ArticlesSafety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial
Introduction
The MAPK pathway incorporates the enzymes RAS, RAF, ERK, and MEK. In this pathway, membrane-bound receptors signal to proteins that regulate cell proliferation and survival. The MAPK pathway is constitutively activated in many tumour types, including those BRAFV600 mutations and some RAS mutations.1, 2, 3 MEK has emerged as a key anticancer target because inhibition of this enzyme blocks cell proliferation and induces apoptosis.4, 5, 6, 7
Trametinib is a reversible, highly selective allosteric inhibitor of MEK1/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.8 In enzymatic and cellular studies, trametinib inhibited kinase activity of MEK1 and MEK2, prevented RAF-dependent MEK phosphorylation, and prolonged inhibition of phosphorylated ERK (a substrate of MEK).8 In-vitro studies undertaken in 94 different cancer cell lines showed cytotoxic responses in seven of ten BRAFV600-mutant cells lines at nanomolar concentrations.8 Cell lines and mouse xenograft models with activating mutations in RAS were also sensitive to trametinib.6 Pharmacokinetic profiling in mice indicated a mean effective half life (t1/2) of 33 h, with a low peak:trough ratio (around 1·6–2·8) after single or repeat dosing of trametinib.8
We undertook an open-label phase 1 study to ascertain the maximum tolerated dose of trametinib in human beings for the first time, and to define the recommended phase 2 dose and regimen of this agent for patients with advanced solid tumours. We also aimed to establish pharmacokinetic, pharmacodynamic, and efficacy data for trametinib in selected tumour types.
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Study design
We undertook this phase 1 study in three parts (appendix, p 1). In part one, we identified the maximum tolerated dose of trametinib by safety, pharmacokinetic, and pharmacodynamic assessments in patients with solid tumours. We assessed three regimens of trametinib, administered orally as tablets: (1) once a day for 21 days, followed by a 7-day break (21/7 regimen); (2) a loading dose on day 1 and day 2, or day 1 only, followed by continuous once-daily dosing (loading dose regimen); and (3)
Results
Between July 31, 2008, and Oct 5, 2010, 206 patients were enrolled and received at least one dose of trametinib (table 1). More than half had received three or more previous regimens. Various primary tumour types were included, and melanoma, non-small-cell lung cancer, colorectal cancer, and pancreatic cancers were the most frequent. Data for patients with melanoma are presented elsewhere.13 At the data cutoff, all but six (3%) patients had discontinued study treatment, most typically for
Discussion
Our findings show that trametinib is fairly well tolerated, with the most common adverse events of rash and diarrhoea easily managed. Early dose-limiting events of central serous retinopathy prevented dose escalation beyond 3 mg a day, which was declared the maximum tolerated dose of trametinib on a continuous daily dosing schedule. However, 3 mg a day was tolerated poorly beyond the first cycle of treatment. Thus, on the basis of safety, long-term tolerability, pharmacokinetic,
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