Non-V600E melanoma

BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

The most common oncogenic point mutation in BRAF mutant melanoma results in substitution of a valine for a glutamic acid at codon 600 (V600E) which comprises 80–90% of BRAF V600 mutations [48]. Pre-clinical experiments and clinical experience suggest that alternate V600 mutations also confer sensitivity to BRAF inhibitors [49]. These genetic alterations do confer sensitivity to approved therapies and may be missed on standard BRAFV600E mutational testing. The second most common BRAF mutation is BRAFV600K which also appears to be quite sensitive to BRAF and MEK inhibition. BRAFV600R mutations also occur infrequently, although in one small series five of six patients with BRAFV600R mutant melanoma experienced an objective response to dabrafenib [41]. Additionally, a patient with melanoma harboring both BRAF V600E and V600M mutations experienced a dramatic response to dabrafenib [50].

Mutations in BRAF at locations other than codon 600 may also occur, most commonly at codon 597. These genetic alterations may occur with a frequency of up to 5% in presumed BRAF wild-type melanoma. Based on pre-clinical and limited clinical experience, these mutations appear to confer sensitivity to MEK inhibitors, including one patient with BRAFL597S mutant melanoma who experienced a partial response to TAK-733, an experimental MEK inhibitor [51]. Pre-clinical data does not clearly define whether these melanomas should be sensitive to BRAF inhibitors although one patient with a BRAFL597R mutation experienced a major response to vemurafenib [52]. Additionally, BRAF fusions have been recently described in melanoma and seem to confer sensitivity to MEK inhibitors in pre-clinical studies. A clinical trial of trametinib for patients with these uncommon BRAF alterations is planned.

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