AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer

Darren A.E. Cross, Susan E. Ashton, Serban Ghiorghiu, Cath Eberlein, Caroline A. Nebhan, Paula J. Spitzler, Jonathon P. Orme, M. Raymond V. Finlay, Richard A. Ward, Martine J. Mellor, Gareth Hughes, Amar Rahi, Vivien N. Jacobs, Monica Red Brewer, Eiki Ichihara, Jing Sun, Hailing Jin, Peter Ballard, Katherine Al-Kadhimi, Rachel RowlinsonTeresa Klinowska, Graham H.P. Richmond, Mireille Cantarini, Dong Wan Kim, Malcolm R. Ranson, William Pao

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923 Citations (Scopus)

Abstract

First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm+) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective thirdgeneration irreversible inhibitor of both EGFRm+sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm+and EGFRm/T790M+mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm+T790M+NSCLC is described as proof of principle. We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M+ mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented.

Original languageEnglish
Pages (from-to)1046-1061
Number of pages16
JournalCancer discovery
Volume4
Issue number9
DOIs
Publication statusPublished - Sep 2014

ASJC Scopus subject areas

  • Oncology

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    Cross, D. A. E., Ashton, S. E., Ghiorghiu, S., Eberlein, C., Nebhan, C. A., Spitzler, P. J., Orme, J. P., Finlay, M. R. V., Ward, R. A., Mellor, M. J., Hughes, G., Rahi, A., Jacobs, V. N., Brewer, M. R., Ichihara, E., Sun, J., Jin, H., Ballard, P., Al-Kadhimi, K., ... Pao, W. (2014). AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer discovery, 4(9), 1046-1061. https://doi.org/10.1158/2159-8290.CD-14-0337