BRAF Inhibitor

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

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II. 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)

III. 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

IV. 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

V. 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)

VI. Dosing

  1. See other references for disease specific dosing protocols

VII. 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

VIII. 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

IX. 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

X. Resources

  1. Dabrafenib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fee1e6b1-e1a5-4254-9f2e-a70e0f8dbdea
  2. Vemurafenib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=38eea320-7e0c-485a-bc30-98c3c45e2763
  3. Encorafenib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=235dfc38-0f0b-4037-b501-7a9f4294740c

XI. References

  1. Proietti (2020) Cancers 12(7):1823 +PMID: 32645969 [PubMed]

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Related Studies

Ontology: Vemurafenib (C3192263)

Definition (NCI) An orally bioavailable, ATP-competitive, small-molecule inhibitor of BRAF(V600E) kinase with potential antineoplastic activity. Vemurafenib selectively binds to the ATP-binding site of BRAF(V600E) kinase and inhibits its activity, which may result in an inhibition of an over-activated MAPK signaling pathway downstream in BRAF(V600E) kinase-expressing tumor cells and a reduction in tumor cell proliferation. Approximately 90% of BRAF gene mutations involve a valine-to-glutamic acid mutation at residue 600 (V600E); the oncogene protein product, BRAF(V600E) kinase, exhibits a markedly elevated activity that over-activates the MAPK signaling pathway. The BRAF(V600E) gene mutation has been found to occur in approximately 60% of melanomas, and in about 8% of all solid tumors, including melanoma, colorectal, thyroid and other cancers.
Definition (NCI_NCI-GLOSS) A substance being studied in the treatment of cancer. BRAF (V600E) kinase is a mutated (changed) form of a cell protein called BRAF. It is found in several types of cancer, including melanoma (a type of skin cancer). Inhibiting this kinase may cause cancer cells to die. BRAF (V600E) kinase is a type of serine/threonine kinase inhibitor and a type of targeted therapy agent.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C551177
SnomedCT 703656005, 702805007
English vemurafenib, Vemurafenib, VEMURAFENIB, 1-propanesulfonamide, n-(3-((5-(4-chlorophenyl)-1h-pyrrolo(2,3-b)pyridin-3-yl)carbonyl)-2,4-difluorophenyl)-, Vemurafenib (substance), Vemurafenib (product)
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: dabrafenib (C3467876)

Definition (NCI) An orally bioavailable inhibitor of B-raf (BRAF) protein with potential antineoplastic activity. Dabrafenib selectively binds to and inhibits the activity of B-raf, which may inhibit the proliferation of tumor cells which contain a mutated BRAF gene. B-raf belongs to the raf/mil family of serine/threonine protein kinases and plays a role in regulating the MAP kinase/ERKs signaling pathway, which may be constitutively activated due to BRAF gene mutations.
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C561627
SnomedCT 703641001, 703646006
English GSK2118436, BRAF Inhibitor GSK2118436, GSK-2118436A, Benzenesulfonamide, N-(3-(5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl)-2-fluorophenyl)-2,6-difluoro-, dabrafenib, Dabrafenib (substance), Dabrafenib, Dabrafenib (product), DABRAFENIB
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: BRAF inhibitor (C3838813)

Concepts Pharmacologic Substance (T121) , Amino Acid, Peptide, or Protein (T116)
SnomedCT 703643003, 703645005
English B-raf inhibitor, BRAF inhibitor (substance), BRAF inhibitor (product), BRAF inhibitor
Derived from the NIH UMLS (Unified Medical Language System)

Related Topics in Pharmacology

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