Impact of NRAS Mutations for Patients with Advanced Melanoma Treated with Immune Therapies

Abstract

Activating NRAS mutations are found in 15-20% of melanomas. Immune therapies have become a mainstay in advanced melanoma treatment. We sought to evaluate whether tumor genotype (e.g. NRAS mutations) correlate with benefit from immune therapy in melanoma. We identified 229 melanoma patients treated with immune therapies (interleukin-2, ipilimumab, or anti-programmed cell-death-1/ligand-1 (PD-1/PD-L1)) at three centers, and compared clinical outcomes following immune therapy for patients with or without NRAS mutations. Of the 229 melanoma patients, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF WT. The NRAS-mutant cohort had superior or a trend to superior outcomes compared to the other cohorts in terms of response to first-line immune therapy (28% vs. 16%, p=0.04), response to any line of immune therapy (32% vs. 20%, p=0.07), clinical benefit (response + stable disease lasting ≥24 weeks; 50% vs. 31%, p<0.01), and progression-free survival (median 4.1 vs. 2.9 months, p=0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort (clinical benefit rate 73% vs. 35%). In an independent group of patient samples, NRAS-mutant melanoma had higher PD-L1 expression (although not statistically significant) compared to other genotypes (8/12 vs. 9/20 samples with ≥1% expression; 6/12 vs 6/20 samples with ≥5% expression), suggesting a potential mechanism for the clinical results. This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared to other genetic subtypes. If confirmed by prospective studies, this may be explained in part by high rates of PD-L1 expression.

Immune-mediated adverse events of anticytotoxic T lymphocyte–associated antigen 4 antibody therapy in metastatic melanoma

“…Activating NRAS mutations, which are found in 15-20% of melanomas, have also been studied in 229 patients with melanoma treated with immune therapies (IL-2, ipilimumab, anti-PD-1 therapy, and anti-PD-L1 therapy) (105). Clinical outcomes were superior in the NRAS- mutant cohort than other cohorts, as demonstrated by improved response to first-line immune therapy, response to any line of immune therapy, clinical benefit, and progression-free survival.…”

Burden of Nonsynonymous Mutations among TCGA Cancers and Candidate Immune Checkpoint Inhibitor Responses

“…The ability to identify the subset of long-term survivors could have an important impact on treatment options, including first-line as well as salvage therapy. Previously a series of studies have examined somatic alterations to identify possible predictive signatures; these have included studies of gene expression signature associated with immune infiltration (14), neoantigen load (15–17), NRAS mutation status (18) and neoantigen-derived tetrapeptide signature (15). Of these, the neoantigen load is most promising, particularly for treatment of melanoma (15,16) and NSCLC (17).…”

Developments in targeted therapy in melanoma

“…24 Relating to immunotherapy, it has recently been shown that harboring an NRAS mutation increases the response rate (RR) to checkpoint inhibitors with no significant impact on OS and progression-free survival (PFS). 28,29 A recent retrospective study affirmed this assumption: although mutational status had no influence on OS in anti-CTLA-4 treated patients, a non-statisticallysignificant trend for superior clinical outcome in NRAS mutant patients was observed. 30 As outlined previously, the third most commonly reported mutation is the inactivating mutation of NF1, which shows similar OS compared to BRAF-mutant, NRASmutant or triple wt melanomas.…”