Abstract A085: BI KRASmulti, a first-in-class, orally bioavailable and direct inhibitor of diverse oncogenic KRAS variants drives tumor regression in preclinical models and validates wild-type amplified KRAS as a therapeutic target

Abstract

Abstract Alterations of KRAS are found in approximately one in seven of all human cancers, making KRAS one of the main oncogenic drivers in cancer. Gain-of-function missense mutations in KRAS are found in ~90% of pancreatic cancer, ~40% of colorectal cancer and ~30% of lung adenocarcinoma. In addition, focal high-level amplification of the KRAS wild-type (wt) allele, an alternative means of activating this oncoprotein, is observed in ~7% of cancers and lacks effective targeted therapies. Thus, there is an urgent need to identify effective therapies to address KRAS-driven tumors. Recently, we have reported the identification of compounds active against a broad range of oncogenic KRAS variants (KRASmulti) that selectively inactivate downstream signaling and tumor growth (Kim et al., Nature 2023). Herein we describe BI 3706674, a novel, potent and orally available small molecule inhibitor of the KRAS oncogene. BI 3706674 binds non-covalently to multiple KRAS mutant alleles, including the KRAS wt allele, in the GDP-bound state and thereby disrupts oncogenic signaling. Using several in vitro assays, we show that BI 3706674 is a) highly selective for KRAS vs HRAS or NRAS; b) blocks the interaction between KRAS mutant/wt and its guanidine exchange factor (GEF) SOS1 and c) shows potent antiproliferative activity in isogeneic cell lines that are dependent on various KRAS mutant alleles. In two large cancer cell line panels, BI 3706674 potently and selectively inhibits proliferation of KRAS mutant cancer cell lines as well as cancer cell lines with an amplification of the KRAS wt allele. Significant pharmacodynamic (PD) biomarker modulation (including inhibition of ERK1/2 phosphorylation and DUSP6 mRNA down-regulation) was observed in cell lines with a KRAS wt relative copy number (CN) > 10, treated with BI 3706674. Amplification of the KRAS wt allele is most frequently observed in gastric (~5%), esophageal (~13%) and gastroesophageal junction cancers (~12%). BI 3706674 was well-tolerated and showed dose-dependent efficacy in cell line-derived and patient-derived xenograft models (CDX and PDX) of human gastric cancer with a KRAS wt CN > 10. A twice daily oral dose of 30 mg/kg was sufficient to induce significant tumor regression. BI 3706674 treatment induced PD biomarker modulation (including inhibition of ERK1/2 phosphorylation, DUSP6 down-regulation, repression of the MAPK Pathway Activity Score (MPAS) signature and Ki67 reduction) in two KRAS wt amplified gastric cancer xenograft models. The depth and duration of PD biomarker responses following treatment correlated well with the doses used in the respective efficacy studies. Finally, these results support the clinical use of biomarkers such as the MPAS signature score and Ki67 to investigate treatment effects elicited by BI 3706674 in tumor biopsies. The KRASmulti inhibitor BI 3706674 is undergoing IND enabling studies and is intended to target tumors driven by KRAS wt amplifications as well as oncogenic KRAS missense mutations. Citation Format: Antonio Tedeschi, Lorenz Herdeis, Valeria Santoro, Fabio Savarese, Birgit Wilding, Matthias Treu, Julian Fuchs, Joachim Bröker, Tobias Wunberg, Michael Gmachl, Rumpel Klaus, Fiorella Schischlik, Jesse Lipp, David H. Peng, Mariah Williams, Charles Deckard, Vandhana Ramamoorthy, Joseph R. Daniele, Jaffer A. Ajani, Funda Meric-Bernstam, Christopher P. Vellano, Joseph R. Marszalek, Timothy P. Heffernan, Darryl McConnell, Mark Pearson, Norbert Kraut, Dorothea Rudolph. BI KRASmulti, a first-in-class, orally bioavailable and direct inhibitor of diverse oncogenic KRAS variants drives tumor regression in preclinical models and validates wild-type amplified KRAS as a therapeutic target [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A085.