Hernexeos (zongertinib)

P1, N=16, Not yet recruiting, Boehringer Ingelheim International GmbH

P3, N=416, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

Zongertinib showed sustained efficacy in previously untreated patients with advanced or metastatic HER2-mutant NSCLC. Treatment-related adverse events were predominantly low-grade. (Funded by Boehringer Ingelheim; Beamion LUNG-1 ClinicalTrials.gov number, NCT04886804.).

This case is the first to elucidate the putative resistance mechanisms to zongertinib in HER2-mutant lung adenocarcinoma might be transformation of adenosquamous with giant-cell carcinoma and acquired HER2 amplification through integrated histological and molecular analyses. These findings highlight the necessity of post-progression biopsy and genomic profiling to characterize resistance evolution and guide subsequent therapy selection.

Following the 2022 approval of the antibody-drug conjugate fam-trastuzumab deruxtecan (T-DXd), the therapeutic landscape of HER2-mutant NSCLC further expanded in 2025 with the regulatory approval of two highly selective oral HER2 tyrosine kinase inhibitors, zongertinib and sevabertinib. We also outline ongoing trials that may further shift first-line standards. In summary, recent breakthroughs in HER2-targeted TKIs and ADCs are transforming outcomes in this rare NSCLC subset, though optimizing sequencing, managing resistance, and improving patient selection through biomarker development remain priorities for future research.

P3, N=400, Recruiting, Boehringer Ingelheim

NSCLCs harboring ECD-ERBB2 mutations are associated with a unique clinico-genomic phenotype and improved outcomes with first-line chemoimmunotherapy. These findings have implications for optimizing treatment strategies in this disease.

Three metabolites were identified and structurally characterized based on accurate mass and fragmentation patterns, revealing metabolic pathways such as oxygenation, demethylation, and epoxide hydrolysis. This is the first report on the method validation for the measurement of zongertinib in biological matrices, which enables clinical development of zongertinib and can be applied for clinical pharmacokinetics and therapeutic drug monitoring in future clinical practice.

P2, N=60, Not yet recruiting, Boehringer Ingelheim

P3, N=400, Recruiting, Boehringer Ingelheim

In the past few years, targeted therapeutic modalities such as antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (the first agent to be granted FDA approval for HER2-mutant NSCLC), alongside selective tyrosine kinase inhibitors (TKIs), including zongertinib and sevabertinib, have demonstrated robust systemic efficacy and notable intracranial penetration. This comprehensive review delineates the molecular landscape and clinical phenotypes of HER2-altered NSCLC, synthesizes interim and mature data from ongoing clinical trials evaluating anti-HER2 therapies, and critically examines efficacy and safety results from different classes of targeted agents. Further research is crucial to uncover potential mechanisms of resistance in NSCLC with HER2 mutations and define sequencing or combinatorial strategies pertinent to optimizing individualized patient management.

P1, N=608, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting