Overall survival according to time-of-day of combined immuno-chemotherapy for advanced non-small cell lung cancer: a bicentric bicontinental study

Feb 21, 2025EBioMedicine

Survival linked to time of day for combined immune and chemotherapy in advanced lung cancer across two continents

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Abstract

The optimal time-of-day for administering immuno-chemotherapy in patients with advanced non-small cell lung cancer is before 11:30 AM, leading to improved overall survival.

Patients receiving treatment before 11:30 AM had an overall survival of 33.0 months compared to 19.5 months for those treated in the afternoon.
An earlier time-of-day administration of immuno-chemotherapy was associated with a hazard ratio for death or progression of 0.47, indicating a significant survival benefit.
The findings were consistent across two separate patient cohorts from Paris and Hunan, confirming the impact of time-of-day on clinical outcomes.
Earlier administration also positively influenced progression-free survival and response rates in both cohorts and the pooled data.

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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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Overall survival according to time-of-day of combined immuno-chemotherapy for advanced non-small cell lung cancer: a bicentric bicontinental study

Abstract

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