2. Academic Validation
  3. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer

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

  • Cancer Discov. 2014 Sep;4(9):1046-61. doi: 10.1158/2159-8290.CD-14-0337.
Darren A E Cross 1,  Susan E Ashton 2,  Serban Ghiorghiu 2,  Cath Eberlein 2,  Caroline A Nebhan 3,  Paula J Spitzler 3,  Jonathon P Orme 4,  M Raymond V Finlay 2,  Richard A Ward 2,  Martine J Mellor 2,  Gareth Hughes 2,  Amar Rahi 2,  Vivien N Jacobs 2,  Monica Red Brewer 3,  Eiki Ichihara 3,  Jing Sun 3,  Hailing Jin 3,  Peter Ballard 2,  Katherine Al-Kadhimi 2,  Rachel Rowlinson 2,  Teresa Klinowska 2,  Graham H P Richmond 2,  Mireille Cantarini 2,  Dong-Wan Kim 5,  Malcolm R Ranson 6,  William Pao 7
Affiliations

Affiliations

  • 1 Oncology Innovative Medicines and Darren.Cross@astrazeneca.com william.pao@vanderbilt.edu.
  • 2 Oncology Innovative Medicines and.
  • 3 Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; and.
  • 4 Discovery Sciences, AstraZeneca, Macclesfield Cheshire;
  • 5 Seoul National University Hospital, Seoul, Republic of Korea.
  • 6 University of Manchester, Christie Hospital, Manchester, United Kingdom;
  • 7 Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee; and Darren.Cross@astrazeneca.com william.pao@vanderbilt.edu.
PMID: 24893891 DOI: 10.1158/2159-8290.CD-14-0337
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 third-generation 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.

Significance: 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.

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