Patients With Distinct BRAF-mutant Melanoma Genotypes May Differentially Respond to Targeted and Immunologic Therapies

PHILADELPHIA – Unlike patients with melanoma bearing BRAF V600E mutations, those whose tumors have V600K mutations may benefit less from BRAF and MEK inhibitors and more from anti-PD-1 immunotherapy, according to results published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“The clinicopathic differences previously observed in V600E and V600K BRAF-mutant melanoma can now be explained by their biology,” said Alexander Menzies, MD, PhD, medical oncologist and associate professor at Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals. “These genotypes should be considered as distinct clinical entities with differing responses to treatments, and they should be managed differently.”

About 40 percent of patients with melanoma bear mutations in the gene BRAF, of which about 70-80 percent are V600E and 20-30 percent are V600K. Patients with BRAF mutations are often treated with targeted therapy, such as BRAF and MEK inhibitors, or anti-PD-1 immunotherapy, said Menzies.

Menzies and colleagues have previously published a study that evaluated the clinicopathic features of patients with BRAF-mutant melanoma. “We wanted to explore the molecular basis for differing clinical phenotypes observed between BRAF V600E and V600K melanomas, whether they have distinct response profiles to targeted treatments and immunotherapy, and the biological rationale for different clinical outcomes,” Menzies noted.

Menzies and colleagues evaluated baseline samples taken from 93 BRAF-mutant melanoma patients treated with targeted therapy (BRAF inhibitors with or without MEK inhibitors). Of these 93 patients, 73 had V600E BRAF-mutant melanoma, while 15 patients had V600K BRAF-mutant melanoma. Baseline samples were analyzed via gene expression profiling and DNA sequencing, and mutant genotypes were correlated with clinical outcomes.

The researchers also evaluated an independent cohort of 103 BRAF-mutant melanoma patients that were treated with anti-PD-1 immunotherapy (pembrolizumab or nivolumab). Of these 103 patients, 84 had V600E BRAF-mutant melanoma, while 19 patients had V600K BRAF-mutant melanoma. Response to immunotherapy based on BRAF genotype was correlated with clinical outcomes.

In the targeted therapy cohort, compared with patients with V600E mutations, those with V600K mutations had less tumor regression and shorter progression-free survival, although these differences were not statistically significant.

In the immunotherapy cohort, patients with V600K mutations had significantly higher progression-free survival compared with patients with V600E mutations (median of 19 and 2.7 months, respectively). While the response rate and overall survival was also higher in patients with V600K mutations compared with patients with V600E mutations, these increases were not statistically significant.

“These findings were likely limited by the small sample size of patients with V600K mutations and relatively short follow-up,” noted Menzies.

Analysis of baseline tumor samples in the targeted therapy cohort showed that patients harboring V600K BRAF mutations had a significantly higher mutational load compared with patients harboring V600E BRAF mutations. Patients harboring V600E mutations had significantly higher expression of ERK pathway genes and significantly lower expression of PI3K-AKT pathway genes compared with patients harboring V600K mutations.

“Patients with V600E mutations have higher activation of the MAPK/ERK signaling cascade, suggesting that their cancers have greater dependence on this pathway for growth and survival,” explained Menzies. “This explains why patients with V600E mutations have a better response to BRAF/MEK inhibitors compared with patients with V600K mutations.”

The enhanced response to anti-PD-1 immunotherapy in V600K patients can be explained by the increased mutational burden compared with V600E patients, noted Menzies. “We have shown that V600K BRAF-mutant melanoma patients derive greater benefit from immunotherapy and less from targeted therapy than those with V600E mutations,” said Menzies. “This suggests that V600K patients should be considered for immunotherapy where possible.”

Additionally, because patients with V600K mutations had increased activation of the PI3K growth and survival pathway, these patients may derive benefit from treatment with PI3K inhibitors, noted Menzies.

Limitations of the study 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, said Menzies.

This study was supported by a Pfizer Australia grant, a Cancer Council NSW grant, and an Australian National Health and Medical Research Council program grant.

Menzies serves on advisory boards for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, and Pierre Fabre.