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Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in lung cancers

Helena A Yu1, Gregory J Riely

  • 1Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Journal of the National Comprehensive Cancer Network : JNCCN
|February 16, 2013
PubMed

Insights

Second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show promise in overcoming resistance to first-generation EGFR TKIs. These newer agents may offer greater efficacy and activity against related mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Epidermal growth factor receptor (EGFR) mutations predict response to EGFR tyrosine kinase inhibitors (TKIs).
  • Acquired resistance to first-generation EGFR TKIs (erlotinib, gefitinib) typically develops within one year.
  • Resistance mechanisms necessitate the development of novel therapeutic strategies.

Purpose of the Study:

  • To review second-generation EGFR TKIs designed to overcome acquired resistance.
  • To discuss agents with broader kinase inhibition or altered EGFR interactions.
  • To explore potential clinical activity against other EGFR family mutations, including HER2.

Main Methods:

  • Literature review of second-generation EGFR TKIs.
  • Discussion of mechanisms of action for agents like afatinib, dacomitinib, XL647, AP26113, and CO-1686.
  • Analysis of potential efficacy compared to first-generation TKIs.

Main Results:

  • Second-generation EGFR TKIs irreversibly bind to the kinase domain, potentially delaying or overcoming resistance.
  • These agents exhibit broader inhibition of related kinases (e.g., HER2).
  • Investigational agents show potential for enhanced efficacy and activity against other oncogenic mutations within the EGFR family.

Conclusions:

  • Second-generation EGFR TKIs represent a promising advancement in targeted cancer therapy.
  • These agents may offer improved outcomes for patients with EGFR-mutated cancers.
  • Further clinical investigation is warranted to establish the full therapeutic potential of these novel TKIs.

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