Abstract PR009: The RAS(ON) multi-selective inhibitor, daraxonrasib (RMC-6236), induces Receptor Tyrosine Kinase (RTK) cell surface expression on pancreatic cancer cells, providing rationale for combinations with RTK targeting agents

Abstract Daraxonrasib (RMC-6236) is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. In a First in Human study, daraxonrasib has demonstrated manageable safety and encouraging early activity in patients with RAS-dependent cancers. Analysis of end of treatment ctDNA samples from patients with pancreatic adenocarcinoma who have benefited from daraxonrasib monotherapy in this Phase 1 trial for over 3 months and eventually exhibited tumor progression has revealed that genomic features of acquired resistance to daraxonrasib monotherapy converge on reactivation of the RAS pathway. These include amplification of the mutant KRAS allele and alterations in receptor tyrosine kinase (RTK) family members such as ERBB2/HER2 gene amplification and MET mutation and fusion events. Here we report that, following daraxonrasib treatment, the cell-surface expression of multiple RTK proteins, including HER2, HER3, MET and EGFR, is increased in the majority of parental and RAS(ON) inhibitor monotherapy-resistant preclinical models. The combination of daraxonrasib with RTK-targeting antibody–drug conjugates (ADCs) leverages two therapeutic modalities: deep tumor-intrinsic RAS-pathway suppression and delivery of a cytotoxic payload with tumor-debulking activity. Using preclinical models of pancreatic adenocarcinoma we show that the combination of daraxonrasib with the HER2 targeting ADC trastuzumab deruxtecan (T-DXd) ​drives deeper and prolonged antitumor activity than daraxonrasib alone. This enhanced activity is observed in both parental and treatment emergent daraxonrasib-resistant Capan-1 (KRAS G12V/12V ) xenograft models and the KP-4 (KRAS G12D/WT , MTAP Del, Myc Amp) xenograft model, in which a monotherapy response to daraxonrasib is followed by on-treatment relapse. We also evaluated the daraxonrasib/T-DXd combination in the PSN-1 (KRAS G12R Amp, Myc Amp) model. PSN-1 exhibits low baseline HER2 expression and shows no HER2 induction following daraxonrasib treatment, either acutely or upon emergence of resistance. Consistent with this profile, T-DXd monotherapy has no activity, and the addition of daraxonrasib provides minimal benefit in either the parental or daraxonrasib-resistant PSN-1 models. In contrast, a defining feature of the KP-4 model is MET positivity with autocrine HGF signaling. In this setting, combining daraxonrasib with MET-targeting agents—either the bispecific EGFR–MET antibody amivantamab or the MET-directed ADC ABBV-399—results in deeper and more durable antitumor activity compared with the respective monotherapies. Collectively, these preclinical data demonstrate that daraxonrasib-mediated upregulation of RTKs creates an opportunity for rational, biomarker-driven combinations, and they further support the clinical evaluation of such combinations as a strategy to pre-empt or overcome emergent resistance. Citation Format: Yongxian Zhuang, Mark Labrecque, Helena Kiefel, Sumit Kar, Vidya Seshadri, Lingyan Jiang, Xing Wei, Ciara Helland, Yu Chi Yang, Jacqueline A. M. Smith, Jingjing Jiang, Mark Merchant, Mallika SIngh, Ida Aronchik. The RAS(ON) multi-selective inhibitor, daraxonrasib (RMC-6236), induces Receptor Tyrosine Kinase (RTK) cell surface expression on pancreatic cancer cells, providing rationale for combinations with RTK targeting agents [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr PR009.