Abstract 581: Identification of potential biomarkers of response to RASMULTI(ON) plus anti-PD-1 combination in preclinical PDAC models

Abstract Mutant KRAS is present in more than 80% pancreatic cancer, promotes cancer cell survival, and protects cancer cells from immune recognition and attack. We have shown that inhibitors of the active state of RAS (RAS (ON) ) promote cancer neoantigen recognition and synergize with immunotherapy in preclinical immunogenic models. 1 We evaluated the impact of RMC-6236, an investigational RASMULTI (ON) inhibitor on anti-tumor activity and tumor microenvironment (TME) remodeling in two congenic KRASG12D/+ GEMM-derived PDAC models resistant to anti-PD-1 therapy - KPCY clone 2 (6694c2) and clone 3 (2838c3), developed by Ben Stanger at UPenn. 2 Daily oral administration of RMC-6236 drove tumor regressions in KPCY clone 3, leading to 10% durable complete responses (CRs). In combination with anti-PD-1, 40% of durable CRs were achieved. However, RMC-6236 only drove tumor growth inhibition in KPCY clone 2, and no combination benefit with anti-PD-1. We conducted preclinical biomarker analyses in the TME and periphery to explore differences in response to RMC-6236 alone and in combination with anti-PD-1 in these models. Assessment of baseline predictive biomarkers in tumors elucidated that the KPCY clone 3 cells developed tumors with lower suppressive myeloid cells (gMDSCs) and higher CD8+ T cell infiltration compared to those derived from KPCY clone 2 cells. IHC analyses showed that T cells in clone 3 were in the tumor core, while CD8+ T cells in clone 2 were at the tumor border (the latter frequently observed in PDAC patients). RMC-6236 induced transformation of the TME in favor of anti-tumor immunity in only the KPCY clone 3 - with decreased immunosuppressive gMDSCs, and increased T cells. Limited modulation of the TME was observed in the KPCY clone 2 cells-derived tumors, and gMDSC levels significantly higher than those in baseline tumors of KPCY clone 3. Peripheral immunophenotyping analyses revealed that baseline peripheral suppressive myeloid cells (mMDSCs) were significantly higher in mice harboring tumors originated from KPCY clone 2 cells, suggestive of a more systemic immunosuppressive status. Studies are ongoing to assess additional peripheral immune signatures of preclinical activity of RMC-6236 in combination with anti-PD-1. Taken together, baseline tumor levels of suppressive myeloid cells (gMDSCs) were shown to be a negative predictive biomarker for treatment outcome to RMC-6236 +/- anti-PD-1 in KRAS mutant preclinical PDAC models. Peripheral mMDSCs were shown to be higher in the mice with tumors from the PDAC model not sensitive to the combination of RMC-6236 with anti-PD-1, suggesting that it could be predictive of poor outcome for this combination. These studies in immune-competent models of RAS mutant PDAC allow us to generate tumor and blood-based biomarkers that may predict outcomes to RAS (ON) inhibitor combinations in the clinic. 1 Menard et al. AACR 2023 2 Li et al. Immunity 2018 Citation Format: Lillian Seu, Marie Menard, Jasmine Lee, Christopher Chow, Cristina Blaj, Mariela Moreno Ayala, Nataliya Shifrin, Avery Salmon, Swetha Ganesh, Philip Wig, Alice Kumamoto, Paola Soto-Perez, Tippy Taavili, Vivian Morton, James W. Evans, Jacqueline A. Smith, Elsa Quintana. Identification of potential biomarkers of response to RASMULTI (ON) plus anti-PD-1 combination in preclinical PDAC models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 581.