zotero 插件