First Approval of Adagrasib for the Treatment of Non-Small Cell Lung Cancer Harboring a KRASG12C Mutation


Cite item

Full Text

Abstract

Adagrasib is an orally bioavailable, highly selective, small-molecule, irreversible covalent inhibitor of KRASG12C. It was approved by the US FDA on December 12, 2022, for patients with tumors harboring the KRASG12C mutation in locally advanced or metastatic non-small cell lung cancer (NSCLC). Herein, synthesis, dosage and administration, mechanism of action, pharmacokinetics, pharmacodynamics, and adverse events of adagrasib are described.

About the authors

Surya De

Department of Chemistry, Conju-Probe

Author for correspondence.
Email: info@benthamscience.net

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249. doi: 10.3322/caac.21660 PMID: 33538338
  2. Thein, K.Z.; Biter, A.B.; Hong, D.S. Therapeutics targeting mutant KRAS. Annu. Rev. Med., 2021, 72(1), 349-364. doi: 10.1146/annurev-med-080819-033145 PMID: 33138715
  3. Corral de la Fuente, E.; Olmedo Garcia, M.E.; Gomez Rueda, A.; Lage, Y.; Garrido, P. Targeting KRAS in non-small cell lung cancer. Front. Oncol., 2022, 11, 792635. doi: 10.3389/fonc.2021.792635 PMID: 35083149
  4. Tian, H; Yang, Z; He, J. Adagrasib: A landmark in the KRASG12C-mutated NSCLC. Med. Comm. (2020), 2022, 3(4), e190. doi: 10.1002/mco2.190
  5. Cox, A.D.; Fesik, S.W.; Kimmelman, A.C.; Luo, J.; Der, C.J. Drugging the undruggable RAS: Mission possible? Nat. Rev. Drug Discov., 2014, 13(11), 828-851. doi: 10.1038/nrd4389 PMID: 25323927
  6. Jänne, P.A.; Riely, G.J.; Gadgeel, S.M.; Heist, R.S.; Ou, S.H.I.; Pacheco, J.M.; Johnson, M.L.; Sabari, J.K.; Leventakos, K.; Yau, E.; Bazhenova, L.; Negrao, M.V.; Pennell, N.A.; Zhang, J.; Anderes, K.; Der-Torossian, H.; Kheoh, T.; Velastegui, K.; Yan, X.; Christensen, J.G.; Chao, R.C.; Spira, A.I. Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. N. Engl. J. Med., 2022, 387(2), 120-131. doi: 10.1056/NEJMoa2204619 PMID: 35658005
  7. Ou, S.H.I.; Jänne, P.A.; Leal, T.A.; Rybkin, I.I.; Sabari, J.K.; Barve, M.A.; Bazhenova, L.; Johnson, M.L.; Velastegui, K.L.; Cilliers, C.; Christensen, J.G.; Yan, X.; Chao, R.C.; Papadopoulos, K.P. First-in-human phase I/IB dose-finding study of Adagrasib (MRTX849) in patients with advanced KRASG12C solid tumors (KRYSTAL-1). J. Clin. Oncol., 2022, 40(23), 2530-2538. doi: 10.1200/JCO.21.02752 PMID: 35167329
  8. Hallin, J.; Engstrom, L.D.; Hargis, L.; Calinisan, A.; Aranda, R.; Briere, D.M.; Sudhakar, N.; Bowcut, V.; Baer, B.R.; Ballard, J.A.; Burkard, M.R.; Fell, J.B.; Fischer, J.P.; Vigers, G.P.; Xue, Y.; Gatto, S.; Fernandez-Banet, J.; Pavlicek, A.; Velastagui, K.; Chao, R.C.; Barton, J.; Pierobon, M.; Baldelli, E.; Patricoin, E.F., III; Cassidy, D.P.; Marx, M.A.; Rybkin, I.I.; Johnson, M.L.; Ou, S.H.I.; Lito, P.; Papadopoulos, K.P.; Jänne, P.A.; Olson, P.; Christensen, J.G. The KRASG12C Inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov., 2020, 10(1), 54-71. doi: 10.1158/2159-8290.CD-19-1167 PMID: 31658955
  9. Sabari, J.K.; Velcheti, V.; Shimizu, K.; Strickland, M.R.; Heist, R.S.; Singh, M.; Nayyar, N.; Giobbie-Hurder, A.; Digumarthy, S.R.; Gainor, J.F.; Rajan, A.P.; Nieblas-Bedolla, E.; Burns, A.C.; Hallin, J.; Olson, P.; Christensen, J.G.; Kurz, S.C.; Brastianos, P.K.; Wakimoto, H. 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., 2022, 28(15), 3318-3328. doi: 10.1158/1078-0432.CCR-22-0383 PMID: 35404402
  10. Fell, J.B.; Fischer, J.P.; Baer, B.R.; Blake, J.F.; Bouhana, K.; Briere, D.M.; Brown, K.D.; Burgess, L.E.; Burns, A.C.; Burkard, M.R.; Chiang, H.; Chicarelli, M.J.; Cook, A.W.; Gaudino, J.J.; Hallin, J.; Hanson, L.; Hartley, D.P.; Hicken, E.J.; Hingorani, G.P.; Hinklin, R.J.; Mejia, M.J.; Olson, P.; Otten, J.N.; Rhodes, S.P.; Rodriguez, M.E.; Savechenkov, P.; Smith, D.J.; Sudhakar, N.; Sullivan, F.X.; Tang, T.P.; Vigers, G.P.; Wollenberg, L.; Christensen, J.G.; Marx, M.A. Identification of the clinical development candidate MRTX849, a covalent KRAS G12C inhibitor for the treatment of cancer. J. Med. Chem., 2020, 63(13), 6679-6693. doi: 10.1021/acs.jmedchem.9b02052 PMID: 32250617
  11. Dunnett-Kane, V.; Nicola, P.; Blackhall, F.; Lindsay, C. Mechanisms of resistance to KRASG12C inhibitors. Cancers, 2021, 13(1), 151. doi: 10.3390/cancers13010151 PMID: 33466360
  12. Christensen, J.G.; Olson, P.; Briere, T.; Wiel, C.; Bergo, M.O. Targeting Kras g12c ‐mutant cancer with a mutation‐specific inhibitor. J. Intern. Med., 2020, 288(2), 183-191. doi: 10.1111/joim.13057 PMID: 32176377
  13. Brazel, D.; Arter, Z.; Nagasaka, M. A long overdue targeted treatment for KRAS mutations in NSCLC: Spotlight on Adagrasib. Lung Cancer, 2022, 13, 75-80. doi: 10.2147/LCTT.S383662 PMID: 36387582
  14. Romero, D. Two new agents target KRASG12C. Nat. Rev. Clin. Oncol., 2020, 17(1), 6. doi: 10.1038/s41571-019-0304-3 PMID: 31772333
  15. Skoulidis, F.; Li, B.T.; Dy, G.K.; Price, T.J.; Falchook, G.S.; Wolf, J.; Italiano, A.; Schuler, M.; Borghaei, H.; Barlesi, F.; Kato, T.; Curioni-Fontecedro, A.; Sacher, A.; Spira, A.; Ramalingam, S.S.; Takahashi, T.; Besse, B.; Anderson, A.; Ang, A.; Tran, Q.; Mather, O.; Henary, H.; Ngarmchamnanrith, G.; Friberg, G.; Velcheti, V.; Govindan, R. Sotorasib for lung cancers with KRAS p.G12C mutation. N. Engl. J. Med., 2021, 384(25), 2371-2381. doi: 10.1056/NEJMoa2103695 PMID: 34096690
  16. Koga, T.; Suda, K.; Fujino, T.; Ohara, S.; Hamada, A.; Nishino, M.; Chiba, M.; Shimoji, M.; Takemoto, T.; Arita, T.; Gmachl, M.; Hofmann, M.H.; Soh, J.; Mitsudomi, T. KRAS secondary mutations that confer acquired resistance to KRASG12C inhibitors, sotorasib and adagrasib, and overcoming strategies: Insights from in vitro experiments. J. Thorac. Oncol., 2021, 16(8), 1321-1332. doi: 10.1016/j.jtho.2021.04.015 PMID: 33971321
  17. Awad, M.M.; Liu, S.; Rybkin, I.I.; Arbour, K.C.; Dilly, J.; Zhu, V.W.; Johnson, M.L.; Heist, R.S.; Patil, T.; Riely, G.J.; Jacobson, J.O.; Yang, X.; Persky, N.S.; Root, D.E.; Lowder, K.E.; Feng, H.; Zhang, S.S.; Haigis, K.M.; Hung, Y.P.; Sholl, L.M.; Wolpin, B.M.; Wiese, J.; Christiansen, J.; Lee, J.; Schrock, A.B.; Lim, L.P.; Garg, K.; Li, M.; Engstrom, L.D.; Waters, L.; Lawson, J.D.; Olson, P.; Lito, P.; Ou, S.H.I.; Christensen, J.G.; Jänne, P.A.; Aguirre, A.J. Acquired resistance to KRAS G12C inhibition in cancer. N. Engl. J. Med., 2021, 384(25), 2382-2393. doi: 10.1056/NEJMoa2105281 PMID: 34161704
  18. Kerr, D.L.; Haderk, F.; Bivona, T.G. Allosteric SHP2 inhibitors in cancer: Targeting the intersection of RAS, resistance, and the immune microenvironment. Curr. Opin. Chem. Biol., 2021, 62, 1-12. doi: 10.1016/j.cbpa.2020.11.007 PMID: 33418513
  19. Cascetta, P.; Marinello, A.; Lazzari, C.; Gregorc, V.; Planchard, D.; Bianco, R.; Normanno, N.; Morabito, A. KRAS in NSCLC: State of the art and future perspectives. Cancers, 2022, 14(21), 5430. doi: 10.3390/cancers14215430 PMID: 36358848
  20. Punekar, S.R.; Velcheti, V.; Neel, B.G.; Wong, K.K. The current state of the art and future trends in RAS-targeted cancer therapies. Nat. Rev. Clin. Oncol., 2022, 19(10), 637-655. doi: 10.1038/s41571-022-00671-9 PMID: 36028717
  21. Surya, K., Ed.; Fundamentals of Cancer Detection, Treatment, and Prevention; Wiley, 2022, pp. 259-284.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers