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Updated: Jan 18, 2026

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Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

Alessandro Leonetti1,2, Sugandhi Sharma2, Roberta Minari1

  • 1Medical Oncology Unit, University Hospital of Parma, 43126, Parma, Italy.

British Journal of Cancer
|October 1, 2019
PubMed

Insights

Patients with advanced non-small cell lung cancer (NSCLC) develop resistance to osimertinib, an EGFR inhibitor. This review details resistance mechanisms and explores strategies to overcome them.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Osimertinib is a third-generation EGFR tyrosine kinase inhibitor effective for advanced NSCLC with EGFR mutations.
  • Acquired resistance to osimertinib is a significant clinical challenge, limiting long-term treatment efficacy.
  • Resistance mechanisms are diverse, involving both EGFR-dependent and independent pathways, influenced by treatment setting.

Purpose of the Study:

  • To review the molecular mechanisms of osimertinib resistance in advanced EGFR-mutated NSCLC.
  • To discuss the differences in resistance mechanisms based on first-line versus second-line osimertinib treatment.
  • To explore potential therapeutic strategies to overcome acquired resistance.

Main Methods:

  • Literature review of studies on osimertinib resistance in NSCLC.
  • Analysis of molecular mechanisms including genetic amplifications, pathway activations, and cellular transformations.
  • Examination of data from repeat plasma genotyping to understand clonal evolution.

Main Results:

  • Key resistance mechanisms include MET/HER2 amplification, RAS-MAPK/PI3K pathway activation, novel fusions, and histological transformation.
  • Resistance patterns differ between first-line and second-line osimertinib use due to varying selection pressures.
  • Tumor heterogeneity and adaptive signaling contribute to the complexity of acquired resistance.

Conclusions:

  • Understanding diverse resistance mechanisms is crucial for developing effective treatment strategies.
  • Targeting acquired resistance pathways may restore sensitivity to osimertinib or offer alternative therapeutic options.
  • Further research into novel approaches is needed to combat osimertinib resistance in NSCLC.

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