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Simple Summary: Over the past years, the introduction of various anti-HER2 therapies has significantly improved the outcome for patients with HER2-positive breast and gastroesophageal carcinomas. HER2 protein overexpression is investigated using immunohistochemistry, gene amplification using fluorescence in situ hybridization, and gene mutation using next-generation sequencing. This review evaluated the predictive and prognostic role of HER2 status in various types of epithelial malignant cancers beyond breast and gastroesophageal cancers, focusing on the published studies, the scoring systems, and assays used and analyzing the clinical parameters and therapeutic approaches used. The evidence about prognostic and predictive roles of HER2 in carcinomas other than breast and gastroesophageal remains investigational but is increasing due to a tumor site-related prognostic and predictive value of the different types of HER2 alterations. The major limitation was that standardized and validated scoring system assays are not well-established for many organs. The oncogene ERBB2, also known as HER2 or c-ERB2, is located on chromosome 17 (q12). It encodes a tyrosine kinase receptor, the human epidermal growth factor receptor 2 (HER2), involved in neoplastic proliferation, tumor angiogenesis, and invasiveness. Over the past years, the introduction of various anti-HER2 therapies has significantly improved outcomes for patients with HER2-positive breast and gastroesophageal carcinomas. More recently, the introduction of a new antibody–drug conjugate, that is trastuzumab deruxtecan, expanded the therapeutic options to low-HER2 breast and gastroesophageal tumors. HER2 protein overexpression is investigated using immunohistochemistry, gene amplification using fluorescence in situ hybridization, and gene mutation using next-generation sequencing. This review evaluated the predictive and prognostic role of HER2 status in various types of epithelial malignant cancers beyond breast and gastroesophageal cancers. We critically analyzed the key published studies, focusing on utilized scoring systems and assays used, and analyzed clinical parameters and therapeutic approaches. Although the evidence about prognostic and predictive roles of HER2 in carcinomas other than breast and gastroesophageal has been widely increasing over the last decade, it still remains investigational, revealing a tumor site-related prognostic and predictive value of the different types of HER2 alterations. However, standardized and validated scoring system assays have not been well-established for many organs. [ABSTRACT FROM AUTHOR]

Simple Summary: There are growing data on targeting HER2 alterations, which include gene mutations, gene amplifications, and protein overexpression, for non-small cell lung cancer (NSCLC). Currently, there are limited targeted therapies approved for NSCLC patients with HER2 alterations, and this remains an unmet clinical need. There has been an influx of research on antibody–drug conjugates, monoclonal antibodies, and tyrosine kinase inhibitors. This review discusses the diagnostic challenges of HER2 alterations in NSCLC and summarizes recent progress in HER2 targeted drugs for both clinicians and researchers treating this patient population. Human epidermal growth factor receptor 2 (HER2), a member of the ERBB family of tyrosine kinase receptors, has emerged as a therapeutic target of interest for non-small cell lung cancer (NSCLC) in recent years. Activating HER2 alterations in NSCLC include gene mutations, gene amplifications, and protein overexpression. In particular, the HER2 exon 20 mutation is now a well clinically validated biomarker. Currently, there are limited targeted therapies approved for NSCLC patients with HER2 alterations. This remains an unmet clinical need, as HER2 alterations are present in 7–27% of de novo NSCLC and may serve as a resistance mechanism in up to 10% of EGFR mutated NSCLC. There has been an influx of research on antibody–drug conjugates (ADCs), monoclonal antibodies, and tyrosine kinase inhibitors (TKIs) with mixed results. The most promising therapies are ADCs (trastuzumab-deruxtecan) and novel TKIs targeting exon 20 mutations (poziotinib, mobocertinib and pyrotinib); both have resulted in meaningful anti-tumor efficacy in HER2 mutated NSCLC. Future studies on HER2 targeted therapy will need to define the specific HER2 alteration to better select patients who will benefit, particularly for HER2 amplification and overexpression. Given the variety of HER2 targeted drugs, sequencing of these agents and optimizing combination therapies will depend on more mature efficacy data from clinical trials and toxicity profiles. This review highlights the challenges of diagnosing HER2 alterations, summarizes recent progress in novel HER2-targeted agents, and projects next steps in advancing treatment for the thousands of patients with HER2 altered NSCLC. [ABSTRACT FROM AUTHOR]