{
  "abstract": "Background Circadian biology suggests that synchronizing immune checkpoint inhibitor (ICI) dosing with morning peaks in immune activation could improve clinical outcomes, but well-powered studies using appropriate causal inference methodology are sparse.Methods We emulated a pragmatic randomized controlled trial of AM versus PM ICI infusions using Veterans Health Administration records from 2010 to 2024. In the emulated trial, stage IV non-small-cell lung cancer patients planned to undergo first-line or second-line ICI would have been randomized to receive the first three infusions in the AM (<12:00 PM) or PM (≥12:00 PM). The primary outcome was overall survival (OS). Marginal structural models with inverse probability of censoring weights estimated the per-protocol effect, accounting for baseline and longitudinal confounding. A historical chemotherapy cohort served as a negative control.Results 4688 patients were eligible for the emulated trial; of these, 1171 received their first three infusions in the AM and 794 in the PM. Median follow-up was 4.7 years. Median survival was 10.3 months (AM) vs 8.1 months (PM). PM dosing was associated with worse OS (HR for PM versus AM 1.15, 95% CI 1.04 to 1.26, p=0.004). In 7951 chemotherapy controls (median follow-up 8.9 years), no time-of-day effect was detected (HR for PM vs AM 1.05, 95% CI 0.98 to 1.12, p=0.15). Results were robust in sensitivity analyses.Conclusions Morning ICI infusions confer a modest but clinically meaningful survival benefit that is absent in chemotherapy controls, supporting a causal chronotherapeutic effect. Scheduling ICIs before noon represents a low-cost, immediately actionable strategy warranting prospective confirmation.",
  "authors": [
    {
      "affiliations": [
        "Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA"
      ],
      "name": "Rachel T Gonzalez"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA",
        "Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA"
      ],
      "name": "Reena Datta"
    },
    {
      "affiliations": [
        "Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan, USA"
      ],
      "name": "Sadiq Rehmani"
    },
    {
      "affiliations": [
        "Section of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA",
        "Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA",
        "Center for Clinical Management Research, Veterans Health Administration, Ann Arbor, MI, 48105"
      ],
      "name": "Garth W Strohbehn"
    },
    {
      "affiliations": [
        "Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan, USA",
        "Section of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA"
      ],
      "name": "Nithya Ramnath"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, Indiana University Melvin, Indianapolis, Indiana, USA"
      ],
      "name": "Shadia Jalal"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA",
        "Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA"
      ],
      "name": "Michael P Dykstra"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA"
      ],
      "name": "Josiah Nieto"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA",
        "Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA"
      ],
      "name": "David Elliott"
    },
    {
      "affiliations": [
        "Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA",
        "Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA"
      ],
      "name": "Matthew J Schipper"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA",
        "Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA",
        "Center for Clinical Management Research, Veterans Health Administration, Ann Arbor, MI, 48105"
      ],
      "name": "Alex K Bryant"
    }
  ],
  "title": "Morning versus afternoon administration of immune checkpoint inhibitors in metastatic non-small-cell lung cancer",
  "uid": "98307489-cb6d-5144-bebc-8e9acc58e94c"
}