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716 Phase 2 study of the HER2-targeting TLR7/8 immune stimulating antibody conjugate (ISAC) BDC-1001 monotherapy +/- nivolumab in patients with HER2+ colorectal, endometrial, or gastroesophageal cancer
  1. Ecaterina Dumbrava1,
  2. Joan Albanell Mestres2,
  3. Paolo Antonio Ascierto3,
  4. Jean-Yves Blay4,
  5. Stéphane Champiat5,
  6. Alfonso Cortes Salgado6,
  7. Antoine Deleuze7,
  8. Marta GilMartin8,
  9. Arielle Heeke9,
  10. Antoine Italiano10,
  11. Yoon-Koo Kang11,
  12. Jeeyun Lee12,
  13. Keun-Wook Lee13,
  14. Agnese Losurdo14,
  15. Michele Magni15,
  16. Kathleen Moore16,
  17. Ana Oaknin Benzaquen17,
  18. Ignacio Ortego Zabalza18,
  19. Haeseong Park19,
  20. Luis Paz-Ares Rodriguez20,
  21. Mark D Pegram21,
  22. Mariano Ponz-Sarvise22,
  23. Drew Rasco23,
  24. Manish Sharma24,
  25. Ardaman Shergill25,
  26. Jean-Philippe Spano26,
  27. Alexander I Spira27,
  28. Cecile Vicier28,
  29. Ivan Victoria29,
  30. Benjamin Weinberg30,
  31. Coya Tapia31,
  32. Jason Ptacek31,
  33. Michael N Alonso31,
  34. Lu Xu31,
  35. Ming Yin31,
  36. Edith A Perez32 and
  37. Bob T Li33
  1. 1The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. 2Hospital del Mar, Barcelona, Spain, Spain
  3. 3IRCCS Instituto Nazionale Dei Tumori Di Napoli Fondazione G. Pascale, Naples, Italy
  4. 4Centre Léon Bérard, Lyon, France
  5. 5Gustave Roussy Comprehensive Cancer Center, Villejuif, France
  6. 6Hospital Universitario Ramon y Cajal, Madrid, Spain
  7. 7Centre Eugène Marquis, Rennes, France
  8. 8Institut Català d’Oncologia, L’Hospitalet, Barcelona, Spain
  9. 9Levine Cancer Institute, Charlotte, NC, USA
  10. 10Institut Bergonié, Bordeaux, France
  11. 11Asan Medical Center, Seoul, Republic of Korea
  12. 12Samsung Medical Center, Seoul, Republic of Korea
  13. 13Seoul National University Bundang Hospital, Seongnam, Republic of Korea
  14. 14Humanitas Cancer Center, Istituto Clinico Humanitas, Milan, Italy
  15. 15Fondazione IRCCS, Instituto Nazionale Dei Tumori, Milan, Italy, Italy
  16. 16Stephenson Oklahoma Cancer Center, Oklahoma City, OK, USA
  17. 17Vall d’Hebron University Hospital, Vall d’Hebron, Institute of Oncology (VHIO), Barcelona, Spain
  18. 18MD Anderson Cancer Center, Madrid, Spain
  19. 19Dana-Farber Cancer Institute, Boston, MA, USA
  20. 20Hospital Universitario 12 de Octubre, Madrid, Spain
  21. 21Stanford University, Stanford, CA, USA
  22. 22Clinica Universidad de Navarra, Pamplona, Spain
  23. 23START, San Antonio, TX, USA
  24. 24START Midwest, Chicago, IL, USA
  25. 25The University of Chicago Medical Center, Chicago, IL, USA
  26. 26Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié Salpêtrière Hospital, Paris, France
  27. 27Virginia Cancer Specialists, Fairfax, VA, USA
  28. 28Institut Paoli-Calmette, Marseille, France
  29. 29Hospital Clinic de Barcelona, Barcelona, Spain
  30. 30Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA
  31. 31Bolt Biotherapeutics, Redwood City, CA, USA
  32. 32Bolt Biotherapeutics, Kenwood, CA, USA
  33. 33Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Despite advances made in management of patients with HER2-driven solid tumors, unmet need remains for novel approaches to improve patient outcomes. 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. 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

The phase 1 dose escalation of the phase 1/2, first-in-human study BBI-20201001 (NCT04278144), was completed and determined 20 mg/kg every 2 weeks (q2w) of BDC-1001 as the recommended phase 2 dose (RP2D) for monotherapy (mono)/combination (combo) regimens,2 leading to the phase 2 portion of the trial. The phase 1 portion showed that BDC-1001 was well tolerated as mono/combo, with grade 1/2 infusion-related reactions as the most common adverse events (29%). Clinical activity was observed in multiple tumor types; outcomes improved as targeted Cmin ≥10mg/mL was reached, particularly at the q2w RP2D. 6 pts (3 mono) had partial response (PR); 12 pts (10 mono) achieved stable disease (SD) ≥24 wks. 14 pts with evaluable HER2+ tumors treated at the RP2D had a clinical benefit rate of 50% (29% confirmed PR, additional 21% SD ≥24wks), tumor shrinkage occurred in 64%, and 36% of pts remain on active Tx. Pharmacodynamic responses in plasma and paired tumor biopsies (protein/gene analyses) demonstrated immune activation consistent with the ISAC technology, and not expected by trastuzumab alone.

This phase 2 (dose expansion) portion of the study is ongoing evaluating BDC-1001 alone and in combination with nivolumab in patients with HER2+ (protein or gene) advanced/metastatic colorectal, endometrial, and gastroesophageal cancers.

Methods This multiarm phase 2 trial will evaluate 20 mg/kg q2w of BDC-1001 as monotherapy (Part 3) and combination with nivolumab (Part 4) using Simon’s 2-stage design in up to 231 patients. The primary objective of the phase 2 will be preliminary antitumor activity of BDC-1001 alone and in combination with nivolumab. Secondary objectives will be safety, pharmacokinetics, and immunogenicity of BDC-1001 alone and in combination with nivolumab. Exploratory objectives will be pharmacodynamic biomarkers in tumor tissue and in peripheral blood, to help elucidate the mechanism of action and identify biomarkers associated with BDC-1001’s biological activity. Enrollment is ongoing in the United States, Europe, and South Korea.

Trial Registration (NCT04278144)


  1. Ackerman SE, Pearson CI, Gregorio JD, et al. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nat Cancer 2021;2:18–33.

  2. Li BT, Pegram MD, Lee KW, Sharma M, Lee J, Spira AI, Hanna GJ, Kang YK, Rasco DW, Moore KN, Weinberg BA, 2023. A phase 1/2 study of a first-in-human immune-stimulating antibody conjugate (ISAC) BDC-1001 in patients with advanced HER2-expressing solid tumors, 2538.

Ethics Approval Protocols, protocol amendments, and informed consents are approved by Institutional review boards or independent ethics committees of participating sites. The study will be conducted in compliance with the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice. All patients will provide written informed consent.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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