RMC-9805 Advanced Drug Monograph

RMC-9805 Medication Report

Name: RMC-9805 Name (English): RMC-9805

Mechanism of Action: RMC-9805 is an orally bioavailable covalent tri-complex inhibitor that selectively targets the active, GTP-bound form of the KRAS G12D mutation (KRASG12D(ON)). Upon oral administration, RMC-9805 first non-covalently binds to cyclophilin A, forming a binary complex. This complex then covalently and irreversibly binds to the KRASG12D(ON) protein at the Asp-12 residue. This interaction prevents KRAS G12D-mediated signaling and the activation of downstream survival pathways, leading to apoptosis in tumor cells expressing this mutation. Additionally, RMC-9805 may abrogate the suppressive tumor microenvironment and enhance anti-tumor immune responses.

Indications and Usage: RMC-9805 is an investigational drug currently being evaluated in Phase 1 clinical trials for the treatment of advanced solid tumors harboring the KRAS G12D mutation. Preliminary data suggest potential activity in:

• Non-small cell lung cancer (NSCLC)
• Pancreatic ductal adenocarcinoma (PDAC)
• Colorectal cancer (CRC)

Clinical Trial Information: RMC-9805 is being investigated in several Phase 1/1b clinical trials, including:

• NCT06040541: A multicenter, open-label study evaluating the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of RMC-9805 as monotherapy and in combination with RMC-6236 in adults with KRAS G12D-mutant solid tumors.
• Other platform studies are evaluating RMC-9805 in combination with standard-of-care therapies or other novel agents in gastrointestinal solid tumors and advanced RAS-mutated NSCLC.

Preliminary Efficacy Data: Initial data from a Phase 1 study in patients with previously treated KRAS G12D-mutant PDAC showed an objective response rate of 30% and a disease control rate of 80% at a candidate recommended Phase 2 dose of 1200 mg daily or 600 mg twice daily. In a subset of efficacy-evaluable NSCLC patients with the KRAS G12D mutation, a 61% objective response rate and an 89% disease control rate were observed at the 1200 mg once daily dose.

Safety and Tolerability: In clinical trials, RMC-9805 has demonstrated an acceptable safety profile. The most common treatment-related adverse events (TRAEs) reported include:

• Nausea
• Diarrhea
• Vomiting
• Rash These TRAEs were mostly Grade 1 or 2 in severity. Grade 3 TRAEs were infrequent. Treatment discontinuation due to TRAEs was uncommon.

Note: RMC-9805 is an investigational agent, and the information provided is based on preliminary data from ongoing clinical trials. The safety and efficacy of RMC-9805 have not yet been established.