Background
Phase III, open-label RCT. N=557 unresectable/metastatic HER2-low breast cancer (IHC 1+ or 2+/ISH-) with 1–2 prior chemotherapy lines for advanced disease. HR+ (n=494) and HR- (n=63); primary endpoint in HR+ cohort. T-DXd (trastuzumab deruxtecan) is an anti-HER2 ADC with a topoisomerase I inhibitor payload and high drug-to-antibody ratio.
Interventions and follow up
Arm A: T-DXd (trastuzumab deruxtecan) 5.4mg/kg IV q21d
Arm B: Physician's choice chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel)
Primary endpoint: PFS in HR+ patients
mFollow up: 18.4 months
Arm B: Physician's choice chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel)
Primary endpoint: PFS in HR+ patients
mFollow up: 18.4 months
Results
PFS (HR+): 10.1 vs 5.4mo, HR 0.51, 95% CI 0.40–0.64, P<.001
OS (HR+): 23.9 vs 17.5mo, HR 0.64, 95% CI 0.48–0.86, P=.003
PFS (overall): 9.9 vs 5.1mo, HR 0.50, 95% CI 0.40–0.63, P<.001
OS (overall): 23.4 vs 16.8mo, HR 0.64, 95% CI 0.49–0.84, P=.001
OS (HR+): 23.9 vs 17.5mo, HR 0.64, 95% CI 0.48–0.86, P=.003
PFS (overall): 9.9 vs 5.1mo, HR 0.50, 95% CI 0.40–0.63, P<.001
OS (overall): 23.4 vs 16.8mo, HR 0.64, 95% CI 0.49–0.84, P=.001
Adverse events
Overall: Grade ≥3 AEs 52.6% vs 67.4%
Pulmonary: Interstitial lung disease 12.1% (grade 3: 0.8%; grade 5/fatal: 0.8%)
GI: Nausea any grade 73.0% (grade ≥3 8.2%)
Hematologic/dermatologic: Grade ≥3 neutropenia 14.7%; alopecia 37.4%
Tolerability: Discontinuation 16.2%
Pulmonary: Interstitial lung disease 12.1% (grade 3: 0.8%; grade 5/fatal: 0.8%)
GI: Nausea any grade 73.0% (grade ≥3 8.2%)
Hematologic/dermatologic: Grade ≥3 neutropenia 14.7%; alopecia 37.4%
Tolerability: Discontinuation 16.2%
Conclusions
T-DXd significantly improved PFS and OS vs chemotherapy in HER2-low HR+ and overall metastatic BC, redefining HER2-low (IHC 1+/2+ ISH-) as an actionable target. Established T-DXd as standard of care in this previously under-recognized subgroup and transformed HER2 testing paradigms.
Key Limitations
ILD is the critical safety concern — 12.1% any-grade with fatal cases (0.8%); pulmonary monitoring and algorithm-based management mandatory. HR- cohort (n=63) underpowered. HER2-low (IHC 1+ or 2+ ISH-) is ~55% of BC, but inter-observer variability at the 1+ threshold may affect eligibility in practice. Not tested head-to-head vs T-DXd in HER2+ disease.
Clinical Context
T-DXd: FDA approved 2022 for HER2-low unresectable/metastatic BC after ≥1 prior chemotherapy in the metastatic setting. ESMO-MCBS 5. Fundamentally changed BC HER2 classification — pathologists now distinguish HER2-low (1+/2+ ISH-) from HER2-zero (0). DESTINY-Breast06 subsequently extended T-DXd benefit to HER2-ultralow tumors.
References