Abstract PO1-20-06: Phase 2 study of novel HER2-targeting, TLR7/8 immune-stimulating antibody conjugate (ISAC) BDC-1001 +/- pertuzumab in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab deruxtecan

Abstract

Abstract Background: Therapies to effectively manage patients (pts) with metastatic HER2+ breast cancer have significantly improved over the years, but improvement is still needed in both efficacy and tolerability. BDC-1001 is an ISAC consisting of a trastuzumab biosimilar conjugated to a proprietary cell membrane impermeable TLR7/8 agonist via a non-cleavable linker, administered IV every 2 weeks. It is designed to trigger the innate immune system and generate a durable tumor-targeted adaptive immune response. Preclinical studies indicate that HER2-targeted ISACs elicit potent and durable immune-mediated antitumor efficacy, leading to complete tumor regression in a TLR- and Fc receptor-dependent manner [1]. Moreover, preclinical studies with a murine surrogate of BDC-1001 (trastuzumab-T785 ISAC) indicate improved anti-tumor activity with trastuzumab-T785 compared with trastuzumab/pertuzumab. In these preclinical studies, the combination of trastuzumab-T785 and pertuzumab demonstrated significantly enhanced efficacy in multiple HER2-expressing tumor models, including those with lower HER2 expression [1]. The addition of pertuzumab decreased the quantity of ISAC required for anti-tumor activity in the JIMT-1 HER2 IHC2+ model. Moreover, the combination of pertuzumab with the ISAC significantly increased the cytokine and chemokine concentrations in the tumor xenografts, compared with monotherapy or trastuzumab/pertuzumab, indicating enhanced myeloid activation in the tumor. These preclinical studies suggest that this combination may enhance the clinical activity of trastuzumab-based ISACs. The completed part of the BDC-1001 dose escalation trial (NCT04278144) demonstrated safety, PK and pharmacodynamic changes compatible with the ISAC mechanism of action, and a wide range of antitumor activity (incl. cases with breast cancer); resulting in a RP2D of 20 mg/kg q2w [2]. Two trials are underway, including a Phase 2 trial in other HER2+ malignancies, and a randomized Phase 2 trial with BDC-1001 alone and in combination with pertuzumab in patients with HER2-positive MBC previously treated with 2 or more prior anti-HER2 therapies, including trastuzumab deruxtecan. Methods: The Phase 2 multicenter, open-label, randomized study (BBI-20231001) is enrolling up to 66 pts with HER2-positive (ASCO/CAP guidelines 2018) MBC previously treated with 2 or more prior anti-HER2 therapies, including trastuzumab deruxtecan as one of the prior therapies. Pts must be 18 years or older, have measurable disease (RECIST v1.1), and have Eastern Cooperative Oncology Group performance status of 0 or 1. Pts will be administered BDC-1001 20 mg/kg every 2 weeks (IV q2w) and randomized 1:1 to receive BDC-1001 as a single agent or in combination with pertuzumab. The trial has a Simon 2-stage design within each arm. The primary objective is to determine the overall response rate per RECIST v1.1 of BDC-1001 alone and in combination with pertuzumab. Secondary objectives will evaluate safety, additional efficacy parameters, pharmacokinetics, and immunogenicity of BDC-1001 alone and in combination with pertuzumab. Exploratory objectives will include pharmacodynamic biomarkers in tumor tissue (baseline and on-treatment biopsies if feasible) and in peripheral blood to elucidate the mechanism of action and seek to identify biomarkers associated with BDC-1001 biological activity with or without pertuzumab. This study is expected to initiate accrual in 2H 2023. For additional information, please contact Bolt Biotherapeutics at 1-650-665-9295 or info@boltbio.com.