Efficacy, safety, and PK/PD of LVGN6051, 4-1BB agonistic antibody, with pembrolizumab in a phase Ib dose expansion in resistant NSCLC, melanoma, and GI malignancy.

2575 Background: LVGN6051 is a 4-1BB agonistic monoclonal antibody with Fc γ-receptor IIB binding designed for selective activation in the tumor microenvironment. A prior phase Ia trial of this combination showed RP2D to be 4 mg/kg LVGN6051 with 200mg pembrolizumab. We explored the activity of this combination in resistant NSCLC, Melanoma, and GI malignancies. Methods: A phase Ib expansion of LVGN6051 2 mg/kg in the first dose followed by 4 mg/kg in combination with pembrolizumab 200 mg IV Q3W was carried out in selected resistant malignancies (NCT04130542). Eligible pts received treatment until progressive disease, unacceptable toxicity, up to 35 cycles, or withdrawal of consent. Results: As of Dec 18, 2023, 48 pts were enrolled and received at least 1 dose of LVGN6051 combination regimen. 33 pts (68.6%) had prior ICI treatment. The median age was 62 years (range 20-89), 30 pts (62.5%) had ECOG PS 1, and the median number of prior therapies was 4. Treatment related adverse events were seen in 33 pts (68.8%) patients with Grade ≥ 3 AE in 18 pts (37.5%) and related SAE in 12 pts (30%). The most common Grade ≥3 AEs were thrombocytopenia (10.4%) and AST/ALT elevation (4.2%). Cmax and AUC were dose proportional and T 1/2 was 1.90-8.91 days. Sustained exposure (>1000 ng/mL) was achieved at 2 and 4 mg/kg Q3W. Anti-drug antibodies of LVGN6051 in low titers were detected in 20 of 48 subjects without apparent effect on PK. While the efficacy evaluation is still ongoing, 2 pts had a PR with one confirmed and another one unconfirmed, and 2 pts had an SD in the NSCLC cohort (n=14). Both patients with a PR had squamous histology and prior progression on pembrolizumab. In the Melanoma cohort (n=22), 1 pt had an unconfirmed CR but confirmed PR, 1 pt had a confirmed PR, and 4 pts had an SD. In the GI malignancy cohort (n=12), 3 pts had an SD. Cumulatively, for Phase Ia and Ib, this study has treated 33 melanoma pts, of whom 30 (90.9%) had prior exposure to ICI. 4 melanoma pts had a CR or PR, and 7 had an SD as the best objective response by RECIST. Melanoma pts with an objective response included 1 mucosal and 1 acral melanoma. The median duration of response for melanoma pts was 128 days (range 97 – >344) with several ongoing responses. Tumor single-cell RNAseq immune profiling was obtained and preliminary analysis shows increased Tem cells and immune pathway activity. Conclusions: Targeting 4-1BB and PD-1 with the combination of LVGN6051 and pembrolizumab appears to be well tolerated at this dose and schedule and shows predictable PK/PD parameters. In patients with ICI resistant Melanoma and NSCLC, durable objective responses were achieved with clinical benefits in patients resistant to prior ICI treatment. Further development of LVGN6051 is warranted. Clinical trial information: NCT04130542 .