Early Morning Checkpoint Inhibitor Infusion and Overall Survival of Patients with Metastatic Cancer: an In-depth Chronotherapeutic Study

Introduction Recent retrospective studies suggest potential large patient’s benefit through proper timing of immune checkpoint inhibitors (ICI). The association between ICI treatment timing and patient survival, neoplastic response and toxicities was investigated, together with interactions with performance status (PS) and sex. Methods A cohort of patients with metastatic or locally advanced solid tumors, who received pembrolizumab, nivolumab, atezolizumab, durvalumab, or avelumab, alone or with concomitant chemotherapy, between November 2015 and March 2021, at the Centre Leon Bérard (France), was retrospectively studied. Results 361 patients were investigated (80% non-small cell lung cancer patients, mean [SD] age: 63 [11] years, 39% of women, 83% PS0-1 at first infusion, 19% received concomitant chemotherapy). ICI were administered from 07:25 to 17:21 and optimal morning/afternoon cut-off was 11:37. Morning infusions were associated with increased OS as compared to afternoon (median 30.3 vs 15.9 months, p=0.0024; HR 1.56 [1.17-2.1], p=0.003). A strong PS-timing interaction was found (PS0-1 patients, HR=1.53 [1.10-2.12], p=0.011; PS2-3 patients, HR=0.50 [0.25-0.97], p=0.042). Morning PS0-1 patients displayed increased OS (median 36.7 vs 21.3 months, p=0.023), partial/complete response rate (58% vs 41%, p=0.027), and grade1-3 toxicities (49% vs 34%, p=0.028). Mortality risk ratio between infusions at worst time-of-day, estimated at 13:36 [12:48-14:23], and in early morning was 5.5-fold ([2-20], p=0.008). Timing differences in toxicities resulted significant only in female patients (women vs men: p<0.001 vs 0.4). Conclusions Early morning ICI infusion was associated with increased OS, response, and toxicities in patients with PS0-1 as compared to later infusions within the day. Prospective randomized trials are needed to confirm this retrospective study. ### Competing Interest Statement Pierre Heudel reported grants from AstraZeneca and personal fees from LILLY, ASTRAZENECA, PFIZER, NOVARTIS, SEAGEN, PIERRE FABRE, MSD, GILEAD outside the submitted work. The other authors declare no conflict of interest. ### Funding Statement This work was supported by the postdoctoral fellowship program of the French Charity "Fondation ARC pour la Recherche sur le Cancer", the French Plan Cancer through the ATIP-Avenir programme, and the French National Institute for Health and Medical Research (INSERM). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Institut Curie gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The source code generated during this study is available online at https://github.com/semolas/early-morning-checkpoint-inhibitors.