Abstract 2942: NRAS mutation as a predictor of response to immune-based therapies in patients with metastatic melanoma
Authors: Iams Wade T. , Johnson Douglas B. , Flavin Marisa , Panageas Katherine , Ayers Gregory D. , Zhao Zhiguo , Iafrate Anthony John , Sullivan Ryan J. , Carvajal Richard D. , Sosman Jeffrey A. , Lovly Christine M. 
Published: May 2015

Abstract
Background: Immune-based therapies are playing an expanding role in the treatment of advanced melanoma. Reliable biomarkers to predict benefit from these agents have not yet been identified. Specifically, the relationship between melanoma genotype and immune-based therapy has not been well characterized. Approximately 15-20% of patients with melanoma harbor an NRAS mutation in their tumor tissue. We assessed whether NRAS mutations impact the response to immune-based therapy in patients with advanced melanoma.
Methods: The current study involved 171 patients from three institutions with advanced melanoma and documented tumor genotype. All patients were treated with immune-based therapy (defined as IL-2, anti-CTLA-4, or anti-PD1/PD-L1 inhibitors). We compared the rates of clinical response between patients with NRAS mutant melanoma and those without NRAS or BRAF mutations (wild type, WT). The primary study end-point was complete or partial response (CR/PR); secondary end-points included clinical benefit (CB; defined as CR/PR or stable disease for &gt;24 weeks), progression-free survival (PFS), and overall survival (OS).
Results: In our study cohort, 59 patients (35%) had NRAS-mutant metastatic melanoma and 112 patients (65%) had WT metastatic melanoma. We observed a significantly higher rate of CR/PR and CB in patients with NRAS-mutant melanoma treated with immune-based therapy compared to patients with WT melanoma (32% vs 18%, p=0.04, for CR/PR; 49% vs 29%, p=0.01, for CB). Within specific immune-therapy types, patients with NRAS-mutant melanoma experienced the greatest benefit in CR/PR compared to patients with WT melanoma when treated with anti-PD1/PD-L1 agents (70% vs 20%, p=0.01). No statistically significant differences in median PFS (4.1 months for NRAS-mutant vs 3.3 months for WT, p=0.22) or median OS (14.6 months for NRAS-mutant vs 15.4 months for WT, p=0.63) were observed.
Conclusions: Patients with NRAS-mutant metastatic melanoma experience a higher rate of CR/PR and CB when treated with immune-based therapy compared to patients with WT metastatic melanoma. The underlying mechanism for this finding merits further exploration, and these data suggest that routine assessment for NRAS mutations in patients with melanoma is warranted.
Citation Format: Wade T. Iams, Douglas B. Johnson, Marisa Flavin, Katherine Panageas, Gregory D. Ayers, Zhiguo Zhao, Anthony John Iafrate, Ryan J. Sullivan, Richard D. Carvajal, Jeffrey A. Sosman, Christine M. Lovly. NRAS mutation as a predictor of response to immune-based therapies in patients with metastatic melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2942. doi:10.1158/1538-7445.AM2014-2942