II. Indications
- Anaplastic Thyroid Cancer (V600E mutation, advanced or metastatic)
- BRAF agent and MEK agent (Dabrafenib PLUS Trametinib)
-
Melanoma
- BRAF agent and MEK agent (e.g. Vemurafenib PLUS Cobimetinib, Encorafenib PLUS Binimetinib)
- Other BRAF positive mutation related cancers treated off-label
- Metastatic Colorectal Cancer (Binimetinib)
- Metastatic Non-Small Cell Lung Cancer (Trametinib)
III. Mechanism
- Mitogen-Activated Protein Kinase (MAPK) Pathway
- Mitogen-Activated Extracellular Signal Regulated Kinase (MEK, MKK, Mitogen-Activated Protein Kinase Kinase)
- MEK Inhibitors
- Inhibit the MAPK pathway by blocking MEK receptors
- Used in BRAF mutations (V600E, V600K)
IV. Medications
- Binimetinib (Mektovi)
- Oral MEK1/2 Inhibitor (noncompetitive binding at ATP sites), blocking neoplasm growth factor signaling
- Risk of Cardiomyopathy, Venous Thromboembolism, hepatotoxicity, Interstitial Lung Disease, Rhabdomyolysis, ocular toxicity, bleeding
- Decrease dosing in moderate to severe hepatic Impairment
- Cobimetinib (Cotellic)
- Oral, specific MEK1 Inhibitor
- Risk of bleeding, Cardiomyopathy, new primary cancers, ocular toxicity, severe skin rashes
- Trametinib (Mekinist)
- In addition to anti-BRAF activity, inhibits Mitogen-Activated Protein Kinase (MEK MAPK/ERK kinase)
- Binds and blocks MEK 1 and 2, blocking growth factor-mediated cell signaling and cellular proliferation
- Trametinib binds both Threonine kinase and Tyrosine Kinase
- Risk of Colitis and risk of gastrointestinal perforation
V. Dosing
- See other references for disease specific dosing protocols
VI. Adverse Effects
- Hemorrhage (Binimetinib, )
- Colitis and risk of gastrointestinal perforation (Trametinib)
- Rhabdomyolysis (Binimetinib, Cobimetinib)
- Interstitial Lung Disease (Binimetinib)
- Hepatotoxicity (Binimetinib, Cobimetinib)
- Venous Thromboembolism (Binimetinib)
- Cardiomyopathy (Binimetinib, Trametinib, Cobimetinib)
- Ocular toxicity (Binimetinib, Cobimetinib)
- Serous Retinopathy
- Retinal vein Occlusion
- Dermatologic
- Severe papulopustular rash (Cobimetinib)
- Severe photosensitivity (Cobimetinib)
- New primary cancers including Skin Cancers (Cobimetinib)
- Other reported adverse effects
VII. Safety
- Avoid in Lactation
- Avoid in pregnancy (all trimesters, pregnancy category X)
- Use reliable Contraception (and for 4 months after completing Trametinib)
- Monitoring
- Echocardiogram after first month and then every 2-3 months (Binimetinib, Trametinib)
- Liver Function Tests (Binimetinib, Cobimetinib)
- Creatine Phosphokinase (Binimetinib)
- Skin exams for at least 6 months after stopping (Cobimetinib)
VIII. Drug Interactions
- Moderate to strong CYP3A4 Inhibitors and Inducers
- Avoid with Cobimetinib
IX. Resources
- Binimetinib
- Trametinib
- Cobimetinib