Abstract LB281: Mechanisms of resistance to the RAS(ON) multi-selective inhibitor daraxonrasib (RMC-6236) in RAS mutant PDAC and potential resolution with RAS(ON) combination therapies
Authors: Sumit Kar, Yongxian Zhuang, Ethan Ahler, Lick P. Lai, Alexander Starodub, Alexander Spira, Salman R. Punekar, Ignacio Garrido-Laguna, Wungki Park, David S. Hong, Anirban Maitra, David Sommerhalder, Minal Barve, Meredith Pelster, Harika Gundlapalli, Vidya Seshadri, Shurui Cai, Mark Labrecque, Wan-Ying Hsieh, Sean Bredeson, Jim Evans, Brett Garrick, Yevgeniy Gindin, Cristina Blaj, Marie Menard, Lingyan Jiang, Elsa Quintana, Matthew Holderfield, Aparna Hegde, Jingjing Jiang, Zeena Salman, W Clay Gustafson, Jacqueline A. Smith, Brian Wolpin, Ida Aronchik, Kevin K. Lin, Andrew J. Aguirre, Mallika Singh
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is driven by oncogenic RAS mutations in &amp;gt;90% of cases. Daraxonrasib (RMC-6236) is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor with broad-spectrum activity against oncogenic mutant and wild-type variants of N, H and KRAS. We reported encouraging efficacy of daraxonrasib at tolerated dose levels of 160 to 300 mg daily as of a data cutoff of 23 Jul 2024 in patients with previously treated, RAS mutant metastatic PDAC, with median progression free survival (PFS) of 7.6 months (95% CI, 5.9 to 11.1) and overall survival (OS), 14.5 months (95% CI, 8.8 to not evaluable). Here, we report preclinical and clinical evidence for potential mechanisms of acquired resistance following monotherapy treatment with daraxonrasib in PDAC. Genomic alterations in baseline and end of treatment ctDNA were compared in 26 patients with PFS&amp;gt;3 months on daraxonrasib. Putative genomic mechanisms of resistance to daraxonrasib were found in 62% (16/26), including acquired amplifications of KRAS in 35% (9/26) of patients. No acquired oncogenic secondary KRAS mutations were observed, distinct from resistance profiles reported for mutant-selective KRAS G12C(OFF) inhibitors, and consistent with the broad RAS inhibitory activity of daraxonrasib. Acquired alterations were observed in RAF (4; 15%), RTKs (3; 12%), PI3K pathway genes (2; 8%), and MYC (1; 4%) of patients. Multiple acquired alterations were detected in ctDNA from 6 patients (23%). Consistent with our clinical findings, alterations driving daraxonrasib resistance in preclinical models in vitro and in vivo included KRAS amplification, alterations in RAF and upregulation of RTKs. We have previously reported acquired Myc amplification as a potential mechanism of resistance to RAS(ON) multi-selective inhibition in preclinical models. Together, our clinical and preclinical data converge on a set of resistance mechanisms that drive genomic reactivation of RAS pathway signaling in PDAC following the selective pressure exerted by daraxonrasib monotherapy, discernible from those reported for mutant-selective KRAS G12C(OFF) inhibitors. We hypothesize that increased therapeutic pressure on RAS signaling, via an increase in total RAS target occupancy, could address these resistance mechanisms. We demonstrate that the combination of daraxonrasib with a mutant-selective RAS(ON) inhibitor (either the RAS(ON) G12C mutant selective inhibitor elironrasib (RMC-6291), or the RAS(ON) G12D mutant selective inhibitor zoldonrasib (RMC-9805)) drove combinatorial benefit and forestalled monotherapy resistance in a series of preclinical models. The RAS(ON) inhibitor doublets of elironrasib or zoldonrasib with daraxonrasib are currently being evaluated in patients with tumors harboring RAS G12C and RAS G12D, respectively. Citation Format: Sumit Kar, Yongxian Zhuang, Ethan Ahler, Lick P. Lai, Alexander Starodub, Alexander Spira, Salman R. Punekar, Ignacio Garrido-Laguna, Wungki Park, David S. Hong, Anirban Maitra, David Sommerhalder, Minal Barve, Meredith Pelster, Harika Gundlapalli, Vidya Seshadri, Shurui Cai, Mark Labrecque, Wan-Ying Hsieh, Sean Bredeson, Jim Evans, Brett Garrick, Yevgeniy Gindin, Cristina Blaj, Marie Menard, Lingyan Jiang, Elsa Quintana, Matthew Holderfield, Aparna Hegde, Jingjing Jiang, Zeena Salman, W Clay Gustafson, Jacqueline A. Smith, Brian Wolpin, Ida Aronchik, Kevin K. Lin, Andrew J. Aguirre, Mallika Singh. Mechanisms of resistance to the RAS(ON) multi-selective inhibitor daraxonrasib (RMC-6236) in RAS mutant PDAC and potential resolution with RAS(ON) combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB281.