Real-world efficacy of first- and second-generation EGFR TKIs in NSCLC with EGFR co-mutations: a Vietnamese cohort study

OBJECTIVE: To compare treatment outcomes between first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR co-mutated non-small cell lung cancer (NSCLC). BACKGROUND: EGFR mutation is one of the most common genetic alterations in 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, dual EGFR mutations were the most common (43%), followed by EGFR combined with PIK3CA (20%), ALK (14%), and KRAS (9%). Multivariate analysis suggested patients with EGFR dual mutations were correlated with higher overall survival (OS) compared with other co-mutation patterns (HR 0.26, 95% CI 0.09-0.76, p = 0.01). 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 (PFS) of 9 months. Subgroup analyses showed significantly longer OS with first-generation TKIs in female patients (27.59 vs. 22.72 months, p = 0.003) and brain metastatic groups (27.59 vs. 10.43 months, p = 0.032), whereas PFS remained comparable (9.10 vs. 7.23 months, p = 0.103). CONCLUSION: First- and second-generation EGFR-TKIs demonstrated comparable overall treatment outcomes in NSCLC patients harboring EGFR co-mutations. However, subgroup analyses suggested potential differences in clinical benefit among female patients and those with brain metastases, warranting further investigation.