Trastuzumab deruxtecan (T-DXd) is the first targeted therapy approved for the treatment of patients with <i>HER2</i>-mutant metastatic NSCLC, but the evidence in those with <i>HER2</i> non-exon 19/20 mutations is scarce.<h4>Methods</h4>We reported treatment information and outcomes of four patients with metastatic NSCLC harboring <i>HER2</i> non-exon 19/20 mutations who were treated with T-DXd.<h4>Results</h4>All the four patients had metastatic lung adenocarcinoma and reached partial response to T-DXd treatment. This evidence concerns the gene ERBB2 and non-small cell lung carcinoma.