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

Sensitizing mutations in the epidermal growth factor receptor () predict response to tyrosine kinase inhibitors (TKIs) and both first- and second-generation TKIs are available as first-line treatment options in patients with advanced -mutant non-small cell lung cancer. Eventual resistance develops with multiple mechanisms identifiable both upon repeat biopsy and in plasma circulating tumor DNA. The gatekeeper mutation is responsible for almost 60% of cases. A number of third-generation TKIs are in clinical development, and osimertinib has been approved by the US Food and Drug Administration for the treatment of patients with mutant lung cancer after failure of initial kinase therapy. Resistance mechanisms are being identified to these novel agents, and the treatment landscape of -mutant lung cancer continues to evolve. The sequence of TKIs may change in the future and combination therapies targeting resistance appear highly promising.