In this retrospective study, we aimed to dissect the molecular characteristics of HER2 alterations in treatment-naïve NSCLC, especially the differences of molecular characteristics between early- and late-stage NSCLC with HER2 alterations, assess the efficacy of afatinib and pyrotinib in HER2-positive NSCLC patients, and uncover the potential resistance mechanism to them. The gene discussed is ERBB2; the disease is non-small cell lung carcinoma.