Abstract 2831: RAS(ON) inhibition in both cancer and immune cells by daraxonrasib drives anti-tumor immunity

Abstract Daraxonrasib (RMC-6236) is an orally bioavailable, RAS(ON) multi-selective, tri-complex inhibitor of oncogenic mutant and wild-type variants of N, H and KRAS, demonstrating broad activity across RAS-mutant cancers. Preclinical studies have shown that daraxonrasib not only suppresses tumor cell proliferation but also promotes a striking remodeling of the tumor microenvironment (TME), characterized by depletion of immunosuppressive myeloid cells (including M2 macrophages) and increased infiltration of T cells. Collectively these changes sensitize tumors to immune checkpoint blockade. We have reported that the combination of daraxonrasib plus pembrolizumab, with or without chemotherapy, demonstrated encouraging preliminary antitumor activity, and was generally well tolerated, in patients with 1L RAS mutant NSCLC.Given that RAS functions as a key immunosuppressive oncogene, a primary driver for the antitumor immune effects of daraxonrasib is tumor-cell intrinsic inhibition of oncogenic RAS. However, it is well established that the RAS-MAPK signaling pathway regulates critical immune processes, including maintenance of M2 macrophages and T cell receptor signaling. Here, we demonstrate that daraxonrasib has direct effects on immune cell populations and that inhibition of wild-type RAS in these cells contributes to antitumor immunity, highlighting a dual mechanism of action for this RAS(ON) multi-selective inhibitor.To determine the tumor-cell independent contributions of RAS (ON) inhibition to antitumor immunity in vivo, we used a syngeneic tumor model intrinsically resistant to daraxonrasib. Daraxonrasib treatment was initiated at the time of tumor implant. In this model, although daraxonrasib alone did not inhibit cell proliferation in vitro or affect tumor growth in vivo, it promoted favorable TME remodeling, including macrophages depletion and increased T cell infiltration. Importantly, daraxonrasib treatment – when initiated at the time of implant – sensitized these tumors to subsequent checkpoint inhibitor therapy. Together, these and earlier preclinical findings reveal that daraxonrasib acts through coordinated RAS(ON) inhibition in both tumor and immune compartments. The impact of RAS(ON) inhibition in the immune compartment includes depletion of M2 macrophages and prevention of T cell exhaustion (as suggested by in-vitro data), leading to an immune-permissive TME that enhances responsiveness to checkpoint blockade. Collectively these preclinical data support the ongoing clinical evaluation of this combination in RAS-driven cancers. Citation Format: Nataliya Tovbis Shifrin, Mariela Moreno Ayala, Cristina Blaj, Kevin Chen, Felix Mbuga, Joaquin Pechuan Jorge, Rashi Raghulan, Rich Liang, Linh Tran, Enrico Payson, Alice Kumamoto, Alexander McNamara, Marie Josette Catherine Menard, Michael Weiss, Lillian Seu, Elsa Quintana. RAS(ON) inhibition in both cancer and immune cells by daraxonrasib drives anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2831.