Moffitt study finds promising first evidence of targeted therapy for NRAS-mutant melanoma

(Press-News.org) Moffitt Cancer Center researchers report the first clinical activity of a RAS inhibitor in patients with NRAS-mutant melanoma. 

The investigational drug daraxonrasib (RMC-6236) and its preclinical counterpart RMC-7977 bind active RAS proteins (NRAS, HRAS, KRAS) and block downstream signaling that drives tumor growth, survival and immune escape. 

In laboratory models, treatment led to increased infiltration of activated T cells, reduction of suppressive immune cells and tumor eradication only when the immune system was intact. 

In the early clinical setting, two patients with NRAS-mutant melanoma were treated with daraxonrasib. One achieved a complete response and the other a partial response, the first ever such outcomes with a RAS inhibitor in this patient population. 

The therapy is currently in a phase 1 trial. Further phase 1 and 2 trials will be required to determine efficacy and safety in larger patient cohorts before this treatment could become widely available. 

TAMPA, Fla. (Nov. 4, 2025) —New research from Moffitt Cancer Center shows that RAS(ON) multi-selective inhibition can directly block tumor growth and activate the immune system, offering the first targeted approach for patients with NRAS-mutant melanoma, an aggressive form of skin cancer with limited treatment options beyond immune checkpoint inhibitors. Results from the study were published in Cancer Immunology Research. It shows the potential for durable responses, laying the groundwork for future clinical trials and a possible new standard of care. 

What makes NRAS-mutant melanoma so difficult to treat compared to other types of melanoma? 
Unlike patients with BRAF-mutant melanoma, who can benefit from multiple FDA-approved targeted therapy combinations, people with NRAS-mutant disease have no such options. The standard of care currently relies on immune checkpoint inhibitors, which work well for some patients but not for all. Many either fail to respond or eventually develop resistance. For this group, once immunotherapy stops working, treatment options are extremely limited. That’s why developing a targeted therapy for NRAS-mutant melanoma has been such an important and unmet need in the field. 

How does daraxonrasib (RMC-6236) or its preclinical counterpart RMC-7977 actually work inside the body? 
RAS proteins act as powerful molecular switches that drive cancer growth. Mutant RAS is stuck in the “on” position, continuously signaling the tumor to grow, survive and evade immune attack. Daraxonrasib is part of a new class of drugs designed to target the active, or “on,” form of RAS, something researchers have struggled to achieve for decades. By binding to active RAS proteins (NRAS, HRAS, and KRAS), these drugs block the downstream MAPK signaling pathway that fuels tumor growth. This not only causes cancer cells to stop dividing and die but also makes the tumor more visible to the immune system. 

What role did the immune system play in the treatment responses observed in this study? 
The immune response turned out to be critical. Treatment with the RAS inhibitor led to a surge in activated CD4+ and CD8+ T cells, the key immune cells that recognize and kill tumor cells. It also reduced populations of myeloid-derived suppressor cells, which normally help tumors evade the immune system. In laboratory experiments, when these T cells were depleted, the drug was no longer able to eliminate tumors. This tells us that the drug is not just acting directly on the cancer but is also working hand-in-hand with the body’s immune defenses to achieve durable responses. 

Were there any patients involved in this study, and if so, what kinds of results did they experience? 

Two Moffitt patients with advanced NRAS-mutant melanoma were treated as part of an early clinical trial of daraxonrasib. One patient experienced a complete response, meaning no detectable tumor remained on scans, while the other had a partial response with significant tumor shrinkage. This is a landmark moment because it’s the first evidence that an RAS inhibitor can work in this specific group of melanoma patients. If these early findings hold up in larger trials, this could represent the first targeted therapy ever developed for NRAS-mutant melanoma. 

What are the next steps before this therapy could be more widely available to patients? 
Daraxonrasib is currently in a phase 1 clinical trial, which primarily focuses on establishing safety, tolerability and optimal dosing. Once this phase is complete, the drug will need to move into phase 2 and 3 trials to evaluate its efficacy in larger, more diverse patient groups. If it demonstrates meaningful and durable benefit with manageable side effects, it could eventually lead to FDA approval and a new standard of care. But it’s important to note that this process takes time, and these next stages will be essential for confirming the promise we’re seeing now. 

This study was supported in part by Revolution Medicines and the Melanoma Research Alliance. 

About Moffitt Cancer Center 
Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 58 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s scientific excellence, multidisciplinary research, and robust training and education. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, X, Instagram and YouTube. 

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