Abstract 1271: In vitro and in vivo characterization of BI 1823911 - a novel KRASG12C selective small molecule inhibitor
Abstract
KRASG12C mutations are predominantly found in non-small cell lung cancer (NSCLC, 13%), in colorectal cancer (CRC, 3%), and with a lower prevalence in pancreatic ductal adenocarcinoma (PDAC, 1%). The amino acid exchange at position 12 from glycine to cysteine renders RAS insensitive to GAP-catalyzed hydrolysis but not to intrinsic hydrolysis and consequently, KRASG12C is still dependent on GEF stimulation to achieve full activation. The active GTP-loaded form of KRASG12C is favored and leads to activation of downstream signaling and proliferation. A number of recent publications has shown that targeting this mutant form of KRAS, using several covalent KRASG12C inhibitors binding to the inactive GDP-KRASG12C form, leads to anti-proliferative effects and induction of apoptosis in KRASG12C mutant cancer cell lines, CDX and PDX models. Early clinical data for AMG 510 and MRTX849 revealed a response rate of 35-45% in NSCLC and of 7-17% in CRC patients. Here, we show that BI 1823911 has potent anti-proliferative activity in a panel of KRASG12C mutant cancer cell lines with higher or similar potency compared to these two most advanced compounds in clinical development. In a panel of KRASG12C NSCLC cell lines, treatment with BI 1823911 results in downregulation of MAPK pathway-responsive genes, such as DUSP6 and CCND1, and the extent of pathway modulation correlates with sensitivity. Likewise, we observe strong and sustained inactivation of the MAPK pathway at the protein level using p-ERK as a pharmacodynamic (PD) biomarker. A MIA PaCa-2 cell line-derived pancreatic cancer xenograft model was selected for extensive PK/PD/efficacy analyses in vivo. Briefly, BI 1823911 tested at 60 mg/kg showed similar anti-tumor activity compared to both competitor compounds dosed at clinically relevant exposures. Results of the ongoing in-depth PK/PD/efficacy analysis will be shared. Furthermore, BI 1823911 was tested with a daily oral dose of 60 mg/kg in a panel of NSCLC or CRC CDX or PDX mouse models and showed comparable efficacy to AMG 510 and MRTX849, respectively. Preclinical and clinical data suggest that monotherapy with a KRASG12C inhibitor will not be sufficient to achieve durable response. Combination therapy of a KRASG12C inhibitor may therefore lead to enhanced anti-tumor efficacy and may address adaptive resistance mechanisms. Therefore, we selected a panel of KRASG12C mutant cancer cell lines and tested a large set of compounds in combination with BI 1823911 to identify synergistic anti-proliferative activity. Among other MAPK and PI3K pathway inhibitors, a SOS1::KRAS inhibitor was confirmed as promising combination partner. We will show results from in vitro and in vivo combination studies in NSCLC and CRC tumor models that show deep and durable responses upon combination of BI 1823911 with SOS1::KRAS inhibitor BI 1701963 providing a strong rationale for clinical investigation of this combination. Citation Format: Fabio Savarese, Andreas Gollner, Dorothea Rudolph, Jesse Lipp, Johannes Popow, Marco H. Hofmann, Heribert Arnhof, Jörg Rinnenthal, Francesca Trapani, Michael Gmachl, Daniel Gerlach, Joachim Broeker, Peter Ettmayer, Andreas Mantoulidis, Jason Phan, Christian A. Smethurst, Matthias Treu, Alex G. Waterson, Hengyu Lu, Annette Machado, Joseph Daniele, Stephan W. Fesik, Christopher P. Vellano, Timothy P. Heffernan, Joseph R. Marszalek, Darryl B. McConnell, Mark Petronczki, Norbert Kraut, Irene C. Waizenegger. In vitro and in vivo characterization of BI 1823911 - a novel KRASG12C selective small molecule inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1271.
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BI-1823911 can induce concomitant MAPK pathway regulation, G1 cell cycle arrest, and apoptosis.
“By analyzing the dose-and time-dependent combination data of BI-1823911 and KRAS, it was found that BI-1823911 can induce concomitant MAPK pathway regulation, G1 cell cycle arrest, and apoptosis.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [76]
When BI-1823911 was combined with the SOS1 inhibitor BI-1701963, a deeper level of PD regulation was observed.
“When BI-823911 was combined with BI-1701963, an SOS1 inhibitor, a deeper level of PD regulation was observed.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [76]
BI-1823911 demonstrated excellent synergistic anti-proliferation activity when combined with PI3K/mTOR, EGFR inhibitors and SOS1 inhibitors.
“Furthermore, BI-1823911 demonstrated excellent synergistic anti-proliferation activity when combined with PI3K/mTOR, EGFR inhibitors and SOS1 inhibitors.76”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [76]
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- Authors
- Savarese, F., Gollner, A., Rudolph, D., Lipp, J., Popow, J., Hofmann, M. H., Arnhof, H., Rinnenthal, J., Trapani, F., Gmachl, M., Gerlach, D., Broeker, J., Ettmayer, P., Mantoulidis, A., Phan, J., Smethurst, C. A., Treu, M., Waterson, A. G., Lu, H., Machado, A., Daniele, J., Fesik, S. W., Vellano, C. P., Heffernan, T. P., Marszalek, J. R., McConnell, D. B., Petronczki, M., Kraut, N., & Waizenegger, I. C.
- Affiliations
- Boehringer Ingelheim (Austria) (AT)
- 1Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria;
- Vanderbilt University (US)
- The University of Texas MD Anderson Cancer Center (US)
- ORCID
- Gollner, Andreas
- Rudolph, Dorothea
- Lipp, Jesse
- Popow, Johannes
- Hofmann, Marco H.
- Trapani, Francesca
- Gmachl, Michael
- Gerlach, Daniel
- Waterson, Alex G.
- Machado, Annette
- Daniele, Joseph
- Vellano, Christopher P.
- Heffernan, Timothy P.
- Marszalek, Joseph R.
- McConnell, Darryl B.
- Petronczki, Mark
- Kraut, Norbert
- Waizenegger, Irene C.
- Venue
- Cancer Research
- Published
- 2021-07-01
- Volume
- 81
- Issue
- 13_Supplement
- Pages
- 1271-1271
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W3183048476
- Cited by
- 25
- References
- 0
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 6 · 2022: 2 · 2021: 1
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- KRAS G12C inhibitors, KRAS G12C mutation, non-small cell lung cancer, colorectal cancer, pancreatic ductal adenocarcinoma, MAPK signaling, DUSP6, CCND1, ERK1/2 phosphorylation, pharmacodynamic biomarkers, xenograft models, MIA PaCa-2 cells, sotorasib, adagrasib, covalent KRAS inhibitor
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