Overall survival according to time-of-day of combined immuno-chemotherapy for advanced non-small cell lung cancer: a bicentric bicontinental studyResearch in context
Zhe Huang,
Abdoulaye Karaboué,
Liang Zeng,
Adrien Lecoeuvre,
Lemeng Zhang,
Xiao-Mei Li,
Haoyue Qin,
Gabrielle Danino,
Feng Yang,
Marie-Sara Malin,
Li Deng,
Marte Rigal,
Hong Liu,
Xiang Chen,
Qinqin Xu,
Lamiae Grimaldi,
Thierry Collon,
Jing Wang,
René Adam,
Nong Yang,
Boris Duchemann,
Yongchang Zhang,
Francis Lévi
Affiliations
Zhe Huang
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China; Department of Pathology, School of Basic Medical Science, Central South University, Changsha, 410013, China
Abdoulaye Karaboué
Research Unit “Chronotherapy, Cancer, Transplantation”, Faculty of Medicine, Paris-Saclay University, Hospital Paul Brousse, Villejuif, 94800, France; Medical Oncology Unit, GHT Paris Grand Nord-Est, Le Raincy-Montfermeil, Montfermeil, 93770, France
Liang Zeng
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
Adrien Lecoeuvre
Clinical Research Unit, Paris Saclay University and Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin Bicêtre, 94275, France
Lemeng Zhang
Department of Thoracic Oncology, Hunan Cancer Hospital, Changsha, 410013, China
Xiao-Mei Li
Research Unit “Chronotherapy, Cancer, Transplantation”, Faculty of Medicine, Paris-Saclay University, Hospital Paul Brousse, Villejuif, 94800, France
Haoyue Qin
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
Gabrielle Danino
Thoracic and Medical Oncology Unit, Avicenne Hospital, Assistance Publique - Hôpitaux de Paris, Bobigny, 93000, France
Feng Yang
Early Clinical Trial Centre, Office of National Drug Clinical Trial Institution, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
Marie-Sara Malin
Pharmacology Unit, Avicenne Hospital, Assistance Publique - Hôpitaux de Paris, Bobigny, 93000, France
Li Deng
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
Marte Rigal
Pharmacology Unit, Avicenne Hospital, Assistance Publique - Hôpitaux de Paris, Bobigny, 93000, France
Hong Liu
Department of Dermatology, Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Centre of Skin Health and Disease, Xiangya Clinical Research Centre for Cancer Immunotherapy, Xiangya Hospital, Central South University, Changsha, 410013, China
Xiang Chen
Department of Dermatology, Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Centre of Skin Health and Disease, Xiangya Clinical Research Centre for Cancer Immunotherapy, Xiangya Hospital, Central South University, Changsha, 410013, China
Qinqin Xu
Department of Medical Oncology, Qinghai Provincial People's Hospital, Xining, 810000, China
Lamiae Grimaldi
Clinical Research Unit, Paris Saclay University and Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin Bicêtre, 94275, France
Thierry Collon
Medical Oncology Unit, GHT Paris Grand Nord-Est, Le Raincy-Montfermeil, Montfermeil, 93770, France
Jing Wang
Early Clinical Trial Centre, Office of National Drug Clinical Trial Institution, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
René Adam
Research Unit “Chronotherapy, Cancer, Transplantation”, Faculty of Medicine, Paris-Saclay University, Hospital Paul Brousse, Villejuif, 94800, France; Department of Hepatobiliary Surgery, Cancer and Transplantation, AP-HP Paul Brousse Hospital, Paris-Saclay University, Villejuif, 94800, France
Nong Yang
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
Boris Duchemann
Research Unit “Chronotherapy, Cancer, Transplantation”, Faculty of Medicine, Paris-Saclay University, Hospital Paul Brousse, Villejuif, 94800, France; Thoracic and Medical Oncology Unit, Avicenne Hospital, Assistance Publique - Hôpitaux de Paris, Bobigny, 93000, France
Yongchang Zhang
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China; Department of Pathology, School of Basic Medical Science, Central South University, Changsha, 410013, China; Early Clinical Trial Centre, Office of National Drug Clinical Trial Institution, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China; Furong Laboratory, Changsha, 410013, China; Corresponding author. Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China.
Francis Lévi
Research Unit “Chronotherapy, Cancer, Transplantation”, Faculty of Medicine, Paris-Saclay University, Hospital Paul Brousse, Villejuif, 94800, France; Gastro-Intestinal and Medical Oncology Department, Paul Brousse Hospital, Assistance Publique-Hôpitaux de Paris, Villejuif, 94800, France; Department of Statistics, University of Warwick, Coventry, CV4 7AL, United Kingdom; Corresponding author. Research Unit “Chronotherapy, Cancer, Transplantation”, Faculty of Medicine, Paris-Saclay University, Hospital Paul Brousse, Villejuif, 94800, France.
Summary: Background: Circadian rhythms regulate immune cell activity, influencing responses to vaccines, and immune checkpoint inhibitors (ICIs). Early time-of-day administration (ToDA) of singe-agent ICIs has been associated with improved overall survival (OS) in patients with metastatic “immunotherapy sensitive” cancers. However, the impact of ToDA on OS in patients receiving combination therapy with ICIs and chemotherapy for advanced non-small cell lung cancer (NSCLC) remains unclear. Methods: This retrospective study included patients from oncology units in Paris, France (Cohort 1) and Hunan, China (Cohort 2) who received first-line immuno-chemotherapy for stage IIIC or IV NSCLC between January 2018 and October 2023. The primary outcome was OS. The median ToDA of the initial four ICI infusions was computed for each patient. Hazard ratio (HR) for death or progression were determined using cut-off times ranging from 10:30 to 13:00. Kaplan Meier and Cox models were used to estimate OS and progression-free survival (PFS) adjusting for main patient characteristics. Findings: The study included 713 patients (Cohort 1, n = 165; Cohort 2, n = 548). Pembrolizumab was the most common ICI (51%), which was used with either pemetrexed-carboplatin/cisplatin (49%) or paclitaxel-carboplatin (51%). The optimal ToDA cut-off was 11:30, with patients receiving immuno-chemotherapy before 11:30 showing significantly improved OS (33.0 months [95% CI, 27.5–41.0] vs 19.5 months [18.0–22.5]; p < 0.0001). Multivariable analysis confirmed that earlier ToDA was associated with better OS (adjusted HR = 0.47 [95% CI, 0.37–0.60]). ToDA significantly impacted OS in each cohort and for PFS and response rates in each cohort and the pooled data. Interpretation: This sizeable bi-continental study provided real-world evidence that morning administration of standard first-line immuno-chemotherapy was associated with improved clinical outcomes compared to afternoon dosing in patients with NSCLC. Randomised trials are required to validate this finding and inform recommendations for clinical practice. Funding: National Natural Science Foundation of China (82222048, 82003206, 82173338, and 82102747).
