Trastuzumab Rezetecan in ERBB2-Low Advanced Breast Cancer: The HORIZON-Breast06 Randomized Clinical Trial.

Trastuzumab rezetecan (SHR-A1811) has demonstrated encouraging antitumor activity in a global phase 1 trial involving heavily pretreated patients with erythroblastic oncogene B (ERBB2)-low metastatic breast cancer. To compare trastuzumab rezetecan vs physician's choice of chemotherapy in patients with ERBB2-low metastatic breast cancer. This open-label, randomized, multicenter phase 3 trial was conducted at 73 hospitals across China. Eligible patients were females aged 18 to 75 years with centrally confirmed ERBB2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in-situ hybridization [ISH]-negative) unresectable locally recurrent or metastatic breast cancer who had received 1 or fewer prior lines of chemotherapy for metastatic disease, with prior endocrine therapy required for hormone receptor-positive disease. Enrollment began on June 30, 2023, and ended on August 20, 2025. The last day of follow-up for the final analysis for progression-free survival in the current study was March 20, 2026. Patients were randomly assigned (1:1) to receive trastuzumab rezetecan (6.4 mg/kg intravenously every 3 weeks; n = 277) or physician's choice of chemotherapy (n = 274). The primary end point was progression-free survival assessed by blinded independent central review in chemotherapy-naive patients and the overall population. Between June 30, 2023, and August 20, 2025, a total of 551 patients were randomized, with a mean (SD) age of 54.9 (9.9) years. At the data cutoff (March 20, 2026), trastuzumab rezetecan significantly prolonged progression-free survival compared with chemotherapy in the chemotherapy-naive patients (median, 16.6 [95% CI, 14.0-19.4] months vs 6.8 [95% CI, 5.7-7.0] months; hazard ratio, 0.25 [95% CI, 0.19-0.33]; P < .001) and the overall population (median, 16.4 [95% CI, 14.0-16.8] months vs 6.8 [95% CI, 5.7-6.9] months; hazard ratio, 0.27 [95% CI, 0.21-0.34]; P < .001). The benefit was consistent in hormone receptor-negative disease (median progression-free survival: 16.5 vs 6.8 months; hazard ratio, 0.34, [95% CI, 0.22-0.54]) and hormone receptor-positive disease (median progression-free survival: 16.4 vs 6.7 months; hazard ratio, 0.24 [95% CI, 0.18-0.33]). Grade 3 or greater treatment-related adverse events occurred in 84.1% of patients (232/276) with trastuzumab rezetecan and 67.9% (184/271) with chemotherapy, most commonly decreased neutrophil count (180 [65.2%] vs 147 [54.2%]). Trastuzumab rezetecan provided significant progression-free survival benefit over physician's choice of chemotherapy in patients with ERBB2-low advanced breast cancer, with benefit observed across all key subgroups. It exhibited the potential as a new treatment option with a distinct safety profile in this setting. ClinicalTrials.gov Identifier: NCT05814354.