Background
Phase III, open-label RCT. 866 patients with HR+/HER2-expressible (HER2-low: IHC 1+ or 2+ ISH–, n=713; or HER2-ultralow: IHC >0 and <1+, n=153) unresectable or metastatic BC who had received 1–2 prior lines of endocrine therapy but no prior chemotherapy for metastatic disease (chemotherapy-naïve advanced setting). Builds on DESTINY-Breast04 by extending T-DXd to earlier lines and HER2-ultralow tumors.
Interventions and follow up
Arm A: T-DXd (trastuzumab deruxtecan) 5.4mg/kg IV q21d
Arm B: Investigator's choice endocrine therapy (fulvestrant or aromatase inhibitor)
Primary endpoint: PFS in HER2-low patient
mFollow up: 18.6 month
Arm B: Investigator's choice endocrine therapy (fulvestrant or aromatase inhibitor)
Primary endpoint: PFS in HER2-low patient
mFollow up: 18.6 month
Results
PFS (HER2-low): 13.2 vs 8.1mo, HR 0.62, 95% CI 0.51–0.74, P<.001
OS (HER2-low): Not mature; directionally favorable
PFS (HER2-ultralow, exploratory): 13.2 vs 8.3mo, HR 0.78, 95% CI 0.50–1.21
ORR (HER2-low): 56.5% vs 32.3%
OS (HER2-low): Not mature; directionally favorable
PFS (HER2-ultralow, exploratory): 13.2 vs 8.3mo, HR 0.78, 95% CI 0.50–1.21
ORR (HER2-low): 56.5% vs 32.3%
Adverse events
Pulmonary: ILD any grade 11.3% (grade ≥3 1.0%; grade 5 0.3%)
Gastrointestinal: Nausea any grade 68.0% (grade ≥3 3.7%)
Hematologic: Neutropenia grade ≥3 19.5%
Dermatologic: Alopecia 40.1%
Overall: Grade ≥3 AEs 39.3% vs 13.7%; discontinuation 13.8%
Gastrointestinal: Nausea any grade 68.0% (grade ≥3 3.7%)
Hematologic: Neutropenia grade ≥3 19.5%
Dermatologic: Alopecia 40.1%
Overall: Grade ≥3 AEs 39.3% vs 13.7%; discontinuation 13.8%
Conclusions
T-DXd significantly improved PFS vs endocrine therapy as post-endocrine-therapy treatment in HER2-low HR+ mBC, supporting earlier-line use of T-DXd and further expanding its role in the HER2-low population. HER2-ultralow results were exploratory and numerically positive but not statistically significant.
Key Limitations
Key Limitations: OS data immature at primary analysis — PFS as primary endpoint requires validation for survival benefit. ILD risk (11.3% any-grade) requires vigilant monitoring and must be weighed against PFS benefit, particularly in patients with pre-existing pulmonary disease. HER2-ultralow results are hypothesis-generating only — the subgroup was small and not powered for definitive conclusions. Comparison to endocrine therapy (rather than chemotherapy as in DB04) favors T-DXd more readily given ET's lower ORR. Optimal sequencing with CDK4/6 inhibitors and PI3K/AKT agents in earlier lines remains to be defined.
Clinical Context
DESTINY-Breast06 further solidifies T-DXd as a treatment option in HR+/HER2-low mBC after prior endocrine therapy, FDA approved 2024 in chemotherapy-naïve advanced setting. Alongside DB04, these results have fundamentally reshaped HER2 testing in breast cancer. HER2-ultralow designation (IHC >0 and <1+) may eventually become a clinically actionable category pending further data. ESMO-MCBS score pending final OS data.
References
References: Curigliano G et al, NEJM 2024