Background CTLA-4 as an immunotherapeutic target that has been challenged with limited single agent efficacy and high-grade toxicities in the clinic. ADG116 is a fully human anti-CTLA-4 IgG1 monoclonal antibody that targets a unique and a highly conserved epitope of CTLA-4 using the NEObody™ technology platform. ADG116 enables a safer T cell activation via partial CD80/86 ligand blockade and enhances the Treg depletion in the tumor microenvironment via a stronger ADCC. Preclinical studies demonstrated that ADG116 is more potent and better tolerated than ipilimumab. In a Phase 1 dose escalation study, single agent ADG116 has been well-tolerated up to 10 mg/kg when dosed intravenously, once every 3 weeks (Q3W); target lesion size reduction and stable diseases were observed in multiple heavily pre-treated patients including those bearing “cold” tumors.¹ We propose that ADG116 in combination with pembrolizumab may enhance clinical antitumor activity through a simultaneous blockade of the PD-1/PD-L1 and CTLA-4 pathways while still maintaining a favorable safety profile.

Methods This is a Phase 1b/2, open label, multicenter, dose escalation and dose expansion study of ADG116 in combination with pembrolizumab in patients with advanced/metastatic solid tumors. During dose escalation, ADG116 and pembrolizumab are administered intravenously, Q3W. Primary endpoints are safety and tolerability. Secondary endpoints are PK, ORR per RECIST 1.1, and PFS.

Results As of June 30, 2022, 4 patients have been treated by ADG116 (3 mg/kg) + pembrolizumab (200 mg) combination therapy. Patients were 69 (47-74) years-old [median (range)] and have been heavily pre-treated before enrollment: all 4 (100%) had prior chemotherapy, 1 (25%) radiation therapy, 1 (25%) hormonal therapy; 2 (50%) received ≥ 3 prior lines of therapies, but none had been treated with an anti-PD-1/PD-L1, or an anti-CTLA-4 therapy. ADG116 + Pembro combination showed a manageable safety profile with no DLTs. Most common treatment-related adverse events were Grade 1 nausea (50%) and pruritis (50%). One Grade 3 AE (dehydration) was observed after repeated dosing in Cycle 3 (C3D12). Additional safety and efficacy data will be reported.

Conclusions The current safety data supports the regimen of ADG116 (3 mg/kg)/pembrolizumab (200 mg), Q3W for dose expansion, which is a higher dose than that approved for ipilimumab (1 mg/kg) when in combination with nivolumab for several cancer indications. Additional repeat dosing data are being generated to inform the safety, tolerability, and activity of ADG116 in combination with the anti-PD-1 therapy.

Acknowledgements We would like to acknowledge the editorial support from Ami Celeste Knoefler

Trial Registration Clinical trial identification NCT04501276

Reference

1. G Richardson, A Tolcher, et al and P Luo. Phase I dose-finding study of a novel anti-CTLA-4 antibody ADG116 as monotherapy in patients with advanced solid tumors. Annals of Oncology. 2021;32(Suppl 7):S1436-S1437 https://www.annalsofoncology.org/article/S0923-7534(21)04692-5/fulltext

Ethics Approval The study obtained ethics approvals from the following Ethics Committee(s)/Institutional Review Board(s), the number/ID of the approval(s):

1. Salus IRB; ID: IORG0005674

2. Advarra IRB; ID: IORG0000635

All participants of this clinical study gave informed consent before taking part.

Consent Written informed consent was obtained from patients for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.