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Gene mutations may predict melanoma response to immunotherapies

Mar. 12, 2015, 7:58 AM


Melanoma patients whose tumors test positive for mutations in the NRAS gene were more likely to benefit from new immunotherapy drugs, according to a new study led by Vanderbilt-Ingram Cancer Center (VICC) investigators.

Douglas Johnson, M.D., assistant professor of Medicine, and Christine Lovly, M.D., Ph.D., assistant professor of Medicine and Cancer Biology, are co-first authors of the study, conducted in conjunction with colleagues from Memorial Sloan Kettering Cancer Center (MSKCC), New York, and Massachusetts General Hospital (MGH), Boston. The study was published in Cancer Immunology Research.

Douglas Johnson, M.D.


Researchers have discovered several driver mutations in oncogenes like NRAS, BRAF and CKIT and these “drivers” appear to be essential in supporting the cancer. NRAS mutations are found in 15- 20 percent of all melanomas, the most deadly form of skin cancer. However, no targeted therapies have yet been approved for NRAS-driven cancer. It has also been unclear how these gene mutations interact with immunotherapy.

Christine Lovly, M.D., Ph.D.

Vanderbilt investigators first noticed that melanoma patients with NRAS mutations who had been treated with immunotherapies appeared to do better on these therapies. Together with colleagues, they reviewed records of 229 patients at VICC, MSKCC and MGH treated with the immunotherapies ipilimumab, IL-2, or new therapies that inhibit immune checkpoint proteins like programmed cell death protein 1 (PD-1/PD-L-1).

Sixty melanomas harbored NRAS mutations, 53 had BRAF mutations and 116 had no NRAS or BRAF mutations (wild type).

“We found that patients with NRAS-mutant melanoma seemed to respond better to immunotherapy compared with patients whose tumors had other genetic subtypes, and this was especially true for patients treated with anti-PD-1/PD-L1 therapies,” Johnson said.

Twenty-eight percent of patients with NRAS-mutant melanoma had complete or partial responses to first-line immunotherapy compared with 16 percent of patients who had the wild type gene. The clinical benefit rate (CBR) with anti-PD-1/PD-L1 drugs was 73 percent for patients with mutant NRAS versus 35 percent for wild type. The CBR for NRAS-mutant patients treated with ipilimumab was 42 percent versus 19 percent in wild type. Clinical benefit rate was defined as complete or partial response or stable disease lasting 24 weeks or more.

“We studied a small group of patients but the results were quite suggestive,” Johnson said. “This study highlights the need to find predictive markers that can help us understand which patients will respond to therapy.”

Other investigators for the study include Gregory Ayers, M.S., Zhiguo Zhao, M.S., Wade Iams, M.D., Charles Terry, M.D., Elizabeth Berry, M.D., Jeffrey Sosman, M.D., Vanderbilt; Marisa Flavin, M.D., Katherine Panageas, Dr.PH., Marta Colgan, B.S., and Richard Carvajal, M.D., MSKCC; Sarah DeNoble, B.S., A. John Iafrate, M.D., Ph.D., Ryan Sullivan, M.D., MGH.

The research was supported by funding from the National Institutes of Health (K12 CA 0906525, UL1TR000445), VICC, Damon Runyon Cancer Research Foundation, American Cancer Society, Joyce Family Foundation, T.J. Martell Foundation, Bradford Family Foundation, and the Anbinder Fund.

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