Abstract PS2-10-13: Impact of infusion Time-of-Day of Administration (ToDA) of neoadjuvant immunochemotherapy on pathological response in patients with early Triple-negative Breast Cancer treated with KEYNOTE-522 regimen (PEMCLOCK study)

Abstract Background: Neoadjuvant chemotherapy (NAC) combined with pembrolizumab according to KEYNOTE-522 study is the standard treatment for patients (pts) with stage II or III triple-negative breast cancer (TNBC). Circadian rhythms regulate both immune cells function and trafficking, and cancer treatment responses over the 24-hours. Evidence from 31 retrospective studies and one randomized trial supports the benefit of early time-of-day administration (ToDA) of immunotherapy or immunochemotherapy across 10 different cancer types. However, no such data exist for breast cancer patients, nor regarding sex-based differences. Objective: PEMCLOCK evaluates the clinical relevance of ToDA of neoadjuvant pembrolizumab combined with paclitaxel carboplatin for 4 cycles, then by anthracycline cyclophosphamide for 4 cycles for histological tumor response, treatment toxicity, and survival outcomes in pts with high-risk early-stage TNBC. Methods: This French multicenter retrospective study enrolled pts with stage II-III TNBC at 9 cancer centers from 5/2021 to 12/2023. Patients received at least one neoadjuvant pembrolizumab infusion with documented start ToDA. Median ToDA of neoadjuvant pembrolizumab was computed for each patient. The primary endpoint was pathological complete response (pCR) according to the Residual Cancer Burden classification (RCB, 0 to III). Secondary endpoints included treatment-related toxicities and event-free survival. Patients were categorized into early or late ToDA groups based on the overall median of individual median ToDAs across all pembrolizumab infusions. Results: The study included 614 pts with a median follow up of 25 months [95 CI, 24 to 26]. Median age was 49.5 years [IQR: 41.1-58]. Among them, 57% were premenopausal, and 16% carried a constitutional BRCA mutation (12% BRCA1, 4% BRCA2). The median body mass index (BMI) was 25.15 [IQR: 21.8-29.3]. Tumor stages included T1c (8 %), T2 (66 %), and T3-T4 (25 %), with 82% of tumors classified as grade III. Clinically positive axillary nodes were observed in 52 % of pts, with pathological confirmation in 218 cases. Patients received a median number of 8 immunochemotherapy cycles [IQR: 6-8]. The overall median ToDA for pembrolizumab was 12:31 [IQR: 11:34-13:40], which served as the cut-off to define early (n=355) and late (n=252) ToDA groups. Interpatient variability in pembrolizumab ToDA was 4:36 hours [IQR: 3:14-5:44]. Baseline characteristics were balanced between the early and late ToDA groups. A total of 410 patients (67%) achieved pCR (RCB = 0), including 63 % of the patients in the early ToDA group and 74 % in the late ToDA group. There are currently 52 and 35 events for Event-Free Survival and Overall Survival, respectively, thus requiring additional follow up for assessing relevance of ToDA for survival outcomes on the whole study sample. Conclusions: PEMCLOCK is the first real-world large multicenter study which explores the concept of immunochemotherapy ToDA in pts with high-risk early-stage TNBC. Ongoing analyses on treatment-related response, toxicity and survival outcomes along with innovative mathematical modeling approaches will provide a comprehensive understanding to the relations between ToDA and immunochemotherapy efficacy in patients with TNBC. Citation Format: C. Bouchez, D. Loirat, B. Verret, A. De Nonneville, P. Heudel, S. Bécourt, L. Someil, M. Benderra, A. Hardy-Bessard, J. Wasserman, P. Charveriat, F. Giugliano, L. Cabel, Q. Aussedat, F. Levi, K. Desseaux, S. Revillon, S. Brand, A. Ballesta, S. Giacchetti. Impact of infusion Time-of-Day of Administration (ToDA) of neoadjuvant immunochemotherapy on pathological response in patients with early Triple-negative Breast Cancer treated with KEYNOTE-522 regimen (PEMCLOCK study) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-10-13.