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

Detailed Description

This study is a prospective, randomized, open-label, multicenter exploratory clinical trial designed to evaluate the efficacy and safety of immunodynamics-guided optimization of chemoimmunotherapy scheduling in patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. The trial specifically investigates whether individualized scheduling of PD-1 inhibitor infusion, guided by dynamic immune monitoring, can improve antitumor activity compared with standard synchronous or fixed-delay administration.

Rationale and Background

For patients with metastatic NSCLC lacking EGFR, ALK, or other approved targetable alterations, chemoimmunotherapy has become the standard first-line treatment. However, clinical outcomes remain heterogeneous, and not all patients benefit equally. Preclinical and translational evidence suggests that the timing of immune checkpoint blockade relative to chemotherapy exposure may significantly influence immune response, tumor microenvironment remodeling, and overall treatment efficacy. Immunodynamics-the dynamic assessment of immune status during therapy-offers a novel approach to guide individualized administration of immunotherapy, potentially enhancing efficacy while maintaining safety.

Study Objectives

Primary Objective: To compare the objective response rate (ORR) among three treatment arms:

Arm A: Standard synchronous administration of chemotherapy and PD-1 inhibitor.

Arm B: Fixed-delay administration, with PD-1 inhibitor given three days after chemotherapy.

Arm C: Individualized-delay administration, where PD-1 inhibitor infusion timing (Day 2-6) is determined by peripheral blood immunodynamic markers.

Secondary Objectives: To evaluate progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR), safety, and incidence of immune-related adverse events (irAEs).

Exploratory Objectives: To explore the relationship between immune scheduling and peripheral immune dynamics (CD8⁺PD-1⁺ T cells, myeloid-derived suppressor cells [MDSCs], Tregs, cytokines, etc.), as well as the predictive value of these markers for therapeutic outcomes.

Study Design

A total of 246 eligible patients with untreated metastatic, driver gene-negative NSCLC will be randomized in a 1:1:1 ratio into Arms A, B, and C (82 patients per arm). Treatment will consist of four cycles of chemoimmunotherapy followed by PD-1 inhibitor maintenance until disease progression, unacceptable toxicity, or a maximum of 2 years.

Arm A (Standard Synchronous): Chemotherapy and PD-1 inhibitor administered on Day 1 of each cycle.

Arm B (Fixed-Delay): Chemotherapy on Day 1; PD-1 inhibitor on Day 4.

Arm C (Individualized-Delay): Chemotherapy on Day 1; immune markers (CD8⁺PD-1⁺ T cells, MDSCs, Tregs, ± cytokines) measured on Days 2-5; PD-1 inhibitor administered when immunodynamic criteria are met, or on Day 6 as default.

Treatment cycles will repeat every 3 weeks. Imaging will be performed every 6 weeks during the first 48 weeks, then every 9 weeks, using RECIST v1.1 criteria. Patients will be followed for safety and survival after treatment discontinuation.

Endpoints

Primary Endpoint: Objective response rate (ORR) assessed by independent radiologic review committee (IRC).

Secondary Endpoints: PFS, OS, DCR, DOR, safety, incidence and severity of irAEs and treatment-related adverse events.

Exploratory Endpoints: Dynamic immune monitoring parameters, association between immune recovery patterns and clinical outcomes, correlation of PD-L1 expression and immune biomarkers, and exploratory ctDNA analyses if feasible.

Statistical Considerations

The study is powered to detect clinically meaningful improvements in ORR. Stratified CMH tests will be used for ORR comparisons. Kaplan-Meier methods and Cox proportional hazards models will be applied for time-to-event endpoints (PFS, OS, DOR). Exploratory analyses will examine associations between immunodynamic markers and outcomes, and predictive biomarker models will be developed. Safety analyses will summarize adverse events by frequency, grade, and relatedness.

Significance

This trial represents the first randomized study to prospectively test immunodynamics-guided optimization of immunochemotherapy scheduling in NSCLC. By integrating real-time immune monitoring into treatment decision-making, the study aims to generate evidence for precision timing of PD-1 inhibitor administration, potentially enhancing treatment efficacy and safety. Results from this study may inform future clinical practice and contribute to individualized immunotherapy strategies in lung cancer and beyond.

Inclusion criteria

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.

Exclusion criteria

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).

≥ Grade 2 peripheral neuropathy per CTCAE v5.0. Active tuberculosis or suspected TB not ruled out. Positive HIV antibody; active syphilis or untreated positive non-treponemal antibody; uncontrolled HBV/HCV infection per protocol definition.

Live vaccine administration within 30 days before first dose or planned during study.

History of severe hypersensitivity to monoclonal antibodies, PD-1 agents, pemetrexed, carboplatin, or premedications.

Concurrent participation in another interventional clinical trial or use of other investigational products/devices within 4 weeks prior to first dose.

History of drug/alcohol abuse or uncontrolled psychiatric disorders interfering with compliance.

Any other condition judged by the investigator as inappropriate for study participation.