Trastuzumab rezetecan (SHR-A1811) in HER2-low advanced breast cancer (BC): A randomized, phase 3 study (HORIZON-Breast06)

doi:10.1001/jama.2026.21372

HORIZON-Breast06

Patient / Population Intervention / Exposure Comparison Outcome

In patients with HER2-low advanced breast cancer and no more than one prior line of chemotherapy for metastatic disease, trastuzumab rezetecan improved progression-free survival by blinded independent central review compared with physician's choice of chemotherapy.

N

551patients

Design

Randomised (1:1), open-label, multicentre phase 3 trial of trastuzumab rezetecan vs physician's choice of chemotherapy (taxanes, eribulin, capecitabine or gemcitabine) in patients with HER2-low advanced breast cancer who had received ≤1 prior line of chemotherapy for metastatic disease, with prior endocrine therapy required for HR-positive disease (NCT05814354).

Endpoint

Co-primary: PFS by blinded independent central review (BICR) in chemo-naïve patients (0 prior lines of chemotherapy for metastatic disease) and in overall patients.

ResultChemo-naïve patients: median PFS by BICR 16.6 vs 6.8 months with chemotherapy (HR 0.25, 95% CI 0.19-0.33; 1-sided P<0.0001); 12-month PFS rate 65.2% vs 18.9%. Overall patients: median PFS 16.4 vs 6.8 months (HR 0.27, 95% CI 0.21-0.34; 1-sided P<0.0001); 12-month PFS rate 63.1% vs 18.0%. PFS in HR-negative disease 16.5 vs 6.8 months (HR 0.34) and in HR-positive disease 16.4 vs 6.7 months (HR 0.24). ORR in overall patients 75.5% vs 41.2%. OS immature: 12-month OS rate in overall patients 90.6% vs 81.4%, with 66 (23.8%) vs 77 (28.1%) deaths. Grade ≥3 treatment-related adverse events 84.1% vs 67.9%. Interstitial lung disease in 7 patients (2.5%) with trastuzumab rezetecan.

Fan Y, Liu Y, Wang Y, et al. JAMA. 2026; published online 23 October. 10.1001/jama.2026.21372

Discussion & critique

This trial shows a large and consistent PFS benefit by blinded central review in both co-primary populations, after a median follow-up of 18.0 months. The trial was open label, PFS is a surrogate, and OS is immature: the abstract reports no OS hazard ratio, only a trend. The abstract calls the safety profile favourable, yet grade ≥3 treatment-related adverse events were more common with trastuzumab rezetecan (84.1% vs 67.9%), and it reports no ILD grades, quality-of-life data or definition of HER2-low. Most patients (81.5%) were chemo-naïve, and the study was funded and run by Jiangsu Hengrui Pharmaceuticals.