Background: To date, anti-HER2 monoclonal antibodies are the only immune therapies approved for treating pts with HER2-over-expressing cancers. Intratumoral delivery of immunostimulatory adjuncts such as toll-like receptor (TLR) 7/8 agonists can activate tumor resident antigen-presenting cells (APCs) to promote antitumor immunity. To optimize intratumoral delivery while leveraging favorable preclinical biology we developed a novel, systemically delivered ISAC (BDC-1001). BDC-1001 consists of an investigational trastuzumab biosimilar chemically conjugated to a TLR 7/8 agonist (payload) with an intervening non-cleavable linker. BDC-1001 activates human myeloid APCs and retains antibody-mediated effector functions such as antibody-dependent cellular cytotoxicity/phagocytosis. Our trastuzumab-based ISACs seem to elicit potent and durable immune-mediated antitumor efficacy including tumor regression in a TLR- and Fc receptor-dependent manner in xenograft and syngeneic tumor resistant models (Ackerman et al. Nat Cancer 2020). 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 was initiated in 2020 to evaluate BDC-1001 with or without (±) pembro in pts with HER2-overexpressing or amplified advanced solid tumors. Methods: This phase 1/2 dose-escalation/expansion study will enroll up to 390 pts with HER2-overexpressing (IHC2+ or 3+) or HER2-amplified (by in situ hybridization or next-generation sequencing) advanced solid tumors. Patients may have received prior anti-HER2 therapies. Primary objectives of dose-escalation are safety and tolerability, and establishing a recommended phase 2 dose of BDC-1001 alone administered IV q3w (Part 1) and combined with pembro (Part 2). Primary endpoints of Parts 1 & 2 include assessment of safety and tolerability; dose-limiting immune-related toxicities in a 3+3 design. The dose-expansion phase 2 portion will evaluate preliminary antitumor activity of BDC-1001 alone (Part 3) and with pembro (Part 4) using RECIST v1.1 and iRECIST. The primary endpoint of the phase 2 is best\ overall response rate; with secondary endpoints of duration of response, disease control rate, and progression-free survival. Exploratory objectives include pharmacokinetic parameters and pharmacodynamic biomarkers associated with drug exposure to help elucidate mechanism of action and identify biomarkers to improve selection of pts most likely to benefit from the single therapy or combination. Recruitment is ongoing (NCT04278144).

Citation Format: Manish R. Sharma, Richard D. Carvajal, Daniel Catenacci, Leisha A. Emens, 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, Arielle L. Heeke, Ding Wang, Lawrence Garbo, Sudhir Manda, Jasgit Sachdev, Shelley E. Ackerman, Heidi LeBlanc, David Dornan, Marcin Kowanetz, Michael N. Alonso, Amreen Husain, Edith A. Perez, Ecaterina Ileana Dumbrava. Phase 1/2 study of a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), BDC-1001, alone and in combination with pembrolizumab (pembro) in patients (pts) with HER2-expressing advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT218.