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

Prior treatment

• 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.
• 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.
• Major surgery within 4 weeks prior to first dose or unresolved surgical wounds.
• Live vaccine administration within 30 days before first dose or planned during study.
• Concurrent participation in another interventional clinical trial or use of other investigational products/devices within 4 weeks prior to first dose.

Other illness

• 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.
• 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.
• History of severe hypersensitivity to monoclonal antibodies, PD-1 agents, pemetrexed, carboplatin, or premedications.
• History of drug/alcohol abuse or uncontrolled psychiatric disorders interfering with compliance.
• Any other condition judged by the investigator as inappropriate for study participation.

Other

• Participants meeting any of the following are excluded:
• Brainstem, leptomeningeal, spinal cord metastases, or cord compression.
• Active CNS metastases or carcinomatous meningitis. Treated, stable brain metastases are allowed 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.