Zongertinib and Sevabertinib for Her2-Mutant Non-Small Cell Lung Cancer

Abstract Alterations of exon 20 of the tyrosine kinase areas of HER2 characterize a particular molecular subgroup of non-small cell lung cancer (NSCLC), which is resistant to previously used epidermal growth factor receptor (EGFR)-target therapy and is less sensitive to standard chemotherapy. Despite the improvement in outcomes with antibody drug conjugates, its application is limited by intravenous delivery and clinically relevant toxicity. In this review, the next-generation oral HER2 tyrosine kinase inhibitors, zongertinib and sevabertinib, are reviewed in terms of their development, pharmacology, clinical efficacy, and safety. The two agents were both rationally developed to overcome steric hindrance of exon 20 insertions with minimal wild-type EGFR inhibition. We contrast their mechanistic variations, critical clinical trial results, toxicity data, and new applications on treatment sequencing. Collectively, they constitute a promising treatment option for patients with HER2-mutant NSCLC.