99O_PR KRYSTAL-1: Activity and preliminary pharmacodynamic (PD) analysis of adagrasib (MRTX849) in patients (Pts) with advanced non–small cell lung cancer (NSCLC) harboring KRASG12C mutation
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Clinical trials of multiple KRASG12C inhibitors have shown promising efficacy in advanced, previously treated NSCLC, leading to FDA accelerated approval of adagrasib and sotorasib.
“Clinical trials of multiple KRASG12C inhibitors have shown promising efficacy in advanced, previously treated non–small cell lung cancer (NSCLC), leading to United States Food and Drug Administration (FDA) accelerated approval of two of these therapies (adagrasib and sotorasib) and many others being investigated in this setting (9–17).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [12]
The KRYSTAL-1 abstract (Methods, Results, and Conclusions; page not supplied) reports clinical activity for adagrasib in previously treated, advanced KRAS G12C-mutant NSCLC. It does not report efficacy for multiple inhibitors, sotorasib, or FDA accelerated approval of either therapy; it calls adagrasib investigational. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAdagrasib in a phase 1-2 study produced an objective response rate of 45% in NSCLC and 17% in colorectal cancer.
“An ongoing phase 1–2 study of adagrasib that involves patients with KRASG12C-mutant cancer has shown an objective response rate of 45% among patients with NSCLC11,12 and 17% among those with colorectal cancer.13”
From Acquired Resistance to KRAS <sup>G12C</sup> Inhibition in Cancer (2021) · cites this paper as [11]
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Diverse alterations associated with resistance to KRAS(G12C) inhibition
Zhao, Y., Murciano-Goroff, Y. R., Xue, J. Y., Ang, A., Lucas, J., Mai, T. T., Da Cruz Paula, A. F., Saiki, A. Y., Mohn, D., Achanta, P., et al. (2021) · Nature · doi:10.1038/s41586-021-04065-2 · Cited by 479 · see citing works
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Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer
Dilly, J., Hoffman, M. T., Abbassi, L., Li, Z., Paradiso, F., Parent, B. D., Hennessey, C. J., Jordan, A. C., Morgado, M., Dasgupta, S., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0177 · Cited by 276 · see citing works
Self-citationKRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy
Ryan, M. B., Coker, O., Sorokin, A., Fella, K., Barnes, H., Wong, E., Kanikarla, P., Gao, F., Zhang, Y., Zhou, L., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110993 · Cited by 177 · see citing works
Ricciuti, B., Alessi, J. V., Elkrief, A., Wang, X., Cortellini, A., Li, Y. Y., Vaz, V. R., Gupta, H., Pecci, F., Barrichello, A., et al. (2022) · Annals of Oncology · doi:10.1016/j.annonc.2022.07.005 · Cited by 112 · see citing works
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Ricciuti, B., Son, J., Okoro, J. J., Mira, A., Patrucco, E., Eum, Y., Wang, X., Paranal, R., Wang, H., Lin, M., et al. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-2719 · Cited by 42 · see citing works
Self-citationCotargeting a MYC/eIF4A-survival axis improves the efficacy of KRAS inhibitors in lung cancer
Nardi, F., Perurena, N., Schade, A. E., Li, Z.-H., Ngo, K., Ivanova, E. V., Saldanha, A., Li, C., Gokhale, P. C., Hata, A. N., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci167651 · Cited by 21 · see citing works
“However, fewer than half of patients respond to these agents and responses are temporary (4, 5).”
Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families
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- Authors
- Riely, G. J., Ou, S.-H. I., Rybkin, I., Spira, A., Papadopoulos, K., Sabari, J. K., Johnson, M., Heist, R. S., Bazhenova, L., Barve, M., Pacheco, J. M., Velastegui, K., Cilliers, C., Olson, P., Christensen, J. G., Kheoh, T., Chao, R. C., & Jänne, P. A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of California, Irvine (US)
- Henry Ford Hospital (US)
- Virginia Cancer Specialists (US)
- South Texas Accelerated Research Therapeutics (US)
- NYU Langone’s Laura and Isaac Perlmutter Cancer Center (US)
- Sarah Cannon (US)
- Massachusetts General Hospital (US)
- UC San Diego Health System (US)
- Mary Crowley Cancer Research Center (US)
- University of Colorado Anschutz (US)
- Mirati Therapeutics (United States) (US)
- ORCID
- Venue
- Journal of Thoracic Oncology
- Publisher
- Elsevier BV
- Published
- 2021-04
- Volume
- 16
- Issue
- 4
- Pages
- S751-S752
- ISSN
- 1556-0864 (ISSN-L)
- OpenAlex
- W3145860562
- Cited by
- 77
- References
- 0
- Citations by year
- 2025: 7 · 2024: 12 · 2023: 9 · 2022: 33 · 2021: 16
- FWCI
- 11.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thoracic Oncology (publishedVersion)
- Funders
- Lance Armstrong Foundation
- Armstrong Foundation
- LUNGevity Foundation
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- International Association for the Study of Lung Cancer
- American College of Radiology Imaging Network
- Novocure
- Mirati Therapeutics
- Revolution Medicines
- Puma Biotechnology
- Eisai
- Astellas Pharma
- Genentech
- EMD Serono
- Chugai Pharmaceutical
- Takeda Oncology
- Ignyta
- Loxo Oncology
- Daiichi Sankyo Europe
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- adagrasib, KRAS G12C mutation, non-small cell lung cancer, KRAS inhibitors, pharmacodynamics, drug activity, RAS/MAPK pathway, oral bioavailability, tissue distribution
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