<p>Osimertinib for Front-Line Treatment of Locally Advanced or Metastatic <em>EGFR</em>-Mutant NSCLC Patients: Efficacy, Acquired Resistance and Perspectives for Subsequent Treatments</p>

Abstract: Non-small cell lung cancer (NSCLC) is one of the most efficient models for precision medicine in oncology. The most appropriate therapeutic for the patient is chosen according to the molecular characteristics of the tumor, schematically distributed between immunogenicity and oncogenic addiction. For this last concept, advanced NSCLC with epidermal growth factor receptor ( EGFR ) mutation is one of the most illustrative models. EGFR-tyrosine kinase inhibitors (TKIs) are the therapeutic backbone for this type of tumor. The recent development of a third-generation TKI, osimertinib, has been a new step forward in the treatment of NSCLC patients. In this article, we first review the clinical development of osimertinib and highlight its efficacy results. We then present the most frequent tumor escape mechanisms when osimertinib is prescribed in first line: off-target ( MET amplification, HER2 amplification, BRAF mutation, gene fusions, histologic transformation) and on-target mechanisms ( EGFR mutation). Finally, we discuss subsequent biomarker-driven treatment strategies. Keywords: lung cancer, EGFR mutation, targeted therapy, acquired resistance