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Background Tumor necrosis factor (TNF) is a pro-inflammatory cytokine that induces inflammatory responses and cell death. TNF interacts with two receptors: TNFR1, expressed across various cell types, and TNFR2, mainly expressed on cells of the immune system. Macrophages and regulatory T cells constitutively express TNFR2. In effector T cells, TNFR2 increases after receptor stimulation.TNFR2 is associated with both pro-inflammatory and immunoregulatory functions, is vital for Treg survival, and acts as a potent costimulatory molecule on CD8+ T cells. It promotes inflammation and has emerged as a promising target for cancer immunotherapy.BI-1910 is an agonistic human IgG2 mAb targeting TNFR2. BI-1910 stimulates T cells and enhances the activation of both CD4+ and CD8+ T cells. It binds selectively to human TNFR2 without inhibiting TNF-α binding. In preclinical models, BI-1910 combined with anti-PD-1 showed additive anti-tumor activity, justifying clinical evaluation with pembrolizumab.Methods We report here Phase 1 dose escalation results from a Ph1/2 clinical trial of BI-1910 as single agent in subjects with advanced/metastatic solid tumors who had progressed after standard therapy. Objectives included assessment of safety/tolerability, pharmacokinetics, pharmacodynamics, efficacy of BI-1910 as a monotherapy and in combination with pembrolizumab, and establishment of the recommended Phase 2 dose.Phase 2a will include several cancer subtypes likely to respond to BI-1910 treatment, evaluating single-agent and pembrolizumab combination treatment cohorts.Results As of June 12, 2025, 26 subjects received doses of 4 to 900 mg BI-1910 as a single-agent Q3W. A wide therapeutic dose range was identified, with doses ≥300 mg Q3W being generally well tolerated and resulting in full receptor occupancy. Most adverse events (AEs) were Gr1/2. One Gr3 (asthenia) and no Gr4+ related AEs were recorded. The most common AE was fatigue (23%). No DLTs were reported in 22 evaluable patients. The best clinical response was Stable Disease in 12 patients, of whom five with neuroendocrine, salivary gland, endometrial, and ovarian tumors are currently exhibiting disease control for more than 6 months. Patients with disease control showed T cell activation and proliferation related to treatment ( figures 1 and 2). In SD subjects with a small but measurable decrease in tumor size, an accompanying decreasing levels of ctDNA was seen. Updated results will be presented at the meeting.Conclusions Preliminary dose escalation data are promising. BI-1910 monotherapy shows a favorable safety and tolerability profile, with evidence of early immune activation and several durable disease control cases in heavily pretreated patients.Acknowledgements We sincerely thank all patients, families and support staff for their contribution to this work.Trial Registration EUCT number: 2022-503066-74-00 ClinicalTrials.gov ID: NCT06205706Ethics Approval This study was approved by all involved institutions’ Ethics Boards.Abstract 581 Figure 1Induction of proliferating (Ki-67+) memory CD4+ T cells was observed after BI-1910 monotherapy at doses >100 mg. Sustained T cell proliferation was associated with disease controlAbstract 581 Figure 2CD4+ T cell proliferation was measured day 1-57 after treatment and AUC was calculated for patients receiving >100 mg. Patients exhibiting disease control showed a 3-fold higher expansion of Ki-67+ memory CD4+ T cells during the time to first CT scan