Vemurafenib is a kinase inhibitor used in the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E variant.
BRAF is an intracellular kinase in the mitogen-activated protein kinases (MAPK) pathway. BRAF is involved in regulating important cell functions such as cell growth, division, differentiation, and apoptosis. BRAF is also a proto-oncogene—when mutated it has the ability to transform normal cells into cancerous cells.
Variation in the kinase domain of BRAF have been associated with various cancers. The most common BRAF variant, V600E, constitutively activates the kinase, and causes cell proliferation in the absence of growth factors that would normally be required. The V600E variant is detected in approximately 50% of melanomas (1, 2).
The FDA-approved drug label for vemurafenib states that the presence of BRAF V600E mutation in tumor specimens should be confirmed, using an FDA-approved test, before starting treatment with vemurafenib. The label also states that vemurafenib is not indicated for treatment of patients with wild-type BRAF melanoma (3).
Variations in NRAS, also an oncogene, are found in up to 30% of all malignancies and in approximately 15-20% of melanomas. NRAS variants activate MAPK and have been implicated in in acquired resistance to BRAF inhibitors. Vemurafenib’s label warns that one adverse effect associated with therapy may be the progression of pre-existing chronic myelomonocytic leukemia with NRAS mutation (3). Other adverse effects include arthralgia, rash, alopecia, photosensitivity reaction, pruritus, and skin papilloma.