1495 A phase 1 multicenter study of the safety and efficacy of the NKG2A targeting antibody S095029 as single agent and in combination with anti-PD1 in patients with advanced malignancies

<h3>Background</h3> NKG2A (CD159a) is a C type lectin that heterodimerizes with CD94 creating an inhibitory receptor expressed on immune cells. 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-PD1 IgG1 antibody. Preclinical data demonstrated that S095029 combined with Sym021 results in enhanced antitumor activity. <h3>Methods</h3> This first-in-human, open-label, multicenter study (NCT05162755) evaluates safety, tolerability, preliminary efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of S095029 as monotherapy or combined with Sym021 in patients with advanced solid tumors. Monotherapy regimen included 2doses of S095029 Q2W (one 28-day cycle) followed by single agent Sym021 (Q2W). AEs were defined per CTCAE v5.0. Antitumor activity was evaluated per RECIST 1.1. Exploratory objectives included assessment of cytokine secretion as PD markers and target engagement/receptor occupancy in NKG2A expressing cells in peripheral blood. <h3>Results</h3> As of August 19 2024, 21 patients with heavily pretreated solid tumors were treated with S095029 as single agent (10, 30, 100, 300, 750 and 1500mg) and 20 patients were treated with S095029 (30, 100, 300, 750 and 1500mg) in combination with Sym021 (200mg). S095029 was well tolerated without dose-limiting toxicities for both monotherapy and combination with anti-PD1. MTD was not reached. Two patients (9.5%; uterine sarcoma, porocarcinoma) who received one cycle of S095029 monotherapy followed by Sym021 and 2 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-PD1 treatment. The clinical benefit rate (CR+PR+SD≥ 6 months) by RECIST v1.1 in all enrolled patients (n=41) was 19.5%. S095029 serum concentrations increased with dose for both monotherapy and combination with Sym021. Full receptor occupancy was achieved starting at low doses of 30 mg Q2W. Increases in levels of IFNγ, TNFα and CXCL9 in peripheral blood were detected following treatment with S095029. The recommended Phase 2 dose in combination with PD1 blockade was determined at 1140 mg Q3W. <h3>Conclusions</h3> The anti-NKG2A antibody S095029 in combination with anti-PD1 Sym021 demonstrated a favorable safety profile and exhibited antitumor activity in unselected, heavily pre-treated patients with advanced malignancies. S095029 is currently investigated in combination with anti-PD1 in patients with previously untreated advanced NSCLC with high PDL1 expression (NCT06162572), and in patients with MSI-H/dMMR advanced gastric/GEJ cancer (NCT06116136). <h3>Acknowledgements</h3> This study was sponsored by Servier. <h3>Trial Registration</h3> NCT05162755. <h3>Ethics Approval</h3> Written informed consent was provided by all the patients or their legal guardians before participation in the trial, and approval from the institutional review board or independent ethics committee was obtained at each trial site.