| Summary: | <i>Receptor tyrosine kinase erythroblastic oncogene B2</i> (<i>ERBB2</i>), also known as <i>human epidermal growth factor receptor 2</i> (<i>HER2</i>), represents an oncogenic driver and has been effectively targeted in breast and gastric cancer. Recently, next-generation sequencing (NGS) discovered <i>ERBB2</i> as a promising therapeutic target in metastatic colorectal cancer (mCRC), where it is altered in 3–5% of patients, but no therapies are currently approved for this use. Herein, we present the experience of a single center in diagnosing actionable genetic <i>ERBB2</i> alterations using NGS and utilizing the latest therapeutic options. Between October 2019 and December 2022, a total of 107 patients with advanced CRC underwent molecular analysis, revealing actionable <i>ERBB2</i> mutations in two patients and <i>ERBB2</i> amplifications in two other patients. These findings correlated with immunohistochemical (IHC) staining. Of these four patients, two were treated with trastuzumab-deruxtecan (T-DXd). We present two exemplary cases of patients with actionable <i>ERBB2</i> alterations to demonstrate the effectiveness of T-DXd in heavily pretreated <i>ERBB2</i>-positive mCRC patients and the need for early molecular profiling. To fully exploit the potential of this promising treatment, earlier molecular profiling and the initiation of targeted therapies are essential.
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