Osimertinib making a breakthrough in lung cancer targeted therapy

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the evidence-based first-line treatment for advanced non-small-cell lung cancer that harbors sensitizing EGFR mutations (EGFRm(+)) such as exon 19 deletions and L858R substitutions in exon 21. However, acquired resistance to EGFR TKIs is mostly driven by a second-site EGFR T790M mutation, which negates their inhibitory activity. Osimertinib (AZD9291, Tagrisso™), an oral, third-generation EGFR TKI, has been designed to target the EGFR T790M mutation, while sparing wild-type EGFR. In this up-to-date review, focus is not only on the structure, mechanisms, and pharmacokinetics of osimertinib but also on summarizing clinical trials and making recommendations of osimertinib for patients with non-small-cell lung cancer.

Keywords: T790M mutation; epidermal growth factor receptor; non-small cell lung cancer; osimertinib; tyrosine kinase inhibitors.

Figure 1

Chemical structure of osimertinib.

Figure 2

Schematic illustration of the possible mechanism of osimertinib. Notes: Via the C797 amino acid covalent bond, osimertinib could target the EGFR T790M mutation while sparing wild-type EGFR, thus inhibiting several downstream pathways, such as RAS/RAF/MAPK and PI3K/AKT, that regulate different cellular processes, including DNA synthesis and proliferation. Abbreviation: EGFR, epidermal growth factor receptor.