Alexander M. Menzies, MD
In a study reported in Clinical Cancer Research, Alexander M. Menzies, MD, of Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, and colleagues found that BRAF V600K melanomas are less responsive to BRAF inhibitor with or without MEK inhibitor treatment than V600E melanoma.1 These findings potentially reflect differences in pathway activation, and V600K melanomas exhibit higher mutational load and better response to immunotherapy.
The study included evaluation of baseline tissue and clinical outcome with a BRAF inhibitor with or without MEK inhibitor treatment in 78 patients with V600E mutation and 15 with V600K mutation; 20% of the V600E patients and 33% of the V600K patients received combined BRAF and MEK inhibitors. Pretreatment formalin-fixed paraffin-embedded tumor samples underwent gene-expression profiling and DNA sequencing, with molecular findings validated using The Cancer Genome Atlas (TCGA) data. An independent group of patients with V600E/K mutations was evaluated for response to anti–programmed cell death protein 1 (anti–PD-1) immunotherapy.
Responses to Treatment
Among patients receiving BRAF inhibitor/MEK inhibitor treatment, patients with tumors harboring a V600K mutation vs those with tumors harboring V600E mutations exhibited less tumor regression and shorter progression-free survival, although these differences were not statistically significant.In patients receiving immunotherapy, those with tumors harboringV600K mutations had statistically significantly higher progression-free survival rates (median of 19 and 2.7 months, respectively). Response rates and overall survival were also higher in patients with V600K mutations, but these differences were not statistically significant.
Analysis of baseline tumor samples in the targeted therapy cohort showed that patients with tumors harboring V600K BRAF mutations had a significantly higher mutational load compared to patients with tumors harboring V600E BRAF mutations. Patients with tumors harboring V600E mutations had significantly higher expression of ERK pathway genes and significantly lower expression of PI3K-AKT pathway genes compared with patients with tumors harboring V600K mutations.
The enhanced response to anti–PD-1 immunotherapy in V600K-mutant melanoma can be explained by the increased mutational burden compared with V600E-mutant melanoma, Dr. -Menzies noted. “We have shown that [patients with] V600K BRAF-mutant melanoma derive greater benefit from immunotherapy and less from targeted therapy than those with V600E mutations,” said Dr. Menzies, suggesting that immunotherapy should be considered in this population. Study limitations include the small number of patients with V600K BRAF-mutant melanoma and the lack of validation of these results in a larger cohort of patients treated with immunotherapy. The study was supported by a Pfizer Australia grant, Cancer Council NSW grant, and Australian National Health and Medical Research Council program grant. ■
DISCLOSURE: For full disclosures of the study authors, visit www.clincancerres.aacrjournals.org.
1. Pires da Silva I, Wang KYX, Wilmott JS, et al: Clin Cancer Res 25:1272-1279, 2019.