Mechanisms of resistance to osimertinib

Chiara Lazzari, Vanesa Gregorc, Niki Karachaliou, Rafael Rosell, Mariacarmela Santarpia

Research output: Contribution to journalReview articlepeer-review


The introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has significantly improved the prognosis of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. The most common mechanism of acquired resistance to first- and second-generation EGFR TKIs is represented by the secondary T790M mutation. Osimertinib, a third-generation TKI designed to target both EGFR sensitizing mutations and T790M, was first approved for the treatment of EGFR T790M mutation-positive NSCLC patients in progression after EGFR TKI therapy. The FLAURA study demonstrated that first-line treatment of EGFR mutant patients with osimertinib significantly improved progression free survival (PFS) over first-generation EGFR-TKIs, thus leading to its approval also in this setting. Moreover, osimertinib has shown significant central nervous system (CNS) activity and a favorable safety profile. The current review focuses on the clinical development of osimertinib, the mechanisms of acquired resistance identified in patients receiving osimertinib and the strategies currently under evaluation to overcome resistance.

Original languageEnglish
Pages (from-to)2851-2858
Number of pages8
JournalJournal of Thoracic Disease
Issue number5
Publication statusPublished - May 1 2020


  • Epidermal growth factor receptor (EGFR)
  • Mechanisms of resistance
  • Osimertinib

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine


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