The role of zongertinib, a highly selective tyrosine kinase inhibitor, in targeting HER2 -mutant NSCLC: a bench-to-bedside review

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.