HER2-Mutant Non–Small Cell Lung Cancer: Weighing Antibody-Drug Conjugates, Oral TKIs, and the Evidence Shaping First-Line Care

In this OncLive Peer Exchange®, moderator Dr. Benjamin P. Levy joins Dr. Julia Rotow and Dr. Narjust Florez to discuss advances in the management of HER2-mutant non-small cell lung cancer (NSCLC). The experts review the importance of comprehensive molecular testing and distinguish HER2 mutations from HER2 overexpression and amplification. They examine the role of trastuzumab deruxtecan in previously treated disease, including its efficacy, intracranial activity, and risks of interstitial lung disease (ILD) and pneumonitis. The discussion then focuses on the phase 3 DESTINY-Lung04 trial and its first-line findings, including improvements in progression-free survival and response rates compared with platinum-based chemoimmunotherapy. The panel considers the interpretation of overall survival data, subsequent treatments, and the differing levels of evidence supporting trastuzumab deruxtecan and oral HER2 tyrosine kinase inhibitors, including zongertinib and sevabertinib. The experts also address treatment selection, toxicity management, patient preferences, access barriers, resistance testing, and the role of clinical trials in advancing care.