A phase I/II multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with KRAS G12C mutation.
Abstract
TPS3161 Background: RAS proteins are part of the family of small GTPases which regulate intracellular signaling pathways responsible for cell growth, migration, survival and differentiation. Oncogenic point mutations in RAS in codons 12, 13, and 61 occur in up to one-third of all human cancers and result in constitutive activation of RAS signaling, playing a key role in uncontrolled cellular growth and malignant transformation. Mutant KRASG12C in particular comprises approximately 14% of lung adenocarcinoma and 4% of colon adenocarcinoma, and less commonly in certain other types of cancer. For decades, KRAS was considered undruggable due to its high affinity for GTP/GDP and the lack of a clear binding pocket. Recent discoveries have enabled the development of compounds, including MRTX849, that covalently bind to KRASG12C at the cysteine at residue 12, lock the protein in its inactive GDP-bound conformation, and inhibit KRAS-dependent signal transduction. MRTX849 is a potent, orally-available, mutation-selective small molecule covalent inhibitor of KRASG12C. MRTX849 inhibits KRASG12C signaling in cell lines harboring this mutation, and results in tumor regression in a broad spectrum of KRASG12C animal models. Methods: This multi-center, Phase 1/2, multiple expansion cohort trial evaluates the safety, pharmacokinetics (PK), metabolites, pharmacodynamics, and clinical activity of MRTX849 in patients with advanced solid tumor malignancies with a KRAS (p.G12C) mutation. The study starts with an evaluation of dose and regimen of MRTX849 using a combination of the accelerated titration and modified toxicity probability interval designs, with MRTX849 initially administered once daily in a continuous regimen expressed in 3-week cycles. As potentially viable regimens are identified, Phase 1b expansion cohorts will be opened to provide greater safety and PK data for determination of the recommended Phase 2 dose (RP2D) and regimen. In Phase 2, separate cohorts of patients by histological diagnosis, including non-small cell lung cancer, colorectal, and other solid tumors, will be enrolled and evaluated for clinical activity using a predictive probability design. The study is open for enrollment, and recruitment is ongoing. Clinical trial information: NCT03785249.
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MRTX849 is a potent, highly selective, orally available small-molecule inhibitor of KRASG12C.
“MRTX849 is another potent, highly selective, and orally available small-molecule inhibitor of KRASG12C (42).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [42]
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“NCT03785249 [33] The trial is ongoing and responses to treatment with MRTX849 have been observed in both lung and CRC KRASG12C mutant patients.”
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- Authors
- Papadopoulos, K. P., Ou, S.-H. I., Johnson, M. L., Christensen, J., Velastegui, K., Potvin, D., Faltaos, D., & Chao, R. C.
- Affiliations
- South Texas Accelerated Research Therapeutics (US)
- Chao Family Comprehensive Cancer Center, University of California, Orange, CA;
- Sarah Cannon (US)
- Mirati Therapeutics (United States) (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2019-05-20
- Volume
- 37
- Issue
- 15_suppl
- Pages
- TPS3161-TPS3161
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2946902076
- Cited by
- 37
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 6 · 2021: 8 · 2020: 12 · 2019: 3
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (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
- adagrasib, KRAS G12C mutation, KRAS inhibitors, covalent inhibitors, advanced solid tumors, non-small cell lung cancer, colorectal cancer, pharmacokinetics, pharmacodynamics, safety, recommended phase 2 dose, accelerated titration, Ras signaling, tumor regression, oral small-molecule inhibitor
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