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First-in-human, multicenter, open-label, phase I study of ATOR-1017 (evunzekibart), a 4-1BB antibody, in patients with advanced solid malignancies

Carneiro, Ana LU orcid ; Hahn, Amanda ; Ellmark, Peter LU ; Enell Smith, Karin LU ; Schultz, Lena ; Ambarkhane, Sumeet ; Yachnin, Jeffrey and Ullenhag, Gustav J (2025) In Journal for ImmunoTherapy of Cancer 13.
Abstract

BACKGROUND: ATOR-1017 (evunzekibart) is a human agonistic immunoglobulin G4 antibody targeting the costimulatory receptor 4-1BB (CD137). ATOR-1017 activates T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell death.

METHODS: In this first-in-human, multicenter, phase I study, ATOR-1017 was administered intravenously every 21 days as a monotherapy to patients with advanced, unresectable solid tumors having received multiple standard-of-care treatments. The study used single patient cohorts for rapid dose escalation up to 40 mg; thereafter a modified 3+3 design up to 900 mg. Escalating doses were given until disease progression, unacceptable toxicity, or withdrawal of consent. The primary... (More)

BACKGROUND: ATOR-1017 (evunzekibart) is a human agonistic immunoglobulin G4 antibody targeting the costimulatory receptor 4-1BB (CD137). ATOR-1017 activates T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell death.

METHODS: In this first-in-human, multicenter, phase I study, ATOR-1017 was administered intravenously every 21 days as a monotherapy to patients with advanced, unresectable solid tumors having received multiple standard-of-care treatments. The study used single patient cohorts for rapid dose escalation up to 40 mg; thereafter a modified 3+3 design up to 900 mg. Escalating doses were given until disease progression, unacceptable toxicity, or withdrawal of consent. The primary objective of the study included determination of the maximum tolerated dose (MTD) via assessment of adverse events and dose-limiting toxicities (DLTs). Secondary objectives included determination of the pharmacokinetics, immunogenicity and clinical efficacy assessed with CT scans using immune Response Evaluation Criteria in Solid Tumors. Exploratory objectives included pharmacodynamic (PD) assessment of immune system biomarkers.

RESULTS: Of the 27 patients screened, 25 received treatment with ATOR-1017. The median time on study was 13.1 weeks (range 4.3-92.3). The MTD of ATOR-1017 was not reached. Treatment-related adverse events (TRAEs) were reported in 13 (52%) of 25 patients; most common (≥10%) were fatigue (n=4 (16.0%) patients) and neutropenia (n=3 (12.0%) patients). Five patients experienced a severe (≥ grade 3) TRAE; neutropenia (n=2), febrile neutropenia (n=1), chest pain (n=1), increased liver enzymes (n=1), and leukopenia and thrombocytopenia (n=1). No patients discontinued due to TRAEs and no DLTs were observed. Pharmacokinetic data demonstrated approximate dose-proportional kinetics. Dose-dependent increases in PD biomarkers, including soluble 4-1BB, are indicative of target-mediated biological activity. Best response was stable disease in 13 out of 25 patients (52%), maintained for 6 months or longer in six patients (24%).

CONCLUSIONS: Treatment with ATOR-1017 was safe and well tolerated at all dose levels and demonstrated biological activity. Furthermore, almost one-third of patients experienced long-lasting stable disease in this heavily pretreated population. The encouraging safety and preliminary efficacy data warrant further clinical development of ATOR-1017, possibly in combination with other anticancer agents.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Humans, Neoplasms/drug therapy, Male, Female, Middle Aged, Aged, Adult, Tumor Necrosis Factor Receptor Superfamily, Member 9, Maximum Tolerated Dose, Aged, 80 and over
in
Journal for ImmunoTherapy of Cancer
volume
13
publisher
BMJ Publishing Group
external identifiers
  • pmid:39848688
  • scopus:85216717660
ISSN
2051-1426
DOI
10.1136/jitc-2024-010113
language
English
LU publication?
yes
additional info
© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.
id
fbe61503-ac91-4d4b-83bb-1e0e00a2ef22
date added to LUP
2025-02-12 12:23:34
date last changed
2025-07-17 16:59:34
@article{fbe61503-ac91-4d4b-83bb-1e0e00a2ef22,
  abstract     = {{<p>BACKGROUND: ATOR-1017 (evunzekibart) is a human agonistic immunoglobulin G4 antibody targeting the costimulatory receptor 4-1BB (CD137). ATOR-1017 activates T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell death.</p><p>METHODS: In this first-in-human, multicenter, phase I study, ATOR-1017 was administered intravenously every 21 days as a monotherapy to patients with advanced, unresectable solid tumors having received multiple standard-of-care treatments. The study used single patient cohorts for rapid dose escalation up to 40 mg; thereafter a modified 3+3 design up to 900 mg. Escalating doses were given until disease progression, unacceptable toxicity, or withdrawal of consent. The primary objective of the study included determination of the maximum tolerated dose (MTD) via assessment of adverse events and dose-limiting toxicities (DLTs). Secondary objectives included determination of the pharmacokinetics, immunogenicity and clinical efficacy assessed with CT scans using immune Response Evaluation Criteria in Solid Tumors. Exploratory objectives included pharmacodynamic (PD) assessment of immune system biomarkers.</p><p>RESULTS: Of the 27 patients screened, 25 received treatment with ATOR-1017. The median time on study was 13.1 weeks (range 4.3-92.3). The MTD of ATOR-1017 was not reached. Treatment-related adverse events (TRAEs) were reported in 13 (52%) of 25 patients; most common (≥10%) were fatigue (n=4 (16.0%) patients) and neutropenia (n=3 (12.0%) patients). Five patients experienced a severe (≥ grade 3) TRAE; neutropenia (n=2), febrile neutropenia (n=1), chest pain (n=1), increased liver enzymes (n=1), and leukopenia and thrombocytopenia (n=1). No patients discontinued due to TRAEs and no DLTs were observed. Pharmacokinetic data demonstrated approximate dose-proportional kinetics. Dose-dependent increases in PD biomarkers, including soluble 4-1BB, are indicative of target-mediated biological activity. Best response was stable disease in 13 out of 25 patients (52%), maintained for 6 months or longer in six patients (24%).</p><p>CONCLUSIONS: Treatment with ATOR-1017 was safe and well tolerated at all dose levels and demonstrated biological activity. Furthermore, almost one-third of patients experienced long-lasting stable disease in this heavily pretreated population. The encouraging safety and preliminary efficacy data warrant further clinical development of ATOR-1017, possibly in combination with other anticancer agents.</p>}},
  author       = {{Carneiro, Ana and Hahn, Amanda and Ellmark, Peter and Enell Smith, Karin and Schultz, Lena and Ambarkhane, Sumeet and Yachnin, Jeffrey and Ullenhag, Gustav J}},
  issn         = {{2051-1426}},
  keywords     = {{Humans; Neoplasms/drug therapy; Male; Female; Middle Aged; Aged; Adult; Tumor Necrosis Factor Receptor Superfamily, Member 9; Maximum Tolerated Dose; Aged, 80 and over}},
  language     = {{eng}},
  month        = {{01}},
  publisher    = {{BMJ Publishing Group}},
  series       = {{Journal for ImmunoTherapy of Cancer}},
  title        = {{First-in-human, multicenter, open-label, phase I study of ATOR-1017 (evunzekibart), a 4-1BB antibody, in patients with advanced solid malignancies}},
  url          = {{http://dx.doi.org/10.1136/jitc-2024-010113}},
  doi          = {{10.1136/jitc-2024-010113}},
  volume       = {{13}},
  year         = {{2025}},
}