INTRODUCTION: HER2 is mutated in 2-4% of non-small cell lung cancers (NSCLC) and is associated with poor prognosis. Tyrosine kinase inhibitors (TKIs) targeting HER2 have historically been hampered by insufficient efficacy against exon 20 insertion mutations and lack of specificity, resulting in off-target adverse events. Zongertinib is an oral, irreversible HER2-selective TKI that spares wild-type EGFR, thereby minimizing associated toxicities. Zongertinib was recently approved in the United States (accelerated), China (conditional), and Japan for patients with previously treated advanced HER2-mutant NSCLC. AREAS COVERED: This article outlines the discovery and clinical development of zongertinib that led to these approvals. We discuss the first-in-human Beamion LUNG-1 trial (NCT04886804), in which zongertinib demonstrated encouraging and durable activity, with a manageable safety profile, in patients with HER2-mutant advanced NSCLC. Finally, we summarize ongoing clinical trials of zongertinib, including its assessment as first-line treatment for advanced HER2-mutant NSCLC. EXPERT OPINION: Zongertinib is the first oral TKI approved for HER2-mutant NSCLC and will provide patients with a convenient, tolerable and effective treatment option in an area of significant unmet need. Next steps include its potential transition to a first-line setting, identification of additional indications, and development of novel combination regimens. Why was this review written?For many years, people with a type of lung cancer that has a mutation in a gene called HER2 have had limited treatment options. Zongertinib is a type of medicine specifically designed to treat tumors with defective HER2 and is given as a tablet. Zongertinib has recently become available to doctors; therefore, this article was written to highlight its history and development.What does the review say?The article discusses how scientists designed zongertinib to specifically target the HER2 protein but not closely related proteins, with the aim of minimizing side effects compared with other medicines. The article then summarizes the first clinical trial that investigated zongertinib in humans. In this trial, called Beamion LUNG-1, zongertinib was very effective at shrinking tumors in most people with HER2-mutant lung cancer who had progressed on or did not respond to previous treatment. In most cases, responses lasted for over a year. As expected, few people experienced severe side effects. Finally, the article describes other clinical trials that are ongoing with zongertinib.What influence do the topics addressed in the review have on the wider field?Zongertinib is the first oral targeted medicine available for people with HER2-mutant lung cancer who have failed on previous treatment. It provides a much-needed treatment option in an area of significant unmet need. It will change treatment patterns in everyday clinical practice. eng
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