Treating wild-type BRAF mutated melanoma poses challenges

Banff, Alberta - Various approaches are being initiated to treat wild-type, BRAF mutated melanoma, according to the director of the Melanoma Program and co-leader of the Signal Transduction Program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

Speaking here at the annual Canadian melanoma conference in February, medical oncologist Jeff Sosman, M.D., professor of medicine at the cancer center, discussed management approaches to melanoma where that has a BRAF, wild-type genotype. Dr. Sosman describes these forms of melanoma as heterogeneous disease.

Since the BRAF inhibitors are not effective in patients with wild-type melanoma, alternative therapeutic approaches have to be examined, Dr. Sosman says. Even when responses have been produced with the use of BRAF inhibitors, resistance typically develops within a year of treatment, underlining the need for other treatment approaches.

“There’s no doubt that immunotherapy plays a critical role in the treatment of these patients (those with wild-type melanoma),” Dr. Sosman says. “There are many other genetic changes that make up a consistent theme about what the targeted molecules are in these patients. There are several populations in the BRAF wild-type. We know NRAS is a driver that causes the cancer and plays a key role. We have had difficulty getting a drug that hits the target and effectively blocks it.”

Identifying common mutations

The Cancer Genome Atlas, a project funded by the National Institutes of Health that involves charting the genomic changes in various cancers - including cutaneous melanoma - has revealed that there are a number of common mutations in the BRAF, wild-type group, Dr. Sosman says.

About a third of BRAF, wild-type patients have NRAS mutations; a very small subset of patients have cKit mutant melanoma arising from mucosal, acral, and chronic, sun-damaged sites and make up another proportion of BRAF, wild-type patients. Finally, there are a number of BRAF, non-V600 mutations or BRAF fusion kinases.

“We have recently conducted whole-genome sequencing to find a BRAF mutation in exon 15 called L597R,” Dr. Sosman says.

Researchers found that cells habor BRAF mutants that are sensitive to MEK inhibitors, which serves as a basis for routine screening and a therapeutic paradigm of BRAF mutant melanoma where L597R is present ( Cancer Discovery. 2012;2(9):791-797).

“There are a number of BRAF mutations that don’t involve the V600 allele,” Dr. Sosman says. “They do not inherently appear responsive to the BRAF inhibitors. Even though cKit is exceedingly rare, you should always look for it. It makes up about 15 percent of mucosal or acral melanomas, which are really rare to begin with.”

Targeted treatments

There is no effective targeted therapy that has been generated for NRAS mutant tumors or melanomas which have unknown driver mutations, but some investigators have observed that NRAS mutation may predict benefit compared to wild-type melanomas when immunotherapy was administered.

The use of MEK inhibitors alone is not sufficient to treat wild-type melanomas: one investigation in a mouse model demonstrated that MEK inhibition produced apoptosis but did not succeed in triggering cell cycle arrest. Indeed, other agents combined with MEK inhibitors will likely be a direction of treatment, Dr. Sosman says. Some data has pointed to the combination of LEE011 (CDK4 inhibitor) and MEK 162 (MEK inhibitor) to benefit patients with NRAS melanoma.

At Vanderbilt-Ingram Cancer Center, investigators are sequencing 66 genes relevant to cancer prognosis and therapy, some of which play a more relevant role for melanoma. Hundreds of exons of these genes are being targeted. The identification of mutations in melanoma to date emphasizes the role of the mitogen-activated protein kinases pathway, the pathway through which the mutations activate.

Disclosures: Dr. Sosman has served on advisory boards for GlaxoSmithKline, Bristol-Myers Squibb and Roche-Genentech. He has served as a consultant for Bristol-Myers Squibb, Roche-Genentech and Novartis.

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