RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor that targets both mutant and wild-type variants of canonical RAS isoforms. It has shown potent anticancer activity across RAS-addicted cell lines, particularly those with KRAS mutations at codon 12. Oral administration of RMC-6236 was well tolerated in vivo and led to significant tumor regressions in multiple tumor types in a mouse clinical trial with KRASG12V xenograft models. Pharmacokinetic (PK) and pharmacodynamic (PD) modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Two patients with advanced KRASG12V lung and pancreatic adenocarcinoma treated at 300 mg daily demonstrated initial clinical activity, supporting the ongoing phase II/III clinical trial (NCT05379985). The study highlights the broad-spectrum antitumor activity of RMC-6236 and its potential as a therapeutic option for RAS-driven cancers.RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor that targets both mutant and wild-type variants of canonical RAS isoforms. It has shown potent anticancer activity across RAS-addicted cell lines, particularly those with KRAS mutations at codon 12. Oral administration of RMC-6236 was well tolerated in vivo and led to significant tumor regressions in multiple tumor types in a mouse clinical trial with KRASG12V xenograft models. Pharmacokinetic (PK) and pharmacodynamic (PD) modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Two patients with advanced KRASG12V lung and pancreatic adenocarcinoma treated at 300 mg daily demonstrated initial clinical activity, supporting the ongoing phase II/III clinical trial (NCT05379985). The study highlights the broad-spectrum antitumor activity of RMC-6236 and its potential as a therapeutic option for RAS-driven cancers.