Time-Dependent Efficacy of Nivolumab in Patients with Advanced NSCLC

Accumulating evidence has demonstrated that the functional activity and trafficking of T (CD8) lymphocytes, the primary target cells of nivolumab, and other immune cells are regulated over the 24-hour cycle by the molecular circadian timing system.1 Based on these studies, it was hypothesized that the pharmacologic effects of nivolumab, which targets PD-1 receptors expressed on T-cells, could be affected by circadian clocks.2

In this study, researchers investigated whether increasing the proportion of morning nivolumab infusions could improve efficacy in patients with metastatic non–small-cell lung cancer (NSCLC). Patients received nivolumab (240 mg intravenously every 2 weeks) at a time of day that was randomly allocated for each course by the day-hospital coordinators.2

The median time of actual nivolumab infusions was adjusted for each patient. The study population was split into 3 timing cohorts based on a 24-hour cycle: a “morning” group, in which patients received ≥2/3 of nivolumab infusions before 12:54; an intermediate group, where the patients received ≥1/3 of nivolumab infusions before and 1/3 after 12:54; and an “evening” group, where patients received ≥2/3 of nivolumab infusions after 12:54. Toxicity rates, tumor responses, progression-free survival (PFS), and overall survival (OS) were assessed based on the nivolumab timing group.2

A total of 95 previously treated patients with stage IV NSCLC were retrospectively assigned to a “morning” group (36 patients), an intermediate group (24 patients), and an “evening” group (35 patients). Of the included patients, 76% received nivolumab as second-line therapy.2

Tumor PD-L1 status was positive for 39 of 72 patients (54%). Patient characteristics were similar among the 3 groups, except for liver metastases (41.7%, 8.3%, and 25.7% for “morning,” intermediate, and “evening” groups, respectively; P = .010).

Grade 2-4 fatigue was observed least in the “morning” group (28%) compared with 62% (intermediate) and 40% (“evening”) (P = .027). Median PFS was 11.1 months for the “morning” group, 5.9 months for the intermediate group, and 3.1 months for the “evening” group (P = .002). Median OS was 34.2 months for the “morning” group, 15.3 months (95% confidence interval [CI], 8.0-22.7) for the intermediate group, and 12.4 months (95% CI, 4.0-20.7) for the “evening” group (P = .023). Respective 2-year survival rates were 52.6%, 26.2%, and 15.0%, respectively (P = .002). Multivariable analysis confirmed that the administration of >2/3 nivolumab in the morning was associated with longer PFS (hazard ratio [HR], 0.26, 0.14-0.51; P <.001) and OS (HR, 0.22, 0.10-0.51; P <.001).

The investigators concluded that nivolumab was more effective in the “morning” than in the intermediate or “evening” groups. These findings highlight the importance of randomized and translational circadian timing studies to understand the mechanisms of the chronopharmacology of ICIs to maximize their therapeutic benefits while minimizing the risk of therapeutic resistance.


  1. Karaboué A, Collon T, Pavese I, 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.
  2. Karaboué A, Collon T, Bodiguel V, et al. Nivolumab timing as a major survival predictor in patients with stage IV non–small cell lung cancer. Presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract 9058.

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