Abstract ND07: Discovery of RMC-6291, a tri-complex KRASG12C(ON) inhibitor

Abstract

Abstract The KRASG12C mutation occurs in 11 - 14% of non-small cell lung cancers, ~4% of colorectal cancers, and ~2% of pancreatic cancers in the U.S., and drives these cancers by shifting the cellular equilibrium of KRAS towards the GTP-bound, active state, KRASG12C(ON). The resulting increased levels of KRASG12C(ON) in turn increase signaling output to initiate and support the oncogenic state. RMC-6291 is a potent, orally bioavailable inhibitor of KRASG12C(ON) that forms a tri-complex within tumor cells along with KRASG12C(ON) and cyclophilin A (CypA), driving a near-immediate disruption of RAS effector binding and extinction of KRASG12C(ON) signaling. RMC-6291 treatment produces deep and durable suppression of RAS pathway activity in KRASG12C tumor models and drives profound tumor regressions in vivo. In a mouse clinical trial with a representative panel of xenograft models of KRASG12C NSCLC, RMC-6291 outperformed adagrasib, displaying a potential ‘best-in-class’ profile with an increased number of responses, greater depth of tumor regressions and improved durability of responses. Thus, RMC-6291 is a clinical stage inhibitor of KRASG12C(ON) that potentially overcomes limitations of first-generation KRASG12C(OFF) inhibitors. Citation Format: Jim Cregg, R J. Nichols, Y C. Yang, C J. Schulze, Z Wang, R Dua, J Jiang, N Nasholm, J E. Knox, K Seamon, M Longhi, A Tomlinson, K Chou, S Li, D P. Wildes, M Singh, E S. Koltun, A L. Gill, J A. Smith. Discovery of RMC-6291, a tri-complex KRASG12C(ON) inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND07.