DESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer
A newer antibody-drug conjugate, trastuzumab deruxtecan, kept HER2-positive metastatic breast cancer under control roughly four times longer than the previous standard, T-DM1, and later lengthened survival.
Open-label phase 3 trial of 524 patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, randomised 1:1 to trastuzumab deruxtecan (T-DXd, 5.4 mg/kg) or trastuzumab emtansine (T-DM1). Primary endpoint was progression-free survival by blinded independent central review.
At the interim analysis, 12-month PFS was 75.8% vs 34.1% (HR 0.28). The 2023 update reported median PFS 28.8 vs 6.8 months and a significant overall survival benefit (HR 0.64). It moved T-DXd into the second line and is the clearest head-to-head demonstration that ADC design (payload, drug-to-antibody ratio, bystander effect) determines clinical outcome.
- 12-month progression-free survival 75.8% with T-DXd vs 34.1% with T-DM1; HR 0.28 (95% CI 0.22-0.37).
- Confirmed objective response 79.7% vs 34.2%.
- Updated analysis (Lancet 2023): median PFS 28.8 vs 6.8 months; overall survival HR 0.64.
- Drug-related interstitial lung disease/pneumonitis in roughly one in ten T-DXd patients, mostly low grade, with no grade 4-5 events in the primary report.
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.
- Open-label design, though the primary endpoint was assessed by blinded central review.
- Interstitial lung disease requires proactive CT surveillance and dose interruption; fatal cases occurred in other T-DXd trials.
- Many patients had not received pertuzumab-based first-line therapy, so the population differs slightly from today's second line.
- What to give after T-DXd, and whether a TOP1-payload ADC can follow another, remains unresolved.
Pages like this
not linked directly; found by shared links- Key paperDESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group
Shares Sung-Bae Kim, Yeon Hee Park, Seock-Ah Im, Binghe Xu.
- Key paperTROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survival
Shares Seock-Ah Im, Binghe Xu, Payload-class switching as the rule for ADC sequencing, ADC sequencing.
- Key paperDESTINY-Breast06: trastuzumab deruxtecan before any chemotherapy in hormone-receptor-positive, HER2-low or ultralow breast cancer
Shares Giuseppe Curigliano, Seock-Ah Im, Interstitial lung disease (ILD) / pneumonitis, Daiichi Sankyo.
- IdeaDose and schedule optimisation trials specific to antibody-drug conjugates
Shares Drug-to-antibody ratio (DAR), Interstitial lung disease (ILD) / pneumonitis, Payload (ADC), Trastuzumab deruxtecan.
- IdeaUse SLFN11 status to decide which antibody-drug payload to give next
Shares Payload-class switching as the rule for ADC sequencing, ADC sequencing, Payload (ADC), Topoisomerase-I inhibitors (and ADC payloads).
- Key paperASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancer
Shares Sara A. Hurvitz, Javier Cortés, Payload (ADC), Topoisomerase-I inhibitors (and ADC payloads).
- TermDXd
Shares Bystander effect (ADC), Interstitial lung disease (ILD) / pneumonitis, Payload (ADC), Topoisomerase-I inhibitors (and ADC payloads).
- PathwayDrug efflux pumps (ABC transporters)
Shares Bystander effect (ADC), ADC sequencing, Payload (ADC), Topoisomerase-I inhibitors (and ADC payloads).