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

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 are published in Cancer Immunology Research. The findings show the potential for durable responses, laying the groundwork for future clinical trials and a possible new standard of care.

Why NRAS-mutant melanoma is more difficult to treat than 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 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 (“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.

The immune system’s role in the observed treatment responses

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 indicates 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.

Experiences of patients in the study

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.

Next steps toward making this therapy 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.