U-EGFRm were analysed as complex mutations (Group A), Ins20 (Group B), or single mutations (Group C). Group A complex u-EGFRm consisted of double mutations of G719X+E709F, G719X+S768I, G719X+ L861Q, L858R+T790M, L858R+S768I, Del19+S768I, Del19+L747S, or R776C+L861Q. Response to afatinib was significantly higher in Group A and C (70% and 54%, respectively), compared with Group B (13%; pairwise comparison p < 0.001 and 0.013, respectively). Median OS for the entire cohort was 19.9 m (9.7-30.1). Hazard ratio for OS were 0.27 (95% CI 0.10-0-71, p = 0.009) and 0.40 (95% CI 0.17-0.95, p = 0.037) for Group A and C compared to Group B, respectively. afatinib was active in u-EGFRm NSCLC , particularly in complex and single mutations.