Background
Phase 3, open-label, randomized interim analysis at 50 hospitals in China of trastuzumab rezetecan (SHR-A1811, a HER2-directed antibody-drug conjugate) versus pyrotinib plus capecitabine in HER2-positive unresectable/metastatic breast cancer previously treated with a taxane and trastuzumab (or progression within 12 months of (neo)adjuvant anti-HER2 + taxane). 287 patients in the modified intention-to-treat population.
Results
Interventions and follow up: Arm A: Trastuzumab rezetecan 4.8 mg/kg IV on day 1 of each 21-day cycle (n=142).
Arm B: Pyrotinib 400 mg PO once daily continuously + capecitabine 1000 mg/m² PO twice daily (control; n=145).
Primary endpoint: Progression-free survival (PFS).
mFollow up: 15.0 mo (experimental) vs 13.9 mo (control).
Results: PFS: 30.6 vs 8.3 mo; HR 0.22 (95% CI 0.15–0.34); P<.0001; 12-mo PFS 84.7% vs 35.5%.
OS: NR (immature).
ORR: NR in interim report.
Arm B: Pyrotinib 400 mg PO once daily continuously + capecitabine 1000 mg/m² PO twice daily (control; n=145).
Primary endpoint: Progression-free survival (PFS).
mFollow up: 15.0 mo (experimental) vs 13.9 mo (control).
Results: PFS: 30.6 vs 8.3 mo; HR 0.22 (95% CI 0.15–0.34); P<.0001; 12-mo PFS 84.7% vs 35.5%.
OS: NR (immature).
ORR: NR in interim report.
Adverse events
Hematologic (grade ≥3): neutropenia 54% vs 9%, leukopenia 20% vs 3%, thrombocytopenia 11% vs 1%.
Pulmonary: interstitial lung disease 3% (any grade).
Serious TRAE: 13% vs 12%.
Deaths: 1 septic shock (unrelated); 1 control-arm death.
Pulmonary: interstitial lung disease 3% (any grade).
Serious TRAE: 13% vs 12%.
Deaths: 1 septic shock (unrelated); 1 control-arm death.
Conclusions
Trastuzumab rezetecan more than tripled median PFS versus pyrotinib plus capecitabine in previously treated HER2-positive metastatic breast cancer, with a distinct, largely hematologic toxicity profile. It represents a promising new HER2 ADC, though OS is immature.
Key Limitations
Interim analysis with immature OS; conducted entirely in a Chinese population, limiting generalizability; open-label design; the pyrotinib + capecitabine comparator is not the global second-line standard (trastuzumab deruxtecan is preferred in many regions), complicating cross-trial interpretation; ORR and duration-of-response detail not reported.
Clinical Context
Adds another HER2-directed ADC to the later-line HER2-positive metastatic breast cancer landscape, where trastuzumab deruxtecan (DESTINY-Breast03) is the preferred second-line option. Trastuzumab rezetecan is not FDA-approved; development to date is China-based. Positioning versus T-DXd will require head-to-head or global data.