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Abstract CT210: Trial in Process: Phase 1 studies of BI 1701963, a SOS1::KRAS Inhibitor, in combination with MEK inhibitors, irreversible KRASG12C inhibitors or irinotecan.
Abstract
The SOS1i::KRAS inhibitor BI 1701963 is the first direct RAS signaling modifier to enter phase I clinical trials both as a monotherapy as well as in combination. SOS1::KRAS inhibitors exhibit activity against a broad spectrum of KRAS alleles, including the major G12D/V/C and G13D oncoproteins, while sparing the interaction of KRAS with SOS2. Here, we present pre-clinical data showing enhanced pathway modulation and synergistic anti-tumor effects following vertical pathway inhibition of BI 1701963 in combination with mitogen-activated protein kinase inhibitors (MEKi; trametinib and BI 3011441) or KRAS G12C inhibitors (MRTX849 and BI 1823911). Furthermore, SOS1::KRAS inhibitor treatment sensitizes tumor cells to increased DNA damage in combination with irinotecan. Our results highlight the suitability of SOS1::KRAS inhibitors as a backbone in combination therapies targeting KRAS-dependent tumors. Pre-clinical combination data supported the start of multiple phase I trials investigating the safety, tolerability, recommended dose and preliminary efficacy of BI 1701963 alone and in combination with other anti-cancer agents. Combination trials of BI 1701963 with MEKi include cohorts of patients with KRAS mutant solid tumors, such as non-small cell lung cancer (NSCLC), colorectal cancer (CRC), cholangiocarcinoma and pancreatic adenocarcinoma. Trials exploring the combination of BI 1701963 with irreversible KRAS G12C inhibitors (MRTX849 and BI 1823911) will include cohorts of patients with KRAS G12C mutant NSCLC and CRC. In a further study, the combination of BI 1701963 with irinotecan is being evaluated in patients with KRAS mutant CRC. Primary endpoints include dose-limiting toxicities, treatment-emergent or -related adverse events. Secondary endpoints include pharmacokinetic and pharmacodynamic properties of combination regimens and preliminary efficacy. Citation Format: Marco H. Hofmann, Hengyu Lu, Ulrich Duenzinger, Daniel Gerlach, Francesca Trapani, Annette A. Machado, Joseph R. Daniele, Irene Waizenegger, Michael Gmachl, Dorothea Rudolph, Christopher P. Vellano, Marcelo Marotti, Vitomir Vucenovic, Timothy P. Heffernan, Joseph R. Marszalek, Mark P. Petronczki, Norbert Kraut. Trial in Process: Phase 1 studies of BI 1701963, a SOS1::KRAS Inhibitor, in combination with MEK inhibitors, irreversible KRASG12C inhibitors or irinotecan. [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 CT210.
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SOS1 catalyzes RAS-GTP-loading as a GEF and serves as a key node of feedback regulation.
“SOS1 catalyzes RAS-GTP-loading as a GEF24,25 and serves as a key node of feedback regulation23,24.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [25]
Preclinical data show synergistic antiproliferative effects and enhanced antitumor efficacy for SHP2 inhibitor/KRASG12C inhibitor and SOS1 inhibitor/KRASG12C inhibitor combinations.
“Preclinical data has demonstrated synergistic antiproliferative effects and enhanced antitumor efficacy for both the SHP2 inhibitor/KRASG12C inhibitor combination (43) and the SOS1 inhibitor/KRASG12C inhibitor combination (44, 45).”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [45]
In heterozygous KRAS mutant tumor cells, RAS signaling can be supplemented and cross-regulated by RTK-WT RAS signaling.
“In heterozygous KRAS mutant tumor cells, RAS signaling can be supplemented and cross-regulated by RTK-WT RAS signaling.”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [45]
Combining a mutant-specific KRAS inhibitor with a SHP2 or SOS1 inhibitor could block both mutant KRAS and wild-type RAS signaling.
“A combination of a mutant specific KRAS inhibitor with either a SHP2 inhibitor or a SOS1 inhibitor could effectively block mutant KRAS and wild-type RAS signaling (12, 43, 45, 46).”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [45]
In preclinical experiments, combining irinotecan with a SOS1 inhibitor enhances DNA double-strand breaks in a KRAS-mutated tumor model.
“In preclinical experiments, a combination of the topoisomerase I inhibitor irinotecan with a SOS1 inhibitor enhances formation of DNA double strand breaks in a KRAS-mutated tumor model (45, 48).”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [45]
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Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants
Hofmann, M. H., Gerlach, D., Misale, S., Petronczki, M., & Kraut, N. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1331 · Cited by 336
Self-citationThatikonda, V., Lyu, H., Jurado, S., Kostyrko, K., Bristow, C. A., Albrecht, C., Alpar, D., Arnhof, H., Bergner, O., Bosch, K., et al. (2024) · Nature Cancer · doi:10.1038/s43018-024-00800-6 · Cited by 76
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Metadata
- Authors
- Hofmann, M. H., Lu, H., Duenzinger, U., Gerlach, D., Trapani, F., Machado, A. A., Daniele, J. R., Waizenegger, I., Gmachl, M., Rudolph, D., Vellano, C. P., Marotti, M., Vucenovic, V., Heffernan, T. P., Marszalek, J. R., Petronczki, M. P., & Kraut, N.
- Affiliations
- Boehringer Ingelheim (Austria) (AT)
- The University of Texas MD Anderson Cancer Center (US)
- Boehringer Ingelheim (Germany) (DE)
- ORCID
- Venue
- Cancer Research
- Published
- 2021-07-01
- Volume
- 81
- Issue
- 13_Supplement
- Pages
- CT210-CT210
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W3180908193
- Cited by
- 20
- References
- 0
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 1 · 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- KRAS G12C inhibitors, MEK inhibitors, trametinib, irinotecan, combination therapy, KRAS-mutant tumors, non-small cell lung cancer, colorectal cancer, cholangiocarcinoma, pancreatic ductal adenocarcinoma, Ras signaling
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