The role of zongertinib, a highly selective tyrosine kinase inhibitor, in targeting HER2 -mutant NSCLC: a bench-to-bedside review
Year: 2026
Type: article
Abstract: 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.
Institutions: The University of Texas MD Anderson Cancer Center, Royal Marsden NHS Foundation Trust, Institute of Cancer Research, Institute of Cancer Research, Leiden University Medical Center, University Hospital Heidelberg, National Center for Tumor Diseases, German Center for Lung Research, Université Paris-Saclay, National Cancer Center Hospital, Research Institute Hospital 12 de Octubre, Hospital Universitario 12 De Octubre, Third Affiliated Hospital of Harbin Medical University, Boehringer Ingelheim (Germany)
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Boehringer Ingelheim, Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, Sanofi, Gilead Sciences, Celgene, Regeneron Pharmaceuticals, Taiho Pharmaceutical, Novocure, Les Laboratories Pierre Fabre, Seagen, Astellas Pharma, Österreichische Forschungsförderungsgesellschaft, PharmaMar, Ono Pharmaceutical, Genentech, EMD Serono, Chugai Pharmaceutical, Daiichi Sankyo Europe
OpenAlex ID: W7127895122