HER2 Testing and Treatment / NSCLC 07/23/2026

Ep. 2: T-DXd Expands Treatment Opportunities for HER2-Positive 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

  • DESTINY-Lung02 demonstrated durable responses with trastuzumab deruxtecan (T-DXd) in previously treated HER2-mutant non-small cell lung cancer (NSCLC), with the 5.4-mg/kg dose offering improved tolerability.
  • HER2 protein overexpression remains an actionable biomarker, with T-DXd providing meaningful activity beyond HER2-mutant disease.
  • Antibody-drug conjugates (ADCs) have expanded HER2-directed therapy into HER2-low and HER2-ultralow tumors through targeted chemotherapy delivery.

During a recent Clinical Insights discussion, 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 T-DXd’s expanding role in HER2-positive NSCLC. The panel reviewed the clinical evidence supporting T-DXd in both HER2-mutant and HER2-overexpressing disease, highlighting efficacy data, dosing considerations, and biologic rationale for HER2-targeted ADCs.

Dr. Aggarwal reviewed results from the phase 2 DESTINY-Lung02 trial, which evaluated T-DXd at doses of 5.4 and 6.4 mg/kg in patients with previously treated HER2-mutant NSCLC. Both dosing cohorts demonstrated objective response rates of approximately 50% to 56%, with complete response rates ranging from 3% to 8%, while both median progression-free survival and duration of response approached 1 year. 

Although efficacy was comparable between the 2 dose levels, the lower dose produced a more favorable safety profile, particularly with respect to interstitial lung disease (ILD). ILD occurred in approximately 15% of patients receiving 5.4 mg/kg compared with 32% of those treated with 6.4 mg/kg, with most events at the lower dose limited to grade 1 or 2 severity. Dr. Aggarwal noted that, based on these findings, the approved 5.4-mg/kg dose has become her standard approach in clinical practice. She emphasized that prompt recognition and management of ILD remain essential when treating patients with ADCs.

The discussion also explored T-DXd in HER2-overexpressing disease, in which the agent has demonstrated clinically meaningful activity despite lower response rates than those observed in HER2-mutant NSCLC. Dr. Aggarwal explained that patients meeting gastric HER2 3+ criteria have achieved response rates of approximately 25%, comparing favorably with conventional second- and third-line chemotherapy options such as docetaxel. She emphasized that HER2 overexpression should not be overlooked as an actionable biomarker, particularly as comprehensive molecular and protein testing becomes increasingly integrated into routine care. 

Dr. Tarantino placed these findings into the broader context of HER2-targeted therapy, describing how ADCs have transformed the treatment landscape beyond traditional HER2-amplified breast cancer. He explained that T-DXd combines trastuzumab with a potent topoisomerase I inhibitor through a cleavable linker, allowing chemotherapy to be delivered directly to HER2-expressing tumor cells while also generating a bystander effect within the tumor microenvironment. 

The panel discussed how HER2-directed ADCs have fundamentally changed the understanding of HER2 as a therapeutic target, with activity extending beyond HER2-positive disease to HER2-low and HER2-ultralow tumors across multiple solid malignancies.