Targeted drug significantly delays advanced breast cancer progression but increases toxicity, phase III trial reports

In ERBB2-low (HER2-low) advanced breast cancer, antibody-drug conjugates (ADCs) are becoming a key direction. Trastuzumab rezetecan (SHR-A1811) is a HER2-directed ADC that previously showed antitumor activity in a global phase 1 trial in heavily pretreated patients with ERBB2-low metastatic breast cancer, and the HORIZON-Breast06 randomized phase 3 trial published alongside in JAMA was designed to compare it against physician's choice of chemotherapy. Also registered for this drug are phase 2 trial NCT07203729 in HER2-low unresectable/metastatic breast cancer patients with visceral crisis (planned enrollment 184, primary endpoint PFS) , and phase 2 trial NCT07497386 comparing it head-to-head with trastuzumab deruxtecan (planned enrollment 150) .

The HORIZON-Breast06 trial reported here was conducted at 73 hospitals across China. 551 female patients aged 18 to 75 with centrally confirmed ERBB2-low (IHC 1+ or IHC 2+/ISH-negative) unresectable locally recurrent or metastatic breast cancer were randomized 1:1 to trastuzumab rezetecan 6.4 mg/kg intravenously every 3 weeks (n=277) or physician's choice of chemotherapy (n=274); enrollment ran from June 30, 2023 to August 20, 2025, and follow-up for the final PFS analysis ended March 20, 2026 . Median progression-free survival was 16.4 months in the drug group versus 6.8 months with chemotherapy; the hazard ratio for disease progression or death was 0.27; tumor shrinkage occurred in 75.5% versus 41.2%. In chemotherapy-naive patients with no more than one prior line, the paper reported median PFS of 16.6 vs 6.8 months, hazard ratio 0.25 .

These gains came at the cost of toxicity: severe treatment-related adverse events such as blood toxicity or lung inflammation occurred in 84.1% of the drug group versus 67.9% with chemotherapy, and more than half of the drug-treated patients needed at least one dose reduction; the researchers noted that providers must more proactively monitor fluctuations in patients' health markers. Compared with prior material, this study advances the evidence from a phase 1 signal in heavily pretreated patients to a randomized phase 3 setting in patients with no more than one prior chemotherapy line, with median PFS exceeding 16 months in both hormone receptor-positive and hormone receptor-negative subgroups, and shows the drug has a distinct safety profile with potential as a new treatment option .

Overall survival (OS) data, the specific composition of physician's-choice chemotherapy, dose-intensity maintenance details, and longer-term adverse event outcomes were not disclosed in the report or abstract, nor were regulatory filing plans or submission timing; upcoming milestones include the full JAMA publication with longer follow-up and the readout of the head-to-head trial NCT07497386 (needs verification).