May 2015, Vol. 2, No. 3

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NRAS Mutation Impacts Response to Immune Therapies in Melanoma


Among patients with advanced melanoma treated with immunotherapies, those whose tumors had NRAS mutations had better response and treatment outcomes than those whose tumors did not, according to new research.

Douglas B. Johnson, MD, and colleagues determined that 28% of patients with NRAS-mutant melanoma had complete or partial responses to various first-line immunotherapies, compared with 16% of those with wild-type NRAS (Cancer Immunol Res. 2015;3:288-295).

“In a retrospective study, 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 Johnson.

The researchers evaluated the electronic medical records of 229 melanoma patients treated at Vanderbilt-Ingram Cancer Center, Memorial Sloan Kettering Cancer Center, and Massachusetts General Hospital. Patients were treated with ipilimumab (n = 143), interleukin-2 (n = 58), or inhibitors of programmed death 1 or its ligand (PD-1/PD-L1; n = 28).

The study sought to evaluate whether tumor genotype correlates with benefit from immune therapy in melanoma. The researchers identified NRAS mutations (n = 60), BRAF mutations (n = 53), and wild-type NRAS/BRAF status (n = 116) among the patients and compared clinical outcomes among these subsets.

Responses Highest in NRAS-Mutant Tumors

The NRAS-mutant cohort had superior or a trend toward superior outcomes compared with the other cohorts in terms of response to first-line immune therapy (28% vs 16%; P = .04); response to any line of immune therapy (32% vs 20%; P = .07); clinical benefit, that is, response plus stable disease ?24 weeks (50% vs 31%; P <.01); and progression-free survival (median 4.1 vs 2.9 months; P = .09).

Benefit from anti–PD-1/PD-L1 therapy was particularly marked in patients with NRAS mutations, who had a clinical benefit rate of 73%, compared with 35% for NRAS wild-type patients. The researchers proposed these differences stemmed from the greater PD-L1 enrichment in NRAS-mutant tumors. NRAS-mutant tumors were more likely than wild-type tumors to demonstrate membrane staining ?1% and staining ?5%, “suggesting a potential mechanism for the clinical results,” the authors noted.

They noted that “although only small numbers were treated, the clinical benefit rate was unexpectedly high with anti–PD-1 or anti–PD-L1, occurring in 8 of 11 patients with NRAS-mutant melanoma, compared with only 13 of 37 patients in the non–NRAS-mutant cohorts. This finding could have implications for molecular testing and treatment decision making and provides early insights into the complex relationship between tumor genetics and the immune response.”

“We studied a small group of patients, but the results were quite suggestive,” Johnson added.

The study, whose results need confirmation in a prospective trial, highlights the need to find predictive markers of response to immune therapies. “We are currently conducting studies to explain this finding,” he said.

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