Abstract PR012: The RAS(ON) G12D-selective inhibitor RMC-9805 synergizes with anti-PD-1 to extend durability of antitumor activity in KRAS G12D-driven preclinical cancer models

Abstract Activating RAS mutations are among the most common drivers of human cancers. Upregulation of the RAS-MAPK signaling leads to sustained cell proliferation and immune escape via tumor cell-intrinsic modulation of immune molecules and crosstalk with the tumor microenvironment (TME). Major epithelial tumors harboring the G12D variant, the most common oncogenic KRAS mutation, remain an unmet medical need. The investigational agent RMC-9805, a RAS(ON) G12D-selective covalent inhibitor, exhibits potent antitumor activity in xenograft models of KRAS G12D mutant cancers. Here, we assessed the impact of RMC-9805 on antitumor immunity in two KRAS G12D-driven immunocompetent mouse models, including a GEMM-derived model representative of pancreatic ductal adenocarcinoma (PDAC), a RAS-addicted neoplasm refractory to immunotherapy. First, RMC-9805 induced a profound and sustained inhibition of RAS signaling across both models, driving tumor regressions and significantly prolonging progression-free survival (PFS, defined by time to tumor doubling). Next, we observed that the durability of response to RMC-9805 was extended in immunocompetent hosts compared to that in immunodeficient mice, suggesting that RMC-9805 engaged an antitumor immune response. Indeed, RMC-9805 promoted antigen processing and presentation on tumor cells, decreased immunosuppressive myeloid cells and concurrently increased T cell infiltration in tumors, effectively priming the TME in favor of antitumor immunity. Longitudinal TCR sequencing analyses of KRAS G12D tumor-bearing mice further revealed that RMC-9805 increased the TCR repertoire diversity in tumors and induced an expansion of tumor-associated T cells in peripheral blood. An increase in T cell exhaustion markers was observed in tumors treated with RMC-9805, prompting the evaluation of the combination of KRAS G12D inhibition with immune checkpoint blockers in these immunotherapy-resistant preclinical models. RMC-9805 synergized with anti-PD-1, resulting in complete responses, including in the GEMM-derived preclinical PDAC model. We are currently evaluating in preclinical experiments whether the antitumor response observed with RMC-9805 plus anti-PD-1 can be further improved with the addition of chemotherapy, the standard-of-care for PDAC. Collectively, these findings demonstrate that RMC-9805 induces a profound and favorable immune modulation of the TME, enhancing the adaptive antitumor immune response and synergizing with T cell-targeted immunotherapies in RAS G12D-driven preclinical cancer models. These observations suggest a potential for exploring additional combination strategies of the RAS(ON) G12D-selective inhibitor RMC-9805 with immune-stimulating therapies, including checkpoint inhibitors, in the clinic with the intent of optimizing the durability of antitumor activity. Citation Format: Marie Menard, Nataliya Tovbis-Shifrin, Lilit Grigoryan, Jasmine Lee, Cheng Liu, Swetha Ganesh, Linh Tran, Haley Courtney, Ximo Pechuan-Jorge, Felix Mbuga, Rashi Raghulan, Vivian Morton, Paola Soto-Perez, Lillian Seu, Jacqueline AM Smith, Elsa Quintana. The RAS(ON) G12D-selective inhibitor RMC-9805 synergizes with anti-PD-1 to extend durability of antitumor activity in KRAS G12D-driven preclinical cancer models [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr PR012.