In the Journals

NRAS mutations improve response to immunotherapies in advanced melanoma

Show Citation

April 9, 2015

Patients with advanced melanoma who harbored NRAS mutations were more likely to respond to and experience clinical benefit from immunotherapies compared with other genetic subtypes, according to retrospective study results.

The benefit associated with NRAS mutations may be linked to a corresponding increase in programmed cell death ligand-1 (PD-L1) expression in this cohort, results showed.

“Immune therapies are being used increasingly in melanoma and produce long-lasting responses in some patients,” Douglas B. Johnson, MD, MSCI, an assistant professor of medicine and hematologist and oncologist at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, told HemOnc Today. “Despite this promising activity, our ability to predict which patients will respond to treatment is very limited. We assessed patients from three large melanoma centers to determine whether mutations in common melanoma genes predict response to immune therapy.”

Douglas B. Johnson, MD, MSCI

Douglas B. Johnson

Johnson and colleagues had first evaluated clinical, pathologic and therapeutic features that were affected by genotype in their own institution when they observed an association between NRAS mutations and response to immunotherapy, according to study background.

The current analysis included 229 patients with melanoma who were treated with an immunotherapy, including ipilimumab (Yervoy, Bristol-Myers Squibb), interleukin-2 (IL-2) or anti-PD1/PD-L1 agents.

Rates for response and clinical benefit to immunotherapy served as the study’s primary endpoints. Secondary endpoints included OS, PFS and PD-L1 expression.

Overall, 60 patients harbored NRAS mutations, 53 harbored BRAF mutations and 116 had NRAS and BRAF wild-type disease.

A greater proportion of patients in the NRAS-mutant cohort responded to front-line immunotherapy compared with patients in the wild-type cohort (28% vs. 16%; P = .04). The benefit associated with the NRAS mutation persisted but lost significance when the analysis included any line of immunotherapy (32% vs. 20%).

Patients with NRAS-mutated disease were more likely to demonstrate clinical benefit (50% vs. 31%, P < .01) with immunotherapy. The NRAS cohort also demonstrated prolonged PFS (median, 4.1 vs. 2.9 months) and OS (19.5 vs. 15.2 months).

When researchers stratified the analysis according to type of immunotherapy, a greater proportion of patients who harbored NRAS mutations responded to ipilimumab (19% vs. 11%) and achieved clinical benefit from the agent (42% vs. 19%) compared with patients with wild-type or BRAF-mutated disease. Patients with NRAS mutations also demonstrated an improved objective rate response (64% vs. 30%) and clinical benefit rate (73% vs. 35%) with PD-1/PD-L1 antibodies.

“In this study, we found that melanomas with mutations in a gene called NRAS (mutated in 15% to 20% of all melanomas) predicted superior response to immune therapy, compared to those with mutations in BRAF (40% to 50% of melanomas) or tumors without mutations in either gene,” Johnson said. “Intriguingly, responses were especially common in patients treated with anti-PD-1, a particularly promising new class of drugs.”

Researchers evaluated PD-1 expression in 39 archived samples from patients with advanced melanoma. Fifteen of these patients harbored NRAS mutations, 10 harbored BRAF mutations and 14 had wild-type disease. When using 1% and 5% cutoffs, samples from patients with NRAS mutations had higher PD-1 expression than patients without NRAS mutations, although this association did not reach statistical significance.

The researchers acknowledged there was heterogeneity in how immunotherapy responses were monitored since some patients were enrolled on clinical trials, whereas others received treatment as a standard of care. Thus, researchers recommend the need for prospective studies to confirm their observations.

“This study is among the first to identify a clinical link between a common genetic mutation and response to immune therapy,” Johnson said. “To build on this work, we plan to confirm the association in a larger population. We are also conducting laboratory experiments to explore underlying mechanisms for this finding. Hopefully, these efforts and those by many other groups will help guide treatment decision-making surrounding these promising new drugs, and identify additional therapeutic strategies.” – by Anthony SanFilippo

For more information:

Douglas B. Johnson, MD, MSCI, can be reached at Vanderbilt-Ingram Cancer Center, 691 Preston Building, Nashville, TN 37232; email:

Disclosure: Johnson reports no relevant financial disclosures. Other researchers report research funding from AstraZeneca and Novartis, equity ownership in ArcherDx and consultant/advisory roles with BioReference Labs.

itj+ Infographic

itj+ Perspective