Elsevier

The Lancet Oncology

Volume 13, Issue 8, August 2012, Pages 782-789
The Lancet Oncology

Articles
Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial

https://doi.org/10.1016/S1470-2045(12)70269-3Get rights and content

Summary

Background

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.

Methods

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 ClinicalTrials.gov, number NCT00687622.

Findings

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%).

Interpretation

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.

Funding

GlaxoSmithKline.

Introduction

Metastatic melanoma is an aggressive disease, with a median survival of less than 1 year.1 Few effective systemic treatments are available. Most approved drugs, such as dacarbazine, high-dose interleukin 2, and ipilimumab, have response rates of 6–20%1, 2 and are associated with severe toxic effects, including capillary leak syndrome1 and immune-mediated issues.2

The MAPK signalling cascade includes the enzymes RAS, RAF, MEK, and ERK. It is an important pathway in cell proliferation. Constitutive activation of MEK by genetic mutation results in oncogenic transformation of normal cells.3 Activating mutations within the MAPK pathway are common in melanoma. Mutations in the RAS isoform NRAS are seen in 10–20% of cutaneous melanomas and are associated with poor prognosis.4, 5 Mutations in the RAF isoform BRAF are more frequent, arising in 40–60% of cutaneous melanomas.5, 6 More than 80% of BRAF mutations entail substitution of valine with glutamic acid at amino acid residue 600 (Val600Glu, designated BRAFV600E), whereas substitution with lysine (Val600Lys, designated BRAFV600K) takes place in 3–20% of cases.5, 6 In uveal melanoma, which accounts for less than 5% of all melanomas, BRAF mutations are rare, but MAPK-activating mutations in guanine nucleotide 1 binding protein q polypeptide (GNAQ) or guanine nucleotide-binding protein α11 (GNA11) are common, detected in about 80% of cases.7, 8

Potent and selective BRAF inhibitors have been developed, including dabrafenib9 and vemurafenib (approved by the US Food and Drug Administration in 2011).10 However, even in patients with BRAF-mutant melanoma, most will progress, and some have primary resistance to single-agent BRAF-inhibitor treatment.

Trametinib is a reversible, selective allosteric inhibitor of MEK1 and MEK2 (also known as MAP2K1 and MAP2K2) activation and kinase activity, with a half-maximum inhibitory concentration (IC50) of 0·7–0·9 nmol/L for these enzymes.11 Trametinib inhibited proliferation of BRAFV600E melanoma cell lines at concentrations of 1·0–2·5 nmol/L.11 In xenografted tumour models, trametinib showed sustained suppression of ERK phosphorylation and tumour growth inhibition.11

We undertook a phase 1 first-in-human study of trametinib in patients with advanced malignant diseases. The study design and pharmacokinetic, pharmacodynamic, and efficacy data for trametinib in tumours other than melanoma are reported elsewhere.12 In this Article, we report the safety and antitumour activity of trametinib in individuals with advanced melanoma. Translational objectives included investigation of tumour genetic profiles and their association with clinical endpoints.

Section snippets

Study design

This report is a subanalysis of a larger three-part study of trametinib (appendix, p 1).12 In the first part, we identified the maximum tolerated dose of trametinib by safety, pharmacokinetic, and pharmacodynamic assessments in patients with solid tumours. In part two, we assessed safety and efficacy of the recommended phase 2 dose in individuals with selected tumour types. In the third part, we characterised the biologically active dose range of trametinib. We included patients with melanoma

Results

Between July 31, 2008, and Oct 5, 2010, 206 patients with various advanced malignant diseases were enrolled into the parent study. The pharmacokinetic and pharmacodynamic analysis of trametinib and adverse events of the drug in solid tumours other than melanoma are reported elsewhere.12 In this subanalysis, 97 patients with advanced melanoma were enrolled across all parts of the study (table 1). Features of poor prognosis were common, with most people having M1c disease. Of 36 BRAF-mutant

Discussion

Our findings show that trametinib has good clinical activity in patients with melanoma. In individuals with BRAF-mutant melanoma who had not received a BRAF inhibitor previously, a confirmed response rate of 33% was achieved, including two complete responses. Furthermore, trametinib was well tolerated and resulted in acceptable and manageable adverse events. These data suggest that MEK is a valid therapeutic target, and inhibition of MEK provides a novel mechanism by which to treat BRAF-mutant

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