Trametinib — Drug Monograph

Brand names: Mekinist

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Highly selective, allosteric inhibitor of MEK1 and MEK2 (mitogen-activated protein kinase kinase 1/2). MEK is a serine/threonine kinase directly downstream of BRAF in the MAPK signaling cascade. By blocking MEK1/2 phosphorylation and activation, trametinib suppresses ERK signaling and downstream transcription of proliferative and survival genes. Trametinib does not bind to the ATP pocket (non-competitive inhibitor) — it binds to an allosteric site adjacent to the ATP-binding pocket. In combination with the BRAF inhibitor dabrafenib, trametinib prevents the paradoxical MEK/ERK reactivation…

FDA Indications

• Melanoma — BRAF V600E/K, unresectable or metastatic (with dabrafenib)
• Melanoma — BRAF V600E/K, adjuvant, Stage III (with dabrafenib)
• NSCLC — BRAF V600E metastatic (with dabrafenib)
• Anaplastic thyroid carcinoma (ATC) — BRAF V600E locally advanced or metastatic (with dabrafenib)
• Solid tumors — BRAF V600E, unresectable or metastatic, after prior therapy (tumor-agnostic, with dabrafenib)
• Low-grade glioma and high-grade glioma (pediatric) — BRAF V600E (with dabrafenib)

Common Side Effects

• Rash (acneiform/papulopustular — class effect of MEK inhibitors)
• Diarrhea
• Edema (peripheral)
• Fatigue
• Nausea
• Hypertension
• Vomiting
• Dry skin

Clinical Pearl

Trametinib is one of the few drugs with a truly tumor-agnostic approval (BRAF V600E across any solid tumor type). Cardiomyopathy is a MEK inhibitor class effect — LVEF must be measured before starting and every 2–3 months during treatment. Ocular toxicity (retinal pigment epithelial detachment; central serous retinopathy) causes visual symptoms (blurry vision, photopsia, colored visual disturbances) — patients must report promptly, and ophthalmology evaluation is urgent.

Related Therapies & Mechanisms

• Dabrafenib (Tafinlar) — Tyrosine Kinase Inhibitor · NSCLC
• Larotrectinib (Vitrakvi) — Tyrosine Kinase Inhibitor · NSCLC
• Pralsetinib (Gavreto) — Tyrosine Kinase Inhibitor · NSCLC
• Selpercatinib (Retevmo) — Tyrosine Kinase Inhibitor · NSCLC