Hernexeos (zongertinib)

P2, N=25, Not yet recruiting, MedSIR

For EGFR-mutant NSCLC, sequential development of tyrosine kinase inhibitors (TKIs) from first- to third-generation agents-culminating in osimertinib-has markedly improved survival. Similarly, successive generations of ALK inhibitors, including alectinib, brigatinib, and lorlatinib, have extended disease control, particularly within the central nervous system. The introduction of antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan for HER2-mutant NSCLC, and emerging TKIs like zongertinib, represent new therapeutic milestones...Beyond lung cancer, our group, in collaboration with Juntendo University ARO (academic research organization) and fifteen institutions in Japan, conducted the MARBLE phase II trial of atezolizumab plus chemotherapy for thymic carcinoma, achieving a 56% objective response rate and 9.6-month median progression-free survival, supporting potential ICI approval in Japan...The DLL3-targeted BiTE tarlatamab significantly improved overall survival to 13.6 months in the phase III DeLLphi-304 trial for relapsed SCLC, with manageable cytokine release syndrome. Collectively, these advances signify a shift toward biologically driven, molecular-targeted or immune-integrated therapy, aiming to transform lung cancer into a chronic, manageable disease in the future, hopefully.

P1/2, N=181, Recruiting, Boehringer Ingelheim International GmbH

Trastuzumab deruxtecan, zongertinib and sevabertinib have been approved in the United States for the treatment of patients with advanced metastatic HER2 mutated non-small-cell lung cancer (NSCLC). Unfortunately, tumor progression is inevitable in many cases. In this case report, we share our experience with a patient with HER2 mutated NSCLC who responded to the combination of trastuzumab deruxtecan and zongertinib after progressing on each agent when given alone, highlighting the potential for such combinations.

P3, N=400, Recruiting, Boehringer Ingelheim

Three such agents have gained accelerated US Food and Drug Administration (FDA) approval for use in previously treated HER2-mutant NSCLC: the antibody-drug conjugate, trastuzumab deruxtecan; the HER2-specific tyrosine kinase inhibitor (TKI), zongertinib; and the HER2/EGFR TKI, sevabertinib. Zongertinib has also been granted accelerated FDA approval in a first-line setting. The emergence of multiple treatment options highlights the importance of early HER2 mutation testing to guide treatment sequencing and maximize patient benefit.

Trastuzumab deruxtecan (T-DXd) was the first targeted therapy approved for patients with HER2-mutant NSCLC, demonstrating robust and durable responses in about 50% of these patients...On the other hand, novel orally available TKIs with higher specificity and inhibitory potency against HER2 over wild type EGFR such as sevabertinib (a dual HER2/EGFR mutant-selective reversible TKI) or zongertinib (an irreversible HER2-selective TKI that spares EGFR, including mutant EGFR) have further demonstrated deep and durable responses in this disease...In this review, we first describe the molecular landscape and clinical features of HER2-mutant NSCLC. Then, we summarize the clinical and preclinical evidence of HER2-targeted therapies and provide a forward-looking perspective of the treatment landscape of HER2-mutant NSCLC.

Among 74 patients newly diagnosed with HER2-mutant NSCLC who received a daily dose of zongertinib, the objective response rate was 76% and the median progression-free survival was 14.4 months. That bests chemotherapy, to which about 30% of patients typically respond for less than 7 months.

She enrolled in a clinical trial of the selective HER2 tyrosine kinase inhibitor zongertinib (60 mg twice daily) in February 2025 and tolerated therapy well, with mild diarrhea, lactose intolerance, brittle nails, and intermittent muscle cramps...As of January 2026, she has maintained lung-confined disease control for over 11 months without extrapulmonary progression and remains fully functional without symptoms. This case highlights the clinical benefit and tolerability of selective HER2-targeted therapy in HER2-mutant NSCLC and adds to emerging evidence supporting consideration of risk-based lung cancer screening strategies in high-risk never-smoking populations.

Zongertinib has demonstrated clinically meaningful systemic and intracranial activity with a manageable safety profile across multiple cohorts in the phase Ia/Ib Beamion LUNG-1 study, including previously treated, treatment-naïve, post-HER2 antibody-drug conjugate (ADC), non-tyrosine kinase domain mutation, and brain metastases populations. This review summarizes the pharmacologic rationale, clinical efficacy, safety, biomarker analyses, and ongoing phase III development of zongertinib in HER2-mutant NSCLC.

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

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