Impact of infusion timing (IT) on survival outcomes across gastrointestinal (GI) malignancies: A multicenter analysis of circadian rhythm (CR) effects on immune checkpoint inhibitor (ICI) activity.

Abstract

837 Background: A recent randomized trial suggested that CR may influence ICI activity in patients with lung cancer. However, the same has not been established in GI cancers, where reports have shown mixed results with variable definitions of 'early' vs 'late' IT. We evaluated multiple approaches to assess the impact of CR on first-line ICI in GI malignancies. Methods: This retrospective study included patients from three Mayo Clinic sites (N=455). Both previously reported IT cutoffs and a new cutoff derived from ROC analysis were evaluated. Patients were categorized by the median of all ITs, the median of the first four ITs, and whether ≥20% of ITs occurred before the identified cutoff. Univariate and multivariate Cox regression (adjusting for age, MSI status, type of cancer, metastasis status, number of cycles, and receipt of chemotherapy with ICI) assessed associations with OS. KM analyses were performed to illustrate survival differences. The primary endpoint was OS. Results: When patients were categorized based on whether ≥20% of infusions occurred before 14:00 (ROC-derived cutoff), a significant association with OS was observed. On univariate analysis, early infusion timing was associated with improved survival (HR 2.30, 95% CI 1.58–3.32, p <0.001). This remained significant after multivariable adjustment (HR 2.11, 95% CI 1.41–3.16, p < 0.001). Median OS was 14.2 months in the early group vs 3.8 months in the late group (log-rank p < 0.001). Using previously defined cutoffs, categorization by the median IT of all infusions or the median of the first four infusions did not demonstrate a significant association with OS in either univariate or multivariate Cox regression analyses. Conclusions: These findings highlight the potential role of infusion timing as a chronotherapy factor in GI cancers. Given the retrospective design and heterogeneous population, prospective studies are warranted to validate this signal and clarify its clinical relevance. Baseline demographics of patients by infusion timing (early vs late). Variables Early N=412 (%) LateN=43(%) Total N=455(%) p-value Age <70 249(60.4) 21(48.8) 270 (59.3) 0.1 >70 163(39.6) 22(51.2) 185 (40.7) Gender F 118(28.6) 16(37.2) 134 (29.5) 0.3 M 294(71.4) 27(62.8) 321 (70.5) Cancer Type Gastroesophageal 109 (26.5) 8 (18.6) 117 (25.7) 0.1 Hepatocellular 159 (38.6) 24 (55.8) 183 (40.2) Biliary 86 (20.9) 4 (9.3) 90 (19.8) MSI-H 58 (14.1) 7 (16.3) 65 (14.3) Metastasis No 150 (36.4) 22 (51.2) 172 (37.8) 0.1 Yes 262 (63.6) 21 (48.8) 283 (62.2) Immunotherapy Cycle Number <6 189 (45.9) 33 (76.7) 222 (48.8) <0.001 >6 223 (54.1) 10 (23.3) 233 (51.2)