Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies.
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.
Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN.
Douglas B
DB
Johnson
Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN.
Christine M
CM
Lovly
Memorial Sloan-Kettering Cancer Center, New York, NY.
Marisa
M
Flavin
Memorial Sloan-Kettering Cancer Center, New York, NY.
Katherine S
KS
Panageas
Vanderbilt University School of Medicine Center for Quantitative Science, Nashville, TN.
Gregory D
GD
Ayers
Vanderbilt University School of Medicine Center for Quantitative Science, Nashville, TN.
Zhiguo
Z
Zhao
Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN.
Wade T
WT
Iams
Memorial Sloan-Kettering Cancer Center, New York, NY.
Marta
M
Colgan
Massachusetts General Hospital, Boston, MA.
Sarah
S
DeNoble
Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN.
Charles R
CR
Terry
Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN.
Elizabeth G
EG
Berry
Massachusetts General Hospital, Boston, MA.
A John
AJ
Iafrate
Massachusetts General Hospital, Boston, MA.
Ryan J
RJ
Sullivan
Columbia University Medical Center, New York, NY.
Richard D
RD
Carvajal
Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN.
Jeffrey A
JA
Sosman
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000627:therapeutic use; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D012189:Retrospective Studies
D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D000074324:Ipilimumab; D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human