What happened
The phase 3 HORIZON-Breast06 trial randomized 551 women in China with ERBB2-low unresectable or metastatic breast cancer to trastuzumab rezetecan or physician-selected chemotherapy. Median progression-free survival was 16.4 months with the antibody-drug conjugate and 6.8 months with chemotherapy. Overall-survival data were not mature, and grade 3 or higher treatment-related adverse events occurred in 84.1% and 67.9% of patients respectively.
The primary endpoint showed a large progression-free survival difference
Trastuzumab rezetecan is an antibody-drug conjugate designed to deliver a topoisomerase I inhibitor payload to cells with low ERBB2 expression. The open-label trial enrolled patients who had received no more than one prior chemotherapy line for metastatic disease; 81.5% had not received chemotherapy in that setting. Participants were randomized across 73 hospitals to the new drug or one of several chemotherapy regimens selected by their physician.
After a median follow-up of 15.5 months, blinded review found median progression-free survival of 16.4 months with trastuzumab rezetecan and 6.8 months with chemotherapy, corresponding to a hazard ratio of 0.27. The benefit appeared across the prespecified hormone-receptor subgroups. The objective response rate was 75.5% versus 41.2%, but these results do not yet establish a survival advantage.
The safety burden and changing treatment landscape matter
Grade 3 or higher treatment-related adverse events occurred in 232 of 276 patients receiving trastuzumab rezetecan and 184 of 271 receiving chemotherapy. Severe decreases in neutrophils, white blood cells and haemoglobin were particularly common, and half of patients receiving the antibody-drug conjugate required a dose reduction. Interstitial lung disease occurred in seven patients, including three grade 3 or 4 cases. Three treatment-related deaths occurred in the investigational group and two in the chemotherapy group.
All participants were treated in China, overall-survival follow-up remains immature and the control regimens reflect standards when the trial was designed. Other antibody-drug conjugates have since changed care for ERBB2-low disease, so cross-trial comparisons are unreliable and contemporary head-to-head evidence is still needed. This is a trial result, not a regulatory approval or evidence that the drug is available in every country.
Why it matters
The progression-free survival result is clinically important for a group with advanced disease and limited options, including hormone-receptor-positive and -negative cancers. The potential benefit must be weighed against substantial haematologic toxicity, incomplete survival evidence and uncertainty about how the drug compares with newer standards.
What to watch
Mature overall-survival and quality-of-life results, longer monitoring for lung toxicity, multinational trials, regulatory submissions and direct comparisons with current antibody-drug conjugates. Treatment decisions belong with an oncology team.
