Abstract 3340: RMC-5127, a first-in-class, orally bioavailable mutant-selective RASG12V(ON) inhibitor is central nervous system (CNS)-penetrant and demonstrates anti-tumor activity in a preclinical intracranial xenograft model
Authors: Chen Zhe , Eriksson Andre , Lee Bianca , Dinglasan Jay , Montazer Nilufar , Cregg Jim , Edwards Anne , Sanders Kate , Smith Jacqueline A. , Wildes David , Singh Mallika , Wang Zhican , Jiang Jingjing 
Published: March 2024

Abstract
Patients with advanced cancers harboring activating mutations in RAS, particularly those with non-small cell lung cancer, often develop brain metastases leading to increased morbidity and mortality. KRASG12V is the second most frequent RAS mutation in RAS-addicted cancers, including pancreatic cancer (34 %), colorectal cancer (21 %), and non-small cell lung cancer (19%). RMC-5127 is an orally bioavailable, mutant-selective tri-complex inhibitor of the GTP-bound (ON) form of RASG12V. RMC-5127 non-covalently binds to an abundant intracellular chaperone protein cyclophilin A (CypA), resulting in a binary complex that engages RASG12V(ON) to form a high-affinity tri-complex that sterically inhibits RAS binding to effectors. RMC-5127 drove deep suppression of RAS pathway activity, inhibited cell proliferation, and induced apoptosis in a panel of KRASG12V mutant human cancer cells in vitro but only caused submaximal inhibition in the panel of K/N/HRAS wildtype cancer cells, indicative of selectivity for KRASG12V over K/N/HRAS wildtype. Repeated oral dosing of RMC-5127 resulted in profound and durable anti-tumor activity in subcutaneous CDX and PDX models of KRASG12V mutant NSCLC, PDAC, and CRC in vivo. Dose-dependent exposure of RMC-5127 was observed in the whole brain of naïve mice, indicating the compound is brain penetrant. An intracranial xenograft model of KRASG12V tumors was established in immunodeficient mice to assess the CNS anti-tumor activity of RMC-5127. The intracranial tumor exposure of RMC-5127 was comparable with that observed in the whole brains of naïve mice and was sufficient to drive robust pharmacodynamic responses in the brain tumor. Moreover, RMC-5127 exhibited profound and durable anti-tumor activity in the intracranial model, with tumor regressions at well-tolerated doses. The anti-tumor activity of RMC-5127 in intracranial tumors was consistent with that in subcutaneous tumors at equivalent tumor exposures. In conclusion, these preclinical data demonstrate that RMC-5127 is a CNS-penetrant RASG12V(ON) inhibitor and support further study to determine the potential to benefit patients with advanced RASG12V-mutated cancers, including those that have developed or are at risk of developing brain metastases.
Citation Format: Zhe Chen, Andre Eriksson, Bianca Lee, Jay Dinglasan, Nilufar Montazer, Jim Cregg, Anne Edwards, Kate Sanders, Jacqueline A. Smith, David Wildes, Mallika Singh, Zhican Wang, Jingjing Jiang. RMC-5127, a first-in-class, orally bioavailable mutant-selective RASG12V(ON) inhibitor is central nervous system (CNS)-penetrant and demonstrates anti-tumor activity in a preclinical intracranial xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3340.