Background: The clarification of several molecular pathways underlying the tumorigenesis
has led to the development of several targeted drugs that have substantially improved the treatment of
Non-Small-Cell Lung Cancer (NSCLC). The Epidermal Growth Factor Receptor (EGFR) is the target
of several Tyrosine-Kinase Inhibitors (TKIs), some of them approved for treatment and others
currently in clinical development. EGFR-TKIs markedly improve progression-free survival of patients
with advanced NSCLC with EGFR mutations compared with chemotherapy.
Methods: We undertook a structured search of bibliographic databases for peer-reviewed research
literature using a focused review question.
Results: Although first- and second-generation agents offer in target population (with EGFR mutations) a substantial
improvement of outcomes compared with standard chemotherapy, unfortunately, drug resistance develops after initial
benefit, through a variety of mechanisms. Novel- (third) generation EGFR inhibitors have a selective mechanism of action
and are currently in advanced clinical development, producing encouraging results in patients with acquired resistance to
previous generation agents.
Conclusion: The search for new drugs or strategies to overcome the TKI resistance in patients with EGFR mutations is to
be considered a priority for the improvement of outcomes in the treatment of advanced NSCLC, and third-generation
EGFR inhibitors are the most promising approach to the issue.