Understanding HER2 Alterations in NSCLC and Their Evolving Clinical Impact

In this opening segment, Dr. Jacob Sands introduces the clinical framework for evaluating HER2 alterations in non-small cell lung cancer and outlines how recent advances in antibody drug conjugates and TKIs are reshaping treatment sequencing. He explains the historical contrast between HER2 biology in breast cancer, where expression has long guided therapy, and the emerging recognition that HER2 mutation is the more meaningful driver in lung cancer. Early studies of trastuzumab deruxtecan demonstrated that patients with HER2 mutations experienced superior responses and durability compared with those selected by expression alone, establishing mutation as the primary biomarker in NSCLC. Dr. Sands also highlights the complexity of reintroducing HER2 expression into the conversation, noting that its implications differ significantly from breast cancer. He emphasizes that HER2 alterations occur in only 2 to 4 percent of NSCLC, underscoring the importance of precise molecular testing and tailored sequencing strategies as the therapeutic landscape continues to evolve.