Background
Phase III, open-label RCT. 608 patients with HER2+ unresectable or metastatic breast cancer previously treated with T-DM1 and trastuzumab (i.e., 2+ prior lines of anti-HER2 therapy). T-DXd evaluated as third-line+ option vs standard chemotherapy (capecitabine + lapatinib or capecitabine + trastuzumab).
Interventions and follow up
Arm A: T-DXd (trastuzumab deruxtecan) 5.4mg/kg IV q21d
Arm B: Treatment of physician's choice (TPC): capecitabine + lapatinib or capecitabine + trastuzuma
Primary endpoint: Progression-free survival (PFS)
mFollow up: 21.5 month
Arm B: Treatment of physician's choice (TPC): capecitabine + lapatinib or capecitabine + trastuzuma
Primary endpoint: Progression-free survival (PFS)
mFollow up: 21.5 month
Results
PFS: 17.8 vs 6.9mo, HR 0.36, 95% CI 0.28–0.45, P<.001
OS: 39.2 vs 26.5mo, HR 0.66, 95% CI 0.50–0.86, P=.001
ORR: 69.7% vs 29.2%
OS: 39.2 vs 26.5mo, HR 0.66, 95% CI 0.50–0.86, P=.001
ORR: 69.7% vs 29.2%
Adverse events
Pulmonary: ILD any grade 10.4% (T-DXd) vs 0.3% (TPC); grade ≥3 2.0%
Gastrointestinal: Grade ≥3 nausea 7.3%
Hematologic: Grade ≥3 neutropenia 12.6%
Dermatologic: Alopecia any grade 37.7%
Overall: Discontinuation 20.7%
Gastrointestinal: Grade ≥3 nausea 7.3%
Hematologic: Grade ≥3 neutropenia 12.6%
Dermatologic: Alopecia any grade 37.7%
Overall: Discontinuation 20.7%
Conclusions
T-DXd significantly improved PFS (HR 0.36) and OS (~13-month gain) vs chemotherapy in HER2+ mBC after T-DM1 treatment. DESTINY-Breast02 confirmed T-DXd's robust anti-tumor activity in heavily pretreated HER2+ disease and supported its approval in the third-line+ setting.
Key Limitations
Key Limitations: ILD risk (10.4% any-grade) remains a consistent safety concern across all T-DXd trials; mandatory monitoring and prompt intervention are required. The comparator arm included lapatinib-based regimens that are now rarely used, potentially favoring T-DXd vs more modern salvage options. By the time DB02 was published, DB03 had already established T-DXd as second-line standard, meaning this trial primarily applies to patients who received T-DXd at second line and progressed — a scenario not well-addressed by current data.
Clinical Context
T-DXd received FDA approval for HER2+ mBC after ≥1 prior anti-HER2-based regimen based on DESTINY-Breast01 (phase II) and later supported by DB02 OS data. ESMO-MCBS score: 5. In current practice, after DB03 established T-DXd as second-line, DB02 is most relevant for patients who have progressed on second-line T-DXd and require retreatment or rechallenge discussions (unlikely) or for rare patients with T-DM1 first-line exposure in early BC (KATHERINE) who then receive T-DXd in metastatic relapse.
References
References: André F et al, Lancet 2023