OncoMatch/Clinical Trials/Trastuzumab Deruxtecan

Trastuzumab Deruxtecan (Enhertu) Clinical Trials

Trastuzumab deruxtecan (Enhertu, T-DXd, DS-8201) is a HER2-directed antibody-drug conjugate consisting of a trastuzumab antibody linked to a topoisomerase I inhibitor payload, with a high drug-to-antibody ratio of approximately 8 and a bystander-effect mechanism that enables activity in tumors with heterogeneous HER2 expression. It has received multiple FDA approvals across tumor types: HER2-positive breast cancer (DESTINY-Breast03, superior to T-DM1 second-line), HER2-low breast cancer (DESTINY-Breast04, first approved therapy for HER2-low), HER2-mutant NSCLC (DESTINY-Lung02), HER2-positive gastric/GEJ cancer (DESTINY-Gastric01/02), and HER2-positive IHC 3+ unresectable or metastatic solid tumors after prior systemic therapy (2024 tumor-agnostic accelerated approval). In NSCLC specifically, eligibility requires a confirmed HER2-activating mutation — not merely HER2 overexpression by IHC — making mutation testing essential and distinct from breast or gastric indications where IHC/ISH drives eligibility. T-DXd has expanded into early-stage HER2-positive breast cancer, with May 2026 FDA approvals for neoadjuvant use (T-DXd followed by THP for stage II/III disease, DESTINY-Breast11) and adjuvant use (for patients with residual invasive disease after neoadjuvant treatment, DESTINY-Breast05); FDA approval for HR-positive, metastatic HER2-low or HER2-ultralow breast cancer after endocrine therapy progression was granted in January 2025, based on DESTINY-Breast06. Ongoing trials continue exploring additional combinations and sequencing strategies. Patients with pre-existing interstitial lung disease are typically excluded from T-DXd trials due to a known risk of treatment-related ILD/pneumonitis.