NRAS Mutation in Melanoma: A Challenging Target

Among melanomas, BRAF-mutated disease gets the vast majority of attention. Fifty percent of melanomas harbor BRAF mutations, which can be targeted with BRAF inhibitors. However, despite its notoriety, BRAF is not the only important melanoma mutation.

Another melanoma-linked mutation can be found in the NRAS gene. Like BRAF mutations, NRAS mutations are ‘driver mutations’—a tumor with an NRAS mutation is dependent on the mutation for its growth and survival.

Studies show that mutations in the NRAS gene, which lead to a constantly active NRAS protein, are found in approximately 15% of metastatic melanoma patients, although recent studies analyzing more patients and using more sensitive techniques suggest that as many as 25% of patients may have an NRAS mutation.

Because the U.S. Food and Drug Administration (FDA) has approved BRAF-inhibitor treatment, BRAF-mutation testing is now routine for people with metastatic melanoma. But while some clinicians test metastatic melanoma patients for BRAF and NRAS mutations prior to any treatment, many only test for NRAS mutations if a patient is found to be BRAF wild type (no BRAF mutation), since NRAS-targeted therapies are all still in clinical trials.

Melanoma tumors very rarely carry both a BRAF and an NRAS mutation, according to Keith Flaherty, MD, of Massachusetts General Hospital (MGH) and Harvard Medical School, and the director of developmental therapeutics for the MGH Cancer Center. This is true for patients who have not previously been treated with a BRAF inhibitor. But, about 20% of patients who have been treated with a BRAF inhibitor and whose melanoma has progressed have a detectable mutation in NRAS, in addition to the mutation in BRAF.

BRAF-mutated melanoma tumors tend to be faster growing compared to BRAF wild-type tumors, but NRAS-mutated tumors tend to be even more aggressive. “In metastatic patients, if you were to rank the mutations, the prognosis for NRAS is the worst, then BRAF; and if you lack both then you do better, relatively,” Flaherty says.

But while NRAS is an attractive target for therapy, it is a challenging one. Decades of work have not yet yielded any efficient way to block the activity of the mutant NRAS protein. Instead, current drug development efforts focus mostly on targeting the signaling pathways that the NRAS protein activates—the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositide 3-kinase (PI3K) pathway. Both preclinical and clinical evidence shows that a subset of NRAS-mutated melanomas are dependent on the MAPK pathway.

“But the other pathways that NRAS activates are numerous,” Flaherty says. They extend beyond just the MAPK and PI3K pathways.  “One of the challenges in NRAS-mutant melanoma is understanding which of the pathways downstream of RAS are important and for which tumors.”

The likely key, according to Flaherty, is to figure out how to identify subgroups within NRAS-mutant tumors. In other words, it will probably be important to identify which mutation combinations are present in the tumor along with the NRAS mutation. “That is an active area of research, but there have not been any results yet from preclinical studies,” Flaherty says.

Thus far, MEK inhibitors (that affect the MAPK pathway) have been the most successful targeted therapy for NRAS-mutated melanoma. While several MEK inhibitors are in clinical trials for the disease, the most promising, based on early-stage clinical trial data, is MEK162. Results from an ongoing, phase II trial in both BRAF- and NRAS-mutated metastatic melanoma, presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in 2012, show that the drug is active in NRAS-mutated patients. Of the 28 patients in the trial, 6 experienced tumor shrinkage—a 21% response rate; an additional 13 patients had stable disease.

According to Flaherty, the response is not fantastic, but it is promising. “These results reflect the most active single-agent targeted approach [for NRAS-mutated patients] yet studied.” A phase III trial comparing MEK162 to chemotherapy in NRAS-mutated patients is slated to start soon.

Even more effort is focused on combination therapies for NRAS-mutated melanoma. However, combining a MEK and PI3K inhibitor has not been very successful in phase I trials. “It does not appear that there will be a benefit [of the combination] compared to a MEK inhibitor alone,” Flaherty says. But, in his view, it is possible that a subset of NRAS-mutated patients may have incremental benefit from the combination, although these patients have not yet been identified.

Another combination approach is to combine a MEK inhibitor with a CDK4/6 inhibitor. One such combination trial, adding LEE011, a CDK4/6 inhibitor to MEK162 in NRAS-mutated melanoma patients, is about to begin, enrolling approximately 58 patients and funded by the Switzerland-based pharmaceutical company Novartis (LINK). Other trials of this combination approach are currently being planned, according to Flaherty.

Another combination that is gathering enthusiasm pairs a MEK inhibitor with the mouse double minute 2 homolog (MDM2) inhibitor. Preclinical studies suggest that this combination may be more active than a MEK inhibitor alone. These combination trials are still in the development stage, Flaherty says.