Trametinib (Mekinist)

General information

Class/mechanism: Reversible MEK1 (mitogen-activated extracellular signal regulated kinase 1) and MEK2 kinase inhibitor. MEK proteins are upstream and affect cellular proliferation by modulating the activity of the ERK (extracellular signal-related kinase) pathway. BRAF V600E mutations constitutively activate the BRAF pathway, which includes MEK1 and MEK2. By inhibiting MEK1 and MEK2, trametinib inhibits tumor cell growth that would otherwise be stimulated by constitutive activation from certain BRAF mutations.
Route: PO
Extravasation: n/a

• IUPHAR/BPS

For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias such as Micromedex, Lexicomp,UpToDate (courtesy of Lexicomp), or the prescribing information.

Diseases for which it is established (work in progress)

• Hairy cell leukemia
• Low-grade glioma, pediatric
• BRAF-mutated melanoma
• BRAF-mutated NSCLC
• BRAF-mutated anaplastic thyroid cancer

Diseases for which it is used

• BRAF-mutated colorectal cancer
• BRAF-mutated tumors (disease-agnostic)
• Low-grade serous ovarian cancer

Patient drug information

• Trametinib (Mekinist) package insert
• Trametinib (Mekinist) patient drug information (Chemocare)

History of changes in FDA indication

Low-grade glioma, pediatric

• 2023-03-16: FDA approved for pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. (Based on TADPOLE)

Melanoma, BRAF-mutated

• 2013-05-29: FDA approved for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. (Based on METRIC)
• 2014-01-10: Accelerated approval in combination with Dabrafenib (Tafinlar) for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. (Based on COMBI-d and COMBI-MB)
• 2018-04-30: Regular FDA approval with Dabrafenib (Tafinlar) in combination for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. (Based on COMBI-AD)

Non-small cell lung cancer, BRAF-mutated

• 2017-06-22: FDA approved in combination with Dabrafenib (Tafinlar) for patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test. (Based on BRF113928 previously treated & BRF113928 untreated)

Thyroid cancer, BRAF-mutated

• 2018-05-04: FDA approval with Dabrafenib (Tafinlar) in combination for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options. (Based on ROAR)

History of changes in EMA indication

High-grade glioma, pediatric

• 2023-11-09: CHMP recommended marketing authorisation as Spexotras - Spexotras in combination with dabrafenib is indicated for the treatment of paediatric patients aged 1 year and older with high-grade glioma (HGG) with a BRAF V600E mutation who have received at least one prior radiation and/or chemotherapy treatment.

Low-grade glioma, pediatric

• 2023-11-09: CHMP recommended marketing authorisation as Spexotras - Spexotras in combination with dabrafenib is indicated for the treatment of paediatric patients aged 1 year and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.

Melanoma

• 2014-06-30: Initial marketing authorization as Mekinist. Mekinist is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation. (Based on METRIC)
• 2015-08-25: Extension of indication to add a new therapeutic indication for the use in combination of trametinib and dabrafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
• 2018-08-27: Extension of indication to include the combination adjuvant treatment with trametinib and dabrafenib of adult patients with stage III melanoma with a BRAF V600 mutation, following complete resection.

Non-small cell lung cancer

• 2017-03-27: Extension of indication to include the combination treatment with trametinib and dabrafenib of adult patients with advanced non-small cell lung cancer (NSCLC) with a BRAF V600 mutation.

History of changes in Health Canada indication

• 2016-03-11: Initial notice of compliance with conditions
• 2016-05-13: Conditions were met

History of changes in PMDA indication

• 2016-03-28: Initial approval for the treatment of unresectable melanoma with BRAF mutation.
• 2018-03-23: New additional indication for the treatment of unresectable advanced or recurrent BRAF mutation-positive non-small cell lung cancer.
• 2018-07-02: New additional indication and a new dosage indicated for the treatment of BRAF mutation-positive melanoma.
• 2023-11-24: New indication and a new dosage for the treatment of advanced or recurrent BRAF mutation-positive solid tumor (excluding colon/rectal cancer) that is refractory or intolerant to standard therapies.
• 2023-11-24: New indication and a new dosage for the treatment of relapsed or refractory BRAF mutation-positive hairy cell leukemia.

Also known as

• Code names: GSK-1120212, GSK-212, JTP-74057
• Generic name: trametinib dimethyl sulfoxide
• Brand names: Mekinist, Meqsel, Spexotras