Phase 1 multicenter study of the NKG2A targeting antibody S095029 as a single agent and in combination with anti-PD-1 in patients with advanced malignancies

BACKGROUND: NKG2A is a C-type lectin that heterodimerizes with CD94 creating an inhibitory immunoreceptor. S095029 is a fully human monoclonal IgG1 anti-NKG2A antibody with attenuated Fc-effector functions that specifically binds the NKG2A/CD94 heterodimer, blocking the interaction with its ligand HLA-E. Sym021 is an anti-programmed cell death protein 1 (PD-1) IgG1 antibody. Preclinical data demonstrated that S095029 combined with Sym021 increases antitumor activity. METHODS: This first-in-human, open-label, multicenter study (NCT05162755) evaluated safety, tolerability, preliminary efficacy, pharmacokinetics and pharmacodynamics (PD) of S095029 as monotherapy or in combination with Sym021 in patients with advanced solid tumors. Monotherapy regimen included two doses of S095029 every 2 weeks (Q2W) followed by single-agent Sym021 (Q2W). Adverse events were defined per Common Terminology Criteria for Adverse Events V.5.0. Antitumor activity was evaluated per Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1. Cytokine secretion as PD markers and target engagement/receptor occupancy were assessed in peripheral blood. Selected immune markers were assessed by multiplex immunofluorescence on tumor biopsies. RESULTS: As of July 25, 2025, 21 patients with heavily pretreated solid tumors were treated with S095029 as a single agent (10, 30, 100, 300, 750 and 1,500 mg) and 20 patients were treated with S095029 (30, 100, 300, 750 and 1,500 mg) in combination with Sym021 (200 mg). S095029 was well tolerated without dose-limiting toxicities for both monotherapy and combination with anti-PD-1. A maximum tolerated dose was not reached. Two patients (9.5%; uterine sarcoma, porocarcinoma) who received one cycle of S095029 monotherapy followed by Sym021 and two patients (10%; leiomyosarcoma, squamous cell carcinoma of unknown primary) who received S095029 in combination with Sym021 showed confirmed partial responses. None of these patients had received prior anti-PD-1 treatment. The clinical benefit rate (complete response+partial response+stable disease ≥6 months) by RECIST V.1.1 in all enrolled patients was 19.5%. S095029 serum concentrations increased with dose for both monotherapy and combination with Sym021. Full receptor occupancy was achieved starting at 30 mg Q2W. Increases in levels of monokine induced by gamma interferon, macrophage inflammatory protein 1-beta and tumor necrosis factor-α in peripheral blood were detected following treatment with S095029+Sym021 suggesting immune cell activation on treatment. CONCLUSIONS: The anti-NKG2A antibody S095029 in combination with anti-PD-1 Sym021 demonstrated a favorable safety profile and exhibited signal of antitumor activity in unselected, heavily pretreated patients with advanced malignancies. TRIAL REGISTRATION NUMBER: NCT05162755.