{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T05:14:58Z","timestamp":1792818898875,"version":"4.5.0"},"reference-count":22,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"unspecified","delay-in-days":13,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,4,28]]},"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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 (&lt;12:00 PM) or PM (\u226512:00 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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%\u2009CI 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%\u2009CI 0.98 to 1.12, p=0.15). Results were robust in sensitivity analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013830","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T13:21:16Z","timestamp":1778764876000},"page":"e013830","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Morning versus afternoon administration of immune checkpoint inhibitors in metastatic non-small-cell lung cancer"],"prefix":"10.1136","volume":"14","author":[{"given":"Rachel T","family":"Gonzalez","sequence":"first","affiliation":[{"name":"Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reena","family":"Datta","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadiq","family":"Rehmani","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garth W","family":"Strohbehn","sequence":"additional","affiliation":[{"name":"Section of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA"},{"name":"Center for Clinical Management Research, Veterans Health Administration, Ann Arbor, MI, 48105"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nithya","family":"Ramnath","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Section of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shadia","family":"Jalal","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Indiana University Melvin, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P","family":"Dykstra","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3930-0708","authenticated-orcid":false,"given":"Josiah","family":"Nieto","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Elliott","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J","family":"Schipper","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex K","family":"Bryant","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA"},{"name":"Center for Clinical Management Research, Veterans Health Administration, Ann Arbor, MI, 48105"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"2026051406202683000_14.5.e013830.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-090122-050842"},{"key":"2026051406202683000_14.5.e013830.2","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1038\/s41590-024-01859-0","article-title":"Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade","volume":"25","author":"Fortin","year":"2024","journal-title":"Nat Immunol"},{"key":"2026051406202683000_14.5.e013830.3","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1158\/1541-7786.MCR-21-0786","article-title":"Diurnal Expression of PD-1 on Tumor-Associated Macrophages Underlies the Dosing Time-Dependent Antitumor Effects of the PD-1\/PD-L1 Inhibitor BMS-1 in B16\/BL6 Melanoma-Bearing Mice","volume":"20","author":"Tsuruta","year":"2022","journal-title":"Mol Cancer Res"},{"key":"2026051406202683000_14.5.e013830.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-024-02704-9"},{"key":"2026051406202683000_14.5.e013830.5","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00546-5"},{"key":"2026051406202683000_14.5.e013830.6","doi-asserted-by":"crossref","DOI":"10.3390\/cancers14040896","article-title":"Time-Dependent Efficacy of Checkpoint Inhibitor Nivolumab: Results from a Pilot Study in Patients with Metastatic Non-Small-Cell Lung Cancer","volume":"14","author":"Karabou\u00e9","year":"2022","journal-title":"Cancers (Basel)"},{"key":"2026051406202683000_14.5.e013830.7","doi-asserted-by":"crossref","first-page":"1512972","DOI":"10.3389\/fimmu.2024.1512972","article-title":"Effect of immune checkpoint inhibitor time-of-day infusion on survival in advanced biliary tract cancer: a propensity score-matched analysis","volume":"15","author":"Zheng","year":"2024","journal-title":"Front Immunol"},{"key":"2026051406202683000_14.5.e013830.8","doi-asserted-by":"publisher","DOI":"10.1007\/s10388-023-01006-y"},{"key":"2026051406202683000_14.5.e013830.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705327114"},{"key":"2026051406202683000_14.5.e013830.10","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-1449"},{"key":"2026051406202683000_14.5.e013830.11","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1016\/S1470-2045(24)00528-X","article-title":"Effectiveness and safety of immune checkpoint inhibitors in Black patients versus White patients in a US national health system: a retrospective cohort study","volume":"25","author":"Miller","year":"2024","journal-title":"Lancet Oncol"},{"key":"2026051406202683000_14.5.e013830.12","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/S1470-2045(24)00200-6","article-title":"Projected environmental and public health benefits of extended-interval dosing: an analysis of pembrolizumab use in a US national health system","volume":"25","author":"Bryant","year":"2024","journal-title":"Lancet Oncol"},{"key":"2026051406202683000_14.5.e013830.13","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1377\/hlthaff.2023.00102","article-title":"Adopting Weight-Based Dosing With Pharmacy-Level Stewardship Strategies Could Reduce Cancer Drug Spending By Millions","volume":"42","author":"Bryant","year":"2023","journal-title":"Health Aff (Millwood)"},{"key":"2026051406202683000_14.5.e013830.14","doi-asserted-by":"crossref","first-page":"14604582231198020","DOI":"10.1177\/14604582231198021","article-title":"Machine learning-based natural language processing to extract PD-L1 expression levels from clinical notes","volume":"29","author":"Lin","year":"2023","journal-title":"Health Informatics J"},{"key":"2026051406202683000_14.5.e013830.15","doi-asserted-by":"crossref","DOI":"10.1200\/CCI.23.00269","article-title":"Extraction and Imputation of Eastern Cooperative Oncology Group Performance Status From Unstructured Oncology Notes Using Language Models","volume":"8","author":"Xu","year":"2024","journal-title":"JCO Clin Cancer Inform"},{"key":"2026051406202683000_14.5.e013830.16","doi-asserted-by":"crossref","DOI":"10.1002\/cam4.70461","article-title":"De-Mystifying the Clone-Censor-Weight Method for Causal Research Using Observational Data: A Primer for Cancer Researchers","volume":"13","author":"Gaber","year":"2024","journal-title":"Cancer Med"},{"key":"2026051406202683000_14.5.e013830.17","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1007\/s40471-024-00346-2","article-title":"The Clone-Censor-Weight Method in Pharmacoepidemiologic Research: Foundations and Methodological Implementation","volume":"11","author":"Gaber","year":"2024","journal-title":"Curr Epidemiol Rep"},{"key":"2026051406202683000_14.5.e013830.18","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1093\/ije\/dyaa057","article-title":"Reflection on modern methods: trial emulation in the presence of immortal-time bias. Assessing the benefit of major surgery for elderly lung cancer patients using observational data","volume":"49","author":"Maringe","year":"2020","journal-title":"Int J Epidemiol"},{"key":"2026051406202683000_14.5.e013830.19","doi-asserted-by":"crossref","DOI":"10.1016\/j.esmoop.2023.102220","article-title":"Effect of immunotherapy-infusion time of day on survival of patients with advanced cancers: a study-level meta-analysis","volume":"9","author":"Landr\u00e9","year":"2024","journal-title":"ESMO Open"},{"key":"2026051406202683000_14.5.e013830.20","doi-asserted-by":"crossref","first-page":"8516","DOI":"10.1200\/JCO.2025.43.16_suppl.8516","article-title":"Randomized trial of relevance of time-of-day of immunochemotherapy for progression-free and overall survival in patients with non-small cell lung cancer","volume":"43","author":"Zhang","year":"2025","journal-title":"JCO"},{"key":"2026051406202683000_14.5.e013830.21","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1038\/s41591-025-04181-w","article-title":"Time-of-day immunochemotherapy in non-small cell lung cancer: a randomized phase 3 trial","volume":"32","author":"Huang","year":"2026","journal-title":"Nat Med"},{"key":"2026051406202683000_14.5.e013830.22","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mds148"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2025-013830","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T13:21:18Z","timestamp":1778764878000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2025-013830"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":22,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5,14]]},"published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1136\/jitc-2025-013830"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2025-013830","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5]]}}}