Abstract 5900: INCB161734: A novel, potent, and orally bioavailable KRAS G12D selective inhibitor demonstrates antitumor activity in KRAS G12D mutant tumors

Abstract KRAS G12D (G12D) is one of the most frequent oncogenic driver mutations, and is especially common in pancreatic (PDAC) and colorectal (CRC) cancers. Patients with G12D-mutated disease experience poor treatment outcomes, representing a significant unmet medical need. G12D mutation results in constitutively active signaling, including hyperactivation of the ERK and PI3K pathways, which drive cell proliferation and survival. Here we describe INCB161734, a novel, potent, selective, and orally bioavailable small molecule G12D inhibitor that demonstrates in vivo efficacy in G12D-bearing tumor models. INCB161734 binds to both the GDP and GTP forms of the G12D mutant at the switch II pocket with picomolar affinity (KD), and exhibits >80-fold selectivity over wildtype (WT) KRAS. INCB161734 potently inhibits SOS1-dependent GDP/GTP exchange activity in cell-free assays (IC50 <3 nM), and exhibits >40-fold selectivity for G12D versus WT KRAS. Additionally, INCB161734 demonstrates high selectivity for G12D over WT in various cellular assays using G12D mutant versus WT cancer derived cell lines. INCB161734 potently inhibits ERK phosphorylation (a correlate for KRAS activity), with a mean IC50 of 14.3 nM (range: 1.9-45.2 nM) across 7 human and 3 mouse G12D cell lines; mean 21.5% inhibition was observed at 1 μM (maximum tested concentration) across 14 WT cell lines. Likewise, INCB161734 inhibits proliferation of G12D mutant cell lines, with a mean IC50 of 154 nM (range: 8.3-318 nM) across the same 7 human G12D cell lines; <30% inhibition (mean 13%) was observed at 1 μM across the same 14 WT cell lines. Treatment with INCB161734 induces caspase 3/7 cleavage in a PDAC cell line (G12D HPAC), with EC50 <100 nM; caspase 3/7 cleavage in a WT cell line (NCI-H838) was not induced at doses as high as 5 μM. In addition, INCB161734 induced cell cycle arrest (S-phase inhibition) in the G12D HPAC cell line, with IC50 12.8 nM; S-phase inhibition in the WT NCI-H838 cell line only occurred at much higher doses (IC50 >3.3 μM). INCB161734 demonstrates excellent oral bioavailability with good absorption, low clearance, and low metabolic turnover. Orally dosed INCB161734 clearly shows target engagement, generating continuous near-maximal KRAS inhibition in G12D HPAC mouse xenograft tumors for almost the entire dosing interval. INCB161734 is efficacious against multiple types of G12D-mutated tumors and xenografts, resulting in significant tumor growth inhibition, growth arrest and/or regression in multiple PDAC (HPAC, Panc0403, and 2838c3) and CRC (CT26, GP2D, and LS513) mouse tumor models. These preclinical results demonstrate that INCB161734 is a potent, selective, and orally bioavailable KRAS G12D inhibitor, strongly efficacious against KRAS G12D mutant tumors. The potential benefit of INCB161734 for patients with KRAS G12D mutant disease is under investigation in ongoing clinical trials. Citation Format: Matthew R. Farren, Valerie Roman, Alexandra Gallion, Abdellah Allali-Hassani, Alexander Sokolsky, Weixi Kong, Amanda Smith, Hui Wang, Gina Correa, Marc Deller, Leslie B. Epling, Jessica Procak, Guofeng Zhang, Katherine Pecko, Keith Kennedy, Jason Boer, Kerri Kurzeja-Lipinski, Maryanne Covington, Kwang-Jong Chen, Renee Wallower, Jennifer Rocha, Rina Pan, Anthony Perry, Brad Yuska, Xiaozhao Wang, Ricardo Macarron, Sunkyu Kim. INCB161734: A novel, potent, and orally bioavailable KRAS G12D selective inhibitor demonstrates antitumor activity in KRAS G12D mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5900.