Preliminary safety, antitumor activity, and circulating tumor DNA (ctDNA) changes with RMC-9805, an oral, RAS(ON) G12D-selective tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced

724 Background: RMC-9805 is a potent, oral, RAS(ON) G12D-selective, covalent, tri-complex inhibitor targeting the active, GTP-bound state of oncogenic RAS G12D isoforms. Despite low response rates to current standard of care (SOC), no RAS-targeted therapy is approved for G12D PDAC. Methods: In this Phase 1 study (NCT06040541), patients with previously treated, advanced KRAS G12D solid tumors received escalating RMC-9805 doses (150-1200 mg once daily [QD] or 300-600 mg twice daily [BID]). Treatment cycles were every 3 wks. Antitumor activity was assessed every 6 wks the first 24 wks then every 9 wks. Additional patients were enrolled at RMC-9805 doses that cleared the dose-limiting toxicity (DLT) evaluation to further characterize pharmacokinetics, safety, antitumor activity, and biomarkers. Plasma for ctDNA analysis was collected at baseline (BL; cycle 1, day 1 [C1D1] or screening), and on treatment (OT; C2D1 or C3D1). Results: As of Sept 2, 2024, 179 patients with KRAS G12D solid tumors (most having PDAC; n=104 [58%]) received 5 escalating dose levels of RMC-9805 (150-1200 mg daily). No DLTs or Grade 4 or 5 treatment-related adverse events (TRAEs) were reported, and the maximum tolerated dose (MTD) was not reached. Among patients who received a candidate recommended phase 2 dose (RP2D) of 1200 mg daily (1200 mg QD [n=60] or 600 mg BID [n=39]), the most common (≥10% of patients) TRAEs were nausea (27%), diarrhea (20%), vomiting (15%), and rash (10%), all of which were Grade 1 or 2 severity. One Grade 3 TRAE (ALT elevation) was observed in a patient with PDAC and a history of ALT elevation, biliary stenting, and liver metastasis. No patients treated with 1200 mg daily discontinued treatment due to TRAEs and 4% of patients had dose reductions due to TRAEs. In patients with PDAC receiving RMC-9805 daily at 1200 mg QD (n=20) or 600 mg BID (n=20) who enrolled at least 14 wks prior to data cutoff, the objective response rate (confirmed response or pending confirmation) was 30%, and the disease control rate was 80%. Of 28 patients who had KRAS G12D mutations detected in ctDNA at BL and were evaluable for OT assessment, 86% had an OT decrease >50% from BL of detectable KRAS G12D mutations, and 39% had a 100% OT clearance. Updated data will be presented. Conclusions: Oral RMC-9805 showed encouraging initial antitumor activity with early and deep reductions in KRAS G12D ctDNA in patients with KRAS G12D PDAC. Tolerability was favorable relative to SOC chemotherapy for PDAC and manageable. This overall safety profile and antitumor activity support continued evaluation as monotherapy in patients with KRAS G12D PDAC, and in combination with chemotherapy and targeted therapies, including the RAS(ON) multi-selective inhibitor RMC-6236. Clinical trial information: NCT06040541 .