652O Preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC)

RMC-6236 is a novel, oral RASMULTI(ON) inhibitor that is selective for the active, GTP-bound state of both mutant and wild-type variants of the canonical RAS isoforms. Preclinical studies have demonstrated deep and sustained regressions across multiple RASMUT tumor types, particularly PDAC and NSCLC harboring KRAS glycine-12 substitutions (KRASG12X). Patients with previously treated, advanced KRASG12X mutant solid tumors were enrolled at escalating doses (10mg to 160mg once daily (QD)) of single agent RMC-6236. Additional patients with PDAC or NSCLC were enrolled at dose levels that cleared dose-limiting toxicity evaluation. As of April 24, 2023, 22 patients with KRASG12X PDAC (13 G12D, 7 G12V, 2 G12R) and 11 with KRASG12X NSCLC (5 G12D, 4 G12V, 2 G12A) were enrolled, and 14 patients with PDAC and 9 patients with NSCLC continue treatment with RMC-6236. Median prior therapies was 3 (range, 1-7). Treatment-related adverse events (TRAEs) occurring in ≥10% of patients were rash (52%), diarrhea (21%), nausea (21%), and vomiting (15%). The only Grade ≥3 TRAE was in a patient with PDAC who had a Grade 4 large intestine perforation at the site of an invasive tumor that reduced in size on treatment. Preclinical modeling predicts tumor regressions at 80mg QD or higher in humans. Preliminary clinical activity in PDAC and NSCLC was assessed at 80mg and 120mg QD. Among 14 patients (10 PDAC, 4 NSCLC) dosed at least 8 weeks prior to the data cut-off date, the objective response rate was 36% (2 confirmed and 3 unconfirmed; 2/10 PDAC and 3/4 NSCLC). Median time to onset of initial response was 6 weeks (range, 5-11). Disease control rate was 86% (12/14; 8/10 PDAC and 4/4 NSCLC). Tumor reduction was observed in 4 patients with stable disease (range, -2% to -21% by RECIST v1.1). Of the 12 patients with partial response or stable disease, 11 continue on treatment. RMC-6236 exhibits promising anti-tumor activity in patients with KRASG12X PDAC and NSCLC at doses that are well tolerated. Dose escalation is ongoing and data from additional patients will be available at the time of the meeting.