82P The role of circadian rhythms in NSCLC immunotherapy efficacy: A focus on first dose timing

Circadian rhythms are known to influence adaptive immune responses. A seminal study showed that immune checkpoint inhibitors (ICI) infusions administered in the evening (later than 16:30h) to stage IV melanoma patients led to significantly shorter progression-free survival (PFS) and overall survival (OS). Subsequent retrospective studies suggested worse outcomes for metastatic non-small cell lung cancer (NSCLC) patients who received over 20% of their ICI doses in the evening. We hypothesized that the timing of the initial dose could be responsible for this observed effect. We conducted a retrospective review of patients diagnosed with advanced or metastatic NSCLC who initiated palliative first line pembrolizumab treatment between June 2017 and April 2023 at The Christie. Sociodemographic and clinical data were collected. Patients were stratified into two groups based on the timing of their first dose infusion: those before 16:30h (early group) and those after 16:30h (evening group). 276 patients met the inclusion criteria: 237 in the early group and 39 in the evening group. Both cohorts were similar, with no significant differences in sex, ECOG, histology, brain metastases at diagnosis, or PD-L1 expression (≥ or <90%). Inflammatory blood biomarkers (NLR, PLR, PNI) were consistent between groups. The evening group had a significantly shorter median OS (16m vs. 19m; HR 1.5; p=0.047), corroborated by the multivariate analysis (Table). Although median PFS was comparable between groups, the 3-year PFS rates stood at 10% for the evening group and 22% for the early group.Table: 82PMultivariate Cox regression modelHR (95%)PECOG PS0.50 (0.26 - 0.94)0.031Histology (non-squamous)0.76 (0.55 - 1.04)0.083PD-L1 <90%1.58 (1.17 - 2.15)0.003NLR <50.61 (0.45 - 0.82)0.001Evening Group1.63 (1.09 - 2.43)0.018 Open table in a new tab Our findings add to the emerging body of evidence suggesting a link between circadian rhythms and immunotherapy efficacy. While this study indicates a difference in OS based on the timing of the first dose, further prospective research is imperative. Modifying infusion timings could provide a straightforward approach to potentially optimizing patient outcomes.