Phase II Study of the MEK1/MEK2 Inhibitor Trametinib in Patients With Metastatic BRAF-Mutant Cutaneous Melanoma Previously Treated With or Without a BRAF Inhibitor

被引：372

作者：

Kim, Kevin B. ^{[1
]}

Kefford, Richard ^{[2
,3
]}

Pavlick, Anna C. ^{[6
]}

Infante, Jeffrey R. ^{[7
]}

Ribas, Antoni ^{[9
]}

Sosman, Jeffrey A. ^{[8
]}

Fecher, Leslie A. ^{[10
]}

Millward, Michael ^{[4
]}

McArthur, Grant A. ^{[5
]}

Hwu, Patrick

Gonzalez, Rene ^{[12
]}

Ott, Patrick A. ^{[6
]}

Long, Georgina V. ^{[2
,3
]}

Gardner, Olivia S. ^{[11
]}

Ouellet, Daniele ^{[11
]}

Xu, Yanmei ^{[11
]}

DeMarini, Douglas J. ^{[11
]}

Le, Ngocdiep T. ^{[11
]}

Patel, Kiran ^{[11
]}

Lewis, Karl D. ^{[12
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA

[2] Melanoma Inst Australia, Sydney, NSW, Australia

[3] Univ Sydney, Westmead Hosp, Sydney, NSW 2006, Australia

[4] Sir Charles Gairdner Hosp, Perth, WA, Australia

[5] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[6] NYU, Inst Canc, New York, NY USA

[7] Tennessee Oncol, Sarah Cannon Res Inst, Nashville, TN USA

[8] Vanderbilt Univ, Med Ctr, Nashville, TN USA

[9] Univ Calif Los Angeles Hosp, Los Angeles, CA USA

[10] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA

[11] GlaxoSmithKline, Philadelphia, PA USA

[12] Univ Colorado, Ctr Canc, Aurora, CO USA

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2013年 / 31卷 / 04期

关键词：

ORAL MEK INHIBITOR; DOSE-ESCALATION TRIAL; ACQUIRED-RESISTANCE; IMPROVED SURVIVAL; ADVANCED CANCERS; OPEN-LABEL; VEMURAFENIB; PD-0325901;

D O I：

10.1200/JCO.2012.43.5966

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma. Patients and Methods This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily. Results In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed. Conclusion Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor-naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma. J Clin Oncol 31:482-489. (C) 2012 by American Society of Clinical Oncology

引用

页码：482 / 489

页数：8

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