In the phase III HORIZON-Breast01 trial, the HER2-directed antibody-drug conjugate trastuzumab rezetecan significantly improved progression-free survival and showed a distinct safety profile vs pyrotinib plus capecitabine in HER2-positive metastatic breast cancer. The interim analysis, reported by Yao et al in The Lancet Oncology, included patients previously treated with trastuzumab and a taxane.
Study Details
The multicenter, open-label, randomized trial was conducted at 50 hospitals in China. Eligible patients were aged 18 to 75 years and had HER2-positive unresectable or metastatic breast cancer, measurable disease, and an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1. Patients had previously received trastuzumab and a taxane for advanced disease or experienced disease progression within 12 months after neoadjuvant or adjuvant anti-HER2 therapy and taxane-based treatment.
For the primary analysis, 287 patients were randomly assigned to receive intravenous trastuzumab rezetecan at 4.8 mg/kg every 3 weeks or oral pyrotinib plus capecitabine. The primary endpoint was progression-free survival as assessed by blinded independent central review. Secondary endpoints included investigator-assessed progression-free survival, overall survival, objective response rate, duration of response, and safety.
All 287 patients were women, and the median age was 55 years. Baseline characteristics were generally similar between the groups. About half of patients had hormone receptor–positive disease, and 72% had previously received pertuzumab.
Key Findings
At the June 2025 data cutoff, median follow-up was 15 months with trastuzumab rezetecan and 13.9 months with pyrotinib plus capecitabine. Median progression-free survival was 30.6 months with the antibody-drug conjugate vs 8.3 months with pyrotinib plus capecitabine (hazard ratio [HR] = 0.22, P < .0001). At 12 months, 84.7% of patients receiving trastuzumab rezetecan were alive without disease progression vs 35.5% of those receiving pyrotinib plus capecitabine.
The progression-free survival benefit was seen across most prespecified subgroups, including patients who had received one vs at least two prior lines of therapy, those with or without primary trastuzumab resistance, and those with or without prior pertuzumab treatment.
Median overall survival had not yet been reached in either group. The 12-month overall survival rate was 96.3% with the investigational agent and 88.4% in the control group (HR = 0.31). Overall survival data remain immature and require longer follow-up.
The objective response rate was 81.7% with trastuzumab rezetecan vs 55.9% with pyrotinib plus capecitabine. Median duration of response was 27.8 months and 10.9 months, respectively.
Safety
Grade 3 or higher treatment-related adverse events occurred in 70% of patients receiving the antibody-drug conjugate and 63% of those in the control group. The most common grade 3 or higher events with trastuzumab rezetecan were decreased neutrophil count, decreased white blood cell count, and decreased platelet count. Treatment-related serious adverse events occurred in 13% and 12% of patients, respectively.
Interstitial lung disease occurred in four patients, or 3%, in the trastuzumab rezetecan cohort. Events were grade 1 in two patients, grade 2 in one patient, and grade 3 in one patient. One death from septic shock in the investigational group was considered unrelated to treatment, whereas one death of unknown cause in the control group was considered treatment-related.
The investigators noted that the antibody-drug conjugate produced a substantial progression-free survival benefit and higher response rates than pyrotinib plus capecitabine, with a low incidence of interstitial lung disease.
“Trastuzumab rezetecan represents a promising practice changing therapeutic alternative in this patient population,” they concluded.
Erwei Song, MD, of the Department of Breast Tumor Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China, is the corresponding author of the article in The Lancet Oncology.
DISCLOSURE: The study was funded by Jiangsu Hengrui Pharmaceuticals and supported by grants from the National Science and Technology Major Project for the Prevention and Treatment of Cancer, Cardiovascular, Respiratory, and Metabolic Diseases and the Guangdong Provincial Clinical Research Center for Breast Diseases. For full disclosures of the study authors, visit thelancet.com.
