Abstract C019: RMC-5127, a RAS(ON) G12V-selective inhibitor, drives durable tumor regressions and increases T cell infiltration in KRAS G12V-driven syngeneic models

Abstract KRAS G12V is the second most common RAS mutation in RAS-dependent cancers, including pancreatic (34%), colorectal (21%), and non-small cell lung (19%) cancers. RMC-5127 is an orally bioavailable, mutant-selective tri-complex inhibitor that targets the active, GTP-bound (ON) form of RAS G12V. It forms a noncovalent binary complex with the abundant intracellular chaperone protein cyclophilin A, which then engages RAS(ON) G12V to create a high-affinity tri-complex that sterically blocks binding of downstream effector proteins, thereby inhibiting oncogenic signaling. Oncogenic RAS signaling, drives tumorigenesis through MAPK and PI3K pathway activation and promotes immune evasion via tumor cell–intrinsic suppression of interferon signaling, modulation of immunosuppressive cytokines, and downregulation of MHC class I. We previously demonstrated that the RAS(ON) mutant-selective inhibitors elironrasib (RMC-6291) and zoldonrasib (RMC-9805) favorably remodel the tumor immune microenvironment (TME) and induce immune cell-dependent complete regressions in KRAS G12C and G12D models, respectively. Here, we evaluated the antitumor activity of RMC-5127 across syngeneic models representative of KRAS G12V-driven colorectal, pancreatic, and lung cancers, spanning both T cell high and low TMEs. In the T cell-high CT26 colorectal model engineered to express KRAS G12V, oral administration of RMC-5127 induced 40% complete regressions. Although this model is refractory to anti-PD-1, the combination of RMC-5127 with anti-PD-1 achieved 100% durable complete regressions. Re-challenge studies confirmed immunological memory, indicating effective priming of tumor-specific adaptive immunity. Mechanistically, RMC-5127 increased intratumoral T cells, upregulated MHC-I expression, and induced an interferon response gene signature, consistent with enhanced antigen presentation and immune activation. These preclinical data show that RMC-5127 reprograms the TME, amplifies tumor recognition and adaptive immune activation, and confers sensitivity to PD-1 blockade. To extend these findings, we tested RMC-5127 in GEMM-derived pancreatic cancer models engineered to express KRAS G12V (eKPCY2838c3 and eKPCY6419c5) and in a spontaneous KRAS G12V-driven lung cancer model (CMT167). RMC-5127 induced rapid, durable tumor regressions and increased T cell infiltration and MHC-I expression in all models, including in the T cell low model eKPCYc6419c5, demonstrating that RAS(ON) inhibition increases T cell infiltration regardless of baseline TME status. In conclusion, RMC-5127 drives robust, durable tumor regressions across KRAS G12V-driven colorectal, pancreatic and lung models and promotes a more immune active TME characterized by increased T cell infiltration and enhanced antigen recognition in T cell high and low tumors. These preclinical findings are consistent with our previous observations using RAS(ON) G12C and G12D mutant selective inhibitors and collectively support a central role for the active oncogenic state of diverse RAS mutant alleles in immune evasion. Citation Format: Mariela Moreno Ayala, Paola Soto Perez, Antonio Quinones, Swetha Ganesh, Linh Tran, Alice Kumamoto, Jim Evans, Miguel Sandoval, Michael Weiss, Cristina Blaj, Jacqueline Smith, AM.Elsa Quintana. RMC-5127, a RAS(ON) G12V-selective inhibitor, drives durable tumor regressions and increases T cell infiltration in KRAS G12V-driven syngeneic models abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C019.