{
  "abstract": "Background The programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) is used as a biomarker to predict benefit from immune checkpoint blockade (ICB) in patients with non-small cell lung cancer (NSCLC). However, additional biomarkers are needed. The potential of kinase activity profiling of peripheral blood mononuclear cells (PBMCs) for predicting response to ICB was previously shown in a discovery study. The goal of this prospective study is to evaluate the predictive value of blood-based kinase profiling for ICB response in patients with NSCLC and to compare the performance and added value to TPS.Methods Advanced stage patients with NSCLC, treated with anti-programmed cell death protein 1 ICB (±chemotherapy) were included in this multicenter study (N=210 patients). PBMCs were collected prior to ICB treatment and profiled using a peptide microarray with multiple kinase substrates (PamChip). Classification analysis was performed to discriminate between patients with or without progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 <24 weeks after treatment start. A predictive model was first established based on TPS and kinase activity profiles. Subsequently, the performance of the model was tested in a second (validation) cohort.Results In the validation cohort, a significantly higher progression-free survival (PFS) rate was observed for patients with predicted benefit than for patients without predicted benefit according to the kinome-based prediction model (HR=0.56, p=0.01), which tended better compared with TPS alone (HR=0.66, p=0.07). When the kinome-based model was combined with TPS, the difference in PFS between patients with and without predicted benefit was further increased (HR=0.38, p<0.001). PFS rates were also higher for patients with predicted benefit in subgroups with decreased PD-L1 expression (TPS <1% (HR=0.46, p=0.027) and TPS 1–50% (HR=0.20, p=0.005)).Conclusions This study shows the predictive value of kinase activity profiling of PBMCs for ICB response in advanced NSCLC, which was superior compared with TPS. In particular, for patients with NSCLC with TPS <50%, combining TPS with the blood-based kinase test may identify patients with limited benefit from ICB.Trial registration number NTR7015/NL6828.",
  "authors": [
    {
      "affiliations": [
        "Department of Medical Oncology, Erasmus MC Kanker Instituut, Rotterdam, The Netherlands"
      ],
      "name": "Karlijn de Joode"
    },
    {
      "affiliations": [
        "Department of Pulmonary Diseases, University Medical Centre Groningen, Groningen, The Netherlands"
      ],
      "name": "Harry J Groen"
    },
    {
      "affiliations": [
        "Department of Respiratory Diseases, Radboud University Medical Center, Nijmegen, The Netherlands"
      ],
      "name": "Michel van den Heuvel"
    },
    {
      "affiliations": [
        "Department of Respiratory Diseases, Elisabeth-TweeSteden Ziekenhuis, Tilburg, The Netherlands"
      ],
      "name": "Jeroen S Kloover"
    },
    {
      "affiliations": [
        "Department of Pulmonology, Diakonessenhuis Utrecht Zeist Doorn Locatie Utrecht, Utrecht, The Netherlands"
      ],
      "name": "Femke Van Der Meer"
    },
    {
      "affiliations": [
        "Department of Pulmonology, Amphia Hospital, Breda, The Netherlands"
      ],
      "name": "Cor H Van der Leest"
    },
    {
      "affiliations": [
        "Department of Pulmonary Diseases, Catharina Hospital, Eindhoven, The Netherlands"
      ],
      "name": "Ben Van Den Borne"
    },
    {
      "affiliations": [
        "PamDx (formerly PamGene International BV), ’s Hertogenbosch, The Netherlands"
      ],
      "name": "Rik De Wijn"
    },
    {
      "affiliations": [
        "Department of Pulmonary Diseases, Erasmus MC Kanker Instituut, Rotterdam, Netherlands"
      ],
      "name": "Daan P Hurkmans"
    },
    {
      "affiliations": [
        "PamDx (formerly PamGene International BV), ’s Hertogenbosch, The Netherlands"
      ],
      "name": "Dianne M A Van den Heuvel"
    },
    {
      "affiliations": [
        "Emeritus Professor Medical Oncology, VU University Medical Centre Amsterdam, Amsterdam, The Netherlands"
      ],
      "name": "Herbert M Pinedo"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands"
      ],
      "name": "Ellen Kapiteijn"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Erasmus MC Kanker Instituut, Rotterdam, The Netherlands"
      ],
      "name": "Reno Debets"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"
      ],
      "name": "Els M E Verdegaal"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands"
      ],
      "name": "Sjoerd H Van der Burg"
    },
    {
      "affiliations": [
        "PamDx (formerly PamGene International BV), ’s Hertogenbosch, The Netherlands"
      ],
      "name": "John P Groten"
    },
    {
      "affiliations": [
        "Department of Pulmonary Diseases, Erasmus MC Kanker Instituut, Rotterdam, Netherlands"
      ],
      "name": "Joachim G J V Aerts"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Erasmus MC Kanker Instituut, Rotterdam, The Netherlands"
      ],
      "name": "Ron H J Mathijssen"
    }
  ],
  "title": "Blood-based kinase activity profiling to predict response to immune checkpoint inhibitors in patients with advanced stage NSCLC: the prospective IOpener study",
  "uid": "69b59e7f-2c67-50f3-8ad3-8ab0e6959a30"
}