Background: To date, no immune-based therapies beyond anti-HER2 monoclonal antibodies are approved for treating patients (pts) with HER2-driven or -expressing cancers. However, pts still develop progressive disease, and new treatment options that could achieve durable antitumor efficacy are needed. Recent studies indicate that intratumoral delivery of immunostimulatory adjuvants such as toll-like receptor (TLR) 7/8 agonists can activate tumor resident antigen-presenting cells (APCs), driving uptake, processing, and presentation of tumor neoantigens to T cells that mediate antitumor immunity. To overcome limitations associated with intratumoral delivery while leveraging superior preclinical biology, BDC-1001, a novel, systemically delivered ISAC was developed. BDC-1001 consists of an investigational biosimilar of the humanized monoclonal antibody trastuzumab that is chemically conjugated to a TLR 7/8 agonist (payload) with an intervening non-cleavable linker. BDC-1001 activates human myeloid APCs while retaining antibody-mediated effector functions such as antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). Xenograft and syngeneic tumor resistant models indicate that trastuzumab ISACs elicit potent and durable immune-mediated antitumor efficacy including complete tumor regression in a TLR- and Fc receptor-dependent manner (Ackerman et al. Cancer Res. 2019:79 [13 Suppl]; Ackerman et al. J Immunother Cancer. 2019;7:283). Importantly, BDC-1001 did not induce interstitial lung disease, cytokine release syndrome, or thrombocytopenia in non-human primate studies. A four-part phase 1/2, first-in-human study has been initiated that evaluates BDC-1001 with or without (+/-) an immune checkpoint inhibitor targeting PD-1 in pts with HER2-expressing or HER2-amplified advanced/metastatic solid tumors.

Study Description: This phase 1/2 dose-escalation and dose-expansion study is enrolling up to 390 pts with advanced solid tumors that are HER2-expressing (IHC2+ or 3+ protein irrespective of gene amplification) or HER2-amplified (by in situ hybridization or next-generation sequencing) and ineligible for approved anti-HER2 treatments. The primary objectives of the dose-escalation phase are to define safety and tolerability and to determine the recommended phase 2 dose of BDC-1001 as monotherapy (Part 1) and in combination with an immune checkpoint inhibitor (Part 2). Primary endpoints of Parts 1 and 2 include incidence of 1) adverse events and severe adverse events graded according to NCI CTCAE v5.0; 2) dose-limiting toxicities within a 3+3 design; and 3) potential immune-related toxicities. BDC-1001 is administered IV over 60 min q3w at increasing doses. Once safety data are available for BDC-1001, initiation of the immune checkpoint inhibitor combination is planned. The dose-expansion phase 2 portion of the trial will evaluate preliminary antitumor activity of BDC-1001 alone (Part 3) and in combination with an immune checkpoint inhibitor (Part 4) using RECIST v1.1 and iRECIST. The primary endpoint of this dose-expansion phase is overall response rate, with secondary endpoints of duration of response, disease control rate, and progression-free survival. Exploratory objectives will evaluate pharmacokinetic parameters and pharmacodynamic biomarkers associated with drug exposure. These exploratory studies will help elucidate the mechanism of action and seek to identify biomarkers to improve selection of pts most likely to benefit from treatment with BDC-1001 +/- immune checkpoint inhibitor. This global study is currently recruiting pts. For further information, visit ClinicalTrials.gov (NCT04278144).

Citation Format: Ecaterina Ileana Dumbrava, Manish R. Sharma, Richard D. Carvajal, Daniel Catenacci, Leisha A. Emens, Shirish M. Gadgeel, Glenn J. Hanna, Dejan Juric, Yoon-Koo Kang, Jeeyun Lee, Keun-Wook Lee, Bob T. Li, Kathleen Moore, Mark D. Pegram, Paula R. Pohlmann, Drew Rasco, Alexander Spira, Antoinette R. Tan, Shelley E. Ackerman, Heidi LeBlanc, David Dornan, Marcin Kowanetz, Michael N. Alonso, Edith A. Perez. Phase 1/2 study of a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), BDC-1001, as a single agent and in combination with an immune checkpoint inhibitor in patients with advanced HER2-expressing solid tumors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-02.