FDA Grants Accelerated Approval to Zongertinib for HER2-Mutated NSCLC

The FDA has granted accelerated approval to zongertinib (Hernexeos), an HER2-selective tyrosine kinase inhibitor, for the treatment of adult patients with unresectable or metastatic nonsquamous non–small cell lung cancer (NSCLC) harboring HER2 tyrosine kinase domain (TKD) activating mutations who have received prior systemic therapy. This approval, based on the phase 1 Beamion LUNG-1 trial, showed a 75% objective response rate (ORR) among patients previously treated with platinum chemotherapy but no HER2-targeted therapies, with 58% maintaining response for at least six months; patients previously treated with HER2-targeted antibody-drug conjugates showed a 44% ORR. The FDA also approved the Oncomine Dx Target Test as a companion diagnostic to identify eligible patients. Zongertinib is dosed based on patient weight and can be taken with or without food, with warnings for hepatotoxicity, interstitial lung disease, left ventricular dysfunction, and embryo-fetal toxicity included in its prescribing information. Treatment-related adverse events occurred in the majority of patients, mainly diarrhea and rash, but serious adverse events were relatively infrequent, and treatment discontinuations were low. This approval introduces a targeted therapy option for HER2-mutant NSCLC, a subtype with aggressive clinical behavior and limited responsiveness to immunotherapy, addressing a significant unmet need in this patient population.