BRAF Kinase Inhibitor (Dabrafenib) for Treating Metastatic Melanoma
February 14, 2012 | Technology Forecasts
When melanoma is detected at an early stage, surgical resection can prevent further development in most cases.1 For metastasized melanoma, or in cases of nonresectable melanoma, chemotherapy and radiation are typically used; however, neither has been shown to significantly improve survival.2 Adjuvant immunotherapy (e.g., interferon gamma, investigational vaccines, monoclonal antibodies, cytokines) may also be prescribed.2
For patients with metastatic melanoma that is incurable by surgical resection, the current standard of treatment is systemic chemotherapy using dacarbazine.2 Additional treatment options include other chemotherapy regimens (e.g., dacarbazine plus platinum agent combination therapy, paclitaxel-based therapy), biotherapy (e.g., interleukin-2), chemobiotherapy (e.g., dacarbazine plus interleukin-2), palliative surgery, and palliative radiation therapy.2,3 These options may also be used as second-line treatment if a patient's melanoma progresses during first-line treatment.
GlaxoSmithKline (London, United Kingdom) has developed dabrafenib (formerly GSK2118436), a small-molecule inhibitor of the kinase activity of the signal transduction protein BRAF.4 BRAF plays a central role in the RAS/Map Kinase signal transduction pathway, which is essential for cell growth and cell proliferation. Misregulation of this pathway is involved in multiple cancers.5 In particular, BRAFmutations that encode a constitutively active BRAF protein have been identified in approximately 8% of human tumors.5 While only a small fraction of all human tumors harbor an activating BRAF mutation, more than half of melanomas analyzed have been shown to bear such an allele.6 Activated BRAF is proposed to lead to hyperactivation of the downstream ERK/MEK/Map Kinase pathway, upon which melanomas are dependent for growth and survival.6 Therefore, the specific inhibition of oncogenic BRAF kinase activity is a promising pharmacologic target.1,7 If approved for the indications currently under study, dabrafenib would be used to treat advanced or metastatic melanoma that is positive for an activating mutation in the BRAF gene.
The first phase III trial for dabrafenib was announced in January 2011. A regulatory submission in the United States and Europe is not anticipated...