General Information

Mekinist (trametinib) is an orally bioavailable inhibitor of mitogen-activated protein kinase kinase (MEK) with potential antineoplastic activity. Trametinib specifically binds to and inhibits MEK 1 and 2, resulting in an inhibition of growth factor-mediated cell signaling and cellular proliferation in various cancers. MEK 1 and 2, dual specificity threonine/tyrosine kinases often upregulated in various cancer cell types, play a key role in the activation of the RAS/RAF/MEK/ERK signaling pathway that regulates cell growth.

Mekinist is specifically indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. It is not indicated for patients who have received prior BRAF-inhibitor therapy.

Mekinist is supplied as a tablet for oral administration. The recommended dose is 2 mg orally once daily until disease progression or unacceptable toxicity. Take at least 1 hour before or 2 hours after a meal. Do not take a missed dose within 12 hours of the next dose.

Clinical Results

FDA Approval
The FDA approval of Mekinist was based on an international, multi-center, randomized, open label, active-controlled trial in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted. Subjects were randomized to receive Mekinist 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1,000 mg/m2 intravenously every 3 weeks or paclitaxel 175 mg/m2 intravenously every 3 weeks. Treatment continued until disease progression or unacceptable toxicity. The primary efficacy measure was progression-free survival (PFS). Progressive disease occurred in 50% of the Mekinist arm versus 65% of the chemotherapy arm and the median number of months to progressive disease was 4.8 versus 1.5 months.

Mechanism of Action

Mekinist (trametinib) is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo.

Literature References

Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, McArthur GA, Hwu P, Gonzalez R, Ott PA, Long GV, Gardner OS, Ouellet D, Xu Y, DeMarini DJ, Le NT, Patel K, Lewis KD Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. Journal of Clinical Oncology 2013 Feb 1;31(4):482-9