Abstract 1884: Molecular determinants of sensitivity and resistance to the pan-RAS(ON) inhibitor daraxonrasib(RMC-6236) across KRAS-mutant patient-derived models.

Abstract CHAMPIONS Abstract Body: KRAS mutations define a major therapeutic opportunity across solid tumors but often align with limited response durability and resistance to targeted therapies. Daraxonrasib (RMC-6236), a selective pan-RAS(ON) inhibitor, demonstrates activity across KRAS G12X-mutant tumors; however, the molecular and clinical features governing sensitivity or promoting resistance remain incompletely understood. We screened a 50-model KRAS-mutant PDX cohort spanning NSCLC (n=16), colorectal cancer (n=19), and pancreatic ductal adenocarcinoma (n=19). Models reflect clinically relevant KRAS variants and diverse co-mutational landscapes, accompanied by pre-treatment patient histories, enabling classification of responders and non-responders through integration of molecular and clinical contexts. Tumors were evaluated for intrinsic response, and longitudinal sampling captured acquired-resistance outgrowths for subsequent genomic analysis. We performed integrated NGS (omics?) analyses on (i) baseline data from responding vs non-responding models, (ii) resistant tumors emerging after initial regression, and (iii) associations with prior patient treatments. Daraxonrasib produced a broad range of activity across the array of models screened. Heterogeneity in the depth and durability of responses correlated with KRAS allele type, co-driver mutations, and specific pre-treatment exposures. These studies establish an annotated, translational system for defining determinants of RAS(ON) inhibitor response that shape resistance and inform rational therapeutic combination strategies. Citation Format: Kayla Tyskiewicz, Markus Hippich, Tristan Cates, Gervaise Henry, Gilad Silberberg, Nicole Spanburg, Madeline Westcott, Daniel Ciznadija, Michael Boice, Paul Heverly, Frank Smith, Marianna Zipeto, Stefano Cairo, Sebastian Brabetz. Molecular determinants of sensitivity and resistance to the pan-RAS(ON) inhibitor daraxonrasib(RMC-6236) across KRAS-mutant patient-derived models 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 1884.