An Expert Report on BAY-3498264: A Novel SOS1 Inhibitor for KRAS-Mutated Cancers

Executive Summary

This report provides an exhaustive analysis of BAY-3498264, an investigational, oral, small-molecule inhibitor of Son of Sevenless Homologue 1 (SOS1) developed by Bayer for the treatment of advanced KRAS-mutated solid tumors. The therapeutic rationale for this agent is predicated on a significant unmet need in oncology: the limited durability of first-generation direct KRAS G12C inhibitors, which is largely driven by feedback reactivation of the MAPK signaling pathway. By selectively inhibiting the RAS-SOS1 interaction, BAY-3498264 is designed to block this adaptive resistance mechanism, thereby enhancing the depth and duration of response when used in combination with KRAS-targeting agents.

Preclinical data, notably from the American Association for Cancer Research (AACR) 2025 Annual Meeting, provide a robust validation of this hypothesis. Studies in relevant cell lines and patient-derived xenograft models demonstrate that BAY-3498264 prevents the rebound of phospho-ERK signaling induced by the KRAS G12C inhibitor sotorasib and exhibits marked synergistic anti-tumor activity when used in combination. These findings strongly support the advancement of BAY-3498264 into clinical development.

Bayer initiated a first-in-human Phase I clinical trial (NCT06659341) in November 2024. This open-label, dose-escalation study is evaluating BAY-3498264 in combination with sotorasib in patients with advanced solid tumors harboring the KRAS G12C mutation. The primary objectives are to establish the safety, tolerability, and recommended Phase II dose of the combination. The trial's design, which includes patients who have previously progressed on a G12C inhibitor, is strategically positioned to provide early and compelling evidence of the drug's ability to overcome acquired resistance.