Elsevier

The Lancet Oncology

Volume 13, Issue 8, August 2012, Pages 773-781
The Lancet Oncology

Articles
Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial

https://doi.org/10.1016/S1470-2045(12)70270-XGet rights and content

Summary

Background

Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours.

Methods

We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622.

Findings

We enrolled 206 patients (median age 58·5 years, range 19–92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded.

Interpretation

The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination.

Funding

GlaxoSmithKline.

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.

Section snippets

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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