Background Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations represent the most common non-classical EGFR mutations in non-small cell lung cancer (NSCLC), yet effective treatment options have long been lacking.Objective To investigate the clinical characteristics and evaluate the efficacy and survival outcomes of different therapies in Chinese patients with advanced EGFR ex20ins-mutant NSCLC to optimize clinical strategies. Methods Clinical data about patients with advanced EGFR ex20ins-mutant NSCLC treated at the First and the Fifth Medical Centers of Chinese PLA General Hospital from January 1, 2015 to November 1, 2024 were retrospectively analyzed. Next-generation sequencing (NGS) and polymerase chain reaction (PCR) were used to identify insertion subtypes and confirm mutation status. Patients received first-line or subsequent chemotherapy, targeted therapy, or immunotherapy. Treatment response was assessed using RECIST version 1.1. KaplanMeier analysis was employed to calculate median progression-free survival (PFS) and overall survival (OS), and Cox regression models were used to evaluate prognostic factors.Results Totally 62 patients with advanced EGFR ex20ins mutant NSCLC were included. The median age of the patients was 60 years, with 61.7% (38 cases) being female. Twenty-one distinct molecular subtypes were identified, among which EGFR exon 20 p.A767-V769dup was the most prevalent (12/39, 30.8%). Patients receiving first-line treatment achieved a median PFS of 9.4 months (95% CI: 7.4 - 11.5 months). Targeted therapy demonstrated superior efficacy (median PFS: 10.5 months) compared to chemotherapy (median PFS: 8.7 months) and immunotherapy (median PFS: 5.8 months), though the differences were not statistically significant (Plog-rank = 0.792). The OS was 28.7 months (95% CI: 19.5 - 37.9 months). Patients receiving targeted therapy exhibited longer OS (median OS: 31.7 months vs 19.3 months) (HR = 0.79, 95% CI: 0.26 - 2.45, P = 0.684), but the difference was not statistically significant (Plog-rank = 0.683). Notably, patients with near-loop insertion mutations had significantly better prognosis than those with far-loop insertion mutations (median OS: 45.7 months vs 24.9 months)(HR = 0.19, 95% CI: 0.06 - 0.59, P= 0.004) (Plog-rank = 0.001). Among patients receiving targeted therapy, those with near-loop insertion mutations exhibited significantly longer OS compared to those with far-loop insertion mutations (51.3 months vs 6.4 months; HR = 0.10, 95% CI: 0.03 - 0.35, P = 0.000) (Plog-rank = 0.000). Conclusion Targeted therapy demonstrates superior efficacy over chemotherapy and immunotherapy in NSCLC patients with EGFR ex20ins mutations, particularly benefiting those with near-loop insertions by improving OS. Insertion sites serve as a critical determinant of treatment response and OS, and should be a key consideration in clinical decision-making.