RMC-6291 is an orally active and covalent inhibitor of KRAS G12C (ON) . RMC-6291 forms a tri-complex within tumor cells between KRAS G12C (ON) and cyclophilin A (CypA). Thus, RMC-6291 prevents KRAS G12C (ON) from signaling via steric blockade of RAS effector binding. RMC-6291 elicits deep and durable suppression on RAS pathway activity in KRAS G12C tumor models