Recent Data Readouts Help Untangle HER2 Overexpression and Mutation Implications in NSCLC

In today’s episode, Narjust Florez, MD, and Jonathan Wesley Riess, MD, MS, hosted a discussion about the distinction between HER2 overexpression and HER2 mutations in non–small cell lung cancer (NSCLC). Dr Florez is the associate medical director of the Cancer Care Access Program and a physician at Dana-Farber Cancer Institute, as well as an assistant professor of medicine and a faculty member at Harvard Medical School, both in Boston, Massachusetts. Dr Riess is the director of Thoracic Oncology and an associate professor of medicine in the Division of Hematology and Oncology at the University of California (UC) Davis Health Medical Center and the UC Davis Comprehensive Cancer Center in Sacramento.

In our exclusive interview, Drs Florez and Riess clarified that HER2 mutations, commonly exon 20 insertions, are genomic drivers sensitive to TKIs, whereas HER2 overexpression is a protein finding identified by immunohistochemistry (IHC). They discussed the use of fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of patients with HER2 IHC 3+ NSCLC, reviewed efficacy data from the DESTINY-Lung studies, and worked through a treatment sequencing case. Their conversation also addressed toxicity management, particularly aggressive nausea prophylaxis and vigilance for interstitial lung disease, and emphasized the importance of upfront HER2 testing to preserve tissue and save time.