Abstract B119: FMC-376, a dual inhibitor of ON + OFF states of KRAS G12C, is active in sotorasib resistant PDX models

Abstract KRAS G12C is a frequent activating mutation occurring in NSCLC, CRC, PDAC and other tumors that shifts KRAS into the active, GTP-bound (ON) state. KRAS was long considered undruggable until the recent discovery of inhibitors that bind the GDP-bound, inactive (OFF), state of KRAS G12C. The most clinically advanced of these first-generation molecules have demonstrated response rates of 37-43% and 6 to 7-month progression-free survival in lung cancer patients. While this is a significant and important advancement, the majority of patients do not respond and acquired resistance is common. FMC-376 is a novel dual inhibitor of both the ON and OFF states of KRAS G12C. FMC-376 was discovered through the FrontierTM platform, which integrates chemoproteomics, machine-learning, and covalent fragment-based drug discovery. A highly selective and irreversible inhibitor, FMC-376binds covalently to the mutant cysteine in KRAS G12Cand directly blocks the ON and OFF states of the mutant KRAS protein leading to a complete and durable blockade of downstream signaling. This further translates to robust anti-tumor activity in vivo. Profiling of FMC-376 against a panel of KRAS G12C mutant patient derived xenograft (PDX) models of NSCLC, CRC, and PDAC, demonstrated that dual inhibition of both ON and OFFKRAS G12C leads to complete suppression and regression of tumors carrying a broad spectrum of known genomic and non-genomic drivers of clinical resistance to OFF state inhibitors. In models derived from colorectal cancer patients following disease progression with sotorasib or sotorasib in combination with trametinib, FMC-376 demonstrated robust single agent anti-tumor activity. Further, synergistic anti-tumor activity was observed when FMC-376 was combined with Cetuximab. RNAseq analysis of post-treatment tumor samples showed that FMC-376 led to deeper inhibition of KRAS downstream pathways, including cholesterol homeostasis, EMT, and glycolysis, than sotorasib. Combination with cetuximab demonstrated more profound inhibition of multiple pathways, including mTOR signaling and MYC target genes. FMC-376 is a clinical stage dual inhibitor of ON and OFF state KRAS G12C that has the potential to overcome limitations of OFF state inhibitors. A Phase 1/2 study of FMC-376 in patients with locally advanced unresectable or metastatic solid tumors harboring KRAS G12Cmutation is currently on-going (NCT06244771). Citation Format: Yan Wang, Alexey Sorokin, Preeti Kanikarla, Fengqin Gao, Zhensheng Liu, Shayna Simonstein, Karsten Krug, Scott Kopetz, Kevin R. Webster. FMC-376, a dual inhibitor of ON + OFF states of KRAS G12C, is active in sotorasib resistant PDX models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B119.