When you are scheduled to receive immunotherapy (with or without chemotherapy), timing matters - morning administration may help you live longer

Vikas P. Sukhatme, MD, ScD

Introduction

Over the past few years, a remarkable observation has emerged in cancer care: the time of day when patients receive immunotherapy treatments appears to significantly impact how well they respond and how long they live. Recent research from both laboratory studies and patient data suggests that administering immune checkpoint inhibitors (ICIs) - a powerful type of immunotherapy - in the morning rather than the afternoon or evening could substantially improve survival outcomes.

What the Research Shows

Multiple studies (20 as of 4/2025) involving over 4,000 patients across different cancer types - including lung cancer, melanoma, kidney cancer, bladder cancer, esophageal cancer, biliary cancer, liver cancer and stomach cancer - have consistently shown that patients who received their immunotherapy infusions in the morning had better outcomes than those treated later in the day.  We cite a few of these studies:

  • In lung cancer patients (Karaboué et al. 2022, Rousseau et al. 2023), receiving immunotherapy before noon rather than afterward was associated with 3-4 times longer survival.
  • In melanoma patients (Qian et al. 2021), morning immunotherapy nearly doubled overall survival compared to afternoon administration.
  • In kidney cancer patients (Dizman et al. 2023, Patel et al. 2022), early-day infusions significantly improved survival outcomes.
  • In gastrointestinal cancers (Nomura et al. 2023, Ishizuka et al. 2024), morning administration led to better tumor responses and longer survival.

The results are remarkably consistent, with a recent meta-analysis by Landré et al. (2024) finding that early-day administration of immunotherapy nearly doubled progression-free and overall survival compared to later administration.  These data are striking!

Why Timing Matters: The Science Behind the Clock

Our bodies operate on 24-hour cycles called circadian rhythms, which affect virtually every biological function - including our immune system. According to Karaboué et al. (2024) and Landré et al. (2024), these powerful daily rhythms influence:

  • Immune cell trafficking - how immune cells move between blood, lymph nodes, and tissues
  • Cytokine production - important chemical messengers of the immune system
  • T-cell activity - the cells that are key targets of immunotherapy

Laboratory studies in mice (Tsuruta et al. 2022, Wang et al. 2023, Fortin et al. 2024) have shown that the expression of PD-1 (the molecular target of many immunotherapy drugs) on important immune cells (such as so-called MDSCs) follows a daily rhythm, with levels varying significantly throughout the day. When immunotherapy was given at times matching peak PD-1 expression and optimal T cell trafficking into the tumor, the treatment worked better.

The Critical Initial Treatment Period

Several studies highlight that the timing of the first few immunotherapy infusions may be particularly important. Research by Yeung et al. (2023) and Nomura et al. (2023) suggests that receiving the initial 3-4 infusions in the morning appears crucial, with later infusions having less impact on overall outcomes.

This timing effect seems to persist despite the fact that these antibody drugs have very long half-lives (2-3 weeks in the bloodstream) and maintain receptor occupancy for months. Scientists believe this apparent paradox may be explained by how the initial immune response is programmed during the first few treatments, setting the stage for long-term outcomes.

Questions and Considerations

While the evidence is compelling, several questions remain:

  • What is the optimal time? Studies have used different cut-off times (ranging from 11:37 AM to 4:30 PM), making it difficult to pinpoint the exact best time for administration.
  • How can timing matter when these drugs remain active in the body for weeks or months? Researchers believe the answer may lie in how the initial immune response is primed during early treatments.
  • No randomized controlled trials have been conducted yet, although many researchers are calling for them. Some have questioned whether it would be ethical to randomize patients to afternoon treatment given the strong observational evidence for morning administration.

What This Means for Patients

If you or a loved one is receiving immunotherapy for cancer, these studies suggest a simple but potentially powerful approach: ask your treatment team about scheduling your infusions in the morning, especially for the first few treatments.

This timing adjustment requires no new drugs or additional treatments - just a scheduling change that could significantly improve your chances of a better outcome. While we await definitive clinical trials, the consistent findings across multiple cancer types and treatment centers suggest this is a reasonable approach to consider.

Moreover, for those receiving chemotherapy in addition to immunotherapy, there may be a survival advantage to delaying the immunotherapy by 3-4 days after the chemotherapy, rather than receiving it on the same day (see the separate blog on this issue).

References

  1. Karaboué A, Innominato PF, Wreglesworth NI, Duchemann B, Adam R, Lévi FA. Why does circadian timing of administration matter for immune checkpoint inhibitors' efficacy? British Journal of Cancer. 2024; 131: 783.
  2. Landré T, Karaboué A, Buchwald ZS, Innominato PF, Qian DC, Assié JB, Chouaïd C, Lévi F, Duchemann B. Effect of immunotherapy-infusion time of day on survival of patients with advanced cancers: a study-level meta-analysis. ESMO Open. 2024;9(2):102220.
  3. Karaboué A, Collon T, Pavese I, Bodiguel V, Cucherousset J, Zakine E, et al. Time-dependent efficacy of checkpoint inhibitor nivolumab: results from a pilot study in patients with metastatic non-small-cell lung cancer. Cancers (Basel). 2022;14:896.
  4. Rousseau A, Tagliamento M, Auclin E, Aldea M, Frelaut M, Levy A, et al. Clinical outcomes by infusion timing of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer. Eur J Cancer. 2023;182:107-114.
  5. Qian DC, Kleber T, Brammer B, Xu KM, Switchenko JM, Janopaul-Naylor JR, et al. Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study. Lancet Oncol. 2021;22:1777-1786.
  6. Dizman N, Govindarajan A, Zengin ZB, Meza LA, Tripathi N, Sayegh N, et al. Association between time-of-day of immune checkpoint blockade and outcomes in metastatic renal cell carcinoma. Clin Genitourin Cancer. 2023;21(5):530-536.
  7. Patel J, Draper A, Woo Y, et al. Impact of immunotherapy time-of-day infusion on overall survival in patients with metastatic renal cell carcinoma. J Immunother Cancer. 2022;12: 1-10.
  8. Nomura M, Hosokai T, Tamaoki M, Yokoyama A, Matsumoto S, Muto M. Timing of the infusion of nivolumab for patients with recurrent or metastatic squamous cell carcinoma of the esophagus influences its efficacy. Esophagus. 2023;20:722-731.
  9. Ishizuka Y, Narita Y, Sakakida T, Wakabayashi M, Kodama H, Honda K, et al. Impact of time-of-day on nivolumab monotherapy infusion in patients with metastatic gastric cancer. J Clin Oncol. 2024;42:268-268.
  10. Tsuruta A, Shiiba Y, Matsunaga N, Fujimoto M, Yoshida Y, Koyanagi S, Ohdo S. 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. Mol Cancer Res. 2022;20:972-982.
  11. Wang C, Barnoud C, Cenerenti M, Sun M, Caffa I, Kizil B, et al. Dendritic cells direct circadian anti-tumour immune responses. Nature. 2023;614:136-143.
  12. Yeung C, Kartolo A, Tong J, Hopman W, Baetz T. Association of circadian timing of initial infusions of immune checkpoint inhibitors with survival in advanced melanoma. Immunotherapy. 2023;15(11):819-826.
  13. Huo Y, et al. Optimal timing of anti-PD-1 antibody combined with chemotherapy administration in patients with NSCLC. J Immunother Cancer. 2024;12
  14. Fortin BM, Pfeiffer SM, Insua-Rodríguez J, et al. Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade. Nature Immunology. 2024. https://doi.org/10.1038/s41590-024-01859-0