The development of Zongertinib for HER2-mutant NSCLC

Human epidermal growth factor receptor 2 (HER2) mutations are rare in NSCLC and the only FDA approved agent until recently, was trastuzumab deruxtecan in the second line setting. HER2 mutated NSCLC has historically shown worse prognosis compared to other NSCLC and represent an unmet clinical need. Almost 50 % of patients with HER2-mutated non-small cell lung cancer (NSCLC) have brain metastases at diagnosis. Thus, developing an efficacious agent with good blood brain penetration is key. Zongertinib is a HER2 selective tyrosine kinase inhibitor that covalently binds to HER2 receptors, including exon20ins mutations. Zongertinib is safe and effective for patients with HER2-mutated NSCLC based on initial results from preclinical studies and the phase I Beamion LUNG-1 trial showing promising response rates and safety profile ultimately leading to the FDA accelerated approval on August 8, 2025.