title: Trametinib: first global approval.
abstract: Trametinib is an orally bioavailable mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor with antineoplastic activity. The compound specifically binds to MEK1 and MEK2, resulting in inhibition of growth factor-mediated cell signalling and cellular proliferation in various cancers. Originally developed by Japan Tobacco, GlaxoSmithKline has licensed exclusive worldwide rights to the compound and conducted development in a number of different cancer types. Trametinib, as a monotherapy, has been approved in the US for the treatment of unresectable or metastatic malignant melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. The compound, as a monotherapy, has also been submitted for regulatory review in the EU for BRAF mutation-positive malignant melanoma, and is in phase III development in Europe, Argentina, Canada and Oceania. Phase II development is underway for pancreatic cancer, non-small cell lung cancer and relapsed or refractory leukaemias. GlaxoSmithKline is also developing trametinib for use in combination with dabrafenib in BRAF V600 mutation-positive metastatic cutaneous melanoma; the combination is at the preregistration stage in the EU and a phase III clinical programme is underway worldwide. Phase II development for this combination is also underway in colorectal cancer. Several phase I trials have also been initiated to evaluate trametinib in combination with other drugs for the treatment of various solid tumours and haematological malignancies. A paediatric oral solution formulation has been assessed against the oral tablet formulation in a phase I trial. This article summarizes the milestones in the development of trametinib leading to this first approval for unresectable or metastatic BRAF mutation-positive malignant melanoma.
authors.affiliation: Adis R & D Insight, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, 0754, Auckland, New Zealand. dru@adis.com
authors.forename: Cameron J M
authors.initials: CJ
authors.lastname: Wright
authors.forename: Paul L
authors.initials: PL
authors.lastname: McCormack
mesh_terms: D002986:Clinical Trials as Topic; D017277:Drug Approval; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008545:Melanoma / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011728:Pyridones / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000627:therapeutic use*; D012878:Skin Neoplasms; D000096142:Cutaneous Malignant Melanoma
chemical_list: D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2