TY - JOUR
T1 - Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies
AU - Johnson, Douglas B.
AU - Lovly, Christine M.
AU - Flavin, Marisa
AU - Panageas, Katherine S.
AU - Ayers, Gregory D.
AU - Zhao, Zhiguo
AU - Iams, Wade T.
AU - Colgan, Marta
AU - De Noble, Sarah
AU - Terry, Charles R.
AU - Berry, Elizabeth G.
AU - Iafrate, A. John
AU - Sullivan, Ryan J.
AU - Carvajal, Richard D.
AU - Sosman, Jeffrey A.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/3
Y1 - 2015/3
N2 - Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies have become a mainstay in advanced melanoma treatment. We sought to evaluate whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune therapy in melanoma. We identified 229 patients with melanoma treated with immune therapies [IL2, 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 patients with melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild type. The NRAS-mutant cohort had superior or a trend to superior outcomes compared with 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 with 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 with other genetic subtypes. If confirmed by prospective studies, this may be explained in part by high rates of PD-L1 expression.
AB - Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies have become a mainstay in advanced melanoma treatment. We sought to evaluate whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune therapy in melanoma. We identified 229 patients with melanoma treated with immune therapies [IL2, 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 patients with melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild type. The NRAS-mutant cohort had superior or a trend to superior outcomes compared with 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 with 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 with other genetic subtypes. If confirmed by prospective studies, this may be explained in part by high rates of PD-L1 expression.
UR - http://www.scopus.com/inward/record.url?scp=84961546746&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84961546746&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-14-0207
DO - 10.1158/2326-6066.CIR-14-0207
M3 - Article
C2 - 25736262
AN - SCOPUS:84961546746
SN - 2326-6066
VL - 3
SP - 288
EP - 295
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 3
ER -