Circadian immune coherence and readiness as time-aware early endpoints in a real-world NSCLC cohort treated with immune checkpoint inhibitors.

Abstract

e23114 Background: Immune biomarkers guiding immune checkpoint inhibitor (ICI) therapy are commonly assessed as static baseline measurements, despite strong biological evidence that immune function is dynamically regulated over time. Circadian organization influences immune cell trafficking, checkpoint molecule expression, and T-cell effector function, potentially affecting ICI efficacy and toxicity. We investigated whether circadian immune coherence (CIC) and circadian immune readiness (CIR), derived from longitudinal routine hematology, could serve as time-aware early endpoints in real-world patients with non–small cell lung cancer (NSCLC) receiving ICIs. Methods: We performed a retrospective real-world analysis of 90 patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors. Longitudinal complete blood count–derived immune indices were analyzed using AI-enhanced Fourier decomposition to extract oscillatory features, including phase stability across treatment cycles. CIC quantified inter-cycle phase coherence of immune rhythms, while CIR integrated coherence with oscillatory amplitude. Unsupervised clustering identified immune coherence phenotypes. Associations with objective response rate (ORR), progression-free survival (PFS), infusion timing, and immune-related adverse events (irAEs) were evaluated descriptively. Results: Detectable circadian immune oscillations were identified in 76% of patients. Two dominant phenotypes emerged: high circadian immune coherence (n=54) and low coherence (n=36). Patients with high CIC demonstrated longer median PFS (11.8 vs 6.4 months) and higher ORR (48% vs 22%) compared with low-coherence patients. Alignment of immunotherapy infusion with individual coherence peaks was associated with more favorable outcomes, whereas low-coherence patients showed limited sensitivity to timing effects. High CIC was also associated with a lower incidence of grade ≥2 irAEs (19% vs 33%). CIC and CIR provided clinically informative stratification beyond baseline inflammatory indices and static biomarkers. Conclusions: Circadian immune coherence and readiness capture biologically meaningful temporal organization of immune responses during ICI therapy. Early-emerging CIC/CIR phenotypes represent novel, time-aware biomarkers with potential utility for early dynamic risk stratification and optimization of real-world immunotherapy strategies in NSCLC.