Abstract: Objective To analyze the response of epidermal growth factor receptor （EGFR） non-exons-18-21-mutated advanced non-small cell lung cancer （NSCLC） to targeted therapy, immunotherapy, and chemotherapy. Methods This study collected the clinical data of 35 patients with EGFR non-exons-18-21 pure mutation and 65 patients with EGFR non-exons-18-21 compound mutation in the next generation sequencing （NGS） database of Guangdong Lung Cancer Institute （GLCI） from 2016 to 2020, and collected the clinical data of 567 patients with EGFR exons-18-21 mutation in GLCI from 2016 to 2019. Clinicopathological characteristics of the three groups were compared, and the response of patients with EGFR non-exons-18-21 mutations to different treatments were analyzed. Results The clinicopathological characteristics of the EGFR non-exons-18-21 compound mutation group were consistent with those of the EGFR exons-18-21 mutation group, but showed significant differences in gender （P<0.001）, smoking history （P<0.001）, and pathological type （P<0.001） compared with those of the EGFR non-exons-18-21 pure mutation group. In the EGFR non-exons-18-21 compound mutation group, the progression-free survival （PFS） of patients receiving first- or second-generation EGFR-tyrosine kinase inhibitors （TKIs） （n=26） was 9.4 months, which was no significant difference from that of patients with EGFR exons-18-21 mutation with or without propensity score matching （PSM） （before PSM: P=0.76; after PSM: P=0.76）. And the PFS of patients receiving third-generation EGFR-TKIs （n=23） was 9.5 months, which was also no significant difference from that of patients with EGFR exons-18-21 mutation with or without PSM （before PSM: P=0.23; after PSM: P=0.19）. In EGFR non-exons-18-21 pure mutation group, the PFS of patients receiving immunotherapy and chemotherapy were 4.2 months and 5.4 months, respectively. Conclusions After NGS detected EGFR non-exons-18-21 mutation, patients with EGFR non-exons-18-21 compound mutations could also benefit from first- to third-generation EGFR-TKIs. And the response of immunotherapy and chemotherapy in patients with EGFR non-exons-18-21 pure mutations were similar to that of EGFR wild-type NSCLC. In the future, we need to explore the efficacy of EGFR-TKIs in EGFR non-exons-18-21 pure mutated NSCLC.