Abstract A069: RAS(ON) inhibitor in-pathway combinations maximize RAS pathway suppression, and drive deep and durable antitumor activity in KRAS mutant CRC models

Abstract RAS is one of the most frequently mutated oncogenes in colorectal cancer (CRC), occurring in ∼50% of cases. Inactive state mutant selective KRAS G12C (G12C(OFF)) inhibitors in combination with anti-EGFR agents have been approved for the treatment of KRAS G12C mutant CRC patients. While this represents a significant advance, most patients experience disease progression within months. Moreover, the majority of RAS mutant CRC patients, who harbor non-G12C mutations such as RAS G12D/V, still lack effective targeted therapies. We have designed a series of tri-complex inhibitors that selectively target the GTP-bound, active state of RAS (RAS(ON)), thereby mitigating some of the resistance mechanisms observed with inhibitors that preferentially bind to the OFF state. This includes daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor that noncovalently inhibits the GTP-bound state of mutant and wild-type variants of the canonical RAS isoforms (KRAS, NRAS, and HRAS) and the mutant-selective inhibitors elironrasib (RMC-6291) and zoldonrasib (RMC-9805) that covalently engage RAS(ON) G12C and RAS(ON) G12D, respectively. These investigational agents demonstrate profound antitumor activity in preclinical models of RAS mutant NSCLC and PDAC, which has translated into promising monotherapy clinical activity. However, in KRAS mutant CRC models, adaptive reactivation of the RAS pathway leads to heterogeneous responses and tumor relapses. We hypothesize that increased therapeutic pressure on RAS signaling, via in-pathway combinations, could enhance the antitumor activity in RAS mutant CRC, as exemplified by combination therapies of G12C(OFF) or BRAF inhibitors with anti-EGFR therapy. Here we demonstrate that the addition of RAS(ON) multi-selective inhibitors, or the anti-EGFR antibody cetuximab, to RAS(ON) mutant-selective inhibitors leads to sustained RAS/MAPK pathway suppression in KRAS mutant CRC tumors with a corresponding increase in the objective response rates and durability of response in preclinical models compared to monotherapies. Immune checkpoint inhibitors have limited clinical efficacy as monotherapies in microsatellite stable (MSS) CRC. Using a preclinical model of MSS KRAS G12D mutant CRC, we investigated if maximizing RAS pathway inhibition with the RAS(ON) inhibitor doublet of zoldonrasib and daraxonrasib could remodel the tumor microenvironment (TME) and sensitize tumors to immune checkpoint inhibition. The RAS(ON) inhibitor doublet increased tumor T cell infiltration and potentiated T cell function, by enhancing cytokine signaling, and upregulating the antigen presentation machinery. This favorable transformation of the TME translated into a combinatorial benefit with anti-PD-1, resulting in durable complete regressions in all animals (10/10) in comparison to 2/10 for the RAS(ON) doublet alone. Together, these preclinical findings of combinational benefits support the ongoing clinical evaluation of RAS(ON) inhibitor in-pathway combinations in CRC patients harboring RAS G12D or RAS G12C mutations. Citation Format: Xing Wei, Alexey Sorokin, Lingyan Jiang, Avery Salmon, Cristina Blaj, Yu-chi Yang, Ciara Helland, Preeti Kanikarla, Jay Saynonh, Stephanie Chang, Benjamin Maldonato, Linh Tran, Enrico Payson, Miguel Sandoval, Jacqueline A. Smith, Elsa Quintana, Mallika Singh, Scott Kopetz, Jingjing Jiang. RAS(ON) inhibitor in-pathway combinations maximize RAS pathway suppression, and drive deep and durable antitumor activity in KRAS mutant CRC models [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 A069.