Immunodynamics-Guided Optimization of Individualized Immunochemotherapy in Advanced Driver-Negative NSCLC: A Randomized Trial

NCT07190027 | Not Yet Recruiting Phase 1

• 1 other identifier: KY2025-309
• Study Type: interventional
• Target: 246
• Locations: 0 countries
• Sites: N/A

Brief Summary

The goal of this clinical trial is to evaluate whether individualized sequencing of immunotherapy and chemotherapy based on immune dynamics can improve treatment outcomes in adults with advanced non-small cell lung cancer (NSCLC) without driver gene mutations. This study will also assess the safety and feasibility of different infusion strategies. The main questions it aims to answer are: Does optimizing the timing of PD-1 inhibitor infusion relative to chemotherapy improve the objective response rate (ORR)? Does individualized infusion sequencing enhance progression-free survival (PFS) compared to standard or fixed-delay administration? What safety concerns or immune-related adverse events occur with different infusion timing strategies? Researchers will compare three treatment strategies: Group A (Standard Concurrent Group): Immunotherapy and chemotherapy administered on the same day (D1). Group B (Fixed Delay Group): Chemotherapy on D1, followed by PD-1 inhibitor infusion on Day 3. Group C (Individualized Delay Group): Chemotherapy on D1, and PD-1 inhibitor infusion scheduled on D2-D6 based on daily immune monitoring. Participants will: Receive a PD-1 inhibitor (e.g., sintilimab, pembrolizumab, camrelizumab) combined with platinum-based chemotherapy. Attend clinic visits for regular immune monitoring, imaging assessments, and safety checks during each treatment cycle. Undergo blood tests to evaluate immune biomarkers (e.g., CD8⁺PD-1⁺ T cells, MDSC, Treg、IFN-γ、NLR、ALC、CRP) to guide individualized treatment decisions.

Conditions

Advanced Non-Small Cell Lung Cancer (NSCLC)

Keywords

Non-Small Cell Lung Cancer (NSCLC); Driver Gene-Negative NSCLC; Immunochemotherapy Sequencing; Individualized Infusion Timing; Immune Dynamics

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  The proportion of participants who achieve a complete response (CR) or partial response (PR) based on RECIST v1.1 criteria, as assessed by investigators. Imaging assessments will be performed every 6-8 weeks during treatment, and responses will be confirmed at least 4 weeks after initial documentation.

  From baseline until disease progression, death, or completion of treatment, whichever occurs first, up to approximately 36 months.

Secondary Outcomes (4)

• PFS

  From baseline until documented disease progression or death, up to approximately 36 months.

• Overall Survival (OS)

  From baseline until death from any cause, up to approximately 48 months.

• Incidence of Immune-Related Adverse Events (irAEs)

  From baseline through 90 days after the last dose of study treatment, up to approximately 36 months.

• Incidence of Treatment-Related Adverse Events (TRAEs)

  From baseline through 90 days after the last dose of study treatment, up to approximately 36 months.

Other Outcomes (7)

• Proportion and Activation Status of CD8⁺PD-1⁺ T Cells

  From baseline to the end of treatment, up to 36 months.

• Proportion of Regulatory T Cells (Treg)

  From baseline to the end of treatment, up to 36 months.

• Proportion of Myeloid-Derived Suppressor Cells (MDSC)

  From baseline to the end of treatment, up to 36 months.

Study Arms (3)

Arm 2: Fixed Delay Group

EXPERIMENTAL

Patients receive standard chemotherapy on Day 1 of each 21-day cycle. The PD-1 inhibitor is administered with a fixed delay, on Day 4 (3 days after chemotherapy). Combination treatment is given for 4 cycles, followed by PD-1 inhibitor maintenance until disease progression, unacceptable toxicity

Drug: Arm 2：Fixed Delay Group

Arm 1: Standard Synchronous Group

EXPERIMENTAL

Patients receive standard chemotherapy and PD-1 inhibitor concurrently on Day 1 of each 21-day cycle. After 4 cycles of combination therapy, patients continue PD-1 inhibitor maintenance until progression

Drug: Arm 1： Standard Synchronous Group

Arm 3: Individualized Delay Group

EXPERIMENTAL

Patients receive chemotherapy on Day 1 of each 21-day cycle. From Day 2 to Day 5, peripheral blood immunodynamic markers (e.g., CD8⁺PD-1⁺ T cells, MDSCs, Tregs, cytokines) are monitored daily. The PD-1 inhibitor is administered at the optimal time when predefined immunodynamic criteria are met, or on Day 6 if criteria are not met. After 4 cycles of combination therapy, patients continue PD-1 inhibitor maintenance until progression

Drug: Arm 3： Individualized Delay Group

Interventions

Arm 1： Standard Synchronous Group DRUG

Arm 1: Concurrent PD-1 + Chemotherapy (Standard Synchronous Group) Participants in this group will receive PD-1 inhibitor and chemotherapy on the same day (D1) during each treatment cycle.

Also known as: Concurrent PD-1 + Chemotherapy

Arm 1: Standard Synchronous Group

Arm 2：Fixed Delay Group DRUG

Fixed Delay Arm Delayed PD-1 + Chemo PD-1 inhibitor (e.g., Sintilimab/Keytruda/Tislelizumab/Camrelizumab/Toripalimab/Nivolumab/Atezolizumab/Sugemalimab) Immune checkpoint inhibitor + Chemo (Day 3)

Also known as: PD-1 Delayed Administration on D3 (Fixed Delay Group) Participants in this group will receive chemotherapy on D1 and then receive the PD-1 inhibitor on D3 of each cycle.

Arm 2: Fixed Delay Group

Arm 3： Individualized Delay Group DRUG

Arm 3: Individualized PD-1 Timing Based on Immune Window Score (IWS) (Individualized Group) Participants in this group will receive chemotherapy on D1 and undergo daily immune monitoring (CD8⁺PD-1⁺ T cells, Treg, IFN-γ, NLR, ALC, CRP). Based on the immune window score (IWS): If IWS ≥ 2, PD-1 inhibitor will be administered the same day. If IWS = 1-1.5, dosing may be delayed to D3-D5 depending on immune recovery. If IWS remains 0 by D5, PD-1 inhibitor will be administered on D6 as fallback.

Arm 3: Individualized Delay Group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must meet all of the following criteria:
• Voluntarily agree to participate, sign the informed consent form (ICF), and be able to comply with the study procedures.
• Age ≥18 years and ≤75 years at enrollment, both male and female participants are eligible.
• Histologically or cytologically confirmed stage IV non-small cell lung cancer (NSCLC) based on the AJCC 8th edition; if mixed histology exists, classification must be based on the predominant histologic component. Presence of small-cell histology excludes eligibility.
• Negative for actionable driver mutations: no EGFR mutations, ALK rearrangements, or ROS1 fusions. For other targetable alterations (e.g., BRAF V600E, NTRK1/2/3 fusions, MET exon 14 skipping, RET rearrangements), patients are excluded if FDA- or NMPA-approved targeted therapies are available.
• Note: Genetic testing can be conducted locally or via a central laboratory. Pre-existing valid reports are acceptable.
• Estimated life expectancy ≥3 months. At least one measurable lesion per RECIST v1.1 confirmed by IRC; irradiated lesions are not considered measurable unless unequivocal progression is demonstrated.
• ECOG performance status of 0 or 1. No prior systemic therapy for advanced/metastatic NSCLC, except adjuvant or neoadjuvant chemotherapy if the last dose was ≥6 months before recurrence.
• Adequate organ and bone marrow function within 14 days prior to randomization:
• ANC ≥ 1.5 × 10⁹/L Platelets ≥ 100 × 10⁹/L Hemoglobin ≥ 90 g/L Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula) Total bilirubin ≤ 1.5 × ULN (≤3 × ULN for Gilbert's syndrome) AST/ALT ≤ 2.5 × ULN (≤5 × ULN if liver metastases) INR and APTT ≤ 1.5 × ULN unless on therapeutic anticoagulation LVEF ≥ 50% by echocardiography or MUGA Female patients of childbearing potential must test negative for pregnancy within 14 days before enrollment and agree to use effective contraception from ICF signing until 180 days after the last dose. Male participants must also agree to effective contraception during the same period.

You may not qualify if:

• Participants meeting any of the following are excluded:
• Prior thoracic radiotherapy \>30 Gy within 6 months before first dose. Palliative radiotherapy within 7 days before first dose. Requirement for concurrent anti-tumor therapy during the study. Uncontrolled or symptomatic pleural, pericardial, or peritoneal effusions requiring repeated drainage.
• Brainstem, leptomeningeal, spinal cord metastases, or cord compression.
• Active CNS metastases or carcinomatous meningitis. Treated, stable brain metastases are allowed if:
• Clinically stable ≥2 weeks, No evidence of progression, Off corticosteroids ≥3 days prior to treatment initiation. Previous treatment with immune checkpoint inhibitors (PD-1/PD-L1, CTLA-4, etc.), immune agonists, or cellular immunotherapies.
• Use of traditional Chinese medicines or immunomodulatory drugs with anti-cancer activity within 2 weeks before first dose.
• Systemic corticosteroids (\>10 mg prednisone equivalent/day) or other immunosuppressants within 2 weeks prior to first dose.
• Uncontrolled systemic infection, unexplained fever \>38.5°C, or IV antibiotic use \>7 days within 2 weeks prior to first dose.
• History of other malignancies within the past 5 years, except adequately treated cervical carcinoma in situ, basal/squamous cell skin cancer, localized thyroid papillary carcinoma, prostate cancer in remission, or DCIS after curative surgery.
• Active or history of autoimmune disease, including but not limited to: autoimmune hepatitis, interstitial lung disease, uveitis, colitis, hepatitis, pituitary inflammation, vasculitis, nephritis, hyperthyroidism, or hypothyroidism.
• Controlled hypothyroidism with hormone replacement is eligible. Vitiligo, alopecia, type 1 diabetes, resolved childhood asthma, or mild psoriasis without systemic therapy are allowed.
• Clinically significant pulmonary diseases: e.g., steroid-requiring pneumonitis, drug-induced pneumonitis, or moderate-to-severe COPD.
• Major surgery within 4 weeks prior to first dose or unresolved surgical wounds.
• Significant cardiovascular diseases, including:
• MI, unstable angina, stroke, or TIA within 6 months Arterial thromboembolism within 6 months DVT, PE, or severe thrombosis within 3 months Uncontrolled hypertension (SBP ≥160 mmHg or DBP ≥100 mmHg) Myocarditis or NYHA III-IV heart failure History of allogeneic HSCT or organ transplantation (except corneal).

Sponsors & Collaborators

• First Affiliated Hospital of Wenzhou Medical University: lead

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Drug Therapy

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Therapeutics

Central Study Contacts

xiaona xie

CONTACT

86+13758469563; xiexiaona@wmu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Investigator

Study Record Dates

• First Submitted: September 10, 2025
• First Posted: September 24, 2025
• Study Start: November 1, 2025
• Primary Completion: November 1, 2025
• Study Completion (Estimated): November 1, 2028
• Last Updated: September 24, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share