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Ref Type Journal Article
PMID (22805291)
Authors Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, DeMarini DJ, Cox DS, Xu Y, Morris SR, Peddareddigari VG, Le NT, Hart L, Bendell JC, Eckhardt G, Kurzrock R, Flaherty K, Burris HA, Messersmith WA
Title Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial.
Journal The Lancet. Oncology
Vol 13
Issue 8
Date 2012 Aug
Abstract Text 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.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, number NCT00687622.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.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.GlaxoSmithKline.


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Molecular Profile Treatment Approach
HRAS G12S MEK inhibitor (Pan)
HRAS K117R MEK1 Inhibitor
HRAS D33N MEK2 Inhibitor
HRAS G12S MEK1 Inhibitor
HRAS K117E MEK2 Inhibitor
HRAS inact mut MEK1 Inhibitor
HRAS Q61W MEK inhibitor (Pan)
HRAS G13V MEK1 Inhibitor
HRAS G13C MEK inhibitor (Pan)
HRAS G12R MEK inhibitor (Pan)
HRAS G13S MEK2 Inhibitor
HRAS G13V MEK2 Inhibitor
HRAS D33N MEK1 Inhibitor
HRAS G13C MEK1 Inhibitor
HRAS Q61X MEK inhibitor (Pan)
HRAS Q61C MEK1 Inhibitor
HRAS G12T MEK2 Inhibitor
HRAS G12A MEK2 Inhibitor
HRAS G13T MEK2 Inhibitor
HRAS G12C MEK2 Inhibitor
HRAS G12Y MEK2 Inhibitor
HRAS Q61H MEK inhibitor (Pan)
HRAS G13R MEK inhibitor (Pan)
HRAS A59T MEK inhibitor (Pan)
HRAS Q61N MEK1 Inhibitor
HRAS T58I MEK2 Inhibitor
HRAS G12K MEK2 Inhibitor
HRAS G12V MEK inhibitor (Pan)
HRAS Q61K MEK2 Inhibitor
HRAS G12N MEK2 Inhibitor
HRAS G13D MEK1 Inhibitor
HRAS G12R MEK1 Inhibitor
HRAS G12V MEK2 Inhibitor
HRAS G12H MEK2 Inhibitor
HRAS G12X MEK inhibitor (Pan)
HRAS G12L MEK2 Inhibitor
HRAS G13I MEK inhibitor (Pan)
HRAS G12I MEK1 Inhibitor
HRAS G13T MEK1 Inhibitor
HRAS T58I MEK1 Inhibitor
HRAS Q61A MEK inhibitor (Pan)
HRAS G13S MEK1 Inhibitor
HRAS Q61Y MEK2 Inhibitor
HRAS K117R MEK inhibitor (Pan)
HRAS Q61T MEK1 Inhibitor
HRAS G12E MEK2 Inhibitor
HRAS G13I MEK1 Inhibitor
HRAS K117R MEK2 Inhibitor
HRAS G13X MEK1 Inhibitor
HRAS G12I MEK2 Inhibitor
HRAS Q61G MEK inhibitor (Pan)
HRAS Q61K MEK inhibitor (Pan)
HRAS Q61E MEK2 Inhibitor
HRAS Q61C MEK2 Inhibitor
HRAS Q61L MEK1 Inhibitor
HRAS G13D MEK inhibitor (Pan)
HRAS G13R MEK1 Inhibitor
HRAS Q61I MEK1 Inhibitor
HRAS Q61P MEK inhibitor (Pan)
HRAS G13C MEK2 Inhibitor
HRAS G12K MEK1 Inhibitor
HRAS Q61E MEK1 Inhibitor
HRAS A146T MEK inhibitor (Pan)
HRAS Q61L MEK inhibitor (Pan)
HRAS Q61V MEK inhibitor (Pan)
HRAS G12W MEK inhibitor (Pan)
HRAS Q61F MEK2 Inhibitor
HRAS G13X MEK2 Inhibitor
HRAS Q61Y MEK inhibitor (Pan)
HRAS Q61N MEK2 Inhibitor
HRAS D33N MEK inhibitor (Pan)
HRAS Q61I MEK2 Inhibitor
HRAS A146T MEK1 Inhibitor
HRAS Q61W MEK1 Inhibitor
HRAS Q61H MEK2 Inhibitor
HRAS Q61P MEK1 Inhibitor
HRAS Q61A MEK2 Inhibitor
HRAS Q61W MEK2 Inhibitor
HRAS K117N MEK1 Inhibitor
HRAS K117E MEK inhibitor (Pan)
HRAS G13T MEK inhibitor (Pan)
HRAS Q61M MEK inhibitor (Pan)
HRAS A146T MEK2 Inhibitor
HRAS Q61F MEK inhibitor (Pan)
HRAS Q61I MEK inhibitor (Pan)
HRAS G12T MEK1 Inhibitor
HRAS G12D MEK2 Inhibitor
HRAS Q61C MEK inhibitor (Pan)
HRAS A146V MEK2 Inhibitor
HRAS Q61T MEK2 Inhibitor
HRAS G12A MEK1 Inhibitor
HRAS G12D MEK inhibitor (Pan)
HRAS Q61X MEK2 Inhibitor
HRAS G12W MEK1 Inhibitor
HRAS K117N MEK inhibitor (Pan)
HRAS inact mut MEK inhibitor (Pan)
HRAS G12H MEK inhibitor (Pan)
HRAS G12V MEK1 Inhibitor
HRAS G12T MEK inhibitor (Pan)
HRAS Q61E MEK inhibitor (Pan)
HRAS G12N MEK inhibitor (Pan)
HRAS G12Q MEK1 Inhibitor
HRAS Q61R MEK1 Inhibitor
HRAS G12H MEK1 Inhibitor
HRAS G12L MEK inhibitor (Pan)
HRAS Q61K MEK1 Inhibitor
HRAS G12M MEK1 Inhibitor
HRAS K117E MEK1 Inhibitor
HRAS Q61G MEK1 Inhibitor
HRAS G12F MEK inhibitor (Pan)
HRAS G12X MEK2 Inhibitor
HRAS G13D MEK2 Inhibitor
HRAS G12S MEK2 Inhibitor
HRAS G13R MEK2 Inhibitor
HRAS G12F MEK2 Inhibitor
HRAS G12Y MEK1 Inhibitor
HRAS G12C MEK1 Inhibitor
HRAS Q61V MEK1 Inhibitor
HRAS A59T MEK2 Inhibitor
HRAS G12R MEK2 Inhibitor
HRAS G12Q MEK2 Inhibitor
HRAS G13I MEK2 Inhibitor
HRAS G12D MEK1 Inhibitor
HRAS A146V MEK1 Inhibitor
HRAS G12Y MEK inhibitor (Pan)
HRAS Q61Y MEK1 Inhibitor
HRAS G12W MEK2 Inhibitor
HRAS G12M MEK2 Inhibitor
HRAS G12E MEK inhibitor (Pan)
HRAS G12E MEK1 Inhibitor
HRAS G12F MEK1 Inhibitor
HRAS Q61T MEK inhibitor (Pan)
HRAS G12K MEK inhibitor (Pan)
HRAS G12Q MEK inhibitor (Pan)
HRAS A146V MEK inhibitor (Pan)
HRAS Q61M MEK2 Inhibitor
HRAS G12M MEK inhibitor (Pan)
HRAS Q61R MEK2 Inhibitor
HRAS Q61N MEK inhibitor (Pan)
HRAS Q61X MEK1 Inhibitor
HRAS Q61R MEK inhibitor (Pan)
HRAS G12A MEK inhibitor (Pan)
HRAS T58I MEK inhibitor (Pan)
HRAS G12I MEK inhibitor (Pan)
HRAS Q61V MEK2 Inhibitor
HRAS Q61G MEK2 Inhibitor
HRAS Q61M MEK1 Inhibitor
HRAS G12X MEK1 Inhibitor
HRAS Q61F MEK1 Inhibitor
HRAS G13S MEK inhibitor (Pan)
HRAS G13X MEK inhibitor (Pan)
HRAS G13V MEK inhibitor (Pan)
HRAS Q61P MEK2 Inhibitor
HRAS A59T MEK1 Inhibitor
HRAS G12C MEK inhibitor (Pan)
HRAS G12N MEK1 Inhibitor
HRAS Q61L MEK2 Inhibitor
HRAS K117N MEK2 Inhibitor
HRAS Q61H MEK1 Inhibitor
HRAS G12L MEK1 Inhibitor
HRAS Q61A MEK1 Inhibitor
HRAS inact mut MEK2 Inhibitor
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown pancreatic cancer not applicable Trametinib Phase I Actionable In a Phase I trial, 42% (11/26) of pancreatic cancer patients demonstrated a decrease in tumor formation when treated with Mekinist (trametinib) (PMID: 22805291). 22805291