Trastuzumab Rezetecan Improves Progression-Free Survival in Previously Treated HER2-Positive Metastatic Breast Cancer

Clinical Summary: 

• Design/Population: This phase 3 trial compared trastuzumab rezetecan with pyrotinib plus capecitabine in patients with previously treated HER2-positive unresectable or metastatic breast cancer.
• Key Outcomes: Trastuzumab rezetecan significantly prolonged progression-free survival compared with pyrotinib plus capecitabine, reducing the risk of disease progression or death by 78%. The safety profile differed between treatment groups and was characterized primarily by hematologic toxicities with trastuzumab rezetecan.
• Clinical Relevance: These findings support trastuzumab rezetecan as a potential new treatment option for patients with previously treated HER2-positive metastatic breast cancer.

Interim results from the phase 3 HORIZON-Breast01 trial demonstrated that trastuzumab rezetecan significantly improved progression-free survival (PFS) compared with pyrotinib plus capecitabine in patients with previously treated HER2-positive metastatic breast cancer, supporting the antibody-drug conjugate as a potential new treatment option.

“Pyrotinib plus capecitabine is the current standard treatment for patients with HER2-positive advanced or metastatic breast cancer after trastuzumab and chemotherapy,” stated Herui Yao, MD, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China, and coauthors. “We aimed to evaluate the efficacy and safety of trastuzumab rezetecan versus pyrotinib plus capecitabine in this patient population.”

In this multicenter, open-label trial, 287 patients with HER2-positive unresectable or metastatic breast cancer who had previously received trastuzumab and taxane-based chemotherapy or experienced disease progression within 12 months of neoadjuvant anti-HER2 monoclonal antibody and taxane-based therapy were randomized 1:1 to receive either 4.8 mg/kg of trastuzumab rezetecan intravenously on day 1 (n = 142) or 400 mg of once daily pyrotinib plus 1,000 mg/m² of twice daily capecitabine on days 1 through 14 (n = 145) of each 21 day cycle. Randomization was stratified by hormone receptor status and prior lines of chemotherapy for metastatic disease. 

The primary end point was PFS, as assessed by blinded independent central review. A key secondary end point was safety. 

At analysis, median PFS was 30.6 months in the trastuzumab rezetecan arm and 8.3 months in the pyrotinib plus capecitabine arm (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.15 to 0.34; P < .0001), representing a 78% reduction in the risk of disease progression or death. The 12-month PFS rates were 84.7% and 35.5%, respectively. 

The safety profile differed between treatment groups. The most frequently reported grade ≥3 treatment-related adverse events included decreased neutrophil count (54% vs 9%), decreased white blood cell count (20% vs 3%), and decreased platelet count (11% vs 1%). Treatment-related serious adverse events were reported in 13% of patients in the trastuzumab rezetecan arm and 12% of patients in the pyrotinib plus capecitabine arm. Interstitial lung disease was reported in 3% of patients treated with trastuzumab rezetecan. Two treatment-emergent deaths occurred during the study, including one unrelated to trastuzumab rezetecan and one considered related to pyrotinib plus capecitabine.

“Trastuzumab rezetecan improved [PFS] versus pyrotinib plus capecitabine and showed a distinct safety profile in patients with HER2-positive breast cancer, presenting as a potential new treatment option,” concluded Dr Yao et al. 

Source:

Yao H, Zhang Q, Li H, et al. Trastuzumab rezetecan versus pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer (HORIZON-Breast01): Interim analysis of a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. Published online: July 1, 2026. doi: 10.1016/S1470-2045(26)00193-2