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Cox Proportional Hazard Ratios Overestimate Survival Benefit of Immune Checkpoint Inhibitors: Cox-TEL Adjustment and Meta-Analyses of Programmed Death-Ligand 1 Expression and Immune Checkpoint Inhibitor Survival Benefit

  • Emily Pei-Ying Lin
    Affiliations
    Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee

    Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee

    Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan

    Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan
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  • Chih-Yuan Hsu
    Affiliations
    Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee

    Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
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  • Jeng-Fong Chiou
    Affiliations
    Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan

    Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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  • Lynne Berry
    Affiliations
    Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee

    Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
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  • Leora Horn
    Affiliations
    Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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  • Paul Bunn
    Affiliations
    Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado
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  • James Chih-Hsin Yang
    Affiliations
    Department of Oncology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
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  • Pan-Chyr Yang
    Affiliations
    Department of Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan

    Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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  • Alex A. Adjei
    Affiliations
    Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
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  • Yu Shyr
    Correspondence
    Corresponding author. Address for correspondence: Yu Shyr, PhD, Department of Biostatistics, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 1100, Nashville, TN 37203.
    Affiliations
    Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee

    Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee

    Graduate Institute of Data Science, College of Management, Taipei Medical University, Taipei, Taiwan
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Published:August 29, 2022DOI:https://doi.org/10.1016/j.jtho.2022.08.010

      Abstract

      Introduction

      Survival benefit of immune checkpoint inhibitor (ICI) therapy in lung cancer is not fully understood.

      Methods

      PubMed-cataloged publications through February 14, 2022, were queried for randomized controlled trials of ICI in lung cancer, and identified publications were reviewed for inclusion. Reported Cox hazard ratios (HRs) for overall survival were transformed to Cox-TEL HR for ICI short-term survivors (ST-HR) and difference in proportions for patients with long-term survival (LT-DP). Meta-analyses were performed using a frequentist random-effect model. Outcomes of interest were pooled overall survival Cox HR, ST-HR, and LT-DP in NSCLC, stratified by programmed death-ligand 1 (PD-L1) level (primary outcome) and ICI treatment line (secondary).

      Results

      A total of nine publications representing eight clinical trials were selected for meta-analysis. Primary analysis yielded the following metrics for patients with PD-L1 expression less than 1%, more than or equal to 1%, and more than or equal to 50%, respectively: pooled Cox HR, 0.71 (95% confidence interval [CI]: 0.62–0.82), 0.74 (95% CI: 0.68–0.82), and 0.62 (95% CI: 0.54–0.70); pooled ST-HR, 0.91 (95% CI: 0.79–1.05), 0.88 (95% CI: 0.82–0.94), and 0.70 (95% CI: 0.60–0.83); and pooled LT-DP, 0.10 (95% CI: 0.00–0.20), 0.09 (95% CI: 0.06–0.12), and 0.11 (95% CI: 0.05–0.17). Results of secondary analysis revealed LT-DP of approximately 10% across treatment lines.

      Conclusions

      This study reveals an approximately 10% long-term survival probability increment in ICI long-term survivors across PD-L1–positive subpopulations in both ICI treatment lines. Furthermore, ST-HR was consistently poorer than Cox HR. For patients with PD-L1 less than 1%, neither LT-DP nor ST-HR achieved statistical significance. The analysis provides greater insight into the treatment effect of ICI in published trials.

      Keywords

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