Epidermal growth factor receptor tyrosine kinase inhibitor for the treatment of non-small cell lung cancer in the past 30 years (1997–2026)

ABSTRACT: Epidermal growth factor receptor ( EGFR ) is a critical driver gene in non-small cell lung cancer (NSCLC). Since 1997, EGFR tyrosine kinase inhibitors (EGFR-TKIs) have evolved from first-generation agents, such as gefitinib, erlotinib, and icotinib, to second-generation agents like afatinib and dacomitinib, now to third-generation agents, including osimertinib, aumolertinib, furmonertinib, befotertinib, rezivertinib, rilertinib, limertinib, lazertinib, mifanertinib for EGFR L858R, sunvozertinib for EGFR exon 20 insertion (20ins), and zorifertinib for EGFR -sensitive mutation with brain metastases. Throughout this evolution, EGFR-TKIs have become the cornerstone of treatment for EGFR -mutant NSCLC, extending beyond advanced stages to encompass the entire disease spectrum, including perioperative and maintenance therapies, with combination therapies further expanding treatment options. These advancements have significantly improved patient survival and quality of life. However, challenges such as acquired resistance remain significant hurdles in achieving long-term disease control. Over the past 30 years, substantial advancements have been made in the comprehensive management of EGFR -mutant NSCLC. This systemic review provides the history of the development of EGFR-TKI therapy for NSCLC from 1997 to 2026, highlighting clinical milestones, emerging therapies, and future directions in this rapidly evolving field.