2099 - The Impact of the Time of Day of Radiotherapy and Systemic Therapy on Disease Control in Locally Advanced Non-Small Cell Lung Cancer Treated with Chemoradiation and Durvalumab

M. T. McMillan¹, A. F. Shepherd², A. J. Cooper³, A. J. Schoenfeld³, A. J. Wu², C. B. Simone II^2,4, P. Iyengar², D. Gelblum², J. Chaft³, D. R. Gomez², and N. Shaverdian²; ¹Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, ²Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, ³Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, ⁴New York Proton Center, New York, NY

Purpose/Objective(s): The 24-hr circadian clock modulates the expression of numerous genes, including those related to immunity, DNA repair, cellular proliferation, and metabolism. Data have found the time of day of radiotherapy (RT), chemotherapy (CTX), and immune checkpoint blockade to impact disease outcomes across multiple malignancies. We hypothesized that the time of day of RT, CTX, and durvalumab would impact disease control and survival in locally advanced non-small cell lung cancer (NSCLC) treated with CTX-RT followed by consolidative durvalumab. Materials/

Methods: Consecutive patients with unresectable stage III NSCLC treated between May 2017 and August 2022 with definitive CTX-RT followed by consolidative durvalumab were retrospectively reviewed. The time of day of RT and CTX and durvalumab infusions were calculated relative to the time of sunrise and sunset and were associated with disease outcomes and survival. For the time of day of treatment, patients were assigned to 1 of 2 categories: (i) >50% of treatments in the 3 hr before or after sunset or (ii) =50% of treatments in the 3 hr before or after sunset. Variables with a p-value <0.1 on univariable analysis were included in multivariable Cox regressions for overall survival (OS), progression-free survival (PFS), locoregional control (LRC) and distant metastasis-free survival (DMFS).
Results: In total, 178 consecutive patients received definitive CTX-RT followed by consolidative durvalumab. At a median follow up of 48.0 mo from durvalumab initiation, median PFS and OS were 26.2 mo (IQR 8.0-70.0 mo) and 50.0 mo (IQR 20.7 mo-not reached), respectively. Median LRC and DMFS were not reached (IQR 23.0-not reached) and 41.0 mo (IQR 8.6-70.0 mo), respectively. Patients who received >50% of RT within 3 hr of sunset (N=23) were younger (mean: 63.4 vs 68.3 years old, p=0.010) but tended to have a worse ECOG performance status (ECOG 0: 39.1% vs 52.3%, p=0.240) compared to patients who received =50% of RT within 3 hr of sunset (N=155). The RT time-of-day cohorts did not differ with regards to other features including AJCC stage, nodal stage, and genomic alterations. On multivariable analysis, receiving >50% of RT within 3 hr of sunset was independently associated with a reduced risk for distant metastasis (HR 0.31, 95% CI 0.12-0.77, p=0.013) and improved PFS (HR 0.42, 95% CI 0.20-0.88, p=0.023). Subgroup analysis identified this association being strongest in men and/or patients <65 years old. In the overall cohort, receiving >50% of chemotherapy or durvalumab infusions within 3 hours of sunset was not associated with PFS, LRC, DMFS, or OS on univariable analysis (p=0.1 for each).
Conclusion: The time of day of RT may be associated with disease control in subgroups of patients with locally advanced NSCLC. While confirmatory studies are warranted, these data suggest that timing of therapy should be considered to optimize disease outcomes.