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757 Phase 1/2a clinical trial of BI-1808, a monoclonal antibody to tumor necrosis factor receptor 2 (TNFR2) as single agent and in combination with pembrolizumab
  1. Kristoffer Staahl Rohrberg1,
  2. Zsuzsanna Papai2,
  3. Ana Carneiro3,
  4. Istvan Lang4,
  5. Jeffrey Yachnin5,
  6. Sean Lim6,
  7. Lars Ny7,
  8. Rikke H Lovendahl Eefsen8,
  9. Harriet Walter9,
  10. Edvard Abel7,
  11. Kirstie Cleary6,
  12. Robert Oldham6,
  13. Mark Cragg6,
  14. Marie Borggren10,
  15. Susanne Gertsson10,
  16. Petra Holmkvist10,
  17. Ingrid Karlsson10,
  18. Linda Martensson10,
  19. Jan Anders Nilsson10,
  20. Johan E Wallin10,
  21. Michael Chisamore11,
  22. Bjorn Frendeus6,10,
  23. Ingrid Teige10 and
  24. Andres McAllister10
  1. 1Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
  2. 2MH Egeszsegugyi Kozpont Onkologiai, Budapest, Hungary
  3. 3Skåne University Hospital, Lund, Sweden
  4. 4PRA Health Sciences, Budapest, Hungary
  5. 5Karolinska Institute, Solna, Sweden
  6. 6University of Southampton, Southampton, UK
  7. 7Sahlgrenska University Hospital, Gothenburg, Sweden
  8. 8Herlev Hospital, Herlev, Denmark
  9. 9University Hospitals of Leicester NHS Trust, Leicester, UK
  10. 10BioInvent International, Lund, Sweden
  11. 11Merck and Co., Inc., Rahway, NJ, 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 BI-1808 is a human IgG1 monoclonal antibody targeting TNFR2 by blocking the interaction of TNFR2 with its ligand TNF-α, confering FcγR-dependent depletion of intratumoral Tregs and mediating expansion of intratumoral CD8+ T cells. Upon co-administration of BI-1808 and anti-PD-1 surrogate antibodies to immunocompetent tumor-bearing mice, with partial sensitivity to checkpoint blockade, complete cures were observed in all treated mice, indicating a potentially synergistic activity.

Methods Safety and tolerability of BI-1808 as a single agent and in combination with pembrolizumab is currently investigated in the Phase 1/2a trial 19-BI-1808–01 in patients with advanced malignancies or cutaneous T-cell lymphoma (CTCL). The trial consists of Phase 1 Parts A and B (dose escalation with single agent and combination with pembrolizumab, respectively), and Phase 2a Parts A and B (dose expansion with single agent and combination therapy, respectively). Dose escalation uses a modified toxicity probability interval-2 protocol (mTPI-2), investigating ascending dose levels of 25–1000 mg every three weeks (Q3W). Dose escalation aims to select both single agent RP2D and combination RP2D of BI-1808 for Phase 2a.

Patients are sampled for pharmacokinetics (PK) of BI-1808, antidrug-antibodies and pharmacodynamics including lymphocyte subsets, regulatory T cells, memory T-cells, soluble TNFR2 serum concentration (sTNFR2) and BI-1808 receptor occupancy (RO).

Results As of June 19th, 2023, 24 subjects with various advanced solid malignancies received doses of up to 1000 mg BI-1808 as single-agent treatment, and 7 subject received 225 mg doses of BI-1808 with pembrolizumab.

Across the completed monotherapy arm, no Grade 3/4 AEs, AEs related to BI-1808 and no DLTs were observed. No MTD was defined. The number of potentially related AEs of Gr 1/2 are evenly distributed across the dose range, with no target system organ class of special notice identified. Best clinical response recorded are stable disease (SD) in 7/19 evaluable patients in the monotherapy arm. The first dose cohort for BI-1808 at 225 mg in combination with pembrolizumab is currently ongoing.

BI-1808 exhibits a non-linear PK. At doses > 675 mg Q3W, t½ was approximately 1 week resulting in accumulation of drug, with complete RO throughout the dosing interval.

Conclusions Preliminary data from the BI-1808 monotherapy arm from the clinical trial 19-BI-1808–01 is promising. BI-1808 has a favorable safety profile, with no DLTs observed. SD was observed in 7/19 evaluable patients. Doses of 675 mg and higher are expected to provide complete RO throughout the dose interval, and will be further explored in Ph2a.

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