Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies

Douglas B. Johnson, Christine M. Lovly, Marisa Flavin, Katherine S. Panageas, Gregory D. Ayers, Zhiguo Zhao, Wade T. Iams, Marta Colgan, Sarah De Noble, Charles R. Terry, Elizabeth Berry, A. John Iafrate, Ryan J. Sullivan, Richard D. Carvajal, Jeffrey A. Sosman

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)288-295
Number of pages8
JournalCancer Immunology Research
Volume3
Issue number3
DOIs
StatePublished - Mar 1 2015
Externally publishedYes

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Melanoma
Mutation
Therapeutics
CD274 Antigen
Interleukin-2
Retrospective Studies
Genotype
Prospective Studies
Neoplasms

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Johnson, D. B., Lovly, C. M., Flavin, M., Panageas, K. S., Ayers, G. D., Zhao, Z., ... Sosman, J. A. (2015). Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies. Cancer Immunology Research, 3(3), 288-295. https://doi.org/10.1158/2326-6066.CIR-14-0207

Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies. / Johnson, Douglas B.; Lovly, Christine M.; Flavin, Marisa; Panageas, Katherine S.; Ayers, Gregory D.; Zhao, Zhiguo; Iams, Wade T.; Colgan, Marta; De Noble, Sarah; Terry, Charles R.; Berry, Elizabeth; Iafrate, A. John; Sullivan, Ryan J.; Carvajal, Richard D.; Sosman, Jeffrey A.

In: Cancer Immunology Research, Vol. 3, No. 3, 01.03.2015, p. 288-295.

Research output: Contribution to journalArticle

Johnson, DB, Lovly, CM, Flavin, M, Panageas, KS, Ayers, GD, Zhao, Z, Iams, WT, Colgan, M, De Noble, S, Terry, CR, Berry, E, Iafrate, AJ, Sullivan, RJ, Carvajal, RD & Sosman, JA 2015, 'Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies', Cancer Immunology Research, vol. 3, no. 3, pp. 288-295. https://doi.org/10.1158/2326-6066.CIR-14-0207
Johnson, Douglas B. ; Lovly, Christine M. ; Flavin, Marisa ; Panageas, Katherine S. ; Ayers, Gregory D. ; Zhao, Zhiguo ; Iams, Wade T. ; Colgan, Marta ; De Noble, Sarah ; Terry, Charles R. ; Berry, Elizabeth ; Iafrate, A. John ; Sullivan, Ryan J. ; Carvajal, Richard D. ; Sosman, Jeffrey A. / Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies. In: Cancer Immunology Research. 2015 ; Vol. 3, No. 3. pp. 288-295.
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abstract = "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.",
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AU - Zhao, Zhiguo

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