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

Abstract

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<0.001; PD-L1-based: 3-year OS 93.4% vs 79.4% vs 76.1; p=0.035). Conclusions: In early-stage TNBC, time of IO administration may be a driver of efficacy, with opposing effects according to baseline immune milieu. Immune-informed circadian alignment may represent a previously unrecognized determinant of IO efficacy in TNBC. Clinical trial information: NCT02926196 . Outcome AM-dominant3-yr Rate % (95% CI) PM-dominant3-yr Rate % (95% CI) Log-rank p AM vs PM dominant HR (95% CI) TILs High DDFS 90.1 (81.3–99.8) 72.0 (56.4–91.9) 0.064 0.39 (0.13–1.21) OS 97.5 (92.8–100) 76.0 (61.0–94.7) 0.019 0.35 (0.10–1.20) TILs Low DDFS 63.1 (52.6–75.7) 84.7 (75.5–95.1) 0.003 2.61 (1.23–5.55) OS 74.9 (65.2–86.0) 94.3 (88.3–100) 0.003 3.84 (1.30–11.29) PD-L1 high DDFS 100 (100–100) 61.5 (40.0–94.6) 0.015 0.11 (0.01–0.94) OS 100 (100–100) 76.9 (57.1–100) 0.008 0.11 (0.01–1.03) PD-L1 low DDFS 66.4 (57.3–77.0) 83.0 (74.7–92.2) 0.026 1.82 (1.00–3.31) OS 79.8 (71.9–88.6) 91.5 (85.3–98.2) 0.025 2.05 (0.95–4.43)