Background
Phase III, open-label RCT. 557 patients with HER2-low metastatic breast cancer (IHC 1+, or IHC 2+/ISH-negative) who had received 1–2 prior chemotherapy lines, randomized 2:1. ~89% hormone-receptor positive. Median prior therapy lines ~3 (range 1–8), with ≥3 lines in ~60%.
Interventions and follow up
Arm A: Trastuzumab deruxtecan (T-DXd) 5.4 mg/kg IV q3wk
Arm B: Physician's choice chemotherapy (eribulin 51.1%, capecitabine 20.1%, nab-paclitaxel 10.3%, gemcitabine 10.3%, paclitaxel 8.2%)
Primary endpoint: Progression-free survival (PFS) in the hormone-receptor-positive cohort
mFollow up: 18.4 months
Arm B: Physician's choice chemotherapy (eribulin 51.1%, capecitabine 20.1%, nab-paclitaxel 10.3%, gemcitabine 10.3%, paclitaxel 8.2%)
Primary endpoint: Progression-free survival (PFS) in the hormone-receptor-positive cohort
mFollow up: 18.4 months
Results
mPFS (HR+): 10.1mo vs 5.4mo (A vs B), HR 0.51, 95% CI 0.40–0.64, P<.001
mPFS (all patients): 9.9mo vs 5.1mo, HR 0.50, 95% CI 0.40–0.63, P<.001
mOS (HR+): 23.9mo vs 17.5mo, HR 0.64, 95% CI 0.48–0.86, P=.003
mOS (all patients): 23.4mo vs 16.8mo, HR 0.64, 95% CI 0.49–0.84, P<.001
mPFS (all patients): 9.9mo vs 5.1mo, HR 0.50, 95% CI 0.40–0.63, P<.001
mOS (HR+): 23.9mo vs 17.5mo, HR 0.64, 95% CI 0.48–0.86, P=.003
mOS (all patients): 23.4mo vs 16.8mo, HR 0.64, 95% CI 0.49–0.84, P<.001
Adverse events
Hematologic (grade ≥3): Neutropenia 13.7% vs 40.7% (A vs B), anemia 8.1% vs 4.7%, leukopenia 6.5% vs 19.2%, thrombocytopenia 5.1% vs 0.6%
Gastrointestinal (grade ≥3): Nausea 4.6% vs 0
Hepatic (grade ≥3): Increased aminotransferases 3.2% vs 8.1%
Constitutional (grade ≥3): Fatigue 7.5% vs 4.7%
Pulmonary: Adjudicated interstitial lung disease/pneumonitis 12.1% with T-DXd (grade 5 in 0.8%)
Gastrointestinal (grade ≥3): Nausea 4.6% vs 0
Hepatic (grade ≥3): Increased aminotransferases 3.2% vs 8.1%
Constitutional (grade ≥3): Fatigue 7.5% vs 4.7%
Pulmonary: Adjudicated interstitial lung disease/pneumonitis 12.1% with T-DXd (grade 5 in 0.8%)
Conclusions
In HER2-low metastatic breast cancer, trastuzumab deruxtecan significantly prolonged progression-free and overall survival versus physician's choice chemotherapy, establishing HER2-low as a clinically actionable category and a new treatment standard.
Key Limitations
HER2-low IHC scoring (1+ vs 2+/ISH-) has limited interobserver reproducibility, complicating patient selection. Predominantly HR+ population; only ~58 HR-negative patients limit conclusions in that subgroup. Open-label design. Interstitial lung disease (12.1% adjudicated, including fatal events) is an ongoing class safety concern requiring monitoring.
Clinical Context
DESTINY-Breast04 created the HER2-low therapeutic category; FDA approved T-DXd for HER2-low (IHC 1+ or 2+/ISH-) unresectable/metastatic breast cancer (Aug 2022) after prior chemotherapy. ESMO and ASCO guidelines incorporate T-DXd for HER2-low mBC after ≥1 prior chemotherapy line (HR+ disease typically after endocrine-based therapy). ILD monitoring per label.
References