RAS(ON) multi-selective inhibition drives anti-tumor immunity in preclinical models of NRAS-mutant melanoma

Targeted therapies for NRAS-mutant melanoma remain an unmet clinical need. Here, we demonstrate that RMC-7977, a preclinical RAS(ON) multi-selective inhibitor respresentative of the investigational agent daraxonrasib (RMC-6236), elicits potent anti-tumor immune responses across several NRAS-mutant melanoma models. Treatment with RMC-7977 led to rapid tumor regressions driven by inhibition of MAPK signaling, upregulation of MHC and PD-L1 proteins, and enhanced infiltration of CD4? and CD8? T cells. Complete responses was dependent on adaptive immunity, as both CD4? and CD8? T cells were essential for extended survival. Resistance to treatment was marked by reduced T cell infiltration, loss of MHCI expression, and expansion of MDSCs. Combining RMC-7977 with anti-PD-1 boosted T cytotoxic cell infiltration, reprogrammed myeloid cells toward an antigen-presenting phenotype, and improved survival in models resistant to PD-1 blockade. Notably, objective clinical responses were observed in two NRAS-mutant melanoma patients treated with daraxonrasib (RMC-6236) in an ongoing phase I/Ib clinical trial. Overall design: Female, 6-week-old immunocompetent C57BL/6J mice were subcutaneously injected with 1e6 OSUMMER.13 cells into the right flank. The treatment started when tumors reached approximately 100 mm3. Mice were randomized and assigned into 4 groups of 3: IgG2a control, anti-PD-1, RMC-7977, and combination of anti-PD-1 and RMC-7977. The tumors were collected at the desired timepoint, weighed, and processed for single cell RNA sequencing (scRNA-seq).