Correlation of NRAS mutations with clinical response to high-dose IL-2 in patients with advanced melanoma

Abstract

The purpose of this study is to identify clinical and molecular characteristics of melanoma patients that predict response to high-dose interleukin-2 (HD IL-2) to improve patient selection for this approved but toxic therapy. We reviewed the records of 208 patients with unresectable stage III/IV melanoma treated with HD IL-2 at the University of Texas M.D. Anderson Cancer Center (n=100) and the Beth Israel Deaconess Medical Center (n=108) between 2003 and 2009. The BRAF and NRAS mutation status of the tumors was determined for patients with available tissue samples and the mutation status and clinical characteristics were compared with clinical outcomes. Pretreatment serum lactate dehydrogenase levels were available for most patients (n=194). Tissue was available for mutational analysis on a subset of patients (n=103) and the prevalence of mutations was as follows: BRAF 60%, NRAS 15%, WT/WT 25%. In the subset of patients for which mutational analysis was available, there was a significant difference in the response rate based on the mutation status: NRAS 47%, BRAF 23%, and WT/WT 12% (P=0.05). Patients with NRAS mutations had nonstatistically longer overall survival (5.3 vs. 2.4 y, P=0.30) and progression-free survival (214 vs. 70 d, P=0.13). Patients with an elevated lactate dehydrogenase level had a decreased progression-free survival (46 vs. 76 d, P<0.0001), decreased overall survival (0.56 vs. 1.97 y, P<0.0001), and trended toward a decreased response rate (7% vs. 21%, P=0.08). NRAS mutational status is a new candidate biomarkers for selecting patients with melanoma for HD IL-2 treatment.

Figures

Figure 1. Overall and progression free survival in patients with a normal versus elevated LDH

Patients with an elevated serum LDH (n=30) at the start of treatment with HD IL-2 had shorter (A) overall survival (median 0.56 years versus 1.97 years, p

Figure 2. Overall and progression free survival in patients by mutational status

In a three way comparison of BRAF, NRAS, and WT tumor mutation status did not correlate with (A) overall survival (p=0.57) or (B) progression-free survival (p=0.12) among patients treated with HD IL-2 in a three way comparison. Comparing NRAS versus BRAF and WT patients, (C) overall survival (p=0.30) and (D) PFS remain non-statistically different (p=0.13)