Zongertinib: A Novel Therapeutic Advance in HER2-Mutant Non-Small Cell Lung Cancer

Abstract Non-small cell lung cancer (NSCLC) with HER2 mutations represents a rare oncogenic subtype (2–4% of adenocarcinomas) associated with poor prognosis and high incidence of brain metastases. Treatment options have been limited, with trastuzumab deruxtecan (T-DXd) carrying significant interstitial lung disease (ILD) risk and earlier oral tyrosine kinase inhibitors (TKIs) causing dose-limiting epidermal growth factor receptor (EGFR)-related toxicities. Zongertinib (BI 1810631), a novel, oral, irreversible, and highly selective HER2 TKI, was engineered to spare wild-type EGFR, minimizing off-target toxicity. The phase IB Beamion LUNG-1 trial demonstrated profound efficacy with 71% objective response rate (ORR) in the tyrosine kinase domain cohort and median progression-free survival of 12.4 months. Notably, zongertinib maintained activity in T-DXd-resistant disease (48% ORR) and showed no cases of drug-related ILD. Treatment-related adverse events were predominantly mild (grade 1–2), with only 17% experiencing grade 3 events in the primary cohort. Based on compelling safety and efficacy data, zongertinib received Food and Drug Administration accelerated approval on August 8, 2025, and was designated as preferred subsequent therapy in the National Comprehensive Cancer Network guidelines for advanced HER2-mutant NSCLC, fundamentally transforming the treatment landscape for this patient population.