Time-of-day administration of immunotherapy in early-stage triple-negative breast cancer: Immune-dependent chronotherapy effects in the phase III A-BRAVE trial.

1010 Background: Circadian rhythms regulate immune functions, and morning (AM) administration of immunotherapy (IO) is associated with survival in several solid tumors. However, whether time-of-day (ToDa) of IO delivery influences outcomes in early-stage triple-negative breast cancer (TNBC), and whether this effect depends on immune biomarkers, remains unknown. Methods: A-BRAVE randomized patients with high-risk early-stage TNBC to 1 year of adjuvant avelumab or observation. Infusion time of avelumab was retrieved from eCRF. AM-rate was calculated for each patient as the proportion of the first 4 infusions occurring before 12:30 PM (cohort median ToDa) and patients categorized as AM-dominant (AM-rate ≥50%) or PM-dominant. Tumor-infiltrating lymphocytes (TILs) and PD-L1 (Dako 73-10) were centrally assessed on treatment-naive tumor samples. We analyzed distant disease-free survival (DDFS) and overall survival (OS) by adjusted Cox models. Results: ToDa data were available for 221 avelumab-treated patients (94.0%); TILs and PD-L1 were evaluable in 188 (85%) and 195 (88%) of these, respectively. AM-rate was not associated with outcomes. However, ToDa effects were strongly immune-dependent. Increasing AM-rate was associated with improved DDFS and OS in immune-hot tumors (TILs [≥20%] or PD-L1 [≥21] high), but with worse outcomes in immune-cold tumors (TILs or PD-L1 low) (AM-rate*TILs interaction: DDFS p=0.008, OS p=0.001; AM-rate*PD-L1 interaction: DDFS p=0.030, OS p=0.039). These findings were concordant using AM-dominant vs. PM-dominant categorization (Table). Patients receiving immune-aligned treatment (immune-hot/AM-dominant OR immune-cold/PM-dominant) had superior survival compared with immune-misaligned (immune-hot/PM-dominant OR immune-cold/AM-dominant) and the observational arm (TILs-based: 3-year OS 95.7% vs 75.2% vs 78.0%; p