19-BI-1808-01, a phase 1/2a clinical trial of BI-1808, a tumor necrosis factor receptor 2 (TNFR2) blocker/depleter with or without pembrolizumab.
Authors: Kristoffer Staal Rohrberg, Zsuzsanna Papai, Rikke Løvendahl Eefsen, Jeffrey Yachnin, Ana Carneiro, Sean H Lim, Harriet S. Walter, Istvan Lang, Edvard Abel, Kirstie Cleary, Mark Cragg, Robert Oldham, Marie Borggren, Susanne Gertsson, Ingrid Karlsson, Johan Erik Wallin, Michael Jon Chisamore, Ingrid Teige, Björn Frendeus, Andres McAllister
Journal: Journal of Clinical Oncology (2024)

2641 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 .