New Targeted Therapy Approved for HER2-mutated Lung Cancers
The FDA has approved zongertinib for patients with unresectable or metastatic non-squamous non-small cell lung cancer that has HER2 tyrosine kinase domain mutations and has undergone prior treatment.
The U.S. Food and Drug Administration (FDA) has granted accelerated approval to zongertinib (Hernexeos) for the treatment of adult patients with non-squamous non-small cell lung cancer (NSCLC) that is unresectable or metastatic, has been treated with prior systemic therapy, and has activating mutations in the HER2 tyrosine kinase domain (TKD).
The FDA also approved the Oncomine Dx Target Test as a companion diagnostic to detect these HER2 mutations in a patient’s tumor in order to determine their eligibility for treatment with zongertinib.
Zongertinib is a targeted therapy that blocks the activity of the HER2 pathway, which is often overexpressed or mutated in lung cancer. Specifically, zongertinib inhibits the activity of HER2 proteins that harbor mutations in a segment of the protein known as the TKD.
This is the first FDA approval for zongertinib, and the first FDA approval of an oral HER2 inhibitor for patients with lung cancer. Trastuzumab deruxtecan (Enhertu), the only other HER2-targeting therapy approved by the FDA for lung cancers, is administered intravenously, is associated with significant side effects, and appears to be less effective against lung cancers with HER2 mutations than against those with HER2 overexpression.
The approval is based on results from the open-label, multicenter phase I Beamion LUNG-1 clinical trial. The study evaluated zongertinib treatment in patients with unresectable or metastatic non-squamous NSCLC with HER2 TKD mutations that had undergone prior treatment.
Among 71 patients who had previously been treated with chemotherapy but not a HER2 inhibitor or a HER2-targeting antibody-drug conjugate, 75% (53/71) experienced responses, with responses lasting at least six months in 58% (31/53) of patients. Among 34 patients who had previously been treated with both chemotherapy and a HER2-targeting antibody-drug conjugate, 44% (15/34) experienced responses, with responses lasting at least six months in 27% (4/15) of patients. Results from this trial were presented at the AACR Annual Meeting 2025 and featured in an AACR blog post and press release.
The recommended dose for zongertinib is 120 mg orally once per day in patients who weigh less than 90 kg, and 180 mg orally once per day in patients who weigh 90 kg or more.
NSCLC is the most common type of lung cancer, and approximately 2% to 4% of NSCLC tumors harbor an activating mutation in HER2. According to federal statistics, it was estimated that 226,650 individuals would be diagnosed with lung cancer and 124,730 would die of the disease in the United States in 2025.
The FDA rendered its decision on August 8, 2025. Accelerated approval means that continued approval may be contingent upon a confirmatory trial. Please check this FDA web page for information about any accelerated approvals in oncology that may have been subsequently withdrawn and are no longer FDA-approved. Check this resource for updated information on all therapeutics regulated by the FDA.