{
  "abstract": "Background Anti-programmed cell death protein 1 (PD-1) immunotherapy has revolutionized the treatment of stage III and IV melanoma. Real-world data on its resistance is needed to facilitate the development of combinatorial approaches to overcome anti-PD-1 resistance.Objectives To characterize anti-PD-1 resistance and assess whether progressive disease assigned by clinicians is concordant with scan data assessed by independent central reviewers (ICR).Methods A retrospective chart review was conducted in adult patients with stage III/IV melanoma who initiated anti-PD-1 therapy from January 2018 until 12 months before the start of data collection at 22 sites across six countries. Primary resistance and late relapse in the adjuvant setting, and primary, secondary resistance, and late progression in the advanced setting were assigned using Society for Immunotherapy of Cancer definitions. Demographic and clinical characteristics by type of resistance were compared with appropriate univariate tests. Time to resistance (TTR) and overall survival were analyzed using Kaplan-Meier. To compare the concordance of progression assigned by clinicians and ICR, the positive predictive value (PPV) was calculated in a subset of patients.Results Of 981 eligible patients, 738 were included. In the adjuvant setting (n=240), 53 (22.1%) patients developed primary resistance and 60 (25.0%) experienced late relapse. In the advanced setting (n=498), 222 (44.6%), 50 (10.0%), and 64 (12.9%) patients developed primary, secondary resistance, and late progression. Type of resistance significantly differed by country, race, type of BRAF mutation, and PD-L1 expression in both settings; and by sex, disease stage and tumor thickness in the adjuvant setting only (p<0.05). Mean (SD) TTR was 47.7 (1.3) and 24.2 (1.0) months in the adjuvant and advanced setting, respectively. Patients with primary resistance had the poorest overall survival. The PPV of progression assigned by clinicians was 87.2% (95% CI 72.6% to 95.7%).Conclusions This study showed that a substantial proportion of patients with melanoma receiving anti-PD-1 therapy in the adjuvant (47.1%) and advanced (67.5%) settings developed resistance or late relapse/progression, highlighting an unmet medical need. Real-world clinical practice provided a reliable assessment of progression. Factors associated with different types of resistance were identified. Further study is warranted to evaluate their impact on patient risk stratification. (Graphical abstract)",
  "authors": [
    {
      "affiliations": [
        "University of Virginia Cancer Center, Charlottesville, Virginia, USA"
      ],
      "name": "Elizabeth M Gaughan"
    },
    {
      "affiliations": [
        "Seoul National University Hospital, Seoul, South Korea"
      ],
      "name": "Miso Kim"
    },
    {
      "affiliations": [
        "OXON Epidemiology, Madrid, Spain"
      ],
      "name": "Ignacio Mendez"
    },
    {
      "affiliations": [
        "Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia",
        "Melanoma Research Victoria, Melbourne, Victoria, Australia"
      ],
      "name": "Aparna D Rao"
    },
    {
      "affiliations": [
        "University of California San Francisco, San Francisco, California, USA",
        "San Francisco VA Health Care System, San Francisco, California, USA"
      ],
      "name": "Maria Wei"
    },
    {
      "affiliations": [
        "University of California San Francisco, San Francisco, California, USA",
        "San Francisco VA Health Care System, San Francisco, California, USA"
      ],
      "name": "Alexandra So"
    },
    {
      "affiliations": [
        "University of California San Francisco, San Francisco, California, USA",
        "San Francisco VA Health Care System, San Francisco, California, USA"
      ],
      "name": "Xiaochen Zhong"
    },
    {
      "affiliations": [
        "Department of Dermatology, Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, CCC Erlangen-EMN, Friedrich-Alexander- Universität Erlangen-Nürnberg, Erlangen, Germany"
      ],
      "name": "Carola Berking"
    },
    {
      "affiliations": [
        "Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc, Rahway, New Jersey, USA"
      ],
      "name": "Ruixuan Jiang"
    },
    {
      "affiliations": [
        "Seoul National University Hospital, Seoul, South Korea"
      ],
      "name": "Tae Min Kim"
    },
    {
      "affiliations": [
        "Centre Hospitalier Lyon-Sud, Pierre-Benite Cedex, France"
      ],
      "name": "Stéphane Dalle"
    },
    {
      "affiliations": [
        "Institut Gustave-Roussy, Villejuif, France"
      ],
      "name": "Caroline Robert"
    },
    {
      "affiliations": [
        "Weston Park Cancer Centre, University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK"
      ],
      "name": "Sarah Danson"
    },
    {
      "affiliations": [
        "Mount Vernon Cancer Centre, Northwood, UK"
      ],
      "name": "Salma Alam"
    },
    {
      "affiliations": [
        "CHU Grenoble, La Tronche, France"
      ],
      "name": "Julie Charles"
    },
    {
      "affiliations": [
        "Velindre University NHS Trust, Cardiff, UK"
      ],
      "name": "Tessa Davies"
    },
    {
      "affiliations": [
        "Department of Dermatology, Nuremberg Hospital, Paracelsus Medical University, Nuremberg, Germany"
      ],
      "name": "Dirk Debus"
    },
    {
      "affiliations": [
        "Gold Coast University Hospital, Southport, Queensland, Australia"
      ],
      "name": "Marcin Dzienis"
    },
    {
      "affiliations": [
        "Velindre University NHS Trust, Cardiff, UK"
      ],
      "name": "Ricky Frazer"
    },
    {
      "affiliations": [
        "Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"
      ],
      "name": "Christoffer Gebhardt"
    },
    {
      "affiliations": [
        "Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"
      ],
      "name": "Glenn Geidel"
    },
    {
      "affiliations": [
        "Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany"
      ],
      "name": "Jessica C Hassel"
    },
    {
      "affiliations": [
        "Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"
      ],
      "name": "Inga Hansen"
    },
    {
      "affiliations": [
        "Department of Dermatology, Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, CCC Erlangen-EMN, Friedrich-Alexander- Universität Erlangen-Nürnberg, Erlangen, Germany",
        "Dermpath München, Laboratory for Dermatopathology, Oral Pathology and Molecular Pathology, Munich, Germany"
      ],
      "name": "Markus Vincent Heppt"
    },
    {
      "affiliations": [
        "Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"
      ],
      "name": "Lina Hildebrandt"
    },
    {
      "affiliations": [
        "Cleveland Clinic, Cleveland, Ohio, USA"
      ],
      "name": "James M Isaacs"
    },
    {
      "affiliations": [
        "Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea"
      ],
      "name": "Koung Jin Suh"
    },
    {
      "affiliations": [
        "Seoul National University Hospital, Seoul, South Korea"
      ],
      "name": "Bhumsuk Keam"
    },
    {
      "affiliations": [
        "Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea"
      ],
      "name": "Yu Jung Kim"
    },
    {
      "affiliations": [
        "Centre Eugène Marquis, Rennes-Cedex, France"
      ],
      "name": "Thierry Lesimple"
    },
    {
      "affiliations": [
        "Department of General and Oncologic Dermatology, Ambroise Paré hospital, APHP, & EA 4340 “Biomarkers in cancerology and hemato-oncology”, UVSQ, Université Paris-Saclay, Boulogne-Billancourt, France"
      ],
      "name": "Philippe Saiag"
    },
    {
      "affiliations": [
        "OXON Epidemiology, Madrid, Spain"
      ],
      "name": "Alicia Delibes"
    },
    {
      "affiliations": [
        "OXON Epidemiology, Madrid, Spain",
        "University of Bath, Bath, UK"
      ],
      "name": "Rosemarie Barnett"
    },
    {
      "affiliations": [
        "Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc, Rahway, New Jersey, USA"
      ],
      "name": "Clemens Krepler"
    },
    {
      "affiliations": [
        "OXON Epidemiology, Madrid, Spain"
      ],
      "name": "Kavita Gandhi"
    },
    {
      "affiliations": [
        "OXON Epidemiology, Madrid, Spain",
        "London School of Hygiene and Tropical Medicine, London, UK"
      ],
      "name": "Nawab Qizilbash"
    },
    {
      "affiliations": [
        "Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc, Rahway, New Jersey, USA"
      ],
      "name": "Irene M Shui"
    },
    {
      "affiliations": [
        "Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc, Rahway, New Jersey, USA"
      ],
      "name": "Xiang-Lin Tan"
    },
    {
      "affiliations": [
        "Massachusetts General Brigham Cancer Institute, Boston, Massachusetts, USA"
      ],
      "name": "Ryan J Sullivan"
    }
  ],
  "title": "Resistance to anti-PD-1 immunotherapy for stage III and IV melanoma: a global chart review study",
  "uid": "2ee2eb9c-4a57-5405-b787-ec7cb9b69951"
}