{
  "abstract": "Background This first-in-human clinical study explored lomvastomig, an immunoglobulin G1-based Fc-silenced bispecific antibody that simultaneously blocks the immune checkpoint receptors programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain-3.Methods Lomvastomig was characterized in cell cultures and preclinically in cancer mouse models. The phase 1, open-label, multicenter clinical study of lomvastomig included a dose-escalation part in patients with advanced and/or metastatic solid tumors and an expansion part with four tumor-specific cohorts, which enrolled checkpoint inhibitor (CPI)-experienced patients with melanoma and non-small-cell lung cancer (NSCLC) and CPI-naïve patients with SCLC and esophageal squamous cell carcinoma (ESCC). Primary and secondary objectives included safety/tolerability, maximum tolerated dose (MTD)/recommended dose for expansion (RDE), pharmacokinetics, drug receptor occupancy, and antitumor activity.Results 39 and 95 patients were enrolled in the dose-escalation and expansion parts, respectively. Lomvastomig was well tolerated up to the highest tested dose of 2,100 mg every 2 weeks (Q2W). One dose-limiting toxicity was reported at 1,200 mg (grade 3 troponin T increase). No MTD was reached, and 2,100 mg Q2W was established as the RDE. Linear pharmacokinetics across the studied dose range suggested target saturation. Peripheral blood drug receptor occupancy on CD3+ and CD8+ was saturated at >90% throughout treatment for doses ≥70 mg. Objective responses were observed at 2,100 mg lomvastomig during dose-escalation (21%; n=19), and in the CPI-experienced melanoma (8%, n=38) and CPI-naïve ESCC (20%, n=15) expansion cohorts.Conclusions Lomvastomig had a tolerable and manageable safety profile at 2,100 mg Q2W. Clinical activity was limited in CPI-experienced patients with melanoma and NSCLC, while an encouraging signal was observed in CPI-naïve patients with ESCC.Trial registration number NCT03708328 (registration date: 2018–10-09).",
  "authors": [
    {
      "affiliations": [
        "Department of Oncology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark"
      ],
      "name": "Kristoffer Staal Rohrberg"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Clinica Universidad de Navarra",
        "CIMA and CIBERONC, Pamplona, Spain",
        "Nuffield Department of Medicine, University of Oxford, Oxford, UK"
      ],
      "name": "Ignacio Melero"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Clinica Universidad de Navarra",
        "CIMA and CIBERONC, Pamplona, Spain"
      ],
      "name": "Miguel F Sanmamed"
    },
    {
      "affiliations": [
        "Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain"
      ],
      "name": "Eva Muñoz-Couselo"
    },
    {
      "affiliations": [
        "Medical Oncology, INCLIVA Health Research Institute, Valencia, Spain",
        "CIBERONC, Madrid, Spain"
      ],
      "name": "Andrés Cervantes"
    },
    {
      "affiliations": [
        "Medical Oncology, INCLIVA Health Research Institute, Valencia, Spain"
      ],
      "name": "Valentina Gambardella"
    },
    {
      "affiliations": [
        "Multidisciplinary Oncology and Therapeutic Innovations Department, Aix-Marseille University, Marseille, France"
      ],
      "name": "Laurent Greillier"
    },
    {
      "affiliations": [
        "Med oncology, Hospital Universitario Ramon y Cajal, Madrid, Spain"
      ],
      "name": "Pilar Garrido"
    },
    {
      "affiliations": [
        "Internal Medicine, Yonsei University College of Medicine, Seoul, Korea"
      ],
      "name": "Hye Ryun Kim"
    },
    {
      "affiliations": [
        "Department of Oncology, University of Ulsan College of Medicine, Songpa-gu, Seoul, Korea"
      ],
      "name": "Dae Ho Lee"
    },
    {
      "affiliations": [
        "Early Phase Trials Unit, Institut Bergonie, Bordeaux, France",
        "Faculty of Medicine, University of Bordeaux, Talence, France"
      ],
      "name": "Antoine Italiano"
    },
    {
      "affiliations": [
        "Medical Oncology, Centre Léon Bérard, Lyon, France"
      ],
      "name": "Philippe Alexandre Cassier"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Institut de Cancérologie de l’Ouest, Saint Herblain, France"
      ],
      "name": "Sandrine Hiret"
    },
    {
      "affiliations": [
        "Auckland City Hospital, Auckland, New Zealand"
      ],
      "name": "Sanjeev Deva"
    },
    {
      "affiliations": [
        "Internal Medicine, Seoul National University Hospital, Jongno-gu, Korea"
      ],
      "name": "Tae Min Kim"
    },
    {
      "affiliations": [
        "Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "George R Blumenschein, Jr"
    },
    {
      "affiliations": [
        "Department of Oncology, Herlev Hospital, Copenhagen, Denmark"
      ],
      "name": "Rikke Løvendahl Eefsen"
    },
    {
      "affiliations": [
        "Department of Medicine, Division of Hematology/Oncology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA"
      ],
      "name": "Brian S Henick"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Discovery, Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Mario Perro"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Discovery, Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Pablo Umaña"
    },
    {
      "affiliations": [
        "Institute of Pharmacology and Structural Biology (IPBS) University of Toulouse, CNES Toulouse, Toulouse, Occitanie, France"
      ],
      "name": "Antonio Peixoto"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Discovery, Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Laura Lauener"
    },
    {
      "affiliations": [
        "Roche Innovation Center Zurich, Schlieren, Switzerland"
      ],
      "name": "Patrick Weber"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Early Clinical Development Oncology, Roche Innovation Center Munich, Penzberg, Germany"
      ],
      "name": "Stefan Seeber"
    },
    {
      "affiliations": [
        "Cancer Immunotherapy Discovery, Roche Glycart AG, Schlieren, Switzerland",
        "Department of Biochemistry, Faculty of Chemistry and Pharmacy, Ludwig Maximilian University of Munich, Munich, Germany"
      ],
      "name": "Christian Klein"
    },
    {
      "affiliations": [
        "Genentech Inc, South San Francisco, California, USA"
      ],
      "name": "Brian Higgins"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Early Clinical Development Oncology, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Micol Guidi"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Early Clinical Development Oncology, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Dominik Kraus"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Early Clinical Development Oncology, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Merlind Mücke"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Early Clinical Development Oncology, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Christian Heichinger"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Early Clinical Development Oncology, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Vu-Long Tran"
    },
    {
      "affiliations": [
        "Roche Innovation Center Munich, Penzberg, Germany"
      ],
      "name": "Daniela Schmid"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Early Clinical Development Oncology, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Francesca Michielin"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Early Clinical Development Oncology, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Ting Liu"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Roche UK Ltd, Welwyn Garden City, UK"
      ],
      "name": "Christine McIntyre"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Early Clinical Development Oncology, Roche Innovation Center Basel, Basel, Switzerland"
      ],
      "name": "Henry Kao"
    },
    {
      "affiliations": [
        "Cancer Immunotherapy 3, Roche Innovation Center Zurich, Schlieren, Switzerland",
        "Au ZH, Schweiz, Switzerland"
      ],
      "name": "Laura Codarri Deak"
    },
    {
      "affiliations": [
        "Roche Pharma Research and Early Development, Early Clinical Development Oncology, Roche Innovation Center Munich, Penzberg, Germany"
      ],
      "name": "Christoph Markert"
    },
    {
      "affiliations": [
        "START Madrid-FJD, Early Phase Clinical Trials Unit, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain"
      ],
      "name": "Victor Moreno"
    }
  ],
  "title": "First-in-human study of lomvastomig, a PD-1-TIM-3 bispecific antibody, in patients with advanced and/or metastatic solid tumors",
  "uid": "c541af0d-f6db-58fd-afdb-544217b2c3fc"
}