Based on the randomized phase 3 LungTIME-C01 trial, Huang et al. reported that early time of day (ToD) treatment (before 3 pm) for the first 4 doses improved anti-PD-1 efficacy compared with late ToD treatment (after 3 pm) in patients with stage IIIC–IV NSCLC. For the early ToD group, median PFS and OS were 11.3 and 28.0 months, compared to the late ToD group, which were 5.7 and 16.8 months, respectively. Between both groups, no differences in incidence of immune-related adverse events were observed. Circulating CD8+ T cells increased in the early ToD group, with a higher activated (CD38+ HLA-DR+) versus exhausted (TIM-3+PD-1+) ratio.
Contributed by Shishir Pant
ABSTRACT: Retrospective studies suggest that early time-of-day (ToD) infusions of immunochemotherapy may improve efficacy. However, prospective randomized controlled trials are needed to validate it. In this randomized phase 3 LungTIME-C01 trial, 210 patients with treatment naive stage IIIC-IV non-small cell lung cancer (NSCLC) lacking driver mutations were randomly assigned in a 1:1 ratio to either an early or late ToD group, defined by the administration of the first four cycles of an anti-PD-1 agent before or after 15:00 h. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS) and objective response rate (ORR). After a median follow-up of 28.7 months, the median PFS was 11.3 months (95% confidence interval (CI) = 9.2-13.4) in the early ToD group and 5.7 months (95% CI = 5.2-6.2) in the late ToD group, corresponding to a hazard ratio (HR) for earlier disease progression of 0.40 (95% CI = 0.29-0.55; P < 0.001). The median OS was 28.0 months (95% CI = not estimable (NE)-NE) in the early ToD group and 16.8 months (95% CI = 13.7-19.9) in the late ToD group, corresponding to an HR of an earlier death of 0.42 (95% CI = 0.29-0.60; P < 0.001). Treatment-related adverse events were consistent with the established safety profile, with no new safety signals observed. No significant differences in immune-related adverse events were observed between the two groups. Over the first four cycles, morning circulating CD8+ T cells increased in the early ToD group, whereas they declined in the late ToD group (P < 0.001). Furthermore, the ratio of activated (CD38+ HLA-DR+) versus exhausted (TIM-3+PD-1+) CD8+ T cells was higher in the early ToD group (P < 0.001) compared with the late ToD group (P < 0.001). In summary, our study indicates that early ToD immunochemotherapy substantially improves PFS and OS and is associated with enhanced antitumor CD8+ T cell characteristics compared with late ToD treatment. ClinicalTrials.gov registration: NCT05549037 .
Author Info: (1) Early Phase Clinical Trial Center, Department of Investigational Cancer Therapeutics, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Centra
Author Info: (1) Early Phase Clinical Trial Center, Department of Investigational Cancer Therapeutics, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China. (2) Early Phase Clinical Trial Center, Department of Investigational Cancer Therapeutics, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. (3) Early Phase Clinical Trial Center, Department of Investigational Cancer Therapeutics, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. Third Xiangya Hospital, Central South University, Changsha, China. (4) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. (5) Early Phase Clinical Trial Center, Department of Investigational Cancer Therapeutics, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. (6) 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, China. (7) 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, China. (8) 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, China. (9) 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, China. (10) 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, China. (11) Early Phase Clinical Trial Center, Department of Investigational Cancer Therapeutics, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. (12) Early Phase Clinical Trial Center, Department of Investigational Cancer Therapeutics, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. (13) Early Phase Clinical Trial Center, Department of Investigational Cancer Therapeutics, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China. (14) 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, China. (15) 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, China. (16) Early Phase Clinical Trial Center, Department of Investigational Cancer Therapeutics, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. (17) Early Phase Clinical Trial Center, Department of Investigational Cancer Therapeutics, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. (18) Early Phase Clinical Trial Center, Department of Investigational Cancer Therapeutics, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. (19) Department of Interventional Vascular Surgery, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. (20) Research Unit 'Chronotherapy, Cancer, Transplantation', Faculty of Medicine, Paris-Saclay University, Hospital Paul Brousse, Villejuif, France. (21) Research Unit 'Chronotherapy, Cancer, Transplantation', Faculty of Medicine, Paris-Saclay University, Hospital Paul Brousse, Villejuif, France. Thoracic and Medical Oncology Unit, Avicenne Hospital, Assistance Publique-Hpitaux de Paris, Bobigny, France. (22) Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China. (23) Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. (24) The Chinese University of Hong Kong, Hong Kong, China. tony@clo.cuhk.edu.hk. Department of Clinical Oncology, State Key Laboratory of Translational Oncology Hong Kong, Hong Kong, China. tony@clo.cuhk.edu.hk. (25) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. christoph.scheiermann@unige.ch. Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. christoph.scheiermann@unige.ch. Geneva Center for Inflammation Research (GCIR), Geneva, Switzerland. christoph.scheiermann@unige.ch. Biomedical Center (BMC), Institute for Cardiovascular Physiology and Pathophysiology, Walter Brendel Center for Experimental Medicine (WBex), Faculty of Medicine, Ludwig-Maximilians-Universitt (LMU) Munich, Planegg-Martinsried, Germany. christoph.scheiermann@unige.ch. (26) Research Unit 'Chronotherapy, Cancer, Transplantation', Faculty of Medicine, Paris-Saclay University, Hospital Paul Brousse, Villejuif, France. francis.levi@universite-paris-saclay.fr. Gastro-Intestinal and Medical Oncology Department, Paul Brousse Hospital, Assistance Publique-Hpitaux de Paris, Villejuif, France. francis.levi@universite-paris-saclay.fr. Department of Statistics, University of Warwick, Coventry, United Kingdom. francis.levi@universite-paris-saclay.fr. (27) 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, China. yangnong0217@163.com. Hunan Second People's Hospital, Changsha, China. yangnong0217@163.com. (28) Early Phase Clinical Trial Center, Department of Investigational Cancer Therapeutics, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. zhangyongchang@csu.edu.cn. Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China. zhangyongchang@csu.edu.cn. 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, China. zhangyongchang@csu.edu.cn. Furong Laboratory, Changsha, China. zhangyongchang@csu.edu.cn.
