Human epidermal growth factor receptor 2 (HER2) is a member of the ErbB family of receptor tyrosine kinases, which are involved in the regulation of cell growth and differentiation. HER2 overexpression and amplification are well-known in breast cancer, but they also play a significant role in other cancers, including non-small cell lung cancer (NSCLC). HER2 alterations in NSCLC can include overexpression, gene amplification, and mutations. These alterations are less common in NSCLC compared to breast cancer, but they represent a distinct subset of lung cancer patients with specific therapeutic implications. HER2 overexpression/amplification leads to increased signaling through the HER2 pathway, promoting cell proliferation and survival. HER2 mutations are often found in the kinase domain, these mutations can activate HER2 signaling independently of ligand binding, driving oncogenesis. The heterogeneity of HER2 alterations is a challenge -the diversity of HER2 alterations (overexpression, amplification, mutations) in NSCLC requires tailored therapeutic approaches. The role of ICIs in HER2-positive NSCLC is an area of active investigation. Combining ICIs with targeted therapies against HER2 is being explored to enhance antitumor efficacy through combined mechanisms of action. While targeted therapy is available for some cancers driven by HER2, people living with HER2mutated NSCLC have high unmet needs. In 2022, the US FDA approved the anti-HER ADC trastuzumab deruxtecan (T-DXd, Enhertu®) for the treatment of advanced NSCLC driven by mutant HER2. Trastuzumab deruxtecan was previously approved for the treatment of HER2positive breast cancer, including in patients with low levels of the HER2 protein. Recently, a highly selective and potent small molecule inhibitor of HER2, zongertinib, a HER2 tyrosine kinase inhibitor, has been reported as a potential treatment for patients with NSCLC with a specific mutation in the HER2 gene. These recent approvals co-relate well with the increase in publications over 2020-2022 (Figure and Supporting Information S1) and indicate this concept pair might be one to lookout for in the future.