HER2 Testing and Treatment / NSCLC 07/29/2026

Ep. 4: Biomarker Testing and Safety Considerations in HER2-Mutated NSCLC

A professional woman with dark hair and a friendly smile, wearing business attire, in a corporate environment. Charu Aggarwal, MD, MPH A smiling male medical professional in a suit and glasses at a conference, representing oncology updates and medical research. Samuel Caughron, MD Professional male in a suit, healthcare expert, oncology specialist, headshot for OncUpdates, medical professional portrait, cancer research and treatment authority. Paolo Tarantino, MD Smiling man with beard wearing a white shirt, professional headshot, suitable for oncology or cancer research content, emphasizing healthcare and medical expertise. Rahul Gosain, MD, MBA Oncologist smiling in white coat, highlighting cancer research and treatment expertise, with a bow tie, in a bright medical setting. Rohit Gosain, MD

Key Points

  • Trastuzumab deruxtecan (T-DXd) demonstrates meaningful activity in HER2-mutated non–small cell lung cancer (NSCLC), with DESTINY-Lung02 showing response rates of approximately 50% to 56% and durable responses.
  • HER2 expression is becoming an increasingly important biomarker across tumor types, with data from breast cancer studies such as DESTINY-Breast04 and -06 highlighting the efficacy of T-DXd in HER2-low and HER2-ultralow disease through targeted chemotherapy delivery.
  • Comprehensive biomarker testing is essential to optimize HER2-directed therapy, including up-front NGS, HER2 assessment, and multidisciplinary collaboration.

In this Clinical Insights segment, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, were joined by Charu Aggarwal, MD, MPH, of Penn Medicine; Samuel Caughron, MD, of MAWD Pathology Group; and Paolo Tarantino, MD, of Dana-Farber Cancer Institute. The panel discussed the evolving role of T-DXd across HER2-driven cancers, including HER2-mutated and HER2-expressing NSCLC.

Dr. Aggarwal opened by highlighting data from the DESTINY-Lung02 trial evaluating T-DXd in patients with HER2-mutated NSCLC who had progressed after prior therapies. In the phase 2 study, T-DXd demonstrated response rates of approximately 50% to 56% across evaluated dose cohorts, with median progression-free survival and duration of response approaching 1 year. While both dosing strategies showed efficacy, the 5.4-mg/kg dose was associated with improved tolerability and lower rates of interstitial lung disease (ILD), supporting its use as the approved dose in the HER2-mutated NSCLC setting. The panel also discussed the potential role of T-DXd across HER2-overexpressing disease.

The experts emphasized the importance of comprehensive biomarker testing to identify patients who may benefit from HER2-directed therapies. The panel emphasized the role of pathologists and multidisciplinary teams in ensuring timely testing, including next-generation sequencing, HER2 immunohistochemistry, and reassessment after disease progression when appropriate. They concluded the session by reviewing key safety considerations, including proactive monitoring and management of ILD, nausea, fatigue, neutropenia, and cardiotoxicity.