Overall survival in stage IV EGFR mutation‑positive NSCLC: Comparing first‑, second‑ and third‑generation EGFR‑TKIs (Review)

A substantial (40‑60%) proportion of patients with non‑small cell lung carcinoma (NSCLC) have epidermal growth factor receptor (EGFR) mutations, a crucial therapeutic target in NSCLC. Treatment strategies for patients with advanced‑stage NSCLC have markedly changed, from the empirical use of cytotoxic agents to targeted regimens. EGFR tyrosine kinase inhibitors (TKIs), the first‑line therapy for advanced NSCLC, are reported to be the most effective. Although progression‑free survival (PFS) and objective response rates have long been used as endpoints, meeting these endpoints may not necessarily coincide with an increase in overall survival (OS) among patients with advanced lung cancer. Recently, the FLAURA study with the third‑generation, irreversible, oral EGFR‑TKI, osimertinib, demonstrated an extended median OS by 6.8 months compared with standard EGFR‑TKIs, with a 20% reduction in the risk of mortality [osimertinib, 38.6; EGFR‑TKIs, 31.8; hazard ratio (HR), 0.80; 95% confidence interval (CI), 0.641‑0.997; P=0.046]; this was in addition to meeting the primary endpoint of clinically and statistically significant PFS. Osimertinib was also shown to lead to a statistically significant reduction in the risk of central nervous system disease progression (HR, 0.48; 95% CI, 0.26‑0.86; P=0.014). Notably, 28% of patients remained on osimertinib treatment for 3 years, considerably longer than those in the comparator group (9%). The duration of first subsequent treatment with osimertinib was 25.5 months compared with 13.7 months with standard EGFR‑TKIs (HR, 0.478; 95% CI, 0.393‑0.581; P<0.0001). Thus, the long‑term OS benefit with first‑line osimertinib highlights a promising option in the management of stage IV NSCLC. The present narrative review compares the OS benefit of first‑, second‑ and third‑generation EGFR‑TKIs for patients with stage IV EGFR mutation‑positive NSCLC and discusses their role in disease management.