Early Morning Immune Checkpoint Blockade 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 blockers (ICB). The association between ICB 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 Giacchetti S. Bjarnason G. Garufi C. et al. Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol Off J Am Soc Clin Oncol. 2006; 24: 3562-3569https://doi.org/10.1200/JCO.2006.06.1440 Crossref PubMed Scopus (178) Google Scholar ] years, 39% of women, 83% PS0-1 at first infusion, 19% received concomitant chemotherapy). ICB 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 Lévi F. Okyar A. Dulong S. Innominato P.F. Clairambault J. Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol. 2010; 50: 377-421https://doi.org/10.1146/annurev.pharmtox.48.113006.094626 Crossref PubMed Scopus (331) Google Scholar , 3 Dallmann R. Okyar A. Lévi F. Dosing-Time Makes the Poison: Circadian Regulation and Pharmacotherapy. Trends Mol Med. 2016; 22: 430-445https://doi.org/10.1016/j.molmed.2016.03.004 Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar , 4 Printezi M.I. Kilgallen A.B. Bond M.J.G. et al. Toxicity and efficacy of chronomodulated chemotherapy: a systematic review. Lancet Oncol. 2022; 23: e129-e143https://doi.org/10.1016/S1470-2045(21)00639-2 Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar , 5 Lévi F. Zidani R. Misset J.L. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet Lond Engl. 1997; 350: 681-686https://doi.org/10.1016/s0140-6736(97)03358-8 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar , 6 Lévi F. Misset J.L. Brienza S. et al. A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. High antitumor effectiveness against metastatic colorectal cancer. Cancer. 1992; 69: 893-900https://doi.org/10.1002/1097-0142(19920215)69:4<893::aid-cncr2820690410>3.0.co;2-x Crossref PubMed Google Scholar , 7 Curé H. Chevalier V. Adenis A. et al. Phase II trial of chronomodulated infusion of high-dose fluorouracil and l-folinic acid in previously untreated patients with metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2002; 20: 1175-1181https://doi.org/10.1200/JCO.2002.20.5.1175 Crossref PubMed Scopus (0) Google Scholar , 8 Giacchetti S. Perpoint B. Zidani R. et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2000; 18: 136-147https://doi.org/10.1200/JCO.2000.18.1.136 Crossref PubMed Google Scholar , 9 Innominato P.F. Ballesta A. Huang Q. et al. Sex-dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer: Randomized multicenter EORTC 05011 trial. Cancer Med. 2020; 9: 4148-4159https://doi.org/10.1002/cam4.3056 Crossref PubMed Scopus (34) Google Scholar , 10 Giacchetti S. Dugué P.A. Innominato P.F. et al. Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis. Ann Oncol Off J Eur Soc Med Oncol. 2012; 23: 3110-3116https://doi.org/10.1093/annonc/mds148 Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar , 11 Giacchetti S. Bjarnason G. Garufi C. et al. Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol Off J Am Soc Clin Oncol. 2006; 24: 3562-3569https://doi.org/10.1200/JCO.2006.06.1440 Crossref PubMed Scopus (178) Google Scholar , 12 Reck M. Rodríguez-Abreu D. Robinson A.G. et al. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50. J Clin Oncol Off J Am Soc Clin Oncol. 2021; 39: 2339-2349https://doi.org/10.1200/JCO.21.00174 Crossref PubMed Scopus (412) Google Scholar , 13 Herbst R.S. Giaccone G. de Marinis F. et al. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020; 383: 1328-1339https://doi.org/10.1056/NEJMoa1917346 Crossref PubMed Scopus (830) Google Scholar , 14 Zhou C. Li M. Wang Z. An D. Li B. Adverse events of immunotherapy in non-small cell lung cancer: A systematic review and network meta-analysis. Int Immunopharmacol. 2022; 102108353https://doi.org/10.1016/j.intimp.2021.108353 Crossref Scopus (14) Google Scholar , 15 Wang D.Y. Salem J.E. Cohen J.V. et al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol. 2018; 4: 1721-1728https://doi.org/10.1001/jamaoncol.2018.3923 Crossref PubMed Scopus (1454) Google Scholar , 16 Dolladille C. Ederhy S. Sassier M. et al. Immune Checkpoint Inhibitor Rechallenge After Immune-Related Adverse Events in Patients With Cancer. JAMA Oncol. 2020; 6: 865-871https://doi.org/10.1001/jamaoncol.2020.0726 Crossref PubMed Scopus (262) Google Scholar , 17 Qian D.C. Kleber T. Brammer B. et al. Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study. Lancet Oncol. 2021; 22: 1777-1786https://doi.org/10.1016/S1470-2045(21)00546-5 Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar , 18 Karaboué A. Collon T. Pavese I. et al. Time-Dependent Efficacy of Checkpoint Inhibitor Nivolumab: Results from a Pilot Study in Patients with Metastatic Non-Small-Cell Lung Cancer. Cancers. 2022; 14: 896https://doi.org/10.3390/cancers14040896 Crossref PubMed Scopus (23) Google Scholar , 19 Cortellini A. Barrichello A.P.C. Alessi J.V. et al. A multicentre study of pembrolizumab time-of-day infusion patterns and clinical outcomes in non-small-cell lung cancer: too soon to promote morning infusions. Ann Oncol Off J Eur Soc Med Oncol. 2022; 33: 1202-1204https://doi.org/10.1016/j.annonc.2022.07.1851 Abstract Full Text Full Text PDF Scopus (4) Google Scholar , 20 Rousseau A. Tagliamento M. Auclin E. et al. Clinical outcomes by infusion timing of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer. Eur J Cancer Oxf Engl 1990. 2023; 182: 107-114https://doi.org/10.1016/j.ejca.2023.01.007 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar ], 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 ICB 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.