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Updated: Apr 18, 2026

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
09:38

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Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell

Bin-Chi Liao1, Chia-Chi Lin, James Chih-Hsin Yang

  • 1aDepartment of Oncology bDepartment of Urology cGraduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Current Opinion in Oncology
|January 23, 2015
PubMed
Abstract

Insights

Newer epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) offer improved treatment for non-small cell lung cancer (NSCLC). Second-generation EGFR-TKIs like afatinib are approved, while third-generation drugs target resistance mutations.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • First-generation EGFR-TKIs (gefitinib, erlotinib) are effective for advanced NSCLC with EGFR mutations.
  • Acquired EGFR T790M resistance mutations limit the efficacy of first-generation EGFR-TKIs.
  • Development of novel EGFR-TKIs is crucial to overcome resistance and improve patient outcomes.

Purpose of the Study:

  • To review recent advancements in second and third-generation EGFR-TKIs.
  • To discuss the development of novel EGFR-TKIs designed to overcome EGFR T790M resistance.
  • To highlight the therapeutic potential of these agents in NSCLC treatment.

Main Methods:

  • Review of preclinical and clinical data on second and third-generation EGFR-TKIs.
  • Analysis of drug mechanisms, including binding affinity and selectivity.
  • Evaluation of response rates and resistance profiles in early-phase studies.

Main Results:

  • Second-generation EGFR-TKIs (afatinib, dacomitinib) irreversibly inhibit EGFR and other ErbB family members.
  • Afatinib is approved for first-line treatment of NSCLC with activating EGFR mutations.
  • Third-generation EGFR-TKIs (AZD9291, CO-1686, HM61713) target both activating and T790M resistance mutations while sparing wild-type EGFR, showing promising early results.

Conclusions:

  • Afatinib represents a significant advancement as a first-line treatment option.
  • Third-generation EGFR-TKIs are under active development for patients with acquired T790M resistance.
  • These novel agents hold promise for improving treatment strategies in EGFR-mutated NSCLC.

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