EGFR)-targeted drugs have been the first-line treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC), especially exon 19 deletions and L858R mutation in exon 21. However, there is insufficient evidence for other less common types of EGFR mutations, such as delE709_T710insD (del 18). Recent studies have revealed that these rare genotypes could be targetable if appropriate mutations, such as delE709_T710insD (del 18). Recent studies have revealed that these rare genotypes could be targetable if appropriate EGFR tyrosine kinase inhibitors are selected. Here we reported a stage Ⅳ NSCLC patient with delE709_T710insD mutation who responded well to afatinib, a second-generation TKI. Afatinib had taken good control of the patient's brain metastasis with a progression-free survival of 11 months and an overall survival exceeded 21 months, although he had received multi-line therapy. This case demonstrates EGFR delE709_T710insD is a rare but potentially afatinib responsive mutation in NSCLC, which may contribute to changes in clinical practice and further research into the precise detection and treatment of rare mutations in EGFR.