Abstract 3321: KRASmulti inhibitor BI 3706674, an orally bioavailable, direct inhibitor of diverse oncogenic KRAS variants drives tumor regression in KRASG12V-driven preclinical models
Authors: Peng David Hwa , Tedeschi Antonio , Herdeis Lorenz , Schaaf Otmar , Savarese Fabio , Rocchetti Francesca , Popow Johannes , Huber Heinrich J. , Wilding Birgit , Treu Matthias , Fuchs Julian , Bröeker Joachim , Wunberg Tobias , Schischlik Firoella , Lipp Jesse , Williams Mariah , Chandler Vaness , Deckard Charles E. , Ramamoorthy Vandhana , Daniele Joseph R. , Kopetz Scott , Kim Michael , Gibbons Don L. , Vellano Christopher P. , Marszalek Joseph R. , Heffernan TImothy P. , McConnell Darryl , Pearson Mark , Kraut Norbert , Rudolph Dorothea 
Published: March 2024

Abstract
Alterations of KRAS are observed in approximately one in seven of all human tumors, making KRAS one of the most prevalent oncogenic drivers. Gain-of-function missense mutations in KRAS, leading to its aberrant activation, are found in ~90% of pancreatic cancer, ~40% of colorectal cancer and ~30% of lung adenocarcinoma, with KRASG12V mutations accounting for ~28%, 9% and 6% of the cases, respectively. The poor outcome associated with these tumor types as well as the lack of targeted inhibitors for the KRASG12V-mutant allele calls for the urgent need to identify therapies able to effectively address this allele. BI 3706674 is a novel, potent and orally available small molecule inhibitor of the KRAS oncogene. BI 3706674 binds non-covalently to multiple KRAS mutant alleles, including KRASG12V, in the GDP-bound state, and blocks downstream oncogenic signalling. Here, we show that BI 3706674 has a strong anti-proliferative activity in a panel of KRASG12V-mutant cancer cell lines in vitro, along with significant pharmacodynamic (PD) biomarker modulation (including inhibition of ERK1/2 phosphorylation and down-regulation of DUSP6 mRNA). In vivo, a twice daily oral dose of 30 mg/kg was well tolerated, while inducing tumour regression in several mutant KRASG12V patient-derived xenograft (PDX) models across multiple different tumor types. Feedback activation of upstream signalling pathways including receptor tyrosine kinases, such as the EGFR, has been suggested to limit the efficacy of GDP-KRAS-targeting compounds in preclinical studies. Clinical combination trials involving KRASG12C inhibitors such as adagrasib and sotorasib and anti-EGFR modalities are further supporting these findings. Here we show that a combination with anti-EGFR antibodies (e.g., Cetuximab) potently enhances the response observed for BI 3706674 in models of KRASG12V-mutant colorectal cancer. The deeper response observed upon combination of BI 3706674 with Cetuximab across multiple xenograft models provides a strong rationale for the clinical investigation of this combination therapy. Moreover, based on our in vitro mechanistic studies and ex vivo organoid platform we have identified prospective mechanisms of resistance and opportunity for novel drug combinations with BI 3706674 that can potentially translate into clinical trials.
Citation Format: David Hwa Peng, Antonio Tedeschi, Lorenz Herdeis, Otmar Schaaf, Fabio Savarese, Francesca Rocchetti, Johannes Popow, Heinrich J. Huber, Birgit Wilding, Matthias Treu, Julian Fuchs, Joachim Bröeker, Tobias Wunberg, Firoella Schischlik, Jesse Lipp, Mariah Williams, Vaness Chandler, Charles E. Deckard, Vandhana Ramamoorthy, Joseph R. Daniele, Scott Kopetz, Michael Kim, Don L. Gibbons, Christopher P. Vellano, Joseph R. Marszalek, TImothy P. Heffernan, Darryl McConnell, Mark Pearson, Norbert Kraut, Dorothea Rudolph. KRASmulti inhibitor BI 3706674, an orally bioavailable, direct inhibitor of diverse oncogenic KRAS variants drives tumor regression in KRASG12V-driven preclinical models [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 3321.