A multi-centre, phase 1a/1b dose escalation and expansion study of the HER2-directed antibody–drug conjugate T-Bren (BL-M07D1) in advanced breast cancer and other solid tumours

BACKGROUND: Trastuzumab brengitecan (T-Bren; BL-M07D1) is a HER2-directed antibody-drug conjugate (ADC) comprising a monoclonal antibody, a cathepsin B-cleavable linker, and a potent topoisomerase I inhibitor payload (Ed-04). We aimed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumour activity of T-Bren in patients with advanced breast cancer and other solid tumours. METHODS: This phase 1 dose escalation and expansion study enrolled patients with inoperable locally advanced or metastatic breast cancer or other solid tumours pretreated with systemic therapy. Patients received intravenous T-Bren at doses ranging from 1.0 mg/kg on days 1 and 8 every 3 weeks (D1D8 Q3W) (accelerated titration), to 2.6 mg/kg, 3.2 mg/kg, 3.8 mg/kg, 4.4 mg/kg, 5.0 mg/kg, 5.6 mg/kg, 6.2 mg/kg on day 1 every 3 weeks (D1Q3W) (i3+3 design). Primary objectives were to assess dose-limiting toxicity/maximum tolerated dose (DLT/MTD), and establish the recommended phase 2 dose (RP2D). FINDINGS: Overall, 253 patients were treated: DLTs occurred in two patients treated at 6.2 mg/kg Q3W, including grade 4 neutropenia with myelosuppression and grade 3 thrombocytopaenia in one patient, and grade 4 febrile neutropenia in another. In patients with breast cancer, ORR was 81.5% (66/81) in HER2-positive subgroup, 69.5% (57/82) in hormone receptor-positive/HER2-low disease, and 58.3% (14/24) in hormone receptor-negative/HER2-low disease. Median PFS was 18.2 months, 14.0 months, and 7.2 months in the HER2-positive, HR-positive/HER2-negative, and HR-negative/HER2-negative subgroups, respectively. INTERPRETATION: T-Bren demonstrated a manageable safety profile and clinically meaningful antitumour activity across a broad spectrum of HER2 expression in advanced breast cancer. The 4.4 mg/kg every three weeks regimen was established as the RP2D in breast cancer. FUNDING: This study was funded by the sponsor Baili-Bio (Chengdu) Pharmaceutical Co., Ltd.