Overall survival according to time-of-day of combined immuno-chemotherapy for advanced non-small cell lung cancer: a bicentric bicontinental study
Bibliographic record
Abstract
BACKGROUND: Circadian rhythms regulate immune cell activity, influencing responses to vaccines, and immune checkpoint inhibitors (ICIs). Early time-of-day administration (ToDA) of singe-agent ICIs has been associated with improved overall survival (OS) in patients with metastatic "immunotherapy sensitive" cancers. However, the impact of ToDA on OS in patients receiving combination therapy with ICIs and chemotherapy for advanced non-small cell lung cancer (NSCLC) remains unclear. METHODS: This retrospective study included patients from oncology units in Paris, France (Cohort 1) and Hunan, China (Cohort 2) who received first-line immuno-chemotherapy for stage IIIC or IV NSCLC between January 2018 and October 2023. The primary outcome was OS. The median ToDA of the initial four ICI infusions was computed for each patient. Hazard ratio (HR) for death or progression were determined using cut-off times ranging from 10:30 to 13:00. Kaplan Meier and Cox models were used to estimate OS and progression-free survival (PFS) adjusting for main patient characteristics. FINDINGS: The study included 713 patients (Cohort 1, n = 165; Cohort 2, n = 548). Pembrolizumab was the most common ICI (51%), which was used with either pemetrexed-carboplatin/cisplatin (49%) or paclitaxel-carboplatin (51%). The optimal ToDA cut-off was 11:30, with patients receiving immuno-chemotherapy before 11:30 showing significantly improved OS (33.0 months [95% CI, 27.5-41.0] vs 19.5 months [18.0-22.5]; p < 0.0001). Multivariable analysis confirmed that earlier ToDA was associated with better OS (adjusted HR = 0.47 [95% CI, 0.37-0.60]). ToDA significantly impacted OS in each cohort and for PFS and response rates in each cohort and the pooled data. INTERPRETATION: This sizeable bi-continental study provided real-world evidence that morning administration of standard first-line immuno-chemotherapy was associated with improved clinical outcomes compared to afternoon dosing in patients with NSCLC. Randomised trials are required to validate this finding and inform recommendations for clinical practice. FUNDING: National Natural Science Foundation of China (82222048, 82003206, 82173338, and 82102747).
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".