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Molecular Profiles of BRAF-Mutant Melanomas and Response to Therapy

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Key Points

  • BRAF V600E and V600K–mutant melanomas are biologically distinct subtypes that not only have different clinical phenotypes, but different molecular features and responses to systemic therapies as well.
  • BRAF V600K–mutant melanomas appear to benefit less from BRAF and MEK inhibitors than V600E­-mutant melanomas, potentially due to less reliance on ERK pathway activation. In contrast, these melanomas have higher mutational load and respond better to immunotherapy.

A study investigating the clinicopathologic features of BRAF V600E– and V600K–mutant melanomas and whether genotype affects response to immunotherapy found that the mutations not only have different clinical phenotypes, but also different molecular features and different responses to systemic therapies. Melanomas with a BRAF V600K mutation appear to benefit less from BRAF and MEK inhibitors than BRAF V600E–mutant melanomas and more from anti–programmed cell death protein 1 (PD-1) immunotherapy. The study by da Silva et al was published in Clinical Cancer Research.

The identification of BRAF driver mutations in melanoma has led to the development of specific inhibitors targeting the ERK pathway, which has led to higher response rates and improved survival in patients. About 40% of cutaneous melanomas have BRAF mutations, of which between 70% and 80% are classified as V600E and between 20% and 30% are classified as V600K.

Study Methodology

Pretreatment formalin-fixed, paraffin-embedded melanoma tumors from 93 patients treated with BRAF inhibitors with or without MEK inhibitors underwent gene-expression profiling and DNA sequencing. Of these 93 patients, 73 had BRAF V600E–mutant melanoma, and 15 patients had BRAF V600K–mutant melanoma. The researchers validated the molecular results using data from The Cancer Genome Atlas.

An independent cohort of 103 patients with BRAF V600E/K mutations treated with anti–PD-1 immunotherapy—pembrolizumab or nivolumab—was also examined. Of these 103 patients, 84 had BRAF V600E–mutant melanoma, and 19 patients had BRAF V600K–mutant melanoma.

Response to immunotherapy based on BRAF genotype was correlated with clinical outcomes.

Study Results

The researchers found that in the targeted-therapy cohort, compared with the patients with BRAF V600E mutations, those with BRAF V600K mutations had less tumor regression and shorter progression-free survival, although the differences were not statistically significant.

In the immunotherapy cohort, the researchers found that the patients with BRAF V600K mutations had significantly higher progression-free survival compared to patients with BRAF V600E mutations—a median of 19 vs 2.7 months, respectively. Although the response rate and overall survival were also higher in patients with BRAF V600K mutations compared to the patients with BRAF V600E mutations, these increases were not statistically significant.

BRAF V600K–[mutant] melanomas appear to benefit less from [BRAF and MEK inhibitors] than V600E­–[mutant melanomas], potentially due to less reliance on ERK pathway activation, and greater use of alternative pathways. In contrast, these melanomas have higher mutational load and respond better to immunotherapy,” concluded the study authors.

Clinical Significance

The findings from this study, suggest the study authors, should lead to the development of alternative treatment approaches for specific subtypes of BRAF-mutant melanoma.

“We have shown that [patients with] BRAF V600K–mutant melanoma derive greater benefit from immunotherapy and less from targeted therapy than those with V600E mutations,” said Alexander Menzies, MD, PhD, Associate Professor at the Melanoma Institute Australia and a coauthor of this study, in a statement. “This suggests that [patients with BRAF] V600K [mutations] should be considered for immunotherapy where possible.”

Dr. Menzies is the corresponding author of this study.

Disclosure: Funding for this study was provided by Pfizer Australia, Cancer Council NSW, and the Australian National Health and Medical Research Council. The study authors’ full disclosures can be found at clincancerres.aacrjournals.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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