Effect of Time-of-Day (ToD) for Immunochemotherapy on PFS in NSCLC (LungTIME-C01)

Progression Survival Time According to Time-of-Day (ToD) of Administration of Immunochemotherapy for Advanced Non-small Cell Lung Cancer: A Phase III Randomized Control Trial

This study aims to explore time-of-day of administration of immunochemotherapy on the efficacy for treatment naive advanced non-small cell lung cancer.

Study Overview

• Status: Completed
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Pembrolizumab, Sintilimab

Detailed Description

All the advanced NSCLC patients who were treated with chemotherapy plus pembrolizumab or sitilimab will be randomized to two groups. One for morning group, the patients in this group were treated with chemotherapy plus pembrolizumab or sintilimab before 15:00. One for afternoon group, the patients in this group were treated with chemotherapy plus pembrolizumab or sintilimab after 15:00.

• Study Type: Interventional
• Enrollment (Actual): 210
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410013
      • Hunan Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Study Population

advanced NSCLC

Description

Inclusion Criteria:

1. Understand the requirements and contents of the clinical trial, and provide a signed and dated informed consent form.
2. Age ≥ 18 years.
3. Histopathology or cytology confirmed and recorded local progression or metastatic non-small cell lung cancer without systemic treatment.
4. EGFR, ALK and ROS1 mutations negative confirmed by an accredited local laboratory.
5. ECOG 0-1.
6. Predicted survival ≥ 12 weeks.
7. Adequate bone marrow hematopoiesis and organ function
8. Presence of measurable lesions according to RECIST 1.1.
9. Subjects with stable brain metastases may be included in the study.

Exclusion Criteria:

1. Prior systemic therapy for locally advanced or metastatic disease.

2. Subjects who have received any of the following treatments must be excluded:

   • Ant Treatment with chemotherapy or molecules such as EGFR, VEGFR antibodies within 4 weeks prior to the first dose of study drug.
   • Have received radiation within 14 days prior to the first dose or have not recovered from radiation-related toxicity. Chest and extra-brain palliative radiotherapy, stereotactic radiosurgery, and stereotactic body radiotherapy may be performed 7 days prior to the first dose.
3. Presence of spinal cord compression or meningeal metastasis.
4. History of other malignant tumors within 2 years.
5. Adverse events (except alopecia of any degree) of CTCAE > grade 1 due to prior treatment (e.g., adjuvant chemotherapy, radiotherapy, etc.) prior to the first dose.
6. History of stroke or intracranial hemorrhage within 6 months prior to the first dose.
7. The presence of any severe or poorly controlled systemic disease, including poorly controlled hypertension and active bleeding in the judgment of the investigator.
8. Subjects with persistent or active infection, including but not limited to hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV) and COVID-19 infection.
9. Heart-related diseases or abnormalities
10. Past history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid therapy or interstitial lung disease with active clinical symptoms, immune pneumonia caused by immunotherapy.
11. Refractory nausea and vomiting, chronic gastrointestinal disease, difficulty swallowing drugs, or inability to adequately absorb sunvozertinib or anlotinib due to previous bowel resection.
12. Live vaccine was given 2 weeks before the first medication.
13. Women who are breastfeeding or pregnant.
14. Hypersensitivity to the test drug and the ingredients.
15. Other conditions assessed by the investigator to be unsuitable for participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Morning group; All the patients in this arm will be treated with immunochemotherapy before 15:00.	Drug: Pembrolizumab, Sintilimab; One for morning group, the patients in this group were treated with immunochemotherapy before 15:00. One for afternoon group, the patients in this group were treated with immunochemotherapy after 15:00.; Other Names: time-of-day of administration of immunochemotherapy
Experimental: Arm B: Afternoon group; All the patients in this arm will be treated with immunochemotherapy after 15:00.	Drug: Pembrolizumab, Sintilimab; One for morning group, the patients in this group were treated with immunochemotherapy before 15:00. One for afternoon group, the patients in this group were treated with immunochemotherapy after 15:00.; Other Names: time-of-day of administration of immunochemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	To assess progression-free survival of patients treated by immunochemotherapy according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator, define as first dose to first documented disease progression assessed by investigator or death due to any cause.	Time from first subject dose to study completion, or up to 36 month.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	To assess immunochemotherapy overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator, define as the proportion of subjects who have a complete response (CR) or a partial response (PR)	Time from first dose to last dose, or up to 24 month.
Overall survival (OS)	To assess overall survival, define as first dose to the death of the subject due to any cause.	Time from first subject dose to study completion, or up to 24 month.
Duration of Response (DoR)	To assess duration of response for subjects with CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator , defined as the time from the first documented CR or PR to disease progression or death	Time from first subject dose to study completion, or up to 24 month.

Collaborators and Investigators

• Sponsor: Hunan Province Tumor Hospital
• Investigators: Principal Investigator: Yongchang Zhang, MD, Hunan Cancer Hospital

Publications and helpful links

General Publications

• Huang Z, Zeng L, Ruan Z, Zeng Q, Yan H, Jiang W, Xiong Y, Zhou C, Yang H, Liu L, Dai J, Zou N, Xu S, Wang Y, Wang Z, Deng J, Chen X, Wang J, Xiang H, Li X, Duchemann B, Chen G, Xia Y, Mok T, Scheiermann C, Levi F, Yang N, Zhang Y. Time-of-day immunochemotherapy in non-small cell lung cancer: a randomized phase 3 trial. Nat Med. 2026 Apr;32(4):1233-1240. doi: 10.1038/s41591-025-04181-w. Epub 2026 Feb 2.

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2022
• Primary Completion (Actual): December 2, 2024
• Study Completion (Actual): April 30, 2026

Study Registration Dates

• First Submitted: September 17, 2022
• First Submitted That Met QC Criteria: September 17, 2022
• First Posted (Actual): September 22, 2022

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Non-small Cell Lung Cancer; Immunochemotherapy; Time of day
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; pembrolizumab; sintilimab
• Other Study ID Numbers: INJECTION

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No