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Primary and acquired resistance to first-line Osimertinib to improve the outcome of EGFR-mutated advanced non-small cell lung cancer patients: the challenge is open for new therapeutic strategies

*April 2024*


  • Osimertinib is currently the common first-line therapy in EGFR-mutated non-small cell lung cancer patients.
  • Understanding primary and acquired resistance mechanisms to osimertinib is crucial in choosing subsequent therapy strategy.
  • Treatment after osimertinib must be tailored according to type of progression and detection of resistance mechanisms.
  • Therapeutic strategies targeting resistance mechanisms and molecular-unselected options are showing promising results.
  • Molecular characterization of tissue and plasma at baseline and at time of progression could increase biological knowledge.


The development of targeted therapy in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients has radically changed their clinical perspectives. Current first-line standard treatment for advanced disease is commonly considered third-generation tyrosine kinase inhibitors (TKI), osimertinib. The study of primary and acquired resistance to front-line osimertinib is one of the main burning issues to further improve patients’ outcome.

Great heterogeneity has been depicted in terms of duration of clinical benefit and pattern of progression and this might be related to molecular factors including subtypes of EGFR mutations and concomitant genetic alterations. Acquired resistance can be categorized into two main classes: EGFR-dependent and EGFR-independent mechanisms and specific pattern of progression to first-line osimertinib have been demonstrated.

The purpose of the manuscript is to provide a comprehensive overview of literature about molecular resistance mechanisms to first-line osimertinib, from a clinical perspective and therefore in relationship to emerging therapeutic approaches. Read more.