A research team has reported that a groundbreaking pathway-targeted therapy may be an effective treatment for certain melanoma patients and fill an unmet clinical need for patients with advanced disease.
Martin McMahon, PhD, Senior Director of Preclinical Translation at Huntsman Cancer Institute and Professor of Dermatology at the University of Utah, evaluated an investigative compound of the drug daraxonrasib in NRAS-driven melanoma. Daraxonrasib targets and inhibits RAS; NRAS is a subtype of RAS that is mutated in roughly a quarter of melanoma cases.
The results of phase III trial of daraxonrasib as a treatment for metastatic pancreatic cancer—in which it doubled patients’ life expectancy—recently received a standing ovation from thousands of physicians at the 2026 ASCO Annual Meeting.
“The remarkable success of daraxonrasib in the treatment of pancreatic cancer indicates that we are in an era where even the most recalcitrant RAS-driven cancers can be treated,” said Dr. McMahon. “Our data strongly [support] the potential future clinical utility of treating patients with NRAS-driven melanoma with daraxonrasib.”
Dr. McMahon and his team evaluated the effectiveness of the RAS inhibitor in numerous preclinical models, including melanoma samples from patients. The results of the study have been published by Foth et al in Cancer Research.
“All our NRAS-driven models were very responsive to this RAS inhibitor. It’s actually quite rare that we see shrinkage of NRAS-driven tumors,” said Mona Foth, PhD, research scientist at Huntsman Cancer Institute and first author of the publication. “It’s inspiring to think that these results could potentially lead to a new therapy that will help [patients potentially] overcome their disease.”
Immunotherapy has revolutionized metastatic melanoma care. As Dr. Foth noted, the treatment is effective in about half of melanoma patients, sometimes with deep and durable responses. If immunotherapy fails or becomes less effective, physicians switch to targeted therapies as a secondary line of treatment. Targeted therapies attack oncoproteins and their effectors to kill cancer cells or slow their growth.
“Patients with other mutations like BRAF have access to clinically approved secondary lines of treatment. But patients with NRAS-driven melanoma do not have effective targeted therapies to treat their cancer,” said Dr. McMahon. “Daraxonrasib is a targeted therapy that may provide another path for treatment and hope for patients affected by this devastating disease.”
The team also observed that some of the models became resistant to the drug, as often happens in patients taking pathway-targeted therapies. Resistance to daraxonrasib was tied to mutations in MEK1, a protein downstream of RAS, or to loss of expression of cyclophilin A, a chaperone protein required for the inhibitory action of daraxonrasib toward RAS proteins.
“We will need to do more research to find drug combinations, based on a backbone of daraxonrasib, that will increase the depth and durability of melanoma patient responses,” said Dr. McMahon.
Drs. McMahon and Foth hope the drug will move into a clinical trial for patients who are either ineligible for immunotherapy or whose immunotherapy did not work.
DISCLOSURE: For full disclosures of the study authors, visit aacrjournals.org/cancerres.
