Vemurafenib is the first molecularly targeted
therapy to be licensed in the US and Europe for treatment of advanced
melanoma. Its mechanism of action involves selective inhibition of the mutated BRAF V600E
kinase that leads to reduced signalling through the aberrant
mitogen-activated protein kinase (MAPK) pathway. Its efficacy is restricted to
melanomas carrying the BRAF V600E mutation, which is seen in approximately 50% of all
melanomas. In a randomized phase III trial, it was superior to
dacarbazine in first-line treatment of advanced
melanoma, with an overall response rate (ORR) of 48% (95% CI 42, 45), an estimated 6-month progression-free survival (PFS) of 5.3 versus 1.6 months (hazard ratio [HR] 0.26; 95% CI 0.20, 0.33; p < 0.001) and a statistically superior 12-month overall survival (OS) rate of 55% versus 43% (HR 0.62 [95% CI 0.49, 0.77]).
Vemurafenib is generally well tolerated, but its use can be associated with development of cutaneous
neoplasms such as
squamous cell carcinoma (SCC) and
keratoacanthoma (KA). These lesions can be excised safely without the need for withholding the
drug or reducing its dose. Mechanisms of resistance to
vemurafenib do not involve development of secondary mutations in the
BRAF kinase domain, but may be related to BRAF V600E over-amplification, bypassing mechanisms via upregulation and overexpression of other components in the MAPK signalling cascade or activation of alternative pathways with potential to enhance cell growth, proliferation and survival. Clinical trials to test the efficacy of
vemurafenib in combination with
immunomodulatory agents, such as
ipilimumab, and
MAPK kinase (
MEK) inhibitors, such as
GDC-0973, in the treatment of advanced
melanoma are currently underway. Also under investigation is the use of
vemurafenib in other solid tumours with BRAF mutations, such as
papillary thyroid cancer.