BRAF Inhibitor


BRAF Inhibitor, B-raf proto-oncogene Inhibitor, Dabrafenib, Tafinlar, Vemurafenib, Zelboraf, Encorafenib, Braftovi

  • Indications
  1. Lung Adenocarcinoma (V600E Mutation, metastatic)
  2. Anaplastic Thyroid Cancer (V600E mutation, advanced or metastatic)
    1. BRAF agent and MEK agent (Dabrafenib PLUS Trametinib)
  3. Melanoma (V600E or V600k mutation, metastatic)
    1. BRAF agent and MEK agent (e.g. Vemurafenib PLUS Cobimetinib, Encorafenib PLUS Binimetinib)
  • Contraindications
  1. Wild-type cancers without BRAF V600E Mutation
    1. Wild type cancers (e.g. Melanoma) may be promoted if BRAF V600E is absent
  2. Chronic Myelomonocytic Leukemia with NRAS mutation
    1. Risk of progression
  3. QT Prolongation (Vemurafenib, Encorafenib)
    1. Avoid with QTc >500 ms
    2. Also correct significant Electrolyte abnormalities (e.g. Hypomagnesemia, Hypokalemia) before use
    3. Avoid with other Medication Causes of QTc Prolongation
  • Mechanism
  1. Antineoplastic, small molecule inhibitors of the B-Raf Protein (BRAF proto-oncogene)
    1. Selective for mutated BRAF (esp. BRAFV600 mutation)
  2. B-Raf Inhibitors inhibit the proliferation of tumor cells containing defective B-Raf genes
    1. B-Raf is among the Raf-Mil group of Serine and ThreonineProtein kinases
    2. B-Raf contributes to regulation of the ERK/MAPK Signaling Pathway
  • Medications
  1. Dabrafenib (Tafinlar)
    1. Risk of new primary Squamous Cell Carcinoma (SCC)
  2. Vemurafenib (Zelboraf)
    1. Risk of SCC, Toxic Epidermal Necrolysis, DRESS Syndrome, hepatotoxicity, Pancreatitis, nephrotoxicity
    2. Avoid with moderate to strong CYP3A Inhibitors and Inducers, P-gp substrates and CYP1A2 Substrates
  3. Encorafenib (Braftovi)
    1. Risk of new primary Squamous Cell Carcinoma (SCC), Hemorrhage, Uveitis, QT Prolongation
  4. Trametinib (Mekinst)
    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 (including with perforation)
    5. Risk of Cardiomyopathy (obtain echo for LV EF at 1 month after start, then every 2 to 3 months)
  • Dosing
  1. See other references for disease specific dosing protocols
  • Adverse Effects
  1. New primary Skin Cancers (all BRAF Inhibitors, up to 25% of patients on Vemurafenib)
    1. Squamous Cell Skin Cancer (other squamous cell cancers have been reported)
    2. Basal Cell Skin Cancers may also be increased
  2. Hypersensitivity Reactions
  3. Severe dermatologic reactions (Vemurafenib)
    1. Toxic Epidermal Necrolysis
    2. DRESS Syndrome
  4. Hepatotoxicity (Vemurafenib)
  5. Acute Pancreatitis (Vemurafenib)
  6. Nephrotoxicity (Vemurafenib)
  7. QT Prolongation (Vemurafenib, Encorafenib)
  8. Uveitis (Vemurafenib, Encorafenib)
  9. Hemorrhage (Encorafenib)
  10. Other adverse effects
    1. Phosensitivity
    2. Alopecia
    3. Fatigue
  • Safety
  1. Avoid in Lactation
  2. Avoid in pregnancy (all trimesters, pregnancy category X)
    1. Use reliable Contraception (non-hormonal) for at least 4 weeks after most agents
  3. Monitoring
    1. Dermatologic skin exam (all BRAF Inhibitors)
      1. Perform baseline (before start), then every 2 months (and up to 6 months after completion)
    2. Electrocardiogram (Vemurafenib, Encorafenib)
      1. Evaluate for QT Prolongation at baseline
    3. Additional testing for Vemurafenib
      1. Periodic Liver Function Tests, Lipase and Renal Function tests
  • Drug Interactions
  1. Medication Causes of QTc Prolongation
    1. Avoid with Vemurafenib, Encorafenib
  2. Vemurafenib
    1. Avoid with moderate to strong CYP3A Inhibitors and Inducers, P-gp substrates and CYP1A2 Substrates