HER2 Testing and Treatment / NSCLC 07/25/2026

Ep. 3: Clinical Insights: The Evolving Role of T-DXd in HER2-Mutated and HER2-Expressing Cancers

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

  • HER2-directed therapies are evolving beyond HER2 mutations, with emerging interest in HER2 expression as a potential therapeutic target.
  • Comprehensive biomarker testing, including next-generation sequencing (NGS) and HER2 protein expression analysis, is critical to identify appropriate treatment options.
  • Data from breast cancer trials such as DESTINY-Breast04 and -06 continue to inform future HER2-directed strategies across tumor types.

In this Clinical Insights discussion 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, to discuss the evolving role of HER2-directed therapies across solid tumors. The panel explored emerging data on trastuzumab deruxtecan (T-DXd), HER2 biomarker classification, and the importance of comprehensive testing strategies in patients with non–small cell lung cancer (NSCLC).

Dr. Aggarwal explained that while HER2-targeted therapies are established for selected HER2 alterations, research continues to evaluate broader HER2 expression categories. The panel also emphasized the distinction between HER2 mutations and protein expression, noting that therapies such as zongertinib and sevabertinib are designed specifically for HER2-mutated NSCLC and should not be used based solely on HER2 expression.

The discussion also highlighted the importance of repeat biomarker testing throughout treatment. Dr. Caughron noted that while untreated primary and metastatic tumors generally demonstrate similar biology, treatment pressure can alter tumor characteristics over time. For patients with disease progression, repeat testing through liquid biopsy or tissue rebiopsy may provide valuable information about resistance mechanisms and help guide subsequent therapy decisions. The panel stressed that comprehensive up-front testing, including NGS, PD-L1 evaluation, and HER2 assessment, is critical to avoid missing actionable alterations that may influence treatment options later in the disease course.

Dr. Tarantino reviewed the impact of T-DXd in HER2-low and HER2-ultralow breast cancer. In DESTINY-Breast04, T-DXd improved progression-free survival (PFS), response rates, and overall survival compared with chemotherapy in previously treated HER2-low metastatic breast cancer. More recently, DESTINY-Breast06 demonstrated improved PFS with T-DXd compared with chemotherapy in patients with hormone receptor–positive metastatic breast cancer after endocrine therapy.