Chronotherapy in metastatic non–small cell lung cancer: Clinical outcomes according to immune checkpoint inhibitor administration time during the day in patients treated with first-line chemoimmunotherapy.

Abstract

8575 Background: Although circadian rhythms are known to modulate immune cell function, the effect of immune checkpoint inhibitor (ICI) infusion timing during the day on oncologic outcomes in metastatic non–small cell lung cancer (NSCLC) patients treated with first-line chemoimmunotherapy has not been fully elucidated. Methods: We retrospectively analyzed patients with de novo metastatic NSCLC without actionable oncogenic driver alterations who received first-line chemotherapy plus ICI between January 1, 2018, and October 31, 2025, at two centers. Patients receiving platinum-based doublet chemotherapy plus pembrolizumab and/or nivolumab were included, whereas those treated with dual ICIs (nivolumab plus ipilimumab with platinum-based chemotherapy) were excluded. Infusion times for the first four cycles were recorded, and patients were categorized as the early group if they received ≥2 of the first four ICI cycles before 11:00 a.m., and as the late group if they received ≤1 of the first four ICI cycles before 11:00 a.m. Endpoints were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: We identified 101 eligible patients who met the inclusion criteria, comprising 34 patients in the early group and 67 patients in the late group. Median follow-up was 18.4 months (95% CI 12.4 – 24.4). There were no differences between the early group and the late group in terms of age, gender, body mass index, smoking status, ECOG performance status, stage (IVA vs. IVB), histologic subtype (squamous vs. non-squamous), PD-L1 tumor proportion score ( < 1% vs. 1-49% vs. ≥50%), central nervous system metastases, liver metastases, number of metastatic sites (≤2 vs. ≥3 organ systems), and ICI agent (pembrolizumab vs. nivolumab). The early group demonstrated significantly longer median PFS (14.6 vs. 7.1 months; HR = 0.54 [95% CI 0.31 – 0.93]; p = 0.027) and median OS (not reached vs. 27.3 months; HR = 0.28 [95% CI 0.11 – 0.71]; p = 0.008). Both the ORR (97.1% vs. 56.7%; p < 0.001) and the disease control rate (97.1% vs. 64.2%; p < 0.001) were significantly higher in the early group. The majority of patients who experienced primary progression after the first four cycles were in the late group (24 of 25 patients; 96%). In multivariate analysis, only disease stage (IVB vs. IVA; HR = 2.35 [95% CI 1.05 – 5.26]; p = 0.039) and timing-based group assignment according to the number of the first four ICI infusions administered before 11:00 a.m. (late vs. early; HR = 2.97 [95% CI 1.14 – 7.76]; p = 0.026) were independently associated with OS. Conclusions: Our findings demonstrated that receiving majority (≥2) of the first four ICI infusions before 11:00 a.m. might be associated with better response rates, improved PFS and OS in patients with de novo metastatic NSCLC treated with first-line chemotherapy plus ICI.