{
  "abstract": "Background Immunosuppression mechanisms mediated by regulatory T cells (T regs) can lead to poor clinical outcomes in patients undergoing immune-based therapies. Activation markers, such as inducible T-cell co-stimulator (ICOS), are highly expressed on the surface of tumor-infiltrating Tregs and present as relevant targets for targeted depletion of these cells. Here, we present clinical outcomes from a Phase 1 study (NCT03829501) of an anti-ICOS antibody of alomfilimab (SAR445256 or KY1044) as monotherapy and in combination with the anti-programmed death-ligand 1 (PD-L1) antibody, atezolizumab, in patients with advanced solid tumors.Methods Alomfilimab was administered intravenously once every 3 weeks (Q3W) ±3 days at six dose levels (DLs; 0.8 mg to 240 mg) as monotherapy and five DLs (0.8 mg to 80 mg) in combination with atezolizumab (1,200 mg Q3W ±3 days). Eligible patients must have had advanced metastatic disease as determined by Response Evaluation Criteria in Solid Tumors V.1.1 and no viable treatment options according to National Comprehensive Cancer Network guidelines.Results Overall 38 patients were enrolled in the monotherapy cohort, and 102 patients were enrolled in the combination therapy cohort. Alomfilimab had a manageable safety profile and showed a trend toward modest efficacy in tumor growth control when combined with anti-PD-L1 in selected malignancies. At least one treatment-emergent adverse event was reported in 35 patients (89.7%) in the monotherapy cohort, and in 99 (98%) patients in the combination cohort. Objective response was not observed in the monotherapy cohort. In the combination cohort, seven patients had an objective response. Median time to progression-free survival was 2 months for both cohorts. Furthermore, alomfilimab showed evidence of target engagement on T-cell subsets, specifically cluster of differentiation (CD)4+memory cells, in both single-agent and in combination treatment with atezolizumab. This was accompanied by transient elevation of granulocyte-macrophage colony-stimulating factor, interferon-γ, and tumor necrosis factor-α levels and dose-dependent reduction of ICOS+T regs in the tumor microenvironment.Conclusions Alomfilimab treatment was associated with an acceptable safety profile across both mono and combination approaches, accompanied by decreased ICOS+T regs populations and enhanced CD4+ and CD8+ effector T cells cell activity. Limited clinical activity was observed despite evidence of biological activity.Trial registration number NCT03829501.",
  "authors": [
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA"
      ],
      "name": "Aung Naing"
    },
    {
      "affiliations": [
        "National Taiwan University Hospital, Taipei City, Taiwan"
      ],
      "name": "Chia-Chi Lin"
    },
    {
      "affiliations": [
        "Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida, USA"
      ],
      "name": "Manish R Patel"
    },
    {
      "affiliations": [
        "Istituto Europeo di Oncologia Biblioteca IRCCS, Milan, Lombardy, Italy",
        "Medical Oncology and Hematology Department, University of Milan, Milan, Lombardy, Italy"
      ],
      "name": "Giuseppe Curigliano"
    },
    {
      "affiliations": [
        "Sarah Cannon Research Institute LLC, Nashville, Tennessee, USA"
      ],
      "name": "Howard A. Burris"
    },
    {
      "affiliations": [
        "Advanced Immunotherapy and Cell Therapy Team, Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK"
      ],
      "name": "Fiona Thistlethwaite"
    },
    {
      "affiliations": [
        "Medical Oncology and Hematology Department, University of Milan, Milan, Lombardy, Italy",
        "Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Lombardia, Italy"
      ],
      "name": "Filippo De Braud"
    },
    {
      "affiliations": [
        "Drug Development Unit, Royal Marsden Hospital, The Institute of Cancer Research - Sutton, London, UK"
      ],
      "name": "Anna Minchom"
    },
    {
      "affiliations": [
        "Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy",
        "Universita degli Studi di Napoli Federico II, Naples, Campania, Italy"
      ],
      "name": "Paolo A Ascierto"
    },
    {
      "affiliations": [
        "Kymab, a Sanofi Company, Babraham Research Campus, Cambridge, UK"
      ],
      "name": "Matthew Wake"
    },
    {
      "affiliations": [
        "Sanofi, Frankfurt, Germany"
      ],
      "name": "Mai A Nguyen"
    },
    {
      "affiliations": [
        "Sanofi, Research and Development, Sanofi, Morristown, New Jersey, USA"
      ],
      "name": "Giovanni Abbadessa"
    },
    {
      "affiliations": [
        "Kymab, a Sanofi Company, Babraham Research Campus, Cambridge, UK"
      ],
      "name": "Richard C A Sainson"
    },
    {
      "affiliations": [
        "Sanofi, Cambridge, UK"
      ],
      "name": "Cintia C Palu"
    },
    {
      "affiliations": [
        "Kymab, a Sanofi Company, Babraham Research Campus, Cambridge, UK"
      ],
      "name": "Sonia Quaratino"
    },
    {
      "affiliations": [
        "Sanofi, Cambridge, UK"
      ],
      "name": "Cecilia Deantonio"
    }
  ],
  "title": "First-in-human, phase 1, open-label study of alomfilimab, an anti-ICOS antibody, as a single agent and in combination with anti-PD-L1 in advanced malignancies",
  "uid": "64d89c62-014f-5208-bc5a-d787e3f8744b"
}