A Phase 1 First-Time-in-Human, Open-Label Study of Nelistotug Administered to Patients with Advanced Solid Tumors

PURPOSE: This first-in-human, nonrandomized, multicenter study investigated nelistotug (anti-CD96 monoclonal antibody [mAb]) as monotherapy (Arm A) and in combination with dostarlimab (anti-PD-1 mAb) (Arm B), and dostarlimab plus belrestotug (anti-TIGIT mAb) (Arm F) in patients with recurrent or advanced solid tumors. PATIENTS AND METHODS: Patients received intravenous doses every 3 weeks of nelistotug 2.1-1400 mg, nelistotug 70-1400 mg plus dostarlimab 500 mg, or nelistotug 1400 mg plus dostarlimab 500 mg plus belrestotug 400 mg in Arms A, B and F, respectively. Primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary endpoints included objective response rate, pharmacokinetics, and immunogenicity. Disease control rate and CD96 receptor occupancy were exploratory. RESULTS: 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 2 dose of 1400 mg. No treatment-related fatal AEs were observed. In Arm B, one (3%) patient achieved a complete response and one (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. CONCLUSIONS: 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.

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Publication Details

Journal
Clinical Cancer Research
Published
2026-08-27
DOI
https://doi.org/10.1158/1078-0432.ccr-25-4374
Primary Topic
Monoclonal and Polyclonal Antibodies Research
Type
article
Field-Weighted Citation Impact
0.00

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article

A Phase 1 First-Time-in-Human, Open-Label Study of Nelistotug Administered to Patients with Advanced Solid Tumors

Lillian L. Siu, Reza Mozaffari, Madhu Ramaswamy, Stefan Zajic et al.
Clinical Cancer Research
Monoclonal and Polyclonal Antibodies Research
article

A Phase 1 First-Time-in-Human, Open-Label Study of Nelistotug Administered to Patients with Advanced Solid Tumors

Lillian L. Siu, Reza Mozaffari, Madhu Ramaswamy, Stefan Zajic, Omid Hamid, Noboru Yamamoto, Jordi Rodón, Myung‐Ju Ahn, Patrick Hanafin, Reva Schneider, Hussein Assi, Scott A. Laurie, F. Stephen Hodi, Arindam Dhar, Dong‐Wan Kim, Gary Carlson, Ivan Diaz Padilla, Emily Moore, Hamza Khan
article en

Abstract

PURPOSE: This first-in-human, nonrandomized, multicenter study investigated nelistotug (anti-CD96 monoclonal antibody [mAb]) as monotherapy (Arm A) and in combination with dostarlimab (anti-PD-1 mAb) (Arm B), and dostarlimab plus belrestotug (anti-TIGIT mAb) (Arm F) in patients with recurrent or advanced solid tumors. PATIENTS AND METHODS: Patients received intravenous doses every 3 weeks of nelistotug 2.1-1400 mg, nelistotug 70-1400 mg plus dostarlimab 500 mg, or nelistotug 1400 mg plus dostarlimab 500 mg plus belrestotug 400 mg in Arms A, B and F, respectively. Primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary endpoints included objective response rate, pharmacokinetics, and immunogenicity. Disease control rate and CD96 receptor occupancy were exploratory. RESULTS: 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 2 dose of 1400 mg. No treatment-related fatal AEs were observed. In Arm B, one (3%) patient achieved a complete response and one (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. CONCLUSIONS: 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.

Clinical Cancer Research
The University of Texas MD Anderson Cancer Center (US), Age UK (GB), Ottawa Hospital (CA), Princess Margaret Cancer Centre (CA), Seoul National University Hospital (KR), AVEO Oncology (United States) (US), Mary Crowley Cancer Research Center (US), National Cancer Center (US), Angeles Clinic and Research Institute (US), GlaxoSmithKline (United States) (US), Dana-Farber Cancer Institute (US), GlaxoSmithKline (Canada) (CA), GlaxoSmithKline (Switzerland) (CH), Boston Sports & Shoulder Center (US), Tokyo National Hospital (JP), Sungkyunkwan University (KR)
Amgen, Bristol-Myers Squibb, Pfizer, Incyte, EMD Serono, Daiichi Sankyo Europe
Good health and well-being
Openalex Percentile: Top 11%
Monoclonal and Polyclonal Antibodies Research
DOIOpen Access PDFOpenAlex
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