Abstract A081: Resistance Mechanisms to Monotherapy RAS(ON) Multi-Selective Inhibitor Daraxonrasib (RMC-6236) in RAS Mutant PDAC Inform Therapeutic Combination Strategies

Abstract The development of direct RAS inhibitors has given rise to a revolution in the treatment of RAS-addicted cancers. The investigational agent daraxonrasib (RMC-6236) is an orally bioavailable RAS(ON) multi-selective, tri-complex inhibitor of oncogenic mutant and wild-type variants of N, H and KRAS. We have reported encouraging clinical activity in patients with previously treated RAS mutant metastatic pancreatic ductal adenocarcinoma (PDAC) from our Phase 1/1b clinical trial evaluating daraxonrasib monotherapy in advanced RAS mutant cancers. A registrational clinical trial, RASolute 302 (NCT06625320), is currently ongoing to evaluate daraxonrasib as a second-line treatment for patients with metastatic PDAC. Here we identify and report mechanisms of acquired monotherapy resistance observed through targeted sequencing of over 800 genes in paired pre- and end of treatment ctDNA samples from 37 patients with PDAC from this study, who have exhibited partial response or stable disease with a progression free survival (PFS) of > 3 months followed by subsequent progression on therapy as of clinical data cutoff of January 13, 2025. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (21/37; 57%) of these patient samples. Notably, no acquired oncogenic secondary KRAS mutations were observed in this PDAC cohort, distinct from resistance profiles reported for mutant-selective KRAS G12C(OFF) inhibitors. Conversely, mutant KRAS amplifications were the most prevalent acquired alterations, found in approximately one third (11/37; 30%) of these patient samples. Other genomic alterations included mutations in receptor tyrosine kinase (RTK, 4/37, 11%), MAPK (11/37, 30%) and PI3K (3/37, 8%) pathways. These daraxonrasib monotherapy resistance mechanisms were recapitulated in a suite of preclinical models, which enabled establishment of causal relationships and investigation of therapeutic combination hypotheses. We demonstrate that maximizing RAS inhibition with RAS(ON) inhibitor doublets, use of antibody-based therapies targeting receptor tyrosine kinases, or combinations with DNA damage repair inhibitors are potential strategies for addressing daraxonrasib monotherapy resistance. Our results establish that key daraxonrasib resistance mechanisms drive reactivation of RAS pathway signaling and lay the foundation for combination therapy strategies to improve clinical outcomes with daraxonrasib in patients with PDAC. Citation Format: Ida Aronchik, Sumit Kar, Yongxian Zhuang, Ethan Ahler, Lick P. Lai, Vidya Seshadri, Kevin Yu Chi Yang, Ashenafi Bulle, Marie Menard, Biswadeep Nayak, Mark P. Labrecque, Julien Dilly, Harika Gundlapalli, Lingyan Jiang, Cristina Blaj, Jason Yano, Urszula Wasko-Kornberg, Ciara Helland, Sean Bredeson, Brett Garrick, Yevgeniy Gindin, Brad Sickler, James Evans, Kyle Seamon, Jingjing Jiang, Kian-Huat Lim, Matt Holderfield, Elsa Quintana, Aparna Hegde, Zeena Salman, Jacqueline A. M. Smith, Alexander Starodub, Alexander Spira, Wungki Park, David S. Hong, Minal Barve, Meredith Pelster, David Sommerhalder, Salman R. Punekar, Ignacio Garrido-Laguna, Brian Wolpin, Anirban Maitra, Clay Gustafson, Kevin Lin, Steve Kelsey, Andrew J. Aguirre, Mallika Singh. Resistance Mechanisms to Monotherapy RAS(ON) Multi-Selective Inhibitor Daraxonrasib (RMC-6236) in RAS Mutant PDAC Inform Therapeutic Combination Strategies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A081.