ERBB2 Activating Mutations and Co-Occurring Genomic Alterations in ERBB2-Mutant Lung Cancer

ERBB2 mutations occur in a minority of non-small cell lung cancers, estimated at 1-4% of NSCLC cases. The approved targeted therapies for metastatic ERBB2-mutant NSCLC include trastuzumab-deruxtecan and novel ERBB2 tyrosine kinase inhibitors zongertinib and sevabertinib, with regulatory approval based on data from tumors harboring tyrosine kinase domain mutations.

However, the clinico-genomic features and therapeutic implications of ERBB2 mutations outside the TKD are not well defined. The current understanding emphasizes heterogeneity within ERBB2-mutant NSCLC, as co-occurring genomic alterations may contribute to diverse clinical behavior and potentially influence response to targeted therapies.

Data explicitly detailing the spectrum and frequency of non-TKD ERBB2 alterations, their associated histologic or demographic correlates, and their impact on outcomes remain limited in the published literature. In this context, characterization of tumors with non-TKD ERBB2 mutations, including comprehensive genomic profiling and correlation with treatment response, is an area of ongoing investigation.

Until more evidence emerges, uncertainty persists regarding optimal management and prognostic implications for these non-TKD ERBB2-mutant NSCLCs.