Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• RAS-driven cancers represent a significant portion of human malignancies, with limited targeted therapy options.
• Mutant and wild-type RAS-GTP are key drivers in these cancers, presenting a therapeutic target.
• Existing therapies often fail to address the complexity of RAS signaling.

Purpose of the Study:

• To evaluate RMC-6236, a multi-selective RAS(ON) inhibitor, for its efficacy in RAS-driven cancers.
• To assess the safety and tolerability of RMC-6236 in preclinical and clinical settings.
• To investigate the potential of concurrent inhibition of canonical mutant and wild-type RAS-GTP.

Main Methods:

• In vitro testing of RMC-6236 on RAS-addicted cancer cell lines.
• In vivo studies using KRASG12X xenograft models in mice.
• Translational pharmacokinetic/pharmacodynamic (PK/PD) and PK/efficacy modeling.
• Phase I/Ib clinical trial (NCT05379985) in patients with advanced RAS-driven tumors.

Main Results:

• RMC-6236 demonstrated potent anticancer activity, especially in cell lines with KRAS codon 12 mutations.
• Oral administration of RMC-6236 was well-tolerated in vivo, leading to significant tumor regressions in mouse models.
• PK/PD modeling predicted effective patient dosing for tumor control and objective responses.
• Objective responses were observed in two patients with advanced KRASG12X lung and pancreatic adenocarcinoma.

Conclusions:

• RMC-6236 is the first therapeutic agent to target both mutant and wild-type RAS-GTP concurrently.
• Broad-spectrum RAS-GTP inhibition with RMC-6236 is tolerable and induces significant tumor regressions.
• RMC-6236 shows initial clinical activity, supporting its further evaluation in RAS-driven cancers.