Efficacy and safety of ARX788 for individuals with HER2-positive breast cancer and brain metastases (ACE-Breast-06): a single-arm, phase 2 trial in China.

Background: ARX788 is a next-generation antibody-drug conjugate (ADC) in which an anti-HER2 monoclonal antibody is linked to a monomethyl auristatin F (MMAF) payload. This study aimed to investigate the intracranial efficiency of ARX788 in epidermal growth factor receptor 2 (HER2)-positive breast cancer with active brain metastases. Methods: This prospective, single-arm, phase 2 trial was conducted at a single centre in Shanghai, China. Eligible participants were patients (aged 18-75 years) with HER2-positive breast cancer who had received trastuzumab, taxane, and tyrosine kinase inhibitor (TKI) treatment, and also had at least one measurable active brain metastatic lesion (≥1 cm). Participants received ARX788 at 1.5 mg/kg via intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) in the central nervous system (CNS), defined as the proportion of patients with complete response (CR)/partial response (PR)/stable disease (SD) at ≥24 weeks as per RANO-BM. Secondary endpoints included CNS overall response rate, CNS progression-free survival (PFS), PFS, overall survival, sites of next progression, and safety. Tumour response was assessed every 6 weeks. Both efficacy and safety analyses included patients who had received at least one dose of ARX788. This study is registered with ClinicalTrials.gov, NCT05018702. Findings: Between August 2021 and April 2025, 32 patients were included and treated with ARX788. The median follow-up duration was 15.0 months (range, 1.8-42.5), and two patients were still receiving ARX788 treatment at final data cutoff (April 2025). As for the intracranial efficacy, the CNS CBR was 34.4% (95% CI: 18.6-53.2; 11 of 32 patients) and the proportion of patients with confirmed CNS overall response rate was 25.0% (11.5-43.4). Median CNS PFS was 5.6 (95% CI: 3.0-7.4) months and median PFS was 5.5 (95% CI: 2.8-7.0) months. Data on overall survival were immature at the time of data analysis. As for the sites of next progression, 8.3% of participants had extracranial progression alone, 70.8% had intracranial progression alone, and 20.8% had both intracranial and extracranial progression. Grade ≥3 treatment-related adverse events (TRAEs) occurred in four (12.5%) of 32 patients. The most common grade ≥3 TRAEs were blurred vision (9.4%), interstitial lung disease/pneumonitis (6.3%), keratopathy (6.3%), dry eyes (3.1%), and thrombocytopaenia (3.1%). The rate of grade ≥3 gastrointestinal toxicity was less than 1%. A grade 5 ILD/pneumonitis event occurred in one (3.1%) patient. Interpretation: This phase 2 trial is, to our knowledge, the first study of ARX788 in patients with brain metastases. Whilst acknowledging the limitations of this design, our findings show support for ARX788 as a potential treatment alternative for patients with HER2-positive active brain metastases. Future prospective studies incorporating patient-reported outcomes are needed to better capture the clinical benefit of ARX788. Funding: National Natural Science Foundation of China; National Key Research and Development Program of China; Shanghai Science and Technology Innovation Action Plan; and Beijing Science and Technology Innovation Medical Development Foundation Key Project.