Targeting HER2 in Lung Cancer

Human epidermal growth factor receptor 2 (HER2) amplification and mutations are oncogenic drivers in 2–5% of lung adenocarcinomas. HER2 exon 20 in-frame mutations may be phenotypically related to the non-smoking Asian female population and mutually exclusive of other known lung mutations and HER2 amplification. Although HER2 amplification may be an important mechanism for acquired resistance to epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs), the prognostic and predictive significance of the amplification event appears to be different in non-small cell lung cancer (NSCLC) compared to breast and gastric cancer. Single-agent HER2-targeted antibodies and dimerization inhibitor responses have been limited, however encouraging responses have been seen with TKIs targeting Pan-HER agents and antibody drug conjugates. Based on a small trial, the National Comprehensive Cancer Network (NCCN) recommends HER2 exon 20 insertion mutants who have progressed on chemotherapy be considered for ado-trastuzumab emtansine. Further studies are needed in this population of patients. The type of HER2 alterations (mutation/amplification) needs to be precisely defined, and the most compelling data for targeted approaches currently exists in select HER2 mutation positive patients. Advances and approvals for next generation sequencing (NGS) technology have the potential to facilitate the identification of patients who may derive benefit for treatment options.