Trastuzumab deruxtecan shows durable activity in HER2‐mutant non–small cell lung cancer

Human epidermal growth factor receptor 2 (HER2)–targeted therapies have not yet been approved for patients with non–small cell lung cancer (NSCLC). Now a study in the New England Journal of Medicine shows that the HER2-targeted antibody drug conjugate trastuzumab deruxtecan (T-DXd) produced durable anticancer activity in patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment.1 Ninety-one patients received T-DXd. The centrally confirmed objective response occurred in 55% of these patients, and the median duration of response was 9.3 months. The median progression-free survival was 8.2 months, and the median overall survival was 17.8 months. The median duration of follow-up was 13.1 months. Responses were observed across different HER2 mutation subtypes. Grade 3 or higher drug-related adverse events occurred in 46% of the patients; the most common event was neutropenia, which occurred in 19% of the patients. Adjudicated drugrelated interstitial lung disease (ILD) occurred in 26% of the patients and resulted in the death of 2 patients. “T-DXd is an effective, targeted therapy for patients with HER2-mutant NSCLC and a new treatment option in the secondline setting or beyond. It has potential for a landmark regulatory approval as the first HER2-targeted agent for lung cancer and the first antibody-drug conjugate for lung cancer,” says lead study author Bob Li, MD, a medical oncologist with the Thoracic Oncology and Early Drug Development Service, at the Memorial Sloan Kettering Cancer Center in New York City. “Research is ongoing to minimize the incidence and severity of pneumonitis/ILD, including early recognition and intervention with corticosteroids, and exploring a lower dose of T-DXd as currently pursued in the DESTINYLung02 clinical trial [NCT04644237].” Dr. Li says that he is also exploring the use of T-DXd in the first-line NSCLC setting in the phase 3 DESTINY-Lung04 trial (NCT05048797) and in other solid tumors with activating HER2 mutations in the DESTINY-PanTumor01 trial (NCT04639219). “This study brings forth a new paradigm for a group of patients (HER2 mutant lung cancer) that did not previously have a reliable effective treatment,” says lung cancer expert Edward S. Kim, MD, MBA, physician-in-chief at City of Hope Orange County and vice physician-in-chief at the City of Hope National Medical Center in Duarte, California. “T-DXd is the new standard for patients with HER2-mutant NSCLC.”