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Drugs of interest to pathologists

Drugs related to surgical pathology

Vemurafenib


Author: Him G. Kwee, M.D. (see Reviewers/Authors page)
Revised: 8 November 2011, last major update October 2011
Copyright: (c) 2011, PathologyOutlines.com, Inc.

General
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● Vemurafenib is a BRAF protein kinase inhibitor
● BRAF means v-raf murine sarcoma viral oncogene homolog B1; is a serine / threonine specific protein kinase encoded by the BRAF gene that is a part of the RAS/MAPK pathway regulating the growth, maturation, proliferation, survival and apoptosis of cells
● Vemurafenib interrupts the BRAF/MEK step in the BRAF/MEK/ERK pathway if the BRAF has the V600E mutation (valine replaced by glutamic acid)
● If no V600E mutation, Vemurafenib could stimulate BRAF and may promote tumor growth (N Engl J Med 2010;363:809)

Trade name
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● Zelboraf

Clinical information
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● Approved by US Food and Drug Administration in August 2011 for unresectable or metastatic malignant melanoma that has the BRAF V600E mutation
● Approximate cost: $10,000 per month in 2011

Diagrams
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Signaling pathway after EGFR activation (phosphorylation) by binding of ligand


● EGFR = Epidermal growth factor receptor
● Grb-2 = growth factor receptor-bound protein
● SOS = son of sevenless homolog
● RAS = rat sarcoma viral oncogene homolog
● RAF = proto-oncogene serine / threonine-protein kinase
● MEK = mitogen- activated protein kinase / Erk kinase
● MAPK = mitogen activated protein-kinase

Use for pathologists
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● 50% of melanomas have V600E mutation; cannot predict by histology
● On the same day that the FDA approved the drug, it also approved the test to diagnose this mutation, the Cobas 4800 BRAF 600 mutation test (Roche Molecular Systems), which can be performed on formalin fixed paraffin embedded tissue (FDA News Release, August 17, 2011)
● Side effect of vemurafenib is that 24% of patients develop cutaneous squamous cell carcinoma; may also develop keratoacanthomas and squamous papillomas (Zelboraf, Genentech and package insert)
● Drug cost is comparable to ipilimumab, another FDA approved drug for melanoma (March 2011), which is a human monoclonal antibody that binds CTLA-4 (cytotoxic T lymphocyte associated antigen 4); however, ipilimumab could cause severe and potentially fatal immune mediated enterocolitis, hepatitis and dermatitis (FDA News Release, March 2011)
● Combination therapy with ipilimumab and vemurafenib is being studied in a clinical trial (Roche clinical bulletin, June 2011)
● There are ongoing clinical trials to study the efficacy of vemurafenib in advanced colorectal carcinoma and papillary thyroid carcinoma

End of Drugs > Drugs related to surgical pathology > Vemurafenib


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