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)

被引：298

作者：

Blumenschein, G. R., Jr. ^{[1
]}

Smit, E. F. ^{[2
]}

Planchard, D. ^{[3
]}

Kim, D. -W. ^{[4
]}

Cadranel, J. ^{[5
]}

De Pas, T. ^{[6
]}

Dunphy, F. ^{[7
]}

Udud, K. ^{[8
]}

Ahn, M. -J. ^{[9
]}

Hanna, N. H. ^{[10
]}

Kim, J. -H. ^{[11
]}

Mazieres, J. ^{[12
]}

Kim, S. -W. ^{[13
]}

Baas, P. ^{[14
]}

Rappold, E. ^{[15
]}

Redhu, S. ^{[15
]}

Puski, A. ^{[16
]}

Wu, F. S. ^{[15
]}

Jaenne, P. A. ^{[17
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Houston, TX 77230 USA

[2] Vrije Univ Amsterdam, VU Med Ctr, Dept Pulm Dis, Amsterdam, Netherlands

[3] Gustave Roussy, Med Oncol Dept, Villejuif, France

[4] Seoul Natl Univ Hosp, Dept Internal Med, Seoul 110744, South Korea

[5] Hop Tenon, AP HP, Dept Resp Med, F-75970 Paris, France

[6] European Inst Oncol, Milan, Italy

[7] Duke Univ, Med Ctr, Durham, NC 27706 USA

[8] Koranyi Natl Inst TB & Pulmonol, Budapest, Hungary

[9] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Med,Div Hematol Oncol, Seoul, South Korea

[10] IU Melvin & Bren Simon Canc Ctr, Indianapolis, IN USA

[11] Yonsei Univ, Coll Med, Div Med Oncol, Yonsei Canc Ctr, Seoul, South Korea

[12] CHU Toulouse, Hop Larrey, Toulouse, France

[13] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul, South Korea

[14] Netherlands Canc Inst, Amsterdam, Netherlands

[15] GlaxoSmithKline, Collegeville, PA USA

[16] GlaxoSmithKline Kft, Budapest, Hungary

[17] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Lowe Ctr Thorac Oncol, Boston, MA USA

来源：

ANNALS OF ONCOLOGY | 2015年 / 26卷 / 05期

关键词：

trametinib; MEK inhibitor; docetaxel; NSCLC; KRAS; progression-free survival; GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITORS; MEK INHIBITION; MUTATIONS; SURVIVAL; EFFICACY; ADENOCARCINOMAS; ONCOGENE; BEHAVIOR; CRITERIA;

D O I：

10.1093/annonc/mdv072

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：894 / 901

页数：9

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