Impact of time-of-day (ToD) of single-agent immune-checkpoint inhibitor (ICI) on survival in advanced non–small cell lung cancer (aNSCLC) with PD-L1 ≥ 50%: Analysis of the NOTCH collaborative REAL-SAIF study.

Abstract

8602 Background: There is growing evidence and interest in the role of chrono-immunotherapy. Previous studies showing benefit of earlier ToD were limited by small cohorts with heterogenous groups and ToD cut-offs. Using one of the largest UK cohort, we explored this further. Methods: 896 patients treated with 3-weekly ICI monotherapy between 2017-2023 from 16 UK centres were included in this retrospective study. Early 30-day deaths were excluded. Multiple imputations were used for data missing at random (except ToD) with pooled estimates. The primary endpoint was overall survival (OS). A sinusoidal Cox model was used for multivariate analysis to represent the cyclical nature of ToD. Results: Median OS and progression-free survival (PFS) were 19.1 (95%CI 17.2-20.9) and 10.1 (95%CI 9.2-11.7) months. Baseline demographics were median age 70-years, 50% male, 77.3% non-squamous histology, and 91% pembrolizumab as ICI of choice. Mean C1 and C2 ToD was 13:18 and 13:12 respectively. 44.1% and 66.5% of patients received C2 within 1 and 4 hours from prior ToD. ToD was not correlated with age or socioeconomic deprivation. Age (HR 1.01; p =0.008), male sex (HR 1.25; p =0.005), performance status (PS) ≥2 (HR 1.22; p =0.038), squamous histology (HR 1.30; p =0.004), liver metastasis (HR 1.51; p =0.001), albumin (HR 0.98; p <0.001), and neutrophil-lymphocyte ratio (NLR) (HR 1.60; p <0.031) were associated with OS. PS ≥2 (HR 1.23; p =0.026), squamous histology (HR 1.26; p =0.010), albumin (HR 0.98; p =0.001), and PDL1% (HR 0.99; p =0.012) were associated with PFS. There was no correlation between C1 or C2 ToD with OS/PFS. There was a significant interaction between NLR and C1 ToD for both OS (HR 1.48; p <0.001) and PFS (HR 1.30; p =0.014), with a change in HR <1.0 for high NLR after 14:00 and 12:30 respectively. Conclusions: ToD alone was not associated with survival in aNSCLC ICI monotherapy. NLR has a strong interaction with ToD. A low NLR with early ToD and a high NLR with later ToD were correlated with improved OS/PFS. The relationship of ToD with survival is complex and further research is required before adoption into routine practice. Multivariate Cox model for OS and PFS. PFS[HR (95%CI); p -value] OS[HR (95%CI); p -value] Age 1.00 (1.00-1.01) 0.286 1.01 (1.00-1.02) 0.008 Male sex 1.14 (0.98-1.32) 0.093 1.25 (1.07-1.46) 0.005 Performance status ≥2 1.23 (1.03-1.48) 0.026 1.22 (1.01-1.48) 0.038 Squamous histology 1.26 (1.06-1.50) 0.010 1.30 (1.09-1.56) 0.004 Brain metastasis 1.24 (0.99-1.57) 0.062 1.24 (0.97-1.59) 0.091 Liver metastasis 1.32 (1.03-1.69) 0.029 1.51 (1.17-1.94) 0.001 Albumin 0.98 (0.97-0.99) 0.002 0.98 (0.96-0.99) <0.001 NLR 1.16 (0.76-1.76) 0.498 1.60 (1.05-2.46) 0.031 PDL1% 0.99 (0.99-1.00) 0.012 1.00 (0.99-1.00) 0.091