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Resistance patterns of non-small cell lung cancer treated with third-generation epidermal growth factor

Nana Chen1,2, Feng Zhao1,2, Lu Yang1,2

  • 1Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute Jinan, Shandong, China.

American Journal of Cancer Research
|July 16, 2025
PubMed

Insights

Third-generation EGFR-TKIs are effective for EGFR mutant NSCLC but face resistance. Over 50% of patients experienced original site failure, influenced by sex, CNS metastases, and disease stage.

Area of Science:

  • Oncology
  • Medical Research
  • Pharmacology

Background:

  • Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) represent a preferred treatment for EGFR-mutant non-small cell lung cancer (NSCLC).
  • Therapeutic resistance to EGFR-TKIs presents a significant clinical challenge, necessitating a deeper understanding of resistance mechanisms.

Purpose of the Study:

  • To investigate and delineate the resistance patterns associated with third-generation EGFR-TKIs in patients diagnosed with EGFR-mutant NSCLC.
  • To identify factors influencing the development of specific resistance models.

Main Methods:

  • Retrospective analysis of 104 patients with advanced EGFR-mutant NSCLC who experienced treatment failure with third-generation EGFR-TKIs.
  • Classification of resistance models based on failure site (original site failure, distant site failure, combined failure) and disease progression patterns (oligo-progression, non-oligoprogression).

Main Results:

  • Original site failure (OF) was observed in 58.7% of patients, distant site failure (DF) in 24.0%, and combined failure (ODF) in 17.3%.
  • A high rate of oligo-progression (OP) was noted (76.9%), with primary progression constituting 30.8%.
  • OF was significantly associated with patient sex (OR=3.961, P=0.002), and other factors like central nervous system metastases and disease stage influenced resistance patterns.

Conclusions:

  • More than half of patients treated with third-generation EGFR-TKIs for advanced NSCLC developed original site failure.
  • Resistance patterns are multifactorial, influenced by patient demographics (sex), metastatic site (CNS), and overall disease stage, guiding future therapeutic strategies.
Keywords:
EGFR-TKINon-small cell lung cancerresistance patterns

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