S18 Ep41: Recent Data Readouts Help Untangle HER2 Overexpression and Mutation Implications in NSCLC

Distinguishing between HER2 mutations and HER2 overexpression is critical for optimizing treatment in non-small cell lung cancer. HER2 mutations, typically exon 20 insertions, function as genomic drivers responsive to tyrosine kinase inhibitors. Conversely, HER2 overexpression, identified via gastric scoring criteria in immunohistochemistry, lacks these genomic alterations and is effectively targeted by antibody-drug conjugates like trastuzumab deruxtecan. Clinical management necessitates early biomarker testing to preserve limited tissue and facilitate timely therapeutic decisions. While trastuzumab deruxtecan offers significant clinical benefit, it requires aggressive anti-emetic prophylaxis and vigilant monitoring for potential toxicities, particularly pneumonitis. Because these distinct biological profiles dictate different treatment strategies, precise diagnostic classification remains essential for navigating therapeutic options, including sequencing strategies after initial progression on chemoimmunotherapy or targeted agents.