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Third-Generation Tyrosine Kinase Inhibitors Targeting Epidermal Growth Factor Receptor Mutations in Non-Small Cell

Tristan A Barnes1, Grainne M O'Kane1, Mark David Vincent2

  • 1Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada.

Frontiers in Oncology
|June 17, 2017
PubMed

Insights

Epidermal growth factor receptor (EGFR) mutations predict response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer. Resistance mechanisms, including the T790M mutation, are being identified, driving the evolution of TKI therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Sensitizing mutations in the epidermal growth factor receptor (EGFR) are key predictors of treatment response to EGFR tyrosine kinase inhibitors (TKIs).
  • First- and second-generation EGFR TKIs are established first-line options for advanced EGFR-mutant non-small cell lung cancer (NSCLC).
  • Acquired resistance to EGFR TKIs is a significant clinical challenge, with multiple resistance mechanisms identified.

Purpose of the Study:

  • To review the mechanisms of resistance to EGFR TKIs in NSCLC.
  • To discuss the clinical development and approval of third-generation EGFR TKIs, such as osimertinib.
  • To highlight the evolving treatment landscape and future directions for EGFR-mutant NSCLC.

Main Methods:

  • Literature review of studies on EGFR mutations, TKI resistance, and novel therapeutic agents.
  • Analysis of clinical trial data for third-generation TKIs.
  • Identification of resistance mechanisms through repeat biopsies and circulating tumor DNA analysis.

Main Results:

  • The T790M gatekeeper mutation is a major mechanism of acquired resistance, accounting for approximately 60% of cases.
  • Third-generation TKIs, including osimertinib, show efficacy in patients with EGFR T790M-mutant NSCLC after progression on earlier therapies.
  • Emerging resistance mechanisms to novel agents are being identified, necessitating continuous research.

Conclusions:

  • The treatment landscape for EGFR-mutant NSCLC is dynamic, with ongoing evolution of TKI therapies.
  • Understanding resistance mechanisms is crucial for developing effective treatment strategies.
  • Future therapeutic approaches may involve altered sequencing of TKIs or combination therapies targeting resistance pathways.
Keywords:
T790Mepidermal growth factor receptorlung cancerlung cancer treatmenttyrosine kinase inhibitors

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