Abstract A118: Daraxonrasib, a RAS(ON) multi-selective inhibitor, exhibits potent antitumor activity and combinatorial benefit with standard of care chemotherapy and with anti-PD-1 in preclinical models of KRAS G12R PDAC

Abstract The investigational agent daraxonrasib (RMC-6236) is an oral, RAS(ON) multi-selective, tri-complex inhibitor targeting GTP-bound mutant and wild-type RAS. A registrational clinical trial, RASolute 302 (NCT06625320), is currently ongoing to evaluate daraxonrasib as a second-line treatment for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Oncogenic mutations in KRAS drive the initiation and maintenance of PDAC and are present in over 90% of PDAC cases, most frequently at codon 12 (G12X). Among these, KRAS G12R displays distinct biochemical properties from other G12X variants, including the slowest rate of intrinsic GTPase activity, leading to an accumulation of the active, GTP-bound (ON) state. Additionally, attenuated oncogenic features of KRAS G12R in disease progression and metastasis of PDAC have been reported. Here we describe a detailed characterization of the antitumor activity of daraxonrasib in preclinical models of PDAC harboring KRAS G12R mutations. Daraxonrasib effectively suppressed RAS(ON) signaling and displayed anti-proliferative activity in a panel of KRAS G12R PDAC cell lines in vitro. In KRAS G12R xenograft models, daraxonrasib induced objective responses in 10/14 KRAS G12R PDAC models surveyed, with a significantly improved durability of response as compared to control. The potent antitumor activity of daraxonrasib in KRAS G12R models contrasts with that of pan-KRAS inhibitors that bind preferentially to the inactive, GDP-bound (OFF) state of KRAS (pan-KRAS(OFF) inhibitors) which exhibited limited to no activity. This is anticipated, given the properties of KRAS G12R and the respective mechanisms of action of the inhibitors. The activities of daraxonrasib in combination with standard of care (SOC) chemotherapy, i.e. gemcitabine and nab-paclitaxel (GnP), or leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), or immune checkpoint inhibitors in KRAS G12R PDAC models, were also explored. The addition of either GnP or FOLFIRINOX to daraxonrasib exhibited combinational benefits in xenograft models, leading to improved depth and/or durability of response compared to single agents in vivo. Furthermore, when evaluated in a syngeneic KRAS G12R PDAC model resistant to anti-PD-1 immunotherapy, daraxonrasib favorably remodeled the tumor microenvironment with increased T cell infiltration and decreased granulocytic myeloid derived suppressor cells. Treatment with daraxonrasib sensitized the tumors to anti-PD-1, achieving 7 out 10 complete responses in this model. Overall, these data highlight the attractive antitumor activity of daraxonrasib in preclinical models of KRAS G12R PDAC, as both monotherapy and in combination with SOC chemotherapy or immune checkpoint inhibition. Daraxonrasib is currently being evaluated as monotherapy in patients with previously treated metastatic PDAC (NCT06625320), and in combination with SOC chemotherapy in treatment-naive metastatic PDAC patients (NCT06445062). Citation Format: Urszula N. Wasko-Kornberg, Jasmine Y. Lee, Xing Wei, Yongxian Zhuang, Enrico Payson, Stephanie Chang, Kyle Seamon, Lick P. Lai, Marie Menard, Lingyan Jiang, Mallika Singh, Elsa Quintana, Jingjing Jiang. Daraxonrasib, a RAS(ON) multi-selective inhibitor, exhibits potent antitumor activity and combinatorial benefit with standard of care chemotherapy and with anti-PD-1 in preclinical models of KRAS G12R PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A118.