NRAS MURARION AND RESPONSE TO IMMUNOTHERAPY IN MELANOMA

Researchers investigating whether tumor genotype correlates with benefit from immune therapy in melanoma has found that patients whose tumors had NRAS mutations had better response to immunotherapy and better outcomes than patients whose tumors had other genetic subtypes. The results suggest that immune therapies, especially immune checkpoint inhibitors, may be particularly effective treatment options for NRAS-mutant melanoma. Activating NRAS mutations are found in 15% to 20% of melanomas. The study by Johnson et al is published in Cancer Immunology Research.

Study Methodology

Between 2010 and 2012, the researchers reviewed the electronic medical records of 229 patients with melanoma treated at Vanderbilt-Ingram Cancer Center in Nashville, Memorial Sloan Kettering Cancer Center in New York, and Massachusetts General Hospital in Boston. Of these patients, 143 received ipilimumab (Yervoy), 58 received interleukin (IL)-2 (Proleukin), and 28 received anti–PD-1 (nivolumab [Opdivo] or pembrolizumab [Keytruda]) or anti–PD-L1 (MPDL3280A) therapy.

All patients underwent genotyping for “hotspot” mutations in BRAF and NRAS; most patients also underwent “hotspot” testing of other genes, including CKIT, GNAQ, GNA11, and MEK1. Sixty patients (26%) had tumors with NRAS mutations, 53 (23%) had BRAF mutations, and 116 (51%) had wild-type forms of NRAS and BRAF.

Study Results

The researchers found that 28% of the patients with NRAS-mutant melanoma had complete or partial responses to first-line immunotherapy compared with 16% of those who had the wild-type form of the gene. The clinical benefit rate (complete or partial response, or stable disease lasting 24 weeks or more) with anti–PD-1/PD-L1 agents was 73% for those with NRAS mutations and 35% for those with the normal form of the gene. Patients with NRAS mutations treated with ipilimumab had a trend for better outcome as well.

“In a retrospective study, 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,” said Douglas B. Johnson, MD, Assistant Professor of Medicine at Vanderbilt-Ingram Cancer Center, and lead author of the study. “We studied a small group of patients, but the results were quite suggestive. Our findings need to be confirmed in a prospective study. This study highlights the need to find predictive markers that can help us understand which patients will respond to therapy. Our study will hopefully lead to understanding the biological mechanisms that explain why NRAS mutations predict response. We are currently conducting studies to explain this finding.”

Douglas B. Johnson, MD, is corresponding author of this study.

Funding for this study was provided by the National Institutes of Health, the Damon Runyon Clinical Investigator Award, the American Cancer Society, the Vanderbilt-Ingram Cancer Center, the National Center for Advancing Translational Sciences, the Joyce Family Foundation, the Martell Foundation, the Bradford Family Foundation, and the Anbinder Fund.

Douglas B. Johnson declared no conflicts of interest. Christine Lovly has research grants from Astra-Zeneca and Novartis; A. John Lafrate has ownership in ArcherDX and is on the advisory board of BioReference Labs. For full disclosures of all study authors, visit http://cancerimmunolres.aacrjournals.org.