MEK Inhibitors Overview
- Target: MEK1 and MEK2 (mitogen-activated protein kinase kinases), downstream of BRAF in the MAPK/ERK signaling pathway.
- Rationale: In tumors with BRAF V600E/K mutations, MEK activation drives proliferation. Blocking MEK helps overcome resistance and enhances efficacy when combined with BRAF inhibitors.
FDA-Approved MEK Inhibitors
| Drug (Brand) | Main Indications | Usual Dose | Key Toxicities | Monitoring |
|---|---|---|---|---|
| Trametinib (Mekinist) | BRAF V600E/K+ melanoma (mono or with dabrafenib); adjuvant melanoma; BRAF+ NSCLC (with dabrafenib); anaplastic thyroid cancer (with dabrafenib) | 2 mg PO once daily | Cardiomyopathy (↓LVEF), ocular toxicity (retinal detachment, RVO), rash, diarrhea, ILD, fever (combo) | Echo/MUGA, ophthalmology, BP, fever education |
| Cobimetinib (Cotellic) | BRAF V600E/K+ melanoma (with vemurafenib) | 60 mg PO daily × 21 days of 28-day cycle | Photosensitivity, CPK elevation (myopathy/rhabdomyolysis), hepatotoxicity, ocular toxicity, diarrhea, rash | LFTs, CPK, ophthalmology, dermatology |
| Binimetinib (Mektovi) | BRAF V600E/K+ melanoma (with encorafenib) | 45 mg PO BID | CPK elevation, cardiomyopathy, ocular toxicity, rash, diarrhea, ILD | CPK, Echo, ophthalmology |
| Selumetinib (Koselugo) | Pediatric NF1 with symptomatic, inoperable plexiform neurofibromas | 25 mg/m² PO BID | GI toxicity, CPK elevation, rash, cardiomyopathy, ocular toxicity | Echo, ophthalmology, CPK |
Class Effects (Common to MEK Inhibitors)
- Cardiac: ↓LVEF / cardiomyopathy
- Ocular: retinal vein occlusion, retinal pigment epithelial detachment → vision changes need urgent exam
- Dermatologic: rash, acneiform eruption, photosensitivity
- GI: diarrhea, nausea
- Musculoskeletal: CPK elevation, myopathy/rhabdomyolysis
- Pulmonary: ILD/pneumonitis
- Hepatic: ↑LFTs
- Fever: more common in combination regimens
Pharmacist Pearls
- Always confirm BRAF mutation before combining with a BRAF inhibitor.
- Monotherapy with MEK inhibitors is generally less effective; combination with BRAF inhibitors is standard of care in BRAF+ melanoma, NSCLC, and anaplastic thyroid cancer.
- Counsel patients on: fever management, vision changes, muscle pain/weakness, and photoprotection.
- Regular cardiac and ophthalmologic monitoring is essential.