Trastuzumab rezetecan versus pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer (HORIZON-Breast01): interim analysis of a multicentre, open-label, randomised, controlled, phase 3 trial
Published report from the HORIZON-Breast01 trial registered as NCT05424835, in The Lancet Oncology (2026), chosen as the most cited paper whose own text cites the registry id.
Overview
Background: Trastuzumab rezetecan has shown antitumour activity in a phase 1 trial. Pyrotinib plus capecitabine is the current standard treatment for patients with HER2-positive advanced or metastatic breast cancer after trastuzumab and chemotherapy (taxane or anthracycline). We aimed to evaluate the efficacy and safety of trastuzumab rezetecan versus pyrotinib plus capecitabine in this patient population.
Methods: This interim analysis of a multicentre, open-label, randomised, controlled, phase 3 trial was conducted at 50 hospitals in China. Eligible patients were aged 18-75 years with histologically confirmed HER2-positive unresectable or metastatic breast cancer; previously received a taxane and trastuzumab at the advanced stage or had disease progression within 12 months after (neo)adjuvant treatment with an anti-HER2 monoclonal antibody and taxane-based regimen; had measurable lesions; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1; stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease), using permuted blocks to intravenous trastuzumab rezetecan (4·8 mg/kg) on day 1 of each 21-day cycle or oral pyrotinib 400 mg once per day continuously plus oral capecitabine 1000 mg/m 2 twice per day on days 1-14 of each 21-day cycle. Protocol amendments led to a temporary modification (between Nov 29, 2022, and July 12, 2023) of trastuzumab rezetecan dose to 6·4 mg/kg; primary evaluation focuses on the 4·8 mg/kg group. The primary endpoint was progression-free survival per blinded independent central review in the modified intention-to-treat population 1 (defined as all patients randomly assigned to the trastuzumab rezetecan 4·8 mg/kg or control groups). Results presented here are from a prespecified interim analysis. This study was registered with ClinicalTrials.gov, NCT05424835 (active, not recruiting).
Findings: From Aug 4, 2022, to Aug 9, 2024, 414 patients with HER2-positive metastatic breast cancer were assessed for eligibility, 127 were ineligible and 287 were randomly assigned to trastuzumab rezetecan (n=142) or pyrotinib plus capecitabine (control group; n=145) in the modified intention-to-treat population 1. All 287 patients were female and the median age was 55·0 years (IQR 49·0-60·0). 268 (93%) patients self-reported as Han Chinese and 19 (7%) as other Chinese ethnicity. At data cutoff of the interim analysis on June 30, 2025, after a median follow-up of 15·0 months (IQR 12·9-18·5) for the trastuzumab rezetecan group versus 13·9 months (11·4-17·8) for the control group, 124 progression-free survival events had occurred (37 [26%] vs 87 [60%]). The median progression-free survival was 30·6 months (95% CI 16·8-not reached [NR]) with trastuzumab rezetecan and 8·3 months (6·9-11·0) with pyrotinib plus capecitabine (HR 0·22 [0·15-0·34]; p<0·0001). The 12-month progression-free survival rate was 84·7% (77·0-90·0) in the trastuzumab rezetecan group versus 35·5% (26·8-44·2) in the control group. The most common (grade ≥3) treatment-related adverse events were decreased neutrophil count (77 [54%] with trastuzumab rezetecan vs 13 [9%] with the control), decreased white blood cell count (29 [20%] vs four [3%]), and decreased platelet count (15 [11%] vs two [1%]); whereas treatment-related serious adverse events occurred in 19 (13%) versus 17 (12%). Two adverse events led to death (one [1%] septic shock unrelated to trastuzumab rezetecan treatment and one [1%] unknown reason related to pyrotinib plus capecitabine treatment). Interstitial lung disease occurred in four (3%) patients in the trastuzumab rezetecan group.
Interpretation: Trastuzumab rezetecan improved progression-free survival versus pyrotinib plus capecitabine and showed a distinct safety profile in patients with HER2-positive breast cancer, presenting as a potential new treatment option.
Funding: Jiangsu Hengrui Pharmaceuticals.
Translation: For the Chinese translation of the abstract see Supplementary Materials section.
Indexed on Europe PMC as PubMed record 42385760 (DOI 10.1016/s1470-2045(26)00193-2). Its abstract cites the registry id NCT05424835, which is how it was matched to this trial; no figure has been checked by an editor.
This is the paper Europe PMC returns for registry id NCT05424835 with the most citations, so it is the natural first reading for anyone following the HORIZON-Breast01 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
- Matched to the trial by the registry id cited in the Europe PMC record; the summary reproduces the record's abstract and no figure has been verified against the full paper.