A Phase I First-Time-in-Human, Open-label Study of Nelistotug Administered to Patients with Advanced Solid Tumors

This first-in-human, nonrandomized, multicenter study investigated nelistotug [anti-cluster of differentiation (CD) 96 monoclonal antibody (mAb)] as monotherapy (arm A), in combination with dostarlimab [anti-programmed cell death protein 1 (PD-1) mAb; arm B], and dostarlimab plus belrestotug [anti-T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) mAb; arm F] in patients with recurrent or advanced solid tumors.

Patients received intravenous doses every 3 weeks of nelistotug 2.1 to 1,400 mg, nelistotug 70 to 1,400 mg plus dostarlimab 500 mg, or nelistotug 1,400 mg plus dostarlimab 500 mg plus belrestotug 400 mg in arms A, B, and F, respectively. Primary endpoints were dose-limiting toxicities (DLT) and adverse events (AE). Secondary endpoints included objective response rate, pharmacokinetics, and immunogenicity. Disease control rate and CD96 receptor occupancy were exploratory.

Thirty-six, 33, and 3 patients were included in arms A, B, and F, respectively. No DLTs were observed in any arm, allowing for dose escalation to nelistotug maximum planned dose in arms A and B, with a recommended phase II dose of 1,400 mg. No treatment-related fatal AEs were observed. In arm B, 1 (3%) patient achieved a complete response and 1 (3%) achieved a partial response; no responses were observed in arms A and F. Nelistotug serum concentrations across doses were calculated to be sufficient to saturate the target in the tumor since >95% CD96 receptor occupancy was observed in peripheral blood immune cells.

Nelistotug as monotherapy and in combination with dostarlimab and belrestotug had an acceptable safety and tolerability profile; however, efficacy was limited in this heavily pretreated patient population with advanced solid tumors.