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.

EMILIA2012Landmark

PFS: 9.6 vs 6.4 months (HR 0.65, p<0.001); OS: 30.9 vs 25.1 months (HR 0.68, p<0.001)

New England journal of medicineRCTN=991

Proof

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.

DESTINY-Breast032022Landmark

PFS: HR 0.28 (95% CI 0.22–0.37); 12-month PFS: 75.8% vs 34.1%

New England journal of medicineRCTN=524

DESTINY-Breast042022Landmark

PFS: HR 0.50 (95% CI 0.40–0.63) in HER2-low; OS: HR 0.64 (0.49–0.84)

New England journal of medicineRCTN=557

Extension

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.

TROPiCS-022023Landmark

OS: HR 0.79 (95% CI 0.65–0.96), p=0.02; PFS: HR 0.66 (0.53–0.83)

LancetRCTN=543

Guidelines

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.

Landmark Trials in This Story

EMILIA2012Landmark

Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer

PFS: 9.6 vs 6.4 months (HR 0.65, p<0.001); OS: 30.9 vs 25.1 months (HR 0.68, p<0.001)

New England journal of medicineRCTN=991

DESTINY-Breast032022Landmark

Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer

PFS: HR 0.28 (95% CI 0.22–0.37); 12-month PFS: 75.8% vs 34.1%

New England journal of medicineRCTN=524

DESTINY-Breast042022Landmark

Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer

PFS: HR 0.50 (95% CI 0.40–0.63) in HER2-low; OS: HR 0.64 (0.49–0.84)

New England journal of medicineRCTN=557

TROPiCS-022023Landmark

Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial

OS: HR 0.79 (95% CI 0.65–0.96), p=0.02; PFS: HR 0.66 (0.53–0.83)

LancetRCTN=543

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Frequently Asked Questions

What are antibody-drug conjugates?+

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.