1073TiP - A phase I/IIa first in-human phase I study of BI 1910, a monoclonal antibody agonistic to TNFR2, as a single agent and in combination with pembrolizumab in subjects with advanced solid tumors

Background

Tumor necrosis factor (TNF) is a potent pro-inflammatory cytokine known to induce an inflammatory response and cell death, and anti-TNF drugs are used to treating autoimmune diseases. TNF has two receptors: TNFR1, which is broadly expressed on many different cell types, and TNFR2, with expression mainly expressed restricted to thein the immune system. TNFR2 is a type I transmembrane protein with typically high expression in myeloid cells and specific T cell subsets. Macrophages and Tregs constitutively express TNFR2. In effector T cells TNFR2 expression is upregulated after T cell receptor stimulation. The role of TNFR2 in inflammation is unclear with both proinflammatory and immunoregulatory roles postulated. TNFR2 is shown to both be important for T reg survival, while simultaneously acting as a potent costimulatory molecule on CD8+ T cells thereby promoting inflammatory activity. Given the costimulatory functions of TNFR2 in different immune cells, TNFR2 has in recent years been suggested as a promising novel target for anticancer treatment. We are developing BI-1910, an agonistic human IgG2 mAb targeting TNFR2. BI-1910 agonizes T cells and mediates CD4+ and CD8+ T cell activation. It binds human TNFR2 selectively but does not block the interaction between the receptor and its ligand, TNF-α. BI-1910 combined with anti-PD-1 showed additive anti-tumor effect in preclinical models, providing rationale to clinically evaluate in combination with pembrolizumab.

Trial design

This is a Phase 1/2a dose escalation clinical trial of BI-1910, as single agent and in combination with pembrolizumab, in subjects with advanced/metastatic solid tumors who progressed after standard therapy. It to establish safety/tolerability profile, pharmacokinetics, pharmacodynamics and preliminary efficacy of BI-1910 as monotherapy and in combination. Phase 1 dose escalation is guided by a BLRM design, planned to enroll up to 34 patients. Phase 2a will be performed in advanced/metastatic NSCLC and HCC patients in parallel cohorts. Safety and efficacy of BI-1910 as monotherapy and in combination will be evaluated at two separate dose levels for dose optimization.

Clinical trial identification

NCT06205706.

Editorial acknowledgement

Legal entity responsible for the study

BioInvent International AB.

Funding

BioInvent International AB.

Disclosure

M. Borggren, P. Holmkvist, I. Karlsson, M. Meller, L. Mårtensson, J. Nilsson, M. Vaapil, J.E. Wallin, I. Teige, B. Frendeus, A. McAllister: Financial Interests, Personal and Institutional, Full or part-time Employment: BioInvent. M. Chisamore: Financial Interests, Personal and Institutional, Full or part-time Employment: MSD/Merck&Co. All other authors have declared no conflicts of interest.