Targeting BRAF Mutation in Melanoma Treatment

Melanoma is an aggressive disease with a poor prognosis when diagnosed at an advanced stage. Patients generally do not benefit from traditional chemotherapy but until very recently treatment options have been limited. In 2002, the discovery of a single-base substitution mutation in the BRAF gene that is common in malignant melanoma initiated the development of targeted therapy for the disease.¹

BRAF is found downstream of NRAS in the mitogen-activated protein (MAP) kinase pathway that aids in regulation of cell growth. Although BRAF mutations are seen in multiple cancers, the mutation predominates in melanoma; activating BRAF mutations are found in 40% to 60% of melanoma tumors.^1-5 BRAF mutations and NRAS mutations, which are the second most common mutation found in melanoma, are considered mutually exclusive.³ BRAF mutations occur at early stages of the disease and are preserved through metastatic transformation.³

By far the most common mutation in melanoma, occurring in approximately 90% of patients with the disease, is a point mutation (T1796A) resulting in substitution of glutamic acid for valine at amino acid 600 (V600E BRAF); this substitution has the effect of constitutively activating the BRAF protein kinase, leading to tumor cell growth independent of other kinases or growth signals.^1,3,5

While there are multiple pathways to cell growth, BRAF-mutated tumors rely entirely on MAP kinase pathway activation such that BRAF inhibition checks tumor growth.⁴ This insight led to clinical development of small molecule kinase inhibitors designed to block BRAF. Without BRAF inhibitor treatment, the presence of a BRAF mutation is associated with poor prognosis for patients diagnosed with stage IV melanoma. When these patients receive treatment with a BRAF inhibitor, their prognosis is better than that of stage IV patients lacking the mutation.⁴

BRAF Inhibitors: Current and Potential Options

Vemurafenib, an oral BRAF inhibitor administered twice daily, is the first such agent to demonstrate improved survival and receive approval from the U.S. Food and Drug Administration (FDA). In a phase 1 study with 32 V600E BRAF–positive patients with melanoma, 24 partial responses (PR) and two complete responses (CR) were achieved, for a response rate of 81%. Responses were seen at all metastatic sites as well.²  

In a phase 2 trial of V600 BRAF–positive patients with melanoma who were previously treated, 47% achieved PR and 6% achieved CR. Median progression-free survival (PFS) was 6.8 months, and 18-month overall survival (OS) was 43%. Some responses occurred as long as 6 months after treatment initiation.⁶

In a phase 3 trial comparing vemurafenib with dacarbazine for treatment-naïve metastatic melanoma, significant improvements in PFS and OS were seen with vemurafenib, leading to a 63% reduction in risk of death and 74% reduction in risk of progression (Table 1).⁷ Primary resistance to vemurafenib is seen in fewer than 10% of V600E BRAF–positive patients.⁴

Table 1. BRAF Inhibitors for Advanced/Metastatic Melanoma: Survival in Phase 3 Trials