MEK Inhibitor


MEK Inhibitor, MAP Kinase-ERK Kinase Inhibitor, Mitogen-Activated Protein Kinase Kinase Inhibitor, Binimetinib, Mektovi, Trametinib, Mekinist, Cobimetinib, Cotellic

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