Clinical Trial Summary
Background: Triple negative breast cancer (TNBC) is characterized by an aggressive biological
behaviour responsible for higher risk of recurrence and shorter median survival.
Pembrolizumab, an immune checkpoint inhibitor (ICI) targeting programmed death (PD-1), in
association to chemotherapy showed improvement of event-free survival in patients with
previously untreated stage II or III TNBC and has been approved in Europe since March 2022
for this indication (KEYNOTE-522). Circadian timing system controls many various biological
functions in humans including xenobiotic metabolism and elimination, immune functions, cell
cycle event and apoptosis. Thus, chronotherapeutic approaches have shown improved efficacy
and tolerability in the treatment of different types of cancer, notably in colorectal cancer.
Pronounced circadian rhythms in immune functions are generated by cell-autonomous molecular
clocks in T and B lymphocytes, macrophages, neutrophils, and dendritic cells. Recently, first
evidence of the effect of timing infusion of immune checkpoint inhibitors on prognosis of
patients with cancer has been reported in several retrospective trials. Landre et al.'s
meta-analysis of 7 retrospective studies including 1019 patients who had metastatic cancer
was presented at the American Society of Clinical Oncology (ASCO) meeting in 2023. An early
time-of-day ICI infusions was associated with an increase overall survival (HR: 0.49, [95%
CI: 0.36-0.69] p < 0.0001).
Objectives: The aim is to analyze immunotherapy infusion timing impact on histological
response, toxicity and Event Free-Survival (EFS) in patients with TNBC treated with
Neo-Adjuvant Chemotherapy (NAC) associated with pembroluzimab. Measure of histological
response is the primary objective determined by Residual Cancer Burden (RCB). Secondary
endpoints are Event free Survival (EFS), calculated from the date of diagnosis to invasive
local, regional, or metastatic relapse, contralateral breast cancer, or death from any
cause), toxicity which is assessed by recording adverse events (CT-CAE v5) occurring from
start of treatment to last course.
Methods: Data from patients with histologically proven early TNBC treated from July 2021 to
May 2023 with the association of Pembrolizumab, Paclitaxel Carboplatine followed with
Pembrolizumab Cyclophosphamide Epirubicine (according to KEYNOTE 522 study) will be
collected. Dosing times of each Pembrolizumab and chemotherapy infusions given to consecutive
patients as a neoadjuvant standard treatment, associated with chemotherapy, for early TNBC
are retrieved from hospital records. Adjuvant Pembrolizumab timing intake will be also
recorded as EFS is a secondary endpoint.
Statistics: First, median clock hour of all infusions of Pembrolizumab will be determined.
Then, patients will be dichotomized between "morning' and 'afternoon' groups using 2
cut-offs: 1/ median clock of all infusions of pembrolizumab ('morning group' will include the
patients who receive the majority of Pembrolizumab infusions before this median clock hour
and 'afternoon group', patients who receive the majority of Pembrolizumab infusions after
this median clock hour) and 2/ cut-off optimizing differences of RCB between two groups.
Patient's characteristics, toxicities, tumor response and EFS will be compared.
