{
  "abstract": "Background Response to anti-programmed cell death protein-1 (anti-PD-1) immunotherapy remains limited in patients with metastatic non-small cell lung cancer (NSCLC), whose tumors exhibit low or absent programmed death-ligand 1 (PD-L1) expression, and subsequent second-line therapy has poor efficacy. To address this limitation, we evaluated the efficacy and safety of combined ipilimumab and nivolumab (IPI/NIVO) with subablative radiotherapy (RT) in patients with metastatic NSCLC with negative or low PD-L1 expression, who had progressed on prior anti-PD-1 therapy.Methods This single-arm, prospective phase II trial aimed to enroll 30 evaluable patients with metastatic NSCLC exhibiting low (1–49%) or negative (<1%) PD-L1 tumor expression who had progressed after first-line anti-PD-1 therapy. Primary endpoints were safety, disease control rate (DCR), and objective response rate (ORR) at 6 and 12 weeks, assessed in non-irradiated tumor lesions. Treatment consisted of IPI 1 mg/kg every 6 weeks (Q6W) and NIVO 240 mg every 2 weeks for 6 weeks combined with subablative RT (3×8 Gy to 1–4 lesions). Thereafter, IPI 1 mg/kg Q6W and NIVO 360 mg every 3 weeks were continued.Results In 31 patients of the intention-to-treat population, ORR was 7% and 10% at 6 and 12 weeks, and reached 29% as the best response. DCR was 58% and 39% at 6 and 12 weeks. Overall survival (OS) differed significantly by best response, with a median OS of 3.1, 13.5 and 22.5 months for progressive disease, stable disease and partial/complete response (p<0.001). Baseline sum of longest diameters, together with age, blood inflammatory markers and albumin levels, were prognostic of treatment response. All patients experienced treatment-related adverse events (AEs), with grade 3 as the highest severity in eight patients (26%). Immune-related AEs led to treatment discontinuation in five patients (16%). Early T-cell activation in peripheral blood samples (day 8) was detectable and more pronounced in responders than in progressors.Conclusions In patients with metastatic NSCLC and low or negative tumor PD-L1 expression, IPI/NIVO/RT was able to induce objective clinical responses in a subset of patients who had progressed after first-line anti-PD1 therapy. Treatment was associated with a strong T-cell activation, improved OS and an acceptable safety profile.Trial registration number 2020–001097-29.",
  "authors": [
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands",
        "Cancer Center Amsterdam, Amsterdam, The Netherlands",
        "Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands"
      ],
      "name": "Ezgi B Ulas"
    },
    {
      "affiliations": [
        "Cancer Center Amsterdam, Amsterdam, The Netherlands",
        "Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands",
        "Department of Radiation Oncology, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands"
      ],
      "name": "Nora D Purcell"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands",
        "Cancer Center Amsterdam, Amsterdam, The Netherlands"
      ],
      "name": "Ilias Houda"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands",
        "Cancer Center Amsterdam, Amsterdam, The Netherlands"
      ],
      "name": "Sayed M S Hashemi"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands",
        "Cancer Center Amsterdam, Amsterdam, The Netherlands"
      ],
      "name": "Joris Veltman"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands",
        "Cancer Center Amsterdam, Amsterdam, The Netherlands"
      ],
      "name": "Johannes M A Daniels"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands",
        "Cancer Center Amsterdam, Amsterdam, The Netherlands",
        "Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands"
      ],
      "name": "Marieke F Fransen"
    },
    {
      "affiliations": [
        "Cancer Center Amsterdam, Amsterdam, The Netherlands",
        "Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands",
        "Department of Pathology, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands"
      ],
      "name": "Teodora Radonic"
    },
    {
      "affiliations": [
        "Cancer Center Amsterdam, Amsterdam, The Netherlands",
        "Department of Radiation Oncology, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands"
      ],
      "name": "Linda R Beeloo"
    },
    {
      "affiliations": [
        "Cancer Center Amsterdam, Amsterdam, The Netherlands",
        "Department of Radiation Oncology, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands"
      ],
      "name": "Peter S N van Rossum"
    },
    {
      "affiliations": [
        "Cancer Center Amsterdam, Amsterdam, The Netherlands",
        "Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands",
        "Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands"
      ],
      "name": "Febe van Maldegem"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands"
      ],
      "name": "Nicole Barlo"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands"
      ],
      "name": "Maria Disselhorst"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Dijklander Ziekenhuis, Hoorn, The Netherlands"
      ],
      "name": "Marjolein van Laren"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Dijklander Ziekenhuis, Hoorn, The Netherlands"
      ],
      "name": "Marian A Tiemessen"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Zaans Medical Centre, Zaandam, The Netherlands"
      ],
      "name": "Svitlana Tarasevych"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Tergooi Medical Centre, Hilversum, The Netherlands"
      ],
      "name": "Jan M van Haarst"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Curacao Medical Center, Willemstad, Curaçao"
      ],
      "name": "Peter van Tilburg"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, OLVG, Amsterdam, The Netherlands"
      ],
      "name": "Peter W A Kunst"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, OLVG, Amsterdam, The Netherlands"
      ],
      "name": "Arifa Moons-Pasic"
    },
    {
      "affiliations": [
        "Cancer Center Amsterdam, Amsterdam, The Netherlands",
        "Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands",
        "Department of Radiology and Nuclear Medicine, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands"
      ],
      "name": "Daniela E Oprea-Lager"
    },
    {
      "affiliations": [
        "Department of Radiology and Nuclear Medicine, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands"
      ],
      "name": "Lilian J Meijboom"
    },
    {
      "affiliations": [
        "Department of Clinical Pharmacology and Pharmacy, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands"
      ],
      "name": "Natalja Bouwhuis"
    },
    {
      "affiliations": [
        "Cancer Center Amsterdam, Amsterdam, The Netherlands",
        "Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands",
        "Department of Medical Oncology, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands"
      ],
      "name": "Tanja D de Gruijl"
    },
    {
      "affiliations": [
        "Cancer Center Amsterdam, Amsterdam, The Netherlands",
        "Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands",
        "Department of Radiation Oncology, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands"
      ],
      "name": "Suresh Senan"
    },
    {
      "affiliations": [
        "Cancer Center Amsterdam, Amsterdam, The Netherlands",
        "Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands",
        "Department of Radiation Oncology, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands"
      ],
      "name": "Famke L Schneiders"
    },
    {
      "affiliations": [
        "Department of Pulmonary Medicine, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands",
        "Cancer Center Amsterdam, Amsterdam, The Netherlands",
        "Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands"
      ],
      "name": "Idris Bahce"
    }
  ],
  "title": "Rescue by radiotherapy and anti-CTLA4/PD-1 after failure of anti-PD-1 therapy in patients with metastatic NSCLC: the phase II RECLAIM trial",
  "uid": "89c7c7b8-38bf-5956-960b-0a885c46da55"
}