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The head-to-head ADC trial where Enhertu beat Kadcyla by a wide margin, showing that payload and bystander effect matter.
DESTINY-Breast03, trial NCT03529110 sponsored by Daiichi Sankyo and AstraZeneca and reported in 2021, was the head-to-head antibody-drug conjugate trial in which trastuzumab deruxtecan beat trastuzumab emtansine by a wide margin in HER2-positive metastatic breast cancer after trastuzumab and a taxane, showing that payload and bystander effect matter. It randomised 524 patients, met its primary progression-free survival endpoint by blinded review with a very large effect and a much higher response rate, and showed an overall survival benefit, redefining second-line HER2-positive therapy and validating the DXd platform. OnCo links it to HER2-positive breast cancer, both drugs, Ian E. Krop, Javier Cortés, Sara A. Hurvitz, Sung-Bae Kim, Vall d'Hebron, the ADC roadmap and the DESTINY-Breast03 and KATHERINE papers. Whether T-DM1 retains any role after this result is the open question.
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
524 enrolled.
Step lines join published landmark estimates; the true curve between them is not shown.
Curves show the trial population; they are not a prediction for any one person.
12-month rates from the primary NEJM report (blinded independent review); medians from the 2023 Lancet update.
| Endpoint | Arm | n | Value | HR (95% CI) | p | Source |
|---|---|---|---|---|---|---|
| Progression-free survival (BICR)primary | Trastuzumab deruxtecan | 261 | 28.8 months | 0.33 (0.26 to 0.43) | <0.0001 | link |
| Trastuzumab emtansine | 263 | 6.8 months | ||||
| Overall survival | Trastuzumab deruxtecan | - | 52.6 months | 0.73 (0.56 to 0.94) | - | link |
| Trastuzumab emtansine | - | 42.7 months | ||||
| Objective response rate | Trastuzumab deruxtecan | - | 78.5% | - | - | link |
| Trastuzumab emtansine | - | 35% |
A second publication from the DESTINY-Breast03 trial, later than the first and described in its title as an update or longer-term analysis. Read it with the primary publication linked from the trial page; the record was linked automatically and its figures have not been checked by hand.
For HER2-positive metastatic breast cancer that has progressed after trastuzumab and a taxane, trastuzumab deruxtecan is now the standard second-line treatment and T-DM1 has moved later in the sequence. The benefit is large enough that ADC design, not just the target, is understood to be what matters. Patients need lung monitoring because of the risk of pneumonitis.
HER2-positive breast cancer is now routinely treated before surgery so that the pathology result can guide what comes after: patients with no residual cancer continue trastuzumab (with or without pertuzumab), while those with residual disease switch to T-DM1. This model of using the tumour's response as a test has since been copied in triple-negative and other cancers.
Shares Javier Cortés, Vall d'Hebron University Hospital / VHIO, Daiichi Sankyo, Trastuzumab deruxtecan.
Shares KATHERINE: switching to T-DM1 when HER2-positive breast cancer survives pre-surgery treatment, Daiichi Sankyo, Trastuzumab deruxtecan, Topoisomerase-I inhibitors (and ADC payloads).
Shares HER2-positive breast cancer with brain metastases, Daiichi Sankyo, Trastuzumab deruxtecan, Topoisomerase-I inhibitors (and ADC payloads).
Shares Trastuzumab emtansine, Daiichi Sankyo, Trastuzumab deruxtecan, Topoisomerase-I inhibitors (and ADC payloads).
Shares Daiichi Sankyo, Trastuzumab deruxtecan, Topoisomerase-I inhibitors (and ADC payloads), AstraZeneca.
Shares Daiichi Sankyo, Trastuzumab deruxtecan, Topoisomerase-I inhibitors (and ADC payloads), AstraZeneca.
Shares Daiichi Sankyo, Trastuzumab deruxtecan, Topoisomerase-I inhibitors (and ADC payloads), AstraZeneca.
Shares HER2-positive breast cancer with brain metastases, Trastuzumab deruxtecan, Topoisomerase-I inhibitors (and ADC payloads), HER2-positive breast cancer.