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