Early observations and pilot data that first suggested a new direction
The concept of antibody-drug conjugates (ADCs) — monoclonal antibodies linked to potent cytotoxic payloads, delivering chemotherapy directly to tumour cells — faced decades of setbacks due to linker instability, limited payload potency, and narrow therapeutic windows. The first ADC success in solid tumours came with ado-trastuzumab emtansine (T-DM1), targeting HER2-positive breast cancer.
Landmark RCTs and pivotal trials that established the evidence base
Trastuzumab deruxtecan (T-DXd), a next-generation ADC with a cleavable linker and topoisomerase I payload, transformed the field. DESTINY-Breast03 showed T-DXd was vastly superior to T-DM1 in HER2-positive metastatic breast cancer (HR 0.28 for PFS). DESTINY-Breast04 then redefined HER2 biology entirely by demonstrating efficacy in HER2-low breast cancer — a previously untreatable population — effectively creating a new therapeutic category.
Follow-up studies, subgroup analyses, and real-world validation
ADCs expanded beyond breast cancer and HER2. TROPiCS-02 (2022) demonstrated sacituzumab govitecan (targeting Trop-2) in HR-positive/HER2-negative breast cancer. Enfortumab vedotin (targeting Nectin-4) combined with pembrolizumab became standard first-line therapy in advanced urothelial carcinoma (EV-302). The number of ADCs in clinical development exceeded 200 by 2025, targeting diverse antigens across solid and haematologic malignancies.
Integration into clinical practice guidelines and recommendations
ASCO/CAP updated HER2 testing guidelines to include a HER2-low category (IHC 1+ or IHC 2+/ISH-negative), directly driven by DESTINY-Breast04 results. NCCN guidelines incorporated T-DXd as a preferred option in HER2-positive and HER2-low breast cancer, and sacituzumab govitecan for triple-negative and HR+/HER2- disease.
ASCO/CAP HER2 Testing Update
HER2-low category added to pathology reporting; T-DXd indicated for HER2-low breast cancer
NCCN Breast Cancer Guidelines
T-DXd preferred for HER2+ (after pertuzumab) and HER2-low metastatic breast cancer
Now
Current standard of care and ongoing research directions
ADCs have become one of the fastest-growing drug classes in oncology, with over 200 in clinical development. T-DXd redefined how HER2 status is understood and treated. Current research explores ADC combinations with checkpoint inhibitors, novel targets in NSCLC and colorectal cancer, bispecific ADCs, and strategies to manage interstitial lung disease — the most significant class toxicity.
ADCs are monoclonal antibodies linked to potent cytotoxic drugs via a chemical linker. The antibody delivers the chemotherapy payload directly to tumour cells expressing the target antigen, like a guided missile. This achieves high intra-tumoural drug concentrations while reducing systemic toxicity.
What is HER2-low breast cancer and why does it matter?+
HER2-low refers to breast cancers with low levels of HER2 protein (IHC 1+ or IHC 2+/ISH-negative) — previously considered HER2-negative. DESTINY-Breast04 showed trastuzumab deruxtecan is effective in this group, creating an entirely new treatment category for roughly 50% of breast cancers.
