Background: LVGN6051 is a conditional 4-1BB agonistic monoclonal antibody with Fcγ-receptor IIB selective binding in the tumor microenvironment for optimal activity. Preclinical studies showed potent antitumor activity by LVGN6051 alone and in combination with anti-PD-1 antibody. Methods: We conducted this first in human (FIH) multicenter phase 1 dose escalation study in the US. Eligible pts with advanced solid tumor malignancies received escalating doses of LVGN6051 alone or in combination with pembrolizumab 200 mg IV Q3W until unacceptable toxicity, progressive disease, or withdrawal of consent. Results: As of Jan 23, 2023, 55 pts were enrolled and received LVGN6051 alone with the dose range of 0.003–7 mg/kg (n=18), or combination therapy of LVGN6051 2 mg/kg + pembrolizumab (n=22) or LVGN6051 4 mg/kg + pembrolizumab (n=15). The median age was 58 years (range 20-83) and number of prior therapies was 5; 46 pts (84%) had ECOG PS 1 and 21 pts (38%) had received prior immune checkpoint inhibitors (ICI). In pts who received LVGN6051 alone, the MTD was not reached up to 7 mg/kg and the RP2D was selected as 4 mg/kg IV Q3W for tolerance. The RP2D for combination therapy was established as LVGN6051 4 mg/kg and pembrolizumab 200 mg IV Q3W. Pts received a median of 2.8 months and a mean of 4.0 months (range 0.5 – 19.2) of study treatment. 33 pts (60%) experienced any grade treatment-related adverse events (TRAEs) with noteworthy (> 5%) AST increased (27%), ALT increased (26%), thrombocytopenia (16%), infusion related reaction (IRR) (9%), fatigue (7%), lipase increased (6%), nausea (6%) and chills (6%). 14 pts (25%), 1 mono- and 13 combination therapy, showed ≥ grade 3 TRAEs: AST increased (11%), ALT increased (9%), thrombocytopenia (7%), fatigue (4%), IRR (2%), lipase increased (2%) and nausea (2%). 6 drug-related serious adverse events and 1 DLT (grade 4 thrombocytopenia), all in combination therapy, were reported. In 42 evaluable pts, the disease control rate (DCR) was 50%. Combination therapy showed that target lesions were reduced by 57%, 42% and 48% in melanoma (n=2) and pancreatic cancer (n=1), respectively. Among 11 melanoma pts (10 had progressed on anti-CTLA4 and anti-PD-1 therapy), 2 PR and 5 SD were observed per RECIST 1.1, including one being treated for 19+ months (26+ cycles). Pts with HNSqCC (n=1) and CRPC (n=1) also showed remarkable tumor shrinkage. Paired tumor biopsies for single cell RNAseq biomarker exploration confirmed activation of effector T cells following LVGN6051 treatment. Conclusions: We established the RP2Ds of LVGN6051 alone and in combination with pembrolizumab in this FIH phase 1a study. These regimens were well tolerated. Preliminary efficacy data showed encouraging anti-tumor activity in heavily pretreated pts who had progressed on ICI. Phase 1b dose expansion for the combination therapy is ongoing in pts with melanoma, GI malignancies and NSCLC. Clinical trial information: NCT04130542.