Falchook GS, Lewis KD, Infante JR et al.Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. The Lancet Oncology 13:782-789

Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
The Lancet Oncology (Impact Factor: 24.69). 07/2012; 13(8):782-9. DOI: 10.1016/S1470-2045(12)70269-3
Source: PubMed


MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, and genotyping data for the oral, small-molecule MEK inhibitor trametinib in patients with melanoma.
We undertook a multicentre, phase 1 three-part study (dose escalation, cohort expansion, and pharmacodynamic assessment). The main results of this study are reported elsewhere; here we present data relating to patients with melanoma. We obtained tumour samples to assess BRAF mutational status, and available tissues underwent exploratory genotyping analysis. Disease response was measured by Response Evaluation Criteria in Solid Tumors, and adverse events were defined by common toxicity criteria. This study is registered with, number NCT00687622.
97 patients with melanoma were enrolled, including 81 with cutaneous or unknown primary melanoma (36 BRAF mutant, 39 BRAF wild-type, six BRAF status unknown), and 16 with uveal melanoma. The most common treatment-related adverse events were rash or dermatitis acneiform (n=80; 82%) and diarrhoea (44; 45%), most of which were grade 2 or lower. No cutaneous squamous-cell carcinomas were recorded. Of 36 patients with BRAF mutations, 30 had not received a BRAF inhibitor before; two complete responses (both confirmed) and ten partial responses (eight confirmed) were noted in this subgroup (confirmed response rate, 33%). Median progression-free survival of this subgroup was 5·7 months (95% CI 4·0-7·4). Of the six patients who had received previous BRAF inhibition, one unconfirmed partial response was recorded. Of 39 patients with BRAF wild-type melanoma, four partial responses were confirmed (confirmed response rate, 10%).
Our data show substantial clinical activity of trametinib in melanoma and suggest that MEK is a valid therapeutic target. Differences in response rates according to mutations indicate the importance of mutational analyses in the future.

Download full-text


Available from: Christopher Moy, Dec 10, 2014
  • Source
    • "In a phase 2 study of MEK162, 6 (20%) of 30 patients with metastatic melanoma harboring NRAS mutations had an objective clinical response.44 However, other clinical studies of MEK inhibitors using trametinib or selumetinib in patients with NRAS mutant melanoma failed to show clinical activity.37,45 One of the possible explanations for the failed anticancer activity is that NRAS mutations activate multiple pathways including CDK4 driven cell-cycle progression and PI3K/AKT signaling in addition to MAPK pathway.46,47 "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mitogen-activated protein kinase (MAPK) pathway is a critical oncogenic driver signal in a number of malignancies. The discovery of activating mutations in the MAPK pathway has led to the development of MAPK pathway inhibitors. Selumetinib is a potent and selective inhibitor of MEK1 and MEK2, which are essential downstream molecules in the MAPK pathway. Several preclinical and clinical studies have demonstrated the promising antitumor activity of selumetinib. In this review, we discuss the MAPK pathway in melanoma and summarized data from preclinical and clinical studies of selumetinib for advanced melanoma.
    Full-text · Article · Sep 2014 · OncoTargets and Therapy
  • Source
    • "Dose-limiting toxicities were cutaneous and gastrointestinal, with some ocular events including central serous retinopathy. In a substudy within this clinical trial, a cohort of patients with melanoma was evaluated more specifically.65 Ninety-seven patients with melanoma were included and differentiated by molecular status including BRAFV600E/K (n=36, of whom 30 were not previously treated with a BRAF inhibitor), BRAF wild-type (n=39), BRAF status unknown (n=6), and uveal melanoma (n=16). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Development of selective inhibitors of BRAF has improved the survival of patients with BRAF-mutant melanoma. The progression-free survival after treatment with a BRAF inhibitor is modest, however, and BRAF inhibitors induce cutaneous toxicity, likely due to paradoxical activation of the mitogen-activated protein kinase pathway. Combining selective BRAF and MEK inhibition, such as the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, has been shown to improve the response rate and progression-free survival in patients with advanced melanoma while significantly alleviating the paradoxical activation of mitogen-activated protein kinase. This combination treatment results in a reduction in skin toxicity relative to that seen with a BRAF inhibitor alone; however, addition of the MEK inhibitor adds other toxicities, such as pyrexia and gastrointestinal or ocular toxicity. While combined BRAF-MEK inhibition appears primed to become a standard molecular approach for BRAF-mutant melanoma, the utility of the combination has to be considered in the rapidly changing landscape of immunotherapeutics, such as immune checkpoint blockade using anti-cytotoxic T lymphocyte antigen-4 and anti-programmed death-1/programmed death-L1 antibodies. Here we review the development of the dabrafenib plus trametinib combination, the characteristics of each drug and the combination, and the role of this combination in the management of patients with BRAF-mutant melanoma.
    Full-text · Article · Jun 2014 · Drug, Healthcare and Patient Safety
  • Source
    • "In a phase III study, only trametinib (known as GSK1120212 or JTP-74057), a selective oral inhibitor of MEK1 and 2, has been demonstrated to have impact on clinical efficacy (54,55). Trametenib causes a block of the protein MEK, and is correlated with improved PFS in patients carrying B-RAFV600E/K mutations (56). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cutaneous melanoma is an aggressive cancer with a poor prognosis for patients with advanced disease. The identification of several key molecular pathways implicated in the pathogenesis of melanoma has led to the development of novel therapies for this devastating disease. In melanoma, both the Ras/Raf/MEK/ERK (MAPK) and the PI3K/AKT (AKT) signalling pathways are constitutively activated through multiple mechanisms. Targeting various effectors of these pathways with pharmacologic inhibitors may inhibit melanoma cell growth and angiogenesis. Ongoing clinical trials provide hope to improve progression-free survival of patients with advanced melanoma. This review summarizes the most relevant studies focused on the specific action of these new molecular targeted agents. Mechanisms of resistance to therapy are also discussed.
    Full-text · Article · Jun 2014 · International Journal of Oncology
Show more