{"entity":{"id":"destiny-breast04","kind":"trial","name":"DESTINY-Breast04","aka":[],"tldr":"Created a new category of breast cancer, HER2-low, by showing Enhertu works in tumours previously called HER2-negative.","summary":"DESTINY-Breast04, trial NCT03734029 sponsored by Daiichi Sankyo and AstraZeneca and published in the New England Journal of Medicine in 2022, created a new category of breast cancer, HER2-low, by showing that trastuzumab deruxtecan works in tumours previously called HER2-negative after chemotherapy. It randomised 557 patients to trastuzumab deruxtecan or chemotherapy, met its primary progression-free survival endpoint in the HR-positive cohort and showed an overall survival benefit in all patients, with an exploratory HR-negative cohort pointing the same way, and it drew a standing ovation at ASCO 2022 as roughly half of all breast cancers became eligible for a HER2-directed drug. Whether pathologists can score HER2-low reproducibly is the open question.","status":"positive","asOf":"2026-09-04","links":[{"label":"ClinicalTrials.gov NCT03734029","url":"https://clinicaltrials.gov/study/NCT03734029"},{"label":"DESTINY-Breast04 long-term survival (Nature Medicine 2025)","url":"https://doi.org/10.1038/s41591-025-03981-4"},{"label":"NICE TA992 (29 July 2024): not recommended","url":"https://www.nice.org.uk/guidance/ta992"}],"tags":[],"related":[],"cancers":["breast-hr-positive","tnbc","her2-low-metastatic-breast-cancer","tnbc-metastatic"],"sections":[],"technologies":["adc","topoisomerase-inhibitors"],"targets":[],"drugs":["trastuzumab-deruxtecan"],"companies":["daiichi-sankyo","astrazeneca"],"institutions":[],"pathways":[],"terms":["her2-low"],"trials":[],"people":["shanu-modi"],"bottlenecks":[],"keyPapers":["paper-schettini-her2-low-features-npj-breast-cancer-2021","paper-destiny-breast04-nejm-2022","paper-destiny-breast04-nat-med-2025-update"],"journals":[],"dependsOn":[],"notes":["Triple-negative cohort: 63 of 557 patients (11.3 percent) were hormone-receptor-negative; median progression-free survival in that exploratory cohort 8.5 versus 2.9 months (hazard ratio 0.46) and overall survival favoured trastuzumab deruxtecan at the 32-month follow-up (Nature Medicine 2025: overall cohort 22.9 versus 16.8 months, hazard ratio 0.69). Interstitial lung disease 12.1 percent, 0.8 percent fatal. UK sites (registry, 7): Royal Cornwall Truro, Queen Mary University of London, University College London Hospitals, Royal Free, Western General Edinburgh, Nottingham City, Royal Surrey Guildford. England: NICE TA992 (29 July 2024) does not recommend the drug for HER2-low disease; rapid review GID-TA12551 in development."],"nct":"NCT03734029","phase":"3","setting":"HER2-low metastatic breast cancer after chemotherapy: T-DXd vs chemotherapy","sponsor":"Daiichi Sankyo / AstraZeneca","result":"OS HR 0.64.","started":"2018-12-27","startedType":"actual","yearReported":2022,"enrolled":557,"enrolledBasis":"registry","outcomes":[{"endpoint":"Progression-free survival, HR+ cohort (BICR)","primary":true,"unit":"months","arms":[{"name":"Trastuzumab deruxtecan","n":331,"value":10.1},{"name":"Chemotherapy (TPC)","n":163,"value":5.4}],"hr":0.51,"ci":[0.4,0.64],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2203690"},{"endpoint":"Overall survival, all patients","unit":"months","arms":[{"name":"Trastuzumab deruxtecan","n":373,"value":23.4},{"name":"Chemotherapy (TPC)","n":184,"value":16.8}],"hr":0.64,"ci":[0.49,0.84],"p":"0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2203690"},{"endpoint":"Progression-free survival, HR-negative (TNBC) cohort","unit":"months","arms":[{"name":"Trastuzumab deruxtecan","n":40,"value":8.5,"note":"Exploratory cohort"},{"name":"Chemotherapy (TPC)","n":18,"value":2.9}],"hr":0.46,"ci":[0.24,0.89],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2203690"}],"replication":"Confirmed and extended by DESTINY-Breast06 (HER2-low and ultralow, chemotherapy-naive) with a near-identical PFS hazard ratio."},"route":"/trials/destiny-breast04/","neighbours":{"cancer":[{"id":"her2-low-metastatic-breast-cancer","kind":"cancer","name":"HER2-low and HER2-ultralow metastatic breast cancer","route":"/cancers/her2-low-metastatic-breast-cancer/"},{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"tnbc-metastatic","kind":"cancer","name":"Metastatic triple-negative breast cancer","route":"/cancers/tnbc-metastatic/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"topoisomerase-inhibitors","kind":"technology","name":"Topoisomerase-I inhibitors (and ADC payloads)","route":"/technologies/topoisomerase-inhibitors/"}],"drug":[{"id":"eribulin","kind":"drug","name":"Eribulin","route":"/drugs/eribulin/"},{"id":"her2-testing-assays","kind":"drug","name":"HER2 IHC and ISH companion assays (HercepTest, PATHWAY 4B5, HER2 Dual ISH)","route":"/drugs/her2-testing-assays/"},{"id":"trastuzumab-deruxtecan","kind":"drug","name":"Trastuzumab deruxtecan","route":"/drugs/trastuzumab-deruxtecan/"}],"company":[{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/"},{"id":"daiichi-sankyo","kind":"company","name":"Daiichi Sankyo","route":"/companies/daiichi-sankyo/"}],"term":[{"id":"control-arm","kind":"term","name":"Control arm and comparator (investigator's choice)","route":"/terms/control-arm/"},{"id":"her2-low","kind":"term","name":"HER2-low and HER2-ultralow","route":"/terms/her2-low/"},{"id":"her2-low-and-trop2-adc-eligibility-tnbc","kind":"term","name":"HER2-low eligibility for trastuzumab deruxtecan, and TROP2 ADCs without a test (triple-negative disease)","route":"/terms/her2-low-and-trop2-adc-eligibility-tnbc/"},{"id":"tnbc-symptom-control-palliation","kind":"term","name":"Palliation in advanced triple-negative breast cancer: brain, bone, pleura, skin and end of life","route":"/terms/tnbc-symptom-control-palliation/"}],"person":[{"id":"shanu-modi","kind":"person","name":"Shanu Modi","route":"/people/shanu-modi/"}],"paper":[{"id":"paper-schettini-her2-low-features-npj-breast-cancer-2021","kind":"paper","name":"Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer","route":"/key-papers/paper-schettini-her2-low-features-npj-breast-cancer-2021/"},{"id":"paper-destiny-breast04-nejm-2022","kind":"paper","name":"DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group","route":"/key-papers/paper-destiny-breast04-nejm-2022/"},{"id":"paper-destiny-breast04-nat-med-2025-update","kind":"paper","name":"Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial","route":"/key-papers/paper-destiny-breast04-nat-med-2025-update/"}],"roadmap":[{"id":"adc-generations","kind":"roadmap","name":"ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs","route":"/roadmaps/adc-generations/"},{"id":"tnbc-history","kind":"roadmap","name":"TNBC roadmap: from 'nothing to target' to ADC + immunotherapy first line","route":"/roadmaps/tnbc-history/"},{"id":"tnbc-roadmap","kind":"roadmap","name":"Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem","route":"/roadmaps/tnbc-roadmap/"}],"idea":[{"id":"idea-tnbc-adc-sequencing-trial","kind":"idea","name":"A randomised trial of antibody-drug conjugate sequence in metastatic triple-negative breast cancer","route":"/ideas/idea-tnbc-adc-sequencing-trial/"},{"id":"idea-ai-her2-low-scoring","kind":"idea","name":"AI quantification of HER2-low and HER2-ultralow","route":"/ideas/idea-ai-her2-low-scoring/"},{"id":"idea-tr2-her2-low-reference-materials","kind":"idea","name":"Calibrated reference slides so every lab scores HER2-low the same way","route":"/ideas/idea-tr2-her2-low-reference-materials/"},{"id":"idea-tnbc-her2-ultralow-testing-uptake","kind":"idea","name":"Reflex re-scoring of HER2 0 versus 1+ with digital assistance so every eligible triple-negative patient reaches trastuzumab deruxtecan","route":"/ideas/idea-tnbc-her2-ultralow-testing-uptake/"}],"pairing":[{"id":"her2-low-to-tdxd","kind":"pairing","name":"HER2-low scoring → T-DXd","route":"/pairings/her2-low-to-tdxd/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"}]}}