Epidemiology and Real-World Outcomes in Patients with Human Epidermal Growth Factor Receptor 2 (HER2)-Mutant...

Human epidermal growth factor receptor 2 (HER2) mutations in non-small cell lung cancer (NSCLC) are associated with aggressive disease and poor prognosis. Improved understanding of patient characteristics is vital to advance personalized treatment and improve outcomes. In this structured protocol-based targeted literature review, we assessed the epidemiology and 'real-world' outcomes in patients with HER2-mutant NSCLC by region, and by mutation category (tyrosine kinase domain [TKD] and non-TKD). Across 64 studies, the frequency of HER2 mutations ranged from 1% to 5%. Patients with HER2-mutant NSCLC were more frequently female, never smokers, and exhibited a high burden of central nervous system involvement. The HER2 mutational landscape differed between TKD and non-TKD groups, with non-TKD mutations associated with higher frequencies of concomitant mutations and higher tumor mutational burden. Few studies systematically assessed HER2 mutation oncogenicity; however, TKD mutations appear to be more commonly oncogenic than non-TKD mutations. Further information regarding the oncogenicity of uncommon HER2 mutations is required. Most patients received first-line platinum-doublet chemotherapy or chemoimmunotherapy, with no clear second-line standard of care. Clinical outcomes were modest. There is a clear unmet need for HER2-directed agents. Three such agents have gained accelerated US Food and Drug Administration (FDA) approval for use in previously treated HER2-mutant NSCLC: the antibody-drug conjugate, trastuzumab deruxtecan; the HER2-specific tyrosine kinase inhibitor (TKI), zongertinib; and the HER2/EGFR TKI, sevabertinib. Zongertinib has also been granted accelerated FDA approval in a first-line setting. The emergence of multiple treatment options highlights the importance of early HER2 mutation testing to guide treatment sequencing and maximize patient benefit.