Effect of dual immune checkpoint inhibitors (ICI) by the time of infusion in advanced non–small cell lung cancer (NSCLC): A secondary analysis of CCTG BR34 trial.

8566 Background: There is increasing evidence suggesting the impact of circadian biology on ICI efficacy in solid tumours, though evidence for dual checkpoint blockade is limited. We conducted a secondary analysis of BR.34 to assess whether time of infusion (TOI) correlates with outcomes with durvalumab–tremelimumab ± platinum chemotherapy in advanced EGFR/ALK-negative NSCLC. Methods: Patients were classified into the AM group when ≥80% of the PD-1 inhibitor infusions were started before 13:00 (threshold based on prior literature); otherwise, they were placed into the PM group. OS and PFS were analyzed using Cox models adjusted for imbalanced baseline factors. Sensitivity analyses were performed to assess correlations with other TOI thresholds. Results: TOI was evaluable for 296/301 patients; 186 were AM and 110 PM. PM infusion was associated with longer median OS (19.1 vs 13.4 months (m); HR 0.58, 95% CI 0.41–0.82) and median PFS (8.3 vs 4.1 m; HR 0.67, 95% CI 0.51–0.88). The improvement in OS associated with the PM group was consistent across both arms. In the multivariable analyses, PM administration remained associated with improved OS (adjusted HR (aHR) 0.62, 95% CI 0.44–0.88) and PFS (aHR 0.73, 95% CI 0.55–0.96). Sensitivity analyses using an alternative threshold of ≥60% of the PD-1 inhibitor infusions started before 1300 yielded consistent trends. Using a median TOI of 11:00 AM as an additional threshold, later infusions were also associated with longer OS (HR 0.77, 95% CI 0.56–1.05), with similar trends across both treatment arms. There was no apparent difference in fatal adverse events (n = 4), with two in the AM and two in the PM group. Serious adverse effects that led to therapy discontinuation also did not significantly differ between AM vs. PM in the IO-alone group (3 vs. 5) or the IO-chemo group (6 vs. 4). Conclusions: Afternoon infusion of dual ICI ± chemotherapy was associated with improved survival in BR.34, in contrast to earlier reports with anti-PD-1 therapy. These findings highlight the potential for regimen- and disease-specific chronotherapeutic effects and support the need for prospective trials across tumour types and of different checkpoint inhibitor combinations. References: 1. Leighl NB, et al. J Thorac Oncol. 2022;17(3):434–445. 2. Karaboué A, et al. Br J Cancer. 2024;131:783–796. Baseline factors. Baseline Factors IO-AM (n) IO-PM (n) IO-CHEMO-AM (n) IO-CHEMO-PM (n) Sex (F/M) 41/54 28/25 42/49 27/30 Age (<65/ ≥ 65) 48/47 84/64 36/55 32/25 ECOG (0/1) 22/73 23/30 26/65 20/37 Disease Stage (IVA/IVB) 26/69 22/31 34/57 19/38 Histological subtype (NSq/Sq) 77/18 44/9 73/18 48/9 Liver Metastases (N/Y) 78/17 42/11 68/23 50/7 Brain Metastases (N/Y) 76/19 45/8 82/9 44/13 PD-L1 Expression (<1/1-49/ ≥ 50%/Unknown) 37/25/20/13 23/19/7/4 33/27/16/15 22/17/13/5 TMB (<20/≥20 mut/MB) 74/21 39/14 69/22 46/11 Nsq = non-squamous, Sq = squamous.