A study from the US finds that compared with afternoon infusions, morning infusions of immune checkpoint inhibitors (ICI) confer a modest but clinically meaningful overall survival (OS) benefit to patients with non-small-cell lung cancer (NSCLC).
Circadian rhythms generate predictable morning peaks in immune activity. Therefore, administering ICI therapy in the morning may amplify its efficacy. [Annu Rev Immunol 2024;42:83-102; Nat Immunol 2024;25:1257-1269; Br J Cancer 2024;131:783-796] While a growing body of retrospective studies supports this “chronotherapy” hypothesis, existing evidence is limited by selection bias, time-varying confounding, immortal time bias, and lack of negative-control comparisons. [Lancet Oncol 2021;22:1777-1786; Cancers (Basel) 2022;14:896; Front Immunol 2024;15:1512972]
“The present study addresses these limitations by emulating a pragmatic target randomized trial within the national Veterans Health Administration [VHA],” explained the researchers. “Using the largest-to-date cohort of stage IV NSCLC patients treated with ICIs, we applied a marginal structural model that accounted for time-varying treatment strategies, eliminated immortal-time bias, and balanced both baseline and longitudinal confounding through inverse-probability weighting.” [J Immunother Cancer 2026;14:e013830]
In the emulated trial, 1,171 patients with stage IV NSCLC received their first three infusions of ICI therapy in the morning and 794 patients in the afternoon. A contemporaneous cohort of 7,951 chemotherapy-treated patients, who also received their treatment in the morning or the afternoon, served as negative controls to test residual confounding unrelated to immune mechanisms.
The study was conducted for all stage IV NSCLC patients within the national VHA system who initiated first- (1L) or second-line (2L) ICI therapy (pembrolizumab, nivolumab, or atezolizumab) between 2015 and 2024, or 1L or 2L chemotherapy (cisplatin, carboplatin, paclitaxel, pemetrexed, gemcitabine, etoposide, or docetaxel) between 2010 and 2024 , without exclusions based on performance status or organ function. “This inclusive design was justified by the possibility that all patients undergoing ICI therapy could benefit from optimized infusion timing if it improves survival or response, given the low-risk nature of the scheduling intervention,” highlighted the researchers.
In the primary analysis for the ICI cohort, after a median follow-up of 4.7 years, median OS was 8.11 months in the afternoon vs 10.3 months in the morning arm (adjusted HR [aHR], 1.15; 95 percent confidence interval [CI], 1.04–1.26; p=0.004). At 12 months, the estimated absolute decrement in survival probability in the PM arm was -5.9 percent. No time-of-day effect was detected in the chemotherapy control cohort (median OS in afternoon vs morning groups: 7.2 vs 7.9 months; aHR, 1.05; 95 percent CI, 0.98–1.12; p=0.15).
“The survival benefit [seen in the ICI group] was not observed in a chemotherapy-treated negative control group, supporting a time-of-day–specific effect linked to ICI biology rather than nonspecific prognostic differences,” stated the researchers. “The effect emerged after the second infusion and remained consistent across multiple sensitivity analyses, including alternative time-of-day cutoffs. These findings suggest that rescheduling ICI infusions to the morning may be a low-cost, low-risk strategy to improve outcomes that warrants evaluation in prospective randomized trials.”
The relatively narrow range of analyzed infusion times was one of the potential limitations of the study. The researchers noted that if infusions administered later in the afternoon or evening have a more pronounced negative impact on outcomes, the present study may underestimate the true effect of infusion timing. In addition, the VHA population is predominantly male, which may limit the generalizability of this study’s findings to female patients.