Midday immune checkpoint inhibitor (ICI) infusion influence on survival in patients with metastatic cancer: A real-world chrono-immunotherapy study.

Abstract

11162 Background: Circadian rhythms regulate immune activity, and earlier ICI dosing has been linked to better survival. However, prior findings remain inconsistent, often relying on predefined time categories. To address this, we clustered actual infusion times to assess survival associations in a real-world cohort. Methods: This retrospective study included metastatic cancer patients treated with ICIs. Mean dosing times (up to 24 infusions/patient) were analyzed using circular statistics and clustered via k-means. Overall survival (OS) was defined from ICI initiation to progression, death, or last follow-up, and analyzed via Kaplan-Meier and multivariable Cox regression adjusted for cancer and ICI type. Results: A total of 640 patients (median age 61 years [range 23–87]; 78% male) were included. The most common tumor types were non-small cell lung cancer (52%), renal cell carcinoma (19%), and malignant melanoma (12%), followed by urothelial (5.5%) and small cell lung cancer (4.8%). The majority of patients received nivolumab (74%) or pembrolizumab (11%), while a smaller proportion were treated with other ICIs including atezolizumab (6.3%), avelumab (2%), or ipilimumab-based combinations (5.4%). ECOG performance status was 0–1 in 80% of patients. The most frequent metastatic sites were lymph nodes or soft tissue (78.6%), lungs (48.1%), bones (32.8%), liver (17.7%), and central nervous system (14.2%). Based on mean ICI infusion times, patients were grouped into three clusters: cluster 1 (2:15 PM, n = 76), cluster 2 (1:31 PM, n = 151), and cluster 3 (11:04 AM, n = 413). Median OS was 50.4, 28.2, and 15.7 months in Clusters 2, 1, and 3, respectively (log-rank p = 0.003). In multivariable analysis, Cluster 2 showed improved OS compared to Cluster 1 (Hazard Ratio [HR] 0.52, 95% Confidence Interval [CI] 0.31–0.86, p = 0.01), while no difference was seen between Clusters 3 and 1 (HR 1.13, 95% CI 0.75–1.70, p = 0.59). Conclusions: ICI administration around midday was associated with the longest survival, aligning with circadian peaks in T-cell infiltration, dendritic cell migration, and immune responsiveness. These findings support a personalized chrono-immunotherapy approach based on intrinsic biological rhythms.