Blood-based kinase activity profiling to predict response to immune checkpoint inhibitors in patients with advanced stage NSCLC: the prospective IOpener study

Journal for ImmunoTherapy of Cancer, vol. 14, pp. e013748

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 18

1. Karlijn de Joode

   Erasmus MC Cancer Institute

   Affiliation as printed

   Department of Medical Oncology, Erasmus MC Kanker Instituut, Rotterdam, The Netherlands

2. Harry J.M. Groen

   University Medical Center Groningen

   Affiliation as printed

   Department of Pulmonary Diseases, University Medical Centre Groningen, Groningen, The Netherlands

3. Michel M. van den Heuvel

   Radboud University Nijmegen · Radboud University Medical Center

   Affiliation as printed

   Department of Respiratory Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

4. Jeroen S. Kloover

   Elisabeth-TweeSteden Ziekenhuis

   Affiliation as printed

   Department of Respiratory Diseases, Elisabeth-TweeSteden Ziekenhuis, Tilburg, The Netherlands

5. Femke S. van der Meer

   Diakonessenhuis hospital

   Affiliation as printed

   Department of Pulmonology, Diakonessenhuis Utrecht Zeist Doorn Locatie Utrecht, Utrecht, The Netherlands

6. Cor H. van der Leest

   Amphia Ziekenhuis

   Affiliation as printed

   Department of Pulmonology, Amphia Hospital, Breda, The Netherlands

7. Ben van den Borne

   Catharina Ziekenhuis

   Affiliation as printed

   Department of Pulmonary Diseases, Catharina Hospital, Eindhoven, The Netherlands

8. Rik de Wijn

   PamGene (Netherlands)

   Affiliation as printed

   PamDx (formerly PamGene International BV), ’s Hertogenbosch, The Netherlands

9. Daan P. Hurkmans

   Erasmus MC Cancer Institute

   Affiliation as printed

   Department of Pulmonary Diseases, Erasmus MC Kanker Instituut, Rotterdam, Netherlands

10. Dianne M. A. van den Heuvel

    PamGene (Netherlands)

    Affiliation as printed

    PamDx (formerly PamGene International BV), ’s Hertogenbosch, The Netherlands

11. Herbert M. Pinedo

    Amsterdam UMC Location Vrije Universiteit Amsterdam

    Affiliation as printed

    Emeritus Professor Medical Oncology, VU University Medical Centre Amsterdam, Amsterdam, The Netherlands

12. Ellen Kapiteijn Aachen Department of Medical Oncology

    Leiden University Medical Center

    Affiliation as printed

    Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands

13. Reno Debets

    Erasmus MC Cancer Institute

    Affiliation as printed

    Department of Medical Oncology, Erasmus MC Kanker Instituut, Rotterdam, The Netherlands

14. Els M.E. Verdegaal Aachen Department of Medical Oncology Oncode Institute

    Leiden University Medical Center · Oncode Institute

    Affiliation as printed

    Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands

15. Sjoerd H. van der Burg Aachen Department of Medical Oncology Oncode Institute

    Leiden University Medical Center · Oncode Institute

    Affiliation as printed

    Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands

16. John P. Groten

    PamGene (Netherlands)

    Affiliation as printed

    PamDx (formerly PamGene International BV), ’s Hertogenbosch, The Netherlands

17. Joachim G.J.V. Aerts

    Erasmus MC Cancer Institute

    Affiliation as printed

    Department of Pulmonary Diseases, Erasmus MC Kanker Instituut, Rotterdam, Netherlands

18. Ron H.J. Mathijssen

    Erasmus MC Cancer Institute

    Affiliation as printed

    Department of Medical Oncology, Erasmus MC Kanker Instituut, Rotterdam, The Netherlands