Background: BI-1808 is an IgG1 mAb that target TNFR2 by blocking interaction of TNFR2 with ligand TNF-α, confers FcγR-dependent depletion of Treg and mediates expansion of intratumoral CD8+ T cells. Upon co-administration of murine surrogate antibodies targeting TNFR2 and anti-PD-1 to immunocompetent tumor-bearing mice with partial sensitivity to checkpoint blockade, complete cures were observed in all treated mice. Thus, targeting TNFR2 by this approach offers a promising and novel treatment of cancer paradigm for patients. Methods: Safety and tolerability profile of BI-1808 as a single agent and in combination with pembrolizumab is currently being investigated in the Phase 1/2a clinical trial 19-BI-1808-01, enrolling patients with advanced solid malignancies or T-cell lymphomas, including CTCL. The study consists of Phase 1 dose escalation of single agent and combination with pembrolizumab. Phase 2a consists of dose expansion as single agent and as combination therapy in separate cohorts for OC, NSCLC, TCL/CTCL and Melanoma. Response is assessed according to RECIST and iRECIST. Results:As of Jan 12, 2024, 31 subjects received doses of up to 1000 mg BI-1808 as single-agent Q3W and 13 subjects received BI-1808 at 225 mg or 675 mg in combination with pembrolizumab 200 mg Q3W. Across the completed monotherapy arm dose escalation covering 25 to 1000 mg dose, no Gr3/4 AEs related to BI-1808 monotherapy were observed. Number of potentially related AEs of Gr1/2 have been evenly distributed across the dose range, with no target organ class of notice identified. 5 Gr1/2 IRR were observed, and in the combination arm 1 DLT (colitis) was observed in the 225 mg cohort. Best clinical response recorded in monotherapy arm was 1 iPR out of 20 evaluable patients, and 6 patients showing SD. The iPR was observed in a metastatic GIST patient with 12 prior lines of treatment. After initial pseudo-progression, a robust and ongoing response has been observed in this patient with several target lesions non-detectable and 60% SLD reduction from baseline. In addition, one previously untreated NSCLC showed reduction in several target lesions at 3 months when treatment terminated for unrelated reasons. Interestingly, both patients showed clear signs of T-cell activation in blood and tumor, strongly suggesting that T-cell responses underlie the tumor regressions. In the combination cohort with pembrolizumab 1/4 patients showed SD at 225 mg. At doses of ≥ 675 mg Q3W, BI-1808 t½ was approximately one week leading to accumulation of drug, leading to complete receptor occupancy throughout the dosing interval, a substantial increase in sTNFR2 and a significant reduction of regulatory T-cells. Conclusions: Preliminary data from dose escalation phase is promising. BI-1808 has a favorable safety profile, with early signs of monotherapy activity, and is well tolerated when combined with pembrolizumab. Clinical trial information: NCT04752826.