Review: Treatment of Patients with BRAF V600K-Mutant Melanoma Remains Under-Studied

A new review article offers insights into patients with cutaneous melanomas with BRAF V600K mutations, a subgroup of patients in whom little specific study has occurred.

Writing in the Journal of Clinical Medicine, corresponding author Simone Ribero, MD, PhD, and colleagues said about half of patients with melanomas have a BRAF mutation, and the most common type is V600E. About 1 in 10 patients with a BRAF mutation have a V600K mutation, but no studies have been conducted with the specific aim of identifying the optimal therapy for this patient group, the investigators explained.

Hoping to fill the gap, Ribero, an assistant professor at the University of Turin, and colleagues undertook an analysis of published clinical trials that included patients with V600K mutations to see what commonalities they could find, and to determine which therapies might be most effective.

The existing data appear to suggest that the V600K mutation is more common in White, male, and elderly populations, and particularly in those with a history of chronic sun damage and exposure.

In terms of clinical features, while the trunk is the most common primary site for V600K melanomas, the head and neck regions are also common sites, in contrast with V600E melanomas (33% V600K vs. 11% V600E, respectively). Although V600K melanoma was found in one study to have a shorter time from diagnosis to first distant metastasis, it did not appear to have an effect on overall survival.

Biologically, Ribero and colleagues wrote that the V600K melanoma subtype “seems to be less dependent on the ERK/MAPK pathway, with a higher expression of PI3KB and a strong inhibition of multiple antiapoptotic pathways.”

Effective treatment of patients with V600K mutations seems to be achievable with BRAF and MEK inhibitors and immunotherapy with anti-checkpoint blockers, the investigators said.

“The literature has shown how V600K melanomas represent a specific population with its own peculiarities, but still the approach and the therapeutic path are mostly comparable to the ones for other genetic subtypes of cutaneous melanomas,” the authors said.

For instance, the COLUMBUS trial showed patients with the V600K mutation had a long-term benefit with encorafenib and binimetinib compared with single-agent vemurafenib, the authors noted.

Ribero and colleagues added that future therapeutic targets could involve the PI3K pathway, given the higher expression of PI3KB in this patient group.

“Alpelisib, an inhibitor of PI3KCA recently approved for metastatic breast cancer by the FDA may also be considered in the treatment of melanoma: however, further knowledge should be acquired on the underlying working mechanisms with respect to this tumor,” Ribero and colleagues wrote.

They added that, while study data suggests immunotherapy confers a benefit to patients, there is not enough data to quantify exactly what that benefit is, thus making it impossible to offer a formal recommendation on its use.

The authors concluded significantly more research is needed to better understand how best to treat this particular subgroup and to identify a “gold standard” of treatment.

“Future studies should clarify which therapeutic strategy may be more effective for this specific patient subgroup,” they wrote. “In addition, prognostic factors on treatment response could be usefully investigated.”

Reference:

Nepote A, Avallone G, Ribero S, et al. Current controversies and challenges on BRAF V600K-mutant cutaneous melanoma. J Clin Med. Published online February 4, 2022. doi:10.3390/jcm11030828