Zongertinib (Hernexeos) received accelerated approval from the U.S. Food and Drug Administration (FDA) on February 26, 2026, for adults with unresectable or metastatic non-squamous non–small cell lung cancer (NSCLC) harboring HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations, as identified by an FDA-authorized test.
This approval represents a significant advancement for a molecularly defined subgroup of NSCLC that historically lacked highly effective, mutation-specific oral targeted therapies in the frontline advanced setting. Approval was based on results from the Beamion LUNG-1 study.
Beamion LUNG-1 Trial
Approval was based on results from the Beamion LUNG-1 study, a first-in-human, open-label, multicenter Phase 1a/1b clinical trial evaluating zongertinib in patients with advanced HER2-altered solid tumors, with a dedicated expansion cohort in HER2-mutant NSCLC.
Study Design
Beamion LUNG-1 consists of two components:
- Phase 1a: Dose Escalation
Patients with advanced HER2-altered solid tumors received escalating doses of zongertinib to determine the maximum tolerated dose (MTD) and establish the recommended dose for expansion. Dose-limiting toxicities (DLTs) were assessed during the first 21-day cycle.
- Phase 1b: Dose Expansion
Multiple NSCLC-specific cohorts were enrolled based on HER2 mutation type and clinical context, including:
- HER2 TKD mutations
- Prior HER2 antibody–drug conjugate exposure
- Active brain metastases
- Treatment-naïve advanced disease
Zongertinib was administered orally once daily in continuous 21-day cycles until disease progression or unacceptable toxicity.
Primary endpoints differed by phase:
- Phase 1a: Safety, DLTs, and MTD
- Phase 1b: Objective response rate (ORR), assessed by blinded independent central review per RECIST v1.1
Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), intracranial response (RANO-BM criteria), safety, and patient-reported outcomes.
The trial is non-randomized, uses sequential assignment, and remains ongoing across multiple international sites.
What Is Zongertinib (Hernexeos)?
Zongertinib is an oral, irreversible, highly selective HER2 (ERBB2) tyrosine kinase inhibitor (TKI) developed by Boehringer Ingelheim for cancers driven by HER2 mutations, particularly in NSCLC.
Mechanism of Action
Zongertinib selectively binds to and irreversibly inhibits the mutated HER2 kinase domain. By blocking downstream HER2-driven signaling pathways—including MAPK and PI3K/AKT—it suppresses tumor cell proliferation and survival.Importantly, zongertinib was designed to spare wild-type EGFR, potentially reducing classic EGFR-related toxicities such as severe rash and diarrhea observed with earlier pan-HER inhibitors
Clinical Significance
HER2 mutations occur in approximately 2–4% of NSCLC cases, defining a distinct molecular subgroup. While antibody–drug conjugates have improved outcomes in this setting, the availability of a selective, oral HER2 TKI expands the therapeutic landscape.Zongertinib introduces a precision-targeted option that may offer durable responses with a manageable safety profile, further advancing personalized oncology in lung cancer.
About Non–Small Cell Lung Cancer (NSCLC)
Non–small cell lung cancer accounts for approximately 85% of all lung cancer diagnoses worldwide. It includes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, each with unique biological characteristics.Although NSCLC generally grows more slowly than small cell lung cancer, many patients are diagnosed at advanced stages because early symptoms—such as persistent cough, shortness of breath, chest pain, or fatigue—are often nonspecific.
Modern NSCLC management has been transformed by molecular profiling. Tumors may harbor actionable alterations such as EGFR, ALK, ROS1, KRAS, MET exon 14 skipping, RET fusions, and HER2 mutations, guiding targeted therapies. For patients without driver mutations, immunotherapy—often directed by PD-L1 expression—has significantly improved survival.Comprehensive genomic testing is now central to treatment selection, ensuring patients receive the most appropriate targeted or immune-based therapy.