Real-World Efficacy of First- and Second-Generation EGFR TKIs in NSCLC with EGFR Co-mutations: A Vietnamese Cohort Study

Background EGFR mutation is one of the most common genetic alterations in Non-small cell Lung cancer (NSCLC); however, the management of patients harboring EGFR co-mutations has emerged as a major therapeutic challenge in recent years. Materials and Methods We conducted a retrospective cohort study (2018–2025) at Vietnam National Lung Hospital analyzing 81 treatment-naïve advanced NSCLC patients with EGFR co-mutations identified by next-generation sequencing. Patients received first- or second-generation EGFR-TKIs, with efficacy evaluated using RECIST v1.1 criteria. Results Among 81 patients with EGFR co-mutations, concurrent EGFR mutations were the most common (45.61%), followed by EGFR combined with PIK3CA (21.05%), ALK (14.04%), and KRAS (5.26%). Multivariate analysis showed that patients harboring two concurrent EGFR mutations had significantly improved overall survival (OS) compared with other co-mutation patterns (HR 0.26, 95% CI 0.09–0.76; p = 0.013). No significant differences were observed between first- and second-generation EGFR TKIs in objective response rate (56.5% vs. 73.5%, p = 0.181) or disease control rate, with both achieving a median progression-free survival of 9 months. Notably, first-generation TKIs were associated with longer OS in patients with brain metastases (27.59 vs. 10.43 months, p = 0.032), and female patients demonstrated superior OS compared with males (27.59 vs. 22.72 months, p = 0.003). Conclusion These findings suggest EGFR co-mutation patients show differential TKI responses, emphasizing personalized treatment strategies based on mutation profiles and patient characteristics.