Abstract CT154: BDC-3042, a first-in-class Dectin-2 agonist, in patients with advanced malignancies: Results from the first-in-human dose-escalation study

Abstract Background: Dectin-2 is an immune-activating pattern recognition receptor that promotes immune responses against various microbial pathogens. Dectin-2 is expressed by myeloid cells including tumor-associated macrophages (TAMs), which are generally thought to inhibit anti-tumor immune responses and limit the efficacy of checkpoint inhibitors and other therapies. BDC-3042 is a first-in-class, agonistic monoclonal antibody targeting Dectin-2. Preclinical studies demonstrate that Dectin-2 agonist therapy with BDC-3042 has the potential to reprogram TAMs into immunostimulatory cells that enhance anti-tumor immune responses. Methods: BBI-20233042 is a phase 1/2, first-in-human, dose escalation and expansion study of BDC-3042 in patients with advanced cancers. In the escalation, pts were enrolled to ascending Q2W IV dose level cohorts ranging from 0.03 to 10 mg/kg using a Bayesian Optimal Interval design. The primary objective was safety, with secondary objectives of efficacy and pharmacokinetics (PK). Exploratory objectives included evaluation of peripheral immune biomarkers. Results: As of 31 Jan 2025, 17 pts have been treated in the dose escalation, with a mean age of 61 yrs (51-83) and comprising 6 tumor types (CRC, n=8; NSCLC, 3; ccRCC, 2; ovarian, 2; melanoma, 1; TNBC, 1). Pts received a median of 4 (2-8) lines of prior therapy and 41% (n=7) received prior immunotherapies. There were no DLTs or serious grade 4 related TEAEs observed up to 10 mg/kg. Two pts (12%) experienced grade 3 related TEAEs (muscle weakness, n=1; hypercalcemia, n=1). No cytokine release syndrome (CRS) was reported. The most common TEAE was grade 2 dehydration (n=5). BDC-3042 exhibited linear PK at doses of 0.1 mg/kg and above, with a terminal half-life of approximately 10 days. Peripheral biomarker responses indicative of immune activation were observed, with moderate, generally dose-dependent increases in serum cytokines and chemokines following infusion. Immune cell frequencies in the blood were modulated along with additional signs of immune stimulation, including upregulation of activation markers and PD-1 on T cells. Dose-dependent decreases in Dectin-2 levels were detected in serum and on peripheral monocytes, suggestive of target engagement. Response data are available for 12 pts with 9 having stable disease (SD), 2 extending ≥12 wks; 2 with progressive disease (PD); and 1 not evaluable (NE). These data continue to evolve, as 3 pts are actively receiving treatment at the 10 mg/kg dose. Conclusion: BDC-3042 was well tolerated up to 10 mg/kg and showed encouraging biological activity in a heavily pre-treated population with advanced cancers including 8 CRC pts. The favorable safety, PK, and immunostimulatory effects of BDC-3042 support its further study in selected indications and underscore its combination potential with immune checkpoint inhibitors and other therapies. Citation Format: Ecaterina E. Dumbrava, Ildefonso Ismael Rodriguez, M. Adham Salkeni, Antonio Giordano, Chris Chen, Sheena Sahota, Edith A. Perez, Tai Yu, Katherine Rosenthal, Kristi Balacy, Danlin Cai, Jason Ptacek, Lu Xu, Dawn Colburn, Shelley E. Ackerman, Michael N. Alonso, Justin A. Kenkel, Andrae Vandross. BDC-3042, a first-in-class Dectin-2 agonist, in patients with advanced malignancies: Results from the first-in-human dose-escalation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT154.