NRAS Mutations May Serve as Efficacy Biomarker for Immunotherapies in Melanoma

Patients with NRAS-mutated melanoma had better responses and improved treatment outcomes compared with those who did not harbor the mutation, according to a recent retrospective study.

Douglas B. Johnson, MD

Patients with NRAS-mutated melanoma had better responses and improved treatment outcomes compared with those who did not harbor the mutation, according to a recent retrospective study published in Cancer Immunology Research.

“We found that patients with NRAS-mutant melanoma seemed to respond better to immunotherapy compared with patients whose tumors had other genetic subtypes, and this was especially true for patients treated with anti—PD-1/PD-L1 therapies,” said lead study author Douglas B. Johnson, MD, assistant professor of Medicine at Vanderbilt-Ingram Cancer Center (VICC). “We studied a small group of patients, but the results were quite suggestive.”

Using electronic medical records of 229 melanoma patients treated at VICC, Memorial Sloan Kettering Cancer Center (MSKCC), and Massachusetts General Hospital, Johnson and his team examined 143 patients who received ipilimumab (Yervoy), 58 who received IL-2 therapy, and 28 who received anti—PD-1/PD-L1 agents as first-line therapy.

Sixty patients had tumors with NRAS mutations, 53 had BRAF mutations, and 116 had the normal forms of both genes. Compared with those who had the normal form of NRAS, patients with NRAS mutations had slightly higher levels of PD-L1.

Twenty-eight percent of patients with NRAS-mutant melanoma had complete or partial responses with first-line immunotherapy, compared with 16% of those who had the normal form of the gene (P = .04). The response to any line of immunotherapy was 32% for patients with NRAS mutations, compared with 20% in the control arm (P = .07).

The clinical benefit rate (complete or partial response, or stable disease lasting ≥24 weeks) was 50% among patients with NRAS mutations vs 31% in the control group (P <.01). Median progression-free survival was 4.1 months in the NRAS-mutation group and 2.9 months for patients without the mutation (P = .09).

In patients treated with anti—PD-1/PD-L1 agents, the clinical benefit rate with anti–PD-1/PD-L1 drugs was 73% for those with NRAS mutations and 35% in the control arm. Patients with NRAS mutations had a trend for better outcome when treated with ipilimumab (Yervoy), as well.

Further study is needed to understand the full impact NRAS mutations could have on immunotherapy response rates, said Johnson.

“Our findings need to be confirmed in a prospective study,” he said. “This study highlights the need to find predictive markers that can help us understand which patients will respond to therapy. Our study will hopefully lead to understanding the biological mechanisms that explain why NRAS mutations predict response. We are currently conducting studies to explain this finding.”

Immunotherapies have rapidly become a prominent treatment option for patients with melanoma, starting with the approval of ipilimumab in 2011. The approval opened the door for other immunotherapy treatments for the disease, according to Michael A. Postow, MD, a medical oncologist specializing in melanoma at MSKCC.

“Ipilimumab had a huge impact on the treatment paradigm for melanoma. It was the first drug to ever improve overall survival,” said Postow in an interview with OncLive. “It opened up a whole way of treating patients with immune checkpoint blockade, and this has led to more effective treatment strategies in the same family, with PD-1. It has introduced a whole new field of cancer treatment.”

Following ipilimumab, the PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) were both approved for advanced melanoma last year.

Despite these successes, it is still difficult to determine which immunotherapies will be most effective for which melanoma patients. A link between NRAS mutations and response rates, as shown in the recent VICC study, offers a potential solution.

“Tumor markers that can identify patients who will benefit the most from these therapies is an important step in improving treatment outcomes,” Johnson said.


Johnson DB, Lovly CM, Flavin M, et al. Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies. Cancer Immunol Res. 2015;3(3):288-295.