MEK162 is an orally available inhibitor of MEK1/2 under development in collaboration by Array BioPharma and Novartis. MEK162 has already been in a number of phase II trials and is currently in several Phase III trials for other cancers. Therefore, its safety is already known (though not in combination with imatinib).
Definition from NCI Drug Dicitionary:
MEK162 is an orally available inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) with potential antineoplastic activity. MEK inhibitor MEK162, noncompetitive with ATP, binds to and inhibits the activity of MEK1/2. Inhibition of MEK1/2 prevents the activation of MEK1/2-dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling. This may eventually lead to an inhibition of tumor cell proliferation and an inhibition in production of various inflammatory cytokines including interleukin-1, -6 and tumor necrosis factor. MEK1 and MEK2 are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types.
Information at Manufacturer websites:
Current Trials Relevant to GIST Patients:
Principal investigator Ping Chi, MD PhD and William Tap, MD discuss the trial and its rationale in this short video you can watch.
Groundbreaking research by Chi and colleagues identified transcription factor ETV1 as necessary for GIST growth and survival. ETV1 is activated downstream of KIT via the MAPK pathway and can be targeted using an inhibitor of MEK. You can access the free full text of the background research paper at this link.
The trial is open only to patients with measurable metastatic or advanced GIST who have received no drug therapies other than adjuvant imatinib. The initial Phase Ib arm of the trial will identify the appropriate tolerable dose of MEK162 to be used in combination with 400 mg of imatinib. In the Phase II portion of the trial patients will receive imatinib plus MEK162 until disease progression.
The hope is that this combination therapy will be more effective than imatinib alone, potentially causing greater tumor cell death and longer duration of disease control without development of imatinib resistance.
This trial would be relevant to GIST patients with a BRAF mutation.