Abstract
<jats:p>Tyrosine kinase inhibitors (TKIs) have reshaped the landscape of molecular oncology by enabling selective inhibition of oncogenic signaling pathways while minimizing the systemic toxicity commonly associated with conventional chemotherapy. In response to resistance largely driven by mutations in the epidermal growth factor receptor (EGFR), four successive generations of TKIs have been engineered, each offering incremental gains in therapeutic performance and tolerability. In clinical settings, first-generation agents such as gefitinib prolonged progression-free survival (PFS) to approximately 10 months, doubling the 5-month PFS typically observed with standard chemotherapy. Second-generation inhibitors, including afatinib, further extended PFS to 11.1 months compared with 6.9 months achieved using cisplatin-based regimens. The most pronounced survival advantage has been observed with third-generation TKIs, which increased median overall survival to 38.6 months versus 31.8 months reported for first-generation agents. These improvements stem largely from the ability of newer compounds to counteract resistance mutations, most notably EGFR T790M, while demonstrating improved safety profiles. Nevertheless, acquired resistance driven by emerging variants such as C797S continues to limit long-term efficacy. Investigations from South Korea have shown that third-generation TKIs lack activity against non-small cell lung cancer (NSCLC) harboring the C797S alteration. Although preclinical data have yielded encouraging in vitro and in vivo findings, comprehensive clinical validation remains necessary. Collectively, ongoing optimization of EGFR-directed TKIs reflects sustained progress in combating resistance while striving to enhance durable patient outcomes.</jats:p>