Bi-3406 And Bi 1701963: Potent And Selective Sos1::Kras Inhibitors Induce Regressions In Combination With Mek Inhibitors Or Irinotecan

KRAS is the most frequently mutated oncogene with high prevalence of alterations in pancreatic, colorectal, and non-small cell lung tumors. The alleviation of negative feedback control of KRAS activity upon downstream inhibition has limited the clinical efficacy of MAPK pathway drugs in the KRAS mutant context. The guanine nucleotide exchange factor (GEF) SOS1 is a mediator of this negative feedback control, and the protein is a key activator of KRAS itself. BI 1701963 is the first SOS1::KRAS inhibitor to advance to clinical trials. Both BI 1701963 as well as the previously reported probe compound BI-3406 are orally bioavailable small molecules, designed to bind to the catalytic domain of SOS1, thereby preventing the interaction with KRAS-GDP. In KRAS-dependent cancers, both SOS1::KRAS inhibitors potently reduce the formation of GTP-loaded KRAS, and inhibit MAPK pathway signaling. Both SOS1::KRAS inhibitors exhibit activity on a broad spectrum of KRAS alleles, including all major G12D/V/C and G13D oncoproteins, while sparing the interaction of KRAS with SOS2. This increases the targetable patient population beyond KRAS G12C mutation and suggests a favorable therapeutic window to enable rational combinations. We previously showed that combining the SOS1::KRAS inhibitor BI-3406 with the MEK inhibitor trametinib blocks the negative feedback relief induced by MAPK inhibition. Combining SOS1::KRAS inhibition with trametinib treatment enhances pathway blockade and elicits tumor regressions in vivo in xenograft models driven by mutant KRAS. In this work, we present combination data for the clinical candidate BI 1701963 with the MEK inhibitor trametinib and, in addition, with irinotecan, a key component of the widely used CRC standard-of-care chemotherapy treatment regimen. Both combinations show strong in vivo efficacy in tumor mouse models. The SOS1::KRAS/MEK inhibitor combination results in anti-tumor effects in a broad spectrum of KRAS-mutated CRC PDX models. In addition, extensive biomarker data on the combination of the clinical candidate BI 1701963 with trametinib reveals time- and dose-dependent modulation of transcriptional target genes in the MAPK pathway. Furthermore, we present the first data on the therapeutic effectiveness of combining SOS1::KRAS inhibitors with irinotecan, as well as its underlying mechanism. The SOS1::KRAS inhibitor BI 1701963 is currently in a Phase I clinical trial. This multi-center trial is currently recruiting patients with advanced KRAS-mutated cancers to evaluate safety, tolerability, pharmacokinetic and pharmacodynamic properties, and preliminary efficacy of BI 1701963 alone and in combination with trametinib. Citation Format: Daniel Gerlach, Michael Gmachl, Juergen Ramharter, Jessica Teh, Szu-Chin Fu, Francesca Trapani, Dirk Kessler, Klaus Rumpel, Dana-Adriana Botesteanu, Peter Ettmayer, Heribert Arnhof, Thomas Gerstberger, Christiane Kofink, Tobias Wunberg, Christopher P. Vellano, Timothy P. Heffernan, Joseph R. Marszalek, Mark Pearson, Darryl B. McConnell, Norbert Kraut, Marco H. Hofmann. BI-3406 and BI 1701963: Potent and selective SOS1::KRAS inhibitors induce regressions in combination with MEK inhibitors or irinotecan [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1091.