AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer

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 monoanilino-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.

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

“…The detection of the EGFR T790M mutation in this setting has become clinically necessary because of the development of third-generation EGFR TKIs, such as osimertinib, which are active in the presence of this mutation. 223,224 However, although rare responses have been reported to third-generation inhibitors in EGFR T790Menegative disease, 225 such cases may harbor other resistance mechanisms such as MET or ERBB2 amplification 90,114,226 that may be more effectively targeted by other agents. Therefore, determining appropriate therapy in the setting of secondary clinical resistance to an EGFR inhibitor requires knowledge of the presence or absence of the T790M mutation.…”

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

“…Osimertinib is selective for EGFR-TKIsensitizing mutations and the T790M resistance mutation, with lower activity against wild-type EGFR compared with currently approved EGFR-TKIs (Cross et al, 2014). Osimertinib was recently approved by the US Food and Drug Administration for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after EGFR-TKI therapy.…”

“…Osimertinib clinical activity has been demonstrated in the treatment of patients with EGFR mutant NSCLC after progression on a previous EGFR-TKI owing to the EGFR T790M mutation in the ongoing AURA (NCT01802632) and AURA2 (NCT02094261) studies (Jänne et al, 2015a,b;Mitsudomi et al, 2015;Yang et al, 2015). Preclinical data suggest that osimertinib is principally metabolized by cytochrome P450 (CYP3A4) and produces at least two circulating active metabolites: AZ5104 and AZ7550 (Cross et al, 2014;Planchard et al, 2014).…”

Complications and Economic Burden Associated with Obtaining Tissue for Diagnosis and Molecular Analysis in Patients with Non-Small Cell Lung Cancer (NSCLC) in the US (Preprint)

“…However, the use of mandatory biopsies throughout a patient's treatment is expected to increase as biomarker-driven drug approvals become the norm [16]. Osimertinib is a third-generation, EGFR-TKI that potently and selectively inhibits both EGFR sensitizing and EGFR T790M resistance mutations [5,17,18]. Based on positive results from the AURA trial program and FLAURA first-line study, osimertinib is recommended in the US as a first-line treatment option for patients with EGFR mutation-positive advanced NSCLC and as a second-line treatment for patients with T790M-positive NSCLC following disease progression on a first-line EGFR-TKI therapy (erlotinib, gefitinib, or afatinib) [12,19].…”

“…Despite the high response rates with first-line epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), disease progression occurs in most patients within 9-13 months from treatment initiation, which is frequently due to the development of a resistance mechanism [4,5]. Recent guidelines recommend a postprogression biopsy in patients with NSCLC to guide subsequent treatment decisions [3].…”