{
  "abstract": "Objective W0180 is a humanised IgG1κ antagonistic monoclonal antibody against the V domain-containing immunoglobulin suppressor of T-cell activation (VISTA) designed to enhance antitumour activities by inhibiting the immunosuppressive role of VISTA in myeloid cells and T cells in solid tumours.Methods and analysis Preclinical experiments evaluated the pharmacodynamics and antitumour activity of W0180. A first-in-human phase 1 dose-escalation study investigated the maximum tolerated dose (MTD), safety/tolerability, preliminary efficacy, pharmacokinetics and pharmacodynamics of W0180, both as monotherapy and in combination with pembrolizumab (an anti-programmed cell death protein-1 (PD-1) therapy), with the aim of establishing a recommended dose for expansion (RDE). In the monotherapy arm, cohorts of patients with locally advanced/metastatic solid tumours received once-weekly W0180 at increasing doses (from 3.5 to 600 mg). In the combination therapy arm, patients with relapsed/refractory, advanced/metastatic solid tumours and ≥1 prior anti-PD (ligand)-1 therapy line received W0180 (60 or 300 mg)+pembrolizumab.Results W0180 exhibited pH-independent blockade of the VISTA-ligand interaction in vitro and showed antitumour activity in a syngeneic preclinical murine model expressing human VISTA. In the phase 1 study, of the 33 patients in the monotherapy (n=24) or combination therapy (n=9) arms, 28 contributed to dose determination. Dose-limiting toxicities were Grade 2 cerebral infarction and Grade 3 infusion-related reaction (IRR; n=1 each). The study was terminated prematurely in the dose-escalation phase (due to a business decision by the sponsor) before the MTD/RDE was reached. Common related treatment-emergent adverse events were IRR and fatigue; most were of mild severity. No patients achieved Response Evaluation Criteria in Solid Tumours objective response; two had prolonged stable disease (SD; one from each arm). Biomarker analysis suggested a dose-dependent pharmacodynamic effect of W0180.Conclusion W0180 demonstrated manageable safety, preliminary signs of clinical activity with prolonged SD and dose-dependent pharmacodynamics consistent with preclinical data (even though MTD was not reached) in patients with locally advanced/metastatic tumours, both as monotherapy and in combination with anti-programmed cell death protein-1 therapy.Trial registration number NCT04564417.",
  "authors": [
    {
      "affiliations": [
        "Department of Medical Oncology & Clinical Research Unit, Oncopole Claudius Regaud, IUCT-Oncopole, University of Toulouse, Toulouse, France"
      ],
      "name": "Carlos Gomez-Roca"
    },
    {
      "affiliations": [
        "Département d'Innovation Thérapeutique et d’Essais Précoces (DITEP), Gustave Roussy Institute, Villejuif, France",
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Stéphane Champiat"
    },
    {
      "affiliations": [
        "Département d'Innovation Thérapeutique et d’Essais Précoces (DITEP), Gustave Roussy Institute, Villejuif, France"
      ],
      "name": "Francois-Xavier Danlos"
    },
    {
      "affiliations": [
        "Clinica Universidad de Navarra, Madrid, Spain"
      ],
      "name": "Eduardo Castañón Álvarez"
    },
    {
      "affiliations": [
        "Medical Oncology, Centre Léon Bérard, Lyon, France"
      ],
      "name": "Philippe Alexandre Cassier"
    },
    {
      "affiliations": [
        "Pierre Fabre Laboratories, Castres, France"
      ],
      "name": "Elena Dupuy"
    },
    {
      "affiliations": [
        "Pierre Fabre Laboratories, Castres, France"
      ],
      "name": "David Jegou"
    },
    {
      "affiliations": [
        "Pierre Fabre Laboratories, Castres, France"
      ],
      "name": "Marie Primard"
    },
    {
      "affiliations": [
        "Pierre Fabre Laboratories, Castres, France"
      ],
      "name": "Aurélie Pétain"
    },
    {
      "affiliations": [
        "Pierre Fabre Laboratories, Castres, France"
      ],
      "name": "Mathilde Saccareau"
    },
    {
      "affiliations": [
        "Pierre Fabre Laboratories, Castres, France"
      ],
      "name": "Geneviève Gueguen-Dorbes"
    },
    {
      "affiliations": [
        "Pierre Fabre Laboratories, Castres, France"
      ],
      "name": "Claire Fabre"
    },
    {
      "affiliations": [
        "Département d'Innovation Thérapeutique et d’Essais Précoces (DITEP), Gustave Roussy Institute, Villejuif, France"
      ],
      "name": "Aurélien Marabelle"
    },
    {
      "affiliations": [
        "CUN, CIMA and CIBERONC, Universidad de Navarra, Pamplona, Spain",
        "Nuffield Department of Medicine, University of Oxford, Oxford, UK"
      ],
      "name": "Ignacio Melero"
    }
  ],
  "title": "First-in-human phase 1 dose-escalation study of W0180, an anti-VISTA monoclonal antibody, with and without pembrolizumab in patients with locally advanced or metastatic solid tumours",
  "uid": "ca769c25-abb3-5b0c-9f80-46579a1445c5"
}