Cancer Discov. 2014 Jun 3. pii: CD-14-0337. [Epub ahead of print]

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

Cross DA1, Ashton SE2, Ghiorghiu S3, Eberlein C4, Nebhan CA5, Spitzler PJ5, Orme JP6, Finlay MR7, Ward RA3, Mellor MJ8, Hughes G3, Rahi A3, Jacobs VN3,Red Brewer M5, Ichihara E9, Sun J10, Jin H9, Ballard P3, Al-Kadhimi K8, Rowlinson R3, Klinowska T11, Richmond GH12, Cantarini M3, Kim DW13, Ranson MR14, Pao W15.

Author information

• 1Oncology Innovative Medicines, AstraZeneca Darren.Cross@astrazeneca.com.
• 2cancer and infection bioscience, Astrazeneca.
• 3Oncology Innovative Medicines, Astrazeneca.
• 4Oncology, AstraZeneca.
• 5Medicine, Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center.
• 6Discovery Sciences, Astrazeneca.
• 7AstraZeneca, UK.
• 8Oncology iMed, Astrazeneca R&D.
• 9Vanderbilt-Ingram Cancer Center, Vanderbilt University.
• 10Vanderbilt University.
• 11Cancer and Infection Discovery, AstraZeneca.
• 12Global Safety Assessment, AstraZeneca.
• 13Department of Internal Medicine, Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine.
• 14Clinical Experimental Pharmacology, University of Manchester.
• 15Medicine (Division of Hematology/Oncology), Cancer Biology, and Pathology, Microbiology, and Immunology, Vanderbilt-Ingram Cancer Center.

Abstract

First generation EGF receptor tyrosine kinase inhibitors (EGFR TKIs) 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. Pre-clinically, 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 two patients with advanced EGFRm T790M+ NSCLC is described as proof of principle.