Phase I dose-escalation and pharmacodynamic study of STING agonist E7766 in advanced solid tumors

E7766 is a novel stimulator of interferon genes (STING) agonist, capable of potent activation of immune cells and generating strong antitumor response in preclinical murine tumor models. Here we present the safety, efficacy, and biomarker results of the first-in-human phase I/Ib study of intratumoral E7766 in patients with advanced solid tumors. Eligible patients with relapsing/refractory cancers (n=24) were enrolled in dose-escalating cohorts to receive intratumoral injections of E7766 from 75 to 1000 µg. The most frequent treatment-related treatment-emergent adverse events were chills (50.0%; 85.7%), fever (40.0%; 85.7%), and fatigue (30.0%; 35.7%) in patients who received non-visceral and visceral injections, respectively. Eight patients (33.3%) achieved stable disease as their best response per modified Response Evaluation Criteria In Solid Tumors version 1.1 with variability between injected and non-injected lesions. Plasma levels of IFN-α, IFN-β, IFN-γ, TNF-α, IL-6, IP-10, MCP1, and MIP1b transiently increased in all evaluable patients within 10 hours postinjection, then dropped to baseline levels. Levels of blood and tumor gene expression increased in most interferon-related and STING genes tested. Further increases in programmed death ligand 1 and cluster of differentiation 8 expression at both the RNA and protein levels were also observed in some patients across dose levels. In total, E7766 generated on-target pharmacodynamic effects in patients with solid tumors. Further exploration in a homogeneous patient population is necessary to assess efficacy.

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Publication Details

Journal
Journal for ImmunoTherapy of Cancer
Published
2025-02-01
DOI
https://doi.org/10.1136/jitc-2024-010511
Citations
26
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
20.73

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article

Phase I dose-escalation and pharmacodynamic study of STING agonist E7766 in advanced solid tumors

David James Pinato, Patricia LoRusso, Stéphane Champiat, Jason J. Luke et al.
26 citations
Journal for ImmunoTherapy of Cancer
interferon and immune responses
20.73
article

Phase I dose-escalation and pharmacodynamic study of STING agonist E7766 in advanced solid tumors

David James Pinato, Patricia LoRusso, Stéphane Champiat, Jason J. Luke, Peter J. Hosein, Aurélien Marabelle, Maria J. de Miguel, Robert I. Haddad, Dejan Juric, Yuanxin Rong, Xiao-pei Yuan, Andrés Cervantes, Yan Zhang, Anupam M. Desai, Won Seog Kim
article en
26 citations

Abstract

E7766 is a novel stimulator of interferon genes (STING) agonist, capable of potent activation of immune cells and generating strong antitumor response in preclinical murine tumor models. Here we present the safety, efficacy, and biomarker results of the first-in-human phase I/Ib study of intratumoral E7766 in patients with advanced solid tumors. Eligible patients with relapsing/refractory cancers (n=24) were enrolled in dose-escalating cohorts to receive intratumoral injections of E7766 from 75 to 1000 µg. The most frequent treatment-related treatment-emergent adverse events were chills (50.0%; 85.7%), fever (40.0%; 85.7%), and fatigue (30.0%; 35.7%) in patients who received non-visceral and visceral injections, respectively. Eight patients (33.3%) achieved stable disease as their best response per modified Response Evaluation Criteria In Solid Tumors version 1.1 with variability between injected and non-injected lesions. Plasma levels of IFN-α, IFN-β, IFN-γ, TNF-α, IL-6, IP-10, MCP1, and MIP1b transiently increased in all evaluable patients within 10 hours postinjection, then dropped to baseline levels. Levels of blood and tumor gene expression increased in most interferon-related and STING genes tested. Further increases in programmed death ligand 1 and cluster of differentiation 8 expression at both the RNA and protein levels were also observed in some patients across dose levels. In total, E7766 generated on-target pharmacodynamic effects in patients with solid tumors. Further exploration in a homogeneous patient population is necessary to assess efficacy.

Journal for ImmunoTherapy of CancerVol. 13(2)
Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), Beth Israel Deaconess Medical Center (US), Harvard University (US), University of Miami (US), Universitat de València (ES), University of Pittsburgh (US), Instituto de Salud Carlos III (ES), Institut Gustave Roussy (FR), Samsung Medical Center (KR), Yale University (US), Massachusetts General Hospital (US), UPMC Health System (US), Dana-Farber Cancer Institute (US), UPMC Hillman Cancer Center (US), Hospital Universitario HM Sanchinarro (ES), Eisai (United States) (US), INCLIVA Health Research Institute (ES), Imperial College London (GB), Sungkyunkwan University (KR)
National Institute for Health and Care Research, Department of Health and Social Care, Imperial College London, Imperial College Healthcare NHS Trust, Eisai, Imperial Experimental Cancer Medicine Centre, NIHR Imperial Biomedical Research Centre
Good health and well-being
Openalex Percentile: Top 0%
interferon and immune responses
20.73
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