Zongertinib in HER2-Mutant Advanced/Metastatic Solid Tumors: A Narrative Review and Future Prospectives

Abstract

Human epidermal growth factor receptor 2 (HER2) has emerged as a critical therapeutic target in various malignancies, most notably breast and gastric cancers. While significant advances have been made in treating HER2-amplified tumors, therapeutic options for tumors harboring activating HER2 mutations remain comparatively limited. Zongertinib (BI 1810631), a novel, highly selective oral HER2 tyrosine kinase inhibitor (TKI), has demonstrated encouraging activity in HER2-mutant cancers, particularly non-small cell lung cancer (NSCLC). This narrative review examines the molecular rationale, preclinical evidence, and clinical outcomes of zongertinib in HER2-mutant advanced or metastatic solid tumors, with emphasis on NSCLC, and contextualizes its activity across other HER2-altered settings.  Early-phase trials such as Beamion LUNG‑1 have shown promising outcomes in HER2-mutant NSCLC, with objective response rates (ORRs) exceeding 70% and durable disease control. However, no current data support the efficacy of zongertinib in HER2-wildtype tumors lacking overexpression, amplification, or mutation. HER2-altered disease encompasses biologically distinct entities, including HER2-amplified/overexpressed tumors, HER2-low tumors (immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization), and HER2-mutant tumors harboring activating ERBB2 genomic variants. “HER2-indeterminate” refers to tumors with equivocal or discordant HER2 testing results in which genomic profiling may reveal actionable ERBB2 alterations. “HER2-negative” refers specifically to tumors lacking HER2 amplification, overexpression (IHC 0), and activating ERBB2 mutations, and does not include HER2-low or HER2-indeterminate cases. These entities are biologically distinct and may demonstrate differential sensitivity to HER2-directed therapies. Current clinical evidence for zongertinib is strongest in HER2-mutant disease, whereas its role in HER2-low or truly HER2-negative tumors remains investigational. To date, no clinical evidence supports efficacy of zongertinibin tumors lacking HER2 amplification or activating mutation. In conclusion, while zongertinib holds significant promise in the treatment of HER2-mutated cancers, especially NSCLC, its role in HER2-low tumors remains investigational. Further research should prioritize (i) prospective clinical trials enrolling HER2-low or HER2-mutant subgroups, (ii) preclinical studies identifying rational drug combinations to overcome resistance, and (iii) biomarker refinement to distinguish patients most likely to benefit. Such directions can clarify zongertinib’s therapeutic scope across HER2-altered malignancies.