Overall survival according to time-of-day of combined immuno-chemotherapy for advanced non-small cell lung cancer: A bicentric bicontinental study.

2510 Background: Circadian rhythms moderate immune cells trafficking and function over the 24 hours. This could account for the near doubling of overall survival (OS) in patients (pts) receiving immune checkpoint inhibitors (ICIs) as single agents at early times-of-day of administration (ToDA) in retrospective studies. Yet, (i) the cut-off time that differentiates ICI efficacy according to ToDA ranges from 11:30 to 16:30, and (ii) the relevance of ICI timing for OS is unknown in pts receiving immunochemotherapy (ICI-chemo). Methods: These issues are addressed using OS as the primary endpoint in retrospectively-included pts receiving 1st-line ICI-chemo for stage IIIc-IV non-small cell cancer (NSCLC) in France (Cohort 1) or in China (Cohort 2). The median ToDA of the initial four ICI-chemo infusions was computed for each patient. Hazard ratio (HR) functions of an earlier death or an earlier progression were computed for each cohort and for the pooled one, using ToDA cut-off times ranging from 10:30 to 13:00, with 30-minutes increments. Median ToDA of ICI-chemo determined the allocation of patients to “Before” or “After” treatment groups. The temporal relations between HRs and ToDA as a continuous variable were further determined, using Cox models incorporating periodic restricted cubic splines. Patients were dichotomized according to the best cut off ToDA candidate, with OS and PFS being estimated using Kaplan-Meier and compared using log-rank. The association between ToDA and OS, PFS and response rates were evaluated using the Cox and logistic models controlling for main patient characteristics. Results: A total of 713 pts started treatment between 01/2018 and 10/2023 (Cohort 1, 165 pts; Cohort 2, 548 pts; median age, 62 y.o., male sex, 84%; pembrolizumab as ICI, 51%; pemetrexed-carboplatin/cisplatin, 49%; paclitaxel-carboplatin, 51%). HR functions in each cohort and in the pooled one, and the fitted curve using ToDA as a continuous variable identified 11:30 as a likely best cut off time. Median OS was 33.0 months (mo.) [95% CI, 27.5 - 41.0] in the 345 patients, who received 2-4 immunochemotherapy courses before 11:30) compared to 19.5 mo. [18.0 - 22.5] in those, who received 2-4 courses after 11:30 (N = 368) (p<0.0001). In the multivariable analysis, a median ToDA before 11:30 was associated with prolonged OS with an adjusted HR of 0.47 [0.37-0.60]. Statistically significant differences in ToDA effects were found for OS, PFS in each cohort, and for response rate in each cohort and in the pooled data. Conclusions: In this large bi-continental study, ToDA of immunochemotherapy administration before 11:30 was associated with improved OS, PFS and response rates, compared to later ToDA in pts receiving standard first line immunochemotherapy for NSCLC. Randomized trials are needed to confirm this important finding and inform recommendations for clinical practice.