Phase 2 Study of Novel HER2-targeting, TLR7/8 Immune-Stimulating Antibody Conjugate (ISAC) BDC-1001 (trastuzumab Imbotolimod) +/- Pertuzumab (P) in Patients (pts) with HER2-positive Metastatic Breast Cancer (MBC) Previously Treated with Trastuzumab Deruxtecan (T-Dxd).

TPS1121 Background: Therapies to manage pts with HER2+ MBC have significantly improved, but better agents are still needed. BDC-1001 (trastuzumab imbotolimod) is being studied for MBC and other HER2+ cancers. The ISAC BDC-1001 consists of a trastuzumab biosimilar conjugated to a cell membrane impermeable TLR7/8 agonist via a non-cleavable linker and is given IV every 2 wks. Designed to trigger the innate immune system, BDC-1001 causes a durable tumor-targeted adaptive immune response. Early studies show that HER2-targeted ISACs elicit potent and durable immune-mediated antitumor efficacy, and tumor regression, in a TLR- and Fc receptor-dependent manner (1). Preclinical studies with a murine surrogate of BDC-1001 (trastuzumab-T785 ISAC) show better efficacy with trastuzumab-T785 compared to trastuzumab + P. In the BDC-1001 dose-escalation trial (BBI-20201001), 6 PRs and 12 SDs ≥ 24 weeks in 8 tumor types were observed, particularly in 20mg/kg q2w dose cohorts. The most frequent drug-related AE was low grade (grade 1/2) infusion-related reactions (29%) (2). We showed the combination of a surrogate ISAC (trastuzumab-T785) + P significantly enhances efficacy in multiple HER2-expressing tumors, including those with lower HER2 expression (1). The addition of P lowered the quantity of ISAC required for anti-tumor activity in the JIMT-1 HER2 IHC2+ model. The combination of P with the ISAC significantly increased the tumor cytokine and chemokine concentration compared to monotherapy or antibody-alone, indicating enhanced tumor myeloid activation suggesting this combination may enhance the clinical activity of trastuzumab-based ISACs. Methods: The Phase 2 multicenter, open-label, randomized study (BBI-20231001) is enrolling up to 66 patients with HER2-positive (ASCO/CAP 2018) MBC previously treated with 2 or more anti-HER2 therapies including T-DXd. Patients must be > 18 years, have measurable disease, and have ECOG performance status of 0 or 1. Patients will be randomized 1:1 to receive BDC-1001 20mg/kg every 2 weeks with or without P (840mg initial dose, followed by 420mg IV q 3w). Each arm has a Simon 2 stage design. The primary objective is anti-tumor activity of BDC-1001 alone and in combination with P. Secondary objectives will evaluate safety, PK, and immunogenicity of BDC-1001 alone and in combination with P. Exploratory objectives will include PD biomarkers in tumor tissue and in peripheral blood to elucidate the MOA and biomarkers associated with BDC-1001 activity with or without P. This study began accrual in Nov 2023. 1. Ackerman S, et al. Nature Cancer. 2021. 2. Li B, et al. ASCO 2023, Abstract 2538. Clinical trial information: NCT05954143 .