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Acquired resistance to first-line osimertinib is heterogeneous in EGFR-mutant advanced non-small cell lung cancer

Jing Li1, Jieyan Luo2, Zhanjun Dou1

  • 1Respiratory Department, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, Shanxi, China.

Scientific Reports
|June 29, 2026
PubMed

Insights

Resistance to osimertinib in EGFR-mutant non-small cell lung cancer (NSCLC) is driven by diverse mechanisms. Post-progression testing is crucial for guiding effective second-line treatments, though outcomes vary.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), is effective against EGFR-mutant non-small cell lung cancer (NSCLC).
  • Acquired resistance to osimertinib is a significant clinical challenge, necessitating the exploration of resistance mechanisms and optimal second-line therapies.

Purpose of the Study:

  • To investigate the diverse mechanisms of acquired resistance to first-line osimertinib in patients with advanced or metastatic EGFR-mutant NSCLC.
  • To evaluate the efficacy of various second-line treatment strategies following osimertinib progression.

Main Methods:

  • Retrospective analysis of 67 patients with advanced/metastatic EGFR-mutant NSCLC treated with first-line osimertinib from the CAPTRA-LUNG database.
  • Next-generation sequencing (NGS) performed on 42 patients to identify resistance mechanisms.
  • Analysis of subsequent treatment strategies and progression-free survival (PFS).

Main Results:

  • Next-generation sequencing (NGS) identified resistance mechanisms including bypass signaling activation (38%), unknown mechanisms (47%), EGFR-dependent alterations (10%), and histologic transformation (5%).
  • Progression-free survival (PFS) varied significantly across second-line treatments: chemotherapy plus anti-angiogenic agents (1.8-16.8 months), platinum-pemetrexed chemotherapy (1.6-20.7 months), osimertinib plus platinum-pemetrexed (3.9-6.9 months), replacement EGFR-TKI (1.9-4.4 months), and chemotherapy plus immune checkpoint inhibitors (3.8 months).
  • Chemotherapy combined with anti-angiogenic agents showed numerically longer PFS in a small subgroup, but findings are descriptive due to small sample size and treatment heterogeneity.

Conclusions:

  • Acquired resistance to osimertinib in EGFR-mutant NSCLC is driven by heterogeneous mechanisms, including bypass pathway activation and histologic transformation.
  • Post-progression molecular testing and tissue re-biopsy are essential for guiding personalized second-line treatment decisions.
  • Second-line treatment outcomes are variable, highlighting the need for further research into optimizing therapeutic strategies for resistant NSCLC.
Keywords:
Non-small cell lung cancerOsimertinibResistance mechanismSecond-line treatment

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