Effect of Infusion Timing on Pathologic Response to Neoadjuvant Immunotherapy in Resectable Non-Small Cell Lung Cancer (LungTime-C02)

A Prospective Study on the Effect of Infusion Timing of Immune Checkpoint Inhibitors on Pathologic Response in Patients With Resectable Stage II-III Non-Small Cell Lung Cancer Undergoing Neoadjuvant Therapy

This prospective study aims to investigate whether the time of day when immune checkpoint inhibitors (ICIs) are administered affects the efficacy of neoadjuvant immunotherapy in patients with resectable stage II-III non-small cell lung cancer (NSCLC). Eligible patients will receive standard-of-care neoadjuvant ICI plus platinum-based chemotherapy and be randomly assigned to either a morning infusion group (08:00-11:00) or an afternoon infusion group (15:00-18:00). The primary objective is to compare the pathological complete response (pCR) rates between groups. Secondary outcomes include major pathological response (MPR) and event-free survival (EFS). The study will include independent imaging and pathology review for endpoint assessment.

Study Overview

• Status: Recruiting
• Conditions: Resectable Stage II-III Non-Small Cell Lung Cancer (NSCLC)
• Intervention / Treatment: Other: Time of Day-based Assignment for Infusion of Immune Checkpoint Inhibitor (e.g., toripalimab, or pembrolizumab) + platinum-based chemotherapy

Detailed Description

Emerging evidence suggests that the efficacy of immune checkpoint inhibitors (ICIs) may be influenced by the circadian timing of drug administration. Retrospective studies in multiple cancer types have indicated that morning infusion of ICIs might be associated with improved clinical outcomes compared to afternoon infusion. However, no prospective study has evaluated this phenomenon in the setting of neoadjuvant therapy for resectable non-small cell lung cancer (NSCLC).

This prospective, randomized, parallel-group study aims to assess whether the time of day of ICI infusion (morning vs. afternoon) affects the pathological response to neoadjuvant immunotherapy in patients with stage II-III resectable NSCLC.

Eligible patients will receive standard-of-care neoadjuvant treatment, consisting of an immune checkpoint inhibitor (e.g., toripalimab, or pembrolizumab) combined with platinum-based chemotherapy. Patients will be randomly assigned (1:1) to receive all ICI infusions during either the morning window (08:00-11:00) or the afternoon window (15:00-18:00), throughout the neoadjuvant treatment period.

The primary endpoint is the pathological complete response (pCR) rate after neoadjuvant therapy and surgery. Secondary endpoints include major pathological response (MPR), event-free survival (EFS).The study will include independent imaging and pathology review for endpoint assessment.

This study aims to provide prospective evidence on the role of infusion timing in optimizing immunotherapy efficacy. If successful, this approach could offer a simple, cost-effective, and non-invasive strategy to improve outcomes for patients undergoing neoadjuvant immunotherapy.

• Study Type: Interventional
• Enrollment (Estimated): 156
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Yongchang Zhang, professor; Phone Number: +0086 13873123436; Email: zhanglei1152@126.com

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China
      • Recruiting
      • Hunan Cancer Hospital
      • Contact: Yongchang Zhang, MD; Phone Number: +86 13873123436; Email: zhangyongchang@csu.edu.cn
    • Changsha, Hunan, China, 410013
      • Recruiting
      • Hunna Cancer Hospital, Clinical Trails Center
      • Principal Investigator: Yongchang Zhang, MD
      • Contact: Yongchang Zhang, MD; Phone Number: +13873123436; Email: zhangyongchang@csu.edu.cn
      • Contact: Liang Zeng, MD; Phone Number: +8673189762650; Email: 530490930@qq.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Participants must meet all of the following criteria:

1. Age ≥18 and ≤75 years at the time of enrollment.
2. Histologically or cytologically confirmed diagnosis of resectable stage II to III non-small cell lung cancer (NSCLC).
3. Deemed suitable for neoadjuvant immunotherapy combined with platinum-based chemotherapy and subsequent surgical resection based on multidisciplinary team (MDT) assessment.
4. ECOG Performance Status of 0 or 1.
5. No prior systemic antitumor therapy for the current NSCLC diagnosis.
6. Adequate bone marrow, hepatic, renal, and cardiac function based on local laboratory standards.
7. Willing and able to comply with scheduled visits, treatment plans, and other study procedures.
8. Signed informed consent prior to participation.

Exclusion Criteria:

Participants meeting any of the following criteria will be excluded:

1. Presence of EGFR-sensitive mutations (e.g., exon 19del, L858R) or ALK/ROS1 rearrangements.
2. Presence of uncontrolled or symptomatic brain metastases.
3. History of any other malignancy within 3 years prior to enrollment, except for adequately treated basal cell carcinoma, squamous cell skin cancer, or cervical carcinoma in situ.
4. History of prior systemic therapy (immunotherapy, chemotherapy, or targeted therapy) for lung cancer.
5. Known severe allergic reactions to PD-1 or PD-L1 inhibitors (Grade ≥3 by CTCAE).
6. Active autoimmune disease requiring systemic immunosuppression.
7. Active infections, including active HBV, HCV, or HIV infection.
8. Pregnant or breastfeeding women.
9. Any comorbid condition or uncontrolled illness that, in the opinion of the investigator, may interfere with study participation or pose unacceptable risk.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Morning infusion group; • Intervention / treatment: Immune checkpoint inhibitor (one of approved PD 1 agents per investigator choice; e.g., toripalimab / pembrolizumab) administered in the morning window (08:00-11:00) for all ICI infusions during neoadjuvant treatment.; Combined with platinum based chemotherapy per institutional standard (examples: nab paclitaxel 260 mg/m² IV Day 1 Q3W + carboplatin AUC 5 IV Day 1 Q3W; or paclitaxel/cisplatin regimens per local practice).; Neoadjuvant treatment cycles: 4 cycles as per treating physician and local guideline; surgery scheduled after assessment.; Supportive care per routine practice.	Other: Time of Day-based Assignment for Infusion of Immune Checkpoint Inhibitor (e.g., toripalimab, or pembrolizumab) + platinum-based chemotherapy; Patients will be randomly assigned (1:1) to receive all ICI infusions during either the morning window (08:00-11:00) or the afternoon window (15:00-18:00), throughout the neoadjuvant treatment period.
Active Comparator: Afternoon infusion group; • Intervention / treatment: Same systemic regimen as Arm 1, but all ICI infusions administered in the afternoon window (15:00-18:00).; Chemotherapy, number of cycles (4), and surgical decision follow the same rules as Arm 1.; Supportive care per routine practice.	Other: Time of Day-based Assignment for Infusion of Immune Checkpoint Inhibitor (e.g., toripalimab, or pembrolizumab) + platinum-based chemotherapy; Patients will be randomly assigned (1:1) to receive all ICI infusions during either the morning window (08:00-11:00) or the afternoon window (15:00-18:00), throughout the neoadjuvant treatment period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response (pCR) rate	Proportion of patients achieving pathological complete response (no viable tumor cells in resected primary tumor and sampled regional lymph nodes) assessed on surgical specimen after completion of neoadjuvant therapy and surgery.	At the time of surgery, approximately 6-9 weeks after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event Free Survival (EFS)	Time from randomization to disease progression that precludes surgery, recurrence, or death from any cause, whichever occurs first.	From date of randomization to event occurrence (disease progression, recurrence, or death), assessed up to 36 months
Major Pathological Response (MPR) rate	Proportion of patients with ≤10% viable tumor cells in the resected primary tumor specimen.	At the time of surgery, approximately 6-9 weeks after randomization

Collaborators and Investigators

• Sponsor: Hunan Province Tumor Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): December 7, 2025
• Primary Completion (Estimated): October 31, 2028
• Study Completion (Estimated): May 31, 2029

Study Registration Dates

• First Submitted: November 16, 2025
• First Submitted That Met QC Criteria: November 19, 2025
• First Posted (Actual): November 26, 2025

Study Record Updates

• Last Update Posted (Actual): November 26, 2025
• Last Update Submitted That Met QC Criteria: November 19, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: NSCLC; neoadjuvant treatment; Time of day
• Additional Relevant MeSH Terms: Inorganic Chemicals; Platinum Compounds; toripalimab; pembrolizumab
• Other Study ID Numbers: LungTime-C02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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