Abstract 6046: Combination of RAS(ON) mutant-selective and multi-selective inhibitors sensitizes immune-refractory, RAS-driven preclinical models to immunotherapy

Abstract Oncogenic RAS promotes carcinogenesis by sustaining cell proliferation and orchestrating immune escape. We and others have shown that RAS inhibition combined with immune checkpoint blockade (ICB) prolongs durability of response in immunogenic, RAS-driven preclinical models. Clinical data have shown that most patients treated with KRAS G12C(OFF) inhibitors develop resistance through reactivation of the RAS pathway. We have previously demonstrated that the combination of a RAS(ON) G12C-selective inhibitor with a RAS(ON) multi-selective inhibitor can overcome mechanisms of intrinsic and acquired resistance in an immune-refractory preclinical NSCLC model. Here we evaluated if the RAS(ON) doublet combination of RMC-6291 or RMC-9805, a RAS(ON) G12C-selective inhibitor and a RAS(ON) G12D-selective inhibitor, respectively, with the RAS(ON) multi-selective inhibitor RMC-6236 can sensitize traditionally hard to treat, immune-refractory preclinical models to anti-PD-1. In a KRAS G12C NSCLC syngeneic model, RMC-6291, RMC-6236, and the RAS(ON) doublet induced rapid, transient tumor regressions, but some tumors progressed on treatment. This model is refractory to anti-PD-1 monotherapy and the combination of RMC-6291 or RMC-6236 with anti-PD-1 did not achieve significant combination benefit. RMC-6291 and RMC-6236 as single agents and the RAS(ON) doublet induced a similar favorable modulation of the TME, increasing tumor infiltrating lymphocytes and decreasing myeloid cells. Only the RAS(ON) doublet upregulated MHC class I expression, increasing the possibility of recognition of the tumor by T cells. Notably, the RAS(ON) doublet sensitized this model to anti-PD-1, with the triple combination achieving 100% CRs. In a GEMM-derived, KRAS G12D pancreatic model, the combination of RMC-9805 with RMC-6236 achieved RAS pathway inhibition as evidenced by deeper p-ERK suppression, and significantly increased the depth and durability of the antitumor response compared to either single agent alone. Tumors treated with RMC-9805 plus RMC-6236 showed a more profound transformation of the TME, characterized by a decrease in immunosuppressive myeloid cells, an increase in T cell infiltration, and a significant upregulation of the antigen presentation machinery. Combination of the RAS(ON) doublet with anti-PD-1 induced 90% CRs in this immune-refractory model. Collectively, these preclinical findings suggest that the RAS(ON) doublet combination of RAS(ON) mutant-selective and multi-selective inhibitors can reverse the immune-evasion mechanisms governed by oncogenic RAS and sensitize immune-refractory tumors to ICB to induce durable CRs. These preclinical data support the clinical evaluation of the RAS(ON) doublets in combination with ICB in patients with RAS driven cancers. Citation Format: Mariela Moreno Ayala, Cristina Blaj, Marie Menard, Avery Salmon, Jasmine Lee, Swetha Ganesh, Anna Pham, Vivian Morton, Miguel Sandoval, Jacqueline Smith, Elsa Quintana AM. Combination of RAS(ON) mutant-selective and multi-selective inhibitors sensitizes immune-refractory, RAS-driven preclinical models to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6046.