Background
Phase III, multicenter, open-label RCT. 524 patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Patients with stable, treated brain metastases were eligible.
Interventions and follow up
Arm A: Trastuzumab deruxtecan (T-DXd) 5.4 mg/kg IV q3wk
Arm B: Trastuzumab emtansine (T-DM1) 3.6 mg/kg IV q3wk
Primary endpoint: Progression-free survival (PFS) by blinded independent review
mFollow up: 16 months
Arm B: Trastuzumab emtansine (T-DM1) 3.6 mg/kg IV q3wk
Primary endpoint: Progression-free survival (PFS) by blinded independent review
mFollow up: 16 months
Results
mPFS: 25.1mo vs 7.2mo (A vs B), HR 0.28, 95% CI 0.22–0.37, P<.001
12-mo PFS: 75.8% vs 34.1%
12-mo OS: 94.1% vs 85.9%, HR 0.55, 95% CI 0.36–0.86; prespecified significance boundary not crossed
ORR: 79.7% vs 34.2%
12-mo PFS: 75.8% vs 34.1%
12-mo OS: 94.1% vs 85.9%, HR 0.55, 95% CI 0.36–0.86; prespecified significance boundary not crossed
ORR: 79.7% vs 34.2%
Adverse events
Overall (grade ≥3): 45.1% vs 39.8% (A vs B)
Hematologic (any grade): Neutropenia 42.8% vs 11.1%, anemia 30.4% vs 14.2%, leukopenia 30.0% vs 7.7%
Gastrointestinal (any grade): Nausea 72.8% vs 29.5%, vomiting 44.0% vs 5.7%
Constitutional/other (any grade): Fatigue 44.7% vs 29.5%, alopecia 36.2% vs 2.3%
Pulmonary: Adjudicated interstitial lung disease/pneumonitis 10.5% with T-DXd, no grade 4–5 events
Hematologic (any grade): Neutropenia 42.8% vs 11.1%, anemia 30.4% vs 14.2%, leukopenia 30.0% vs 7.7%
Gastrointestinal (any grade): Nausea 72.8% vs 29.5%, vomiting 44.0% vs 5.7%
Constitutional/other (any grade): Fatigue 44.7% vs 29.5%, alopecia 36.2% vs 2.3%
Pulmonary: Adjudicated interstitial lung disease/pneumonitis 10.5% with T-DXd, no grade 4–5 events
Conclusions
In HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, trastuzumab deruxtecan markedly reduced the risk of progression or death versus trastuzumab emtansine, establishing T-DXd as the preferred second-line standard.
Key Limitations
Open-label design introduces potential assessment bias, partly mitigated by blinded independent PFS review. OS data immature at this analysis (boundary not crossed). Interstitial lung disease remains a class concern (10.5% adjudicated) requiring monitoring. Higher rates of nausea, alopecia, and myelosuppression with T-DXd affect tolerability and quality of life.
Clinical Context
DESTINY-Breast03 moved T-DXd from later lines into the second line, displacing T-DM1 as standard of care after trastuzumab/taxane. FDA broadened approval (2022); ESMO and ASCO guidelines endorse T-DXd as preferred second-line therapy. Updated analyses confirmed an OS benefit. ILD monitoring per label.