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The KRYSTAL-1 study of adagrasib — a new trial for KRASG12C-mutated non-small-cell lung cancer

Nature Reviews Clinical Oncology volume 19, pages 677–678 (2022)Cite this article

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The development of covalent, allele-specific inhibitors of KRASG12C represents a major breakthrough in precision oncology. Herein we discuss recent data from the phase II KRYSTAL-1 trial of adagrasib in KRASG12C-mutated non-small-cell lung cancer (NSCLC). This trial showed responses in a subset of patients, including among those with brain metastases, and offers exploratory insights into potential biomarkers of response.

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References

  1. Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013).

    Article  CAS  Google Scholar 

  2. Lito, P., Solomon, M., Li, L.-S., Hansen, R. & Rosen, N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 351, 604–608 (2016).

    Article  CAS  Google Scholar 

  3. Hong, D. S. et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 383, 1207–1217 (2020).

    Article  CAS  Google Scholar 

  4. Skoulidis, F. et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N. Engl. J. Med. 384, 2371–2381 (2021).

    Article  CAS  Google Scholar 

  5. Jänne, P. A. et al. Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. N. Engl. J. Med. 387, 120–131 (2022).

    Article  Google Scholar 

  6. Ou, S. I. et al. First-in-human phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRASG12C solid tumours (KRYSTAL-1). J. Clin. Oncol. https://doi.org/gqd4bm (2022).

  7. Zhao, Y. et al. Diverse alterations associated with resistance to KRAS(G12C) inhibition. Nature 599, 679–683 (2021).

    Article  CAS  Google Scholar 

  8. Awad, M. M. et al. Acquired resistance to KRASG12C inhibition in cancer. N. Engl. J. Med. 384, 2382–2393 (2021).

    Article  CAS  Google Scholar 

  9. Xue, J. Y. et al. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature 577, 421–425 (2020).

    Article  CAS  Google Scholar 

  10. Sabari, J. K. et al. Activity of adagrasib (MRTX849) in brain metastases: preclinical models and clinical data from patients with KRASG12C-mutant non-small cell lung cancer. Clin. Cancer Res. https://doi.org/h6w9 (2022).

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Acknowledgements

Y.R.M-G. has received a Kristina M. Day Young Investigator Award from Conquer Cancer, the ASCO Foundation (endowed by C.M. Baum and C.A. Baum), and has received training through an institutional K30 grant from the NIH (CTSA UL1TR00457). P.L. receives support in part from the Damon Runyon Cancer Research Foundation, NIH NCI (grants 1R01CA23074501 and 1R01CA23026701A1), the Pershing Square Sohn Cancer Research Alliance and The Pew Charitable Trusts. This work is supported by the NIH/NCI Cancer Center Support Grant (P30 CA008748) to Memorial Sloan Kettering Cancer Center.

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Authors and Affiliations

  1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Yonina R. Murciano-Goroff & Piro Lito

  2. Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Piro Lito

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  1. Yonina R. Murciano-Goroff
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  2. Piro Lito
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Correspondence to Piro Lito.

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Competing interests

Y.R.M-G. has received support for travel, accommodation and expenses from AstraZeneca, honoraria from Virology Education and Projects in Knowledge (for a program funded by an educational grant from Amgen) and acknowledges associated institutional research support funded by Elucida Oncology, Endeavor Biomedicines, Hengrui USA/Jiangsu Hengrui Pharmaceuticals, Loxo Oncology at Eli Lilly, Luzsana Biotechnology and Taiho Oncology and royalties from Rutgers University Press and Wolters Kluwer. P.L. is listed as an inventor on patents filed by MSKCC on the treatment of cancers with BRAF or KRAS mutations. P.L. receives institutional research support funded by Amgen, Boehringer Ingelheim, Mirati, Revolution Medicines and Virtec Pharmaceuticals, consulting fees or honoraria from AmMax Bio, Black Diamond Therapeutics, Boehringer Ingelheim, Repare Therapeutics and Revolution Medicines and is a member of the scientific advisory board for Frontier Medicines.

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Murciano-Goroff, Y.R., Lito, P. The KRYSTAL-1 study of adagrasib — a new trial for KRASG12C-mutated non-small-cell lung cancer. Nat Rev Clin Oncol 19, 677–678 (2022). https://doi.org/10.1038/s41571-022-00676-4

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