NRAS mutations predict immunotherapy outcomes in melanoma patients



Patients with advanced melanoma who were treated with immunotherapy responded better if they harbored mutations in the NRAS gene, according to a study published March 3 in Cancer Immunology Research.

Out of 229 cases retrospectively analyzed, 26% had mutations in NRASG12/G13/Q61, 23% had BRAFV600, and 51% were wild type for NRAS and BRAF. Patients received first-line therapy with high-dose IL-2 (25%), ipilimumab (62%), or anti-PD-1/PD-L1 (12%), investigators reported (Cancer Immunol. Res. 2015 March 3).


Complete or partial responses were found in 32% of patients with NRAS-mutant melanomas, compared with 20% of those without NRAS mutations (P = .07). Clinical benefit (defined as complete response, partial response, or stable disease for 24 weeks or longer) was observed in 50% of the NRAS mutant group vs. 30% of the non–mutant NRAS group (P < .01), reported Dr. Douglas B. Johnson of Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tenn., and associates.

Although the numbers for individual agents were small, the NRAS-mutant benefit was most pronounced for immune checkpoint inhibitors, especially anti-PD-1/PD-L1 therapy, where clinical benefit was observed in 8 of 11 NRAS-mutant patients vs. 13 of 37 patients with wild-type NRAS.

“This finding could have implications for molecular testing and treatment decision making, and it provides early insights into the complex relationship between tumor genetics and the immune response,” Dr. Johnson and associates wrote.

Patients with NRAS-mutant melanoma account for 15%-20% of all melanomas, and the mutation is associated with a poorer prognosis. The authors speculate that elevated PD-1 expression may be a factor in inferior prognosis of NRAS-mutant phenotypes as well as the observed improved response to anti-PD-1.

“We studied a small group of patients, but the results were quite suggestive. Our findings need to be confirmed in a prospective study. 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,” Dr. Johnson and his associates said.

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