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

A number of drugs are in development for the treatment of ERBB2(HER2)-mutated NSCLC, including antibody-drug conjugates such as trastuzumab-deruxtecan and tyrosine kinase inhibitors such as zongertinib and sevabertinib. Herein, we report a case of relapsed advanced ERBB2-mutant NSCLC with acquired resistance to zongertinib potentially mediated through ERBB2 amplification and HER2 3+ immunohistochemistry overexpression with subsequent durable response to fifth-line trastuzumab-deruxtecan. We propose this as a mechanism for zongertinib resistance, one that may underpin a biological rationale for future ERBB2 tyrosine kinase inhibitor-antibody-drug conjugate combination therapy.

Secondary endpoints include duration of response, progression-free survival, disease control, occurrence of treatment-emergent adverse events, and health-related quality of life. Recruitment is ongoing in 13 countries globally.Clinical trial registration http://www.clinicaltrials.gov identifier is NCT06581432.

P1, N=97, Recruiting, Iambic Therapeutics Inc.

P2/3, N=93, Not yet recruiting, Boehringer Ingelheim International GmbH, Boehringer Ingelheim Espana S.A.

P1, N=18, Completed, Bayer | Recruiting --> Completed

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.

P3, N=400, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting