BACKGROUND: Circadian rhythms modulate immunity, and a preclinical study suggests that the timing of the first immune checkpoint inhibitor dose affects antitumor efficacy. However, clinical confirmation is scarce. We aimed to evaluate whether the timing of the first pembrolizumab infusion affects outcomes in unresectable non-small cell lung cancer (NSCLC).
METHODS: We retrospectively analyzed patients receiving first-line pembrolizumab monotherapy for unresectable NSCLC between 2017 and 2022 at nine Japanese hospitals. Patients were categorized according to the start of first infusion: early (≤ 11:00 AM) or late (> 11:00 AM). A landmark cohort receiving ≥ 4 cycles was balanced on 14 covariates using propensity score matching. Endpoints were overall survival (OS), progression-free survival (PFS) and severe (grade ≥ 3) immune-related adverse events (irAEs). Sensitivity analysis using inverse probability of treatment weighting (IPTW) was performed.
RESULTS: Among 450 eligible patients, 290 met the landmark criteria and 206 were matched (103 per group). Median follow-up was 62.5 months (95 % CI, 56.4-67.9). The early group demonstrated significantly longer median OS (43.7 vs. 32.4 months; HR, 0.67; 95 % CI, 0.46-0.97; P = 0.03). Median PFS was not significantly different (13.8 vs. 11.6 months; HR, 0.80; 95 % CI, 0.59-1.10; P = 0.17). Severe irAEs were more frequent with early infusion (26.2 % vs. 13.6 %; P = 0.04). IPTW analysis confirmed the OS advantage with early infusion (HR, 0.65; 95 % CI, 0.45-0.94; P = 0.02).
CONCLUSION: Early morning administration of first pembrolizumab infusion was associated with improved OS and more frequent severe irAEs. Initial dose timing may be a simple, feasible variable warranting prospective validation.
Circadian Biology