A Prospective Cohort Study of PD-1 Monoclonal Antibody Combined With Ipilimumab N01 and Chemotherapy in Perioperative Treatment of Resectable Non-small Cell Lung Cancer

Inclusion Criteria:

Patients must meet all of the following inclusion criteria to be eligible for enrollment in this study:

• Patients must sign a written informed consent form (ICF) and be able to comply with protocol-specified visits and related procedures.
• Age ≥18 years.
• Cytologically or histologically confirmed primary non-small cell lung cancer (NSCLC), including adenocarcinoma and squamous cell carcinoma.

Clinical stage IIB (primary tumor >4 cm), IIIA, or IIIB (limited to resectable N2 disease) according to the ninth edition of the lung cancer TNM staging classification established by the International Association for the Study of Lung Cancer (IASLC) and the American Joint Committee on Cancer (AJCC). Resectable N2 disease is defined as non-bulky (short-axis diameter <3 cm), discrete, or single-station N2 involvement. Pathological confirmation is required if N2 or N3 involvement is clinically suspected.

• Patients with non-squamous NSCLC must undergo molecular testing confirming the absence of sensitizing epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements. Molecular testing is not mandatory for patients with squamous NSCLC; however, patients with known sensitizing EGFR mutations or ALK rearrangements must not be enrolled.

• Patients must be considered suitable for curative-intent surgical resection. Pulmonary function must meet the requirements for the planned lung resection (forced expiratory volume in one second [FEV1] ≥50% of the predicted value and maximal voluntary ventilation [MVV] ≥50% of the predicted value), with no contraindications to surgery.

• Patients must be able to provide sufficient qualified tumor tissue specimens for programmed death-ligand 1 (PD-L1) testing during screening.

• At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.

• No prior systemic antitumor therapy or local radiotherapy for NSCLC.

• Adequate organ and bone marrow function, with laboratory values obtained within 7 days before enrollment meeting the following requirements. No blood components, hematopoietic growth factors, albumin, or other intravenous or subcutaneous medications intended to correct hematologic, hepatic, or renal dysfunction are permitted within 14 days before laboratory testing. The specific requirements are as follows:

  1. Adequate hematologic function: Absolute neutrophil count ≥1.5 × 10⁹/L, platelet count ≥100 × 10⁹/L, and hemoglobin ≥100 g/L.
  2. Adequate hepatic function: Total bilirubin ≤1.5 × the upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN; and albumin (ALB) ≥35 g/L.
  3. Adequate renal function: Serum creatinine (Scr) ≤1.5 × ULN; creatinine clearance (CrCl) ≥60 mL/min, calculated using the Cockcroft-Gault formula; and urine protein (UPRO) <2+ on routine urinalysis or 24-hour urinary protein <1 g.
  4. Adequate coagulation function: International normalized ratio (INR) ≤1.5 × ULN and prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤1.5 × ULN within 7 days before study treatment.

• Female patients of childbearing potential must have a negative urine or serum pregnancy test within 7 days before the first administration of study treatment. If the urine pregnancy test is positive, a serum pregnancy test is required.

• Male and female patients at risk of conception must use highly effective contraception (defined as a method with an annual failure rate of <1%) and continue contraception for at least 180 days after discontinuation of study treatment.

Note: Abstinence is acceptable as a contraceptive method if it is the patient's usual lifestyle and preferred method of contraception.

Exclusion Criteria:

Patients meeting any of the following exclusion criteria will not be eligible for enrollment in this study:

• Pathological evidence of small cell carcinoma, neuroendocrine carcinoma, sarcoma, lymphoepithelioma-like carcinoma, salivary gland tumors, or mesenchymal tumor components.
• Tumor invasion of the diaphragm, mediastinum, heart, pericardium, major blood vessels (e.g., aorta), trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina.
• Superior sulcus tumor.
• Presence of tumor nodules in the contralateral lung. If contralateral pulmonary tumor nodules are clinically suspected, biopsy confirmation is required.
• Confirmed or suspected brain metastases.
• Current participation in an interventional clinical study involving treatment, or receipt of another investigational drug or investigational medical device treatment within 4 weeks before randomization.
• Prior treatment with anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti-programmed death-ligand 2 (PD-L2), or anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agents; any other agents targeting T-cell costimulatory or immune checkpoint pathways (e.g., OX40 or CD137); or adoptive cellular immunotherapy.
• Receipt of traditional Chinese herbal medicines or Chinese patent medicines with antitumor indications, or immunomodulatory agents (including thymosin preparations, interferons, or interleukins), within 2 weeks before randomization.
• Receipt of a live attenuated vaccine within 4 weeks before randomization or planned receipt of a live attenuated vaccine during the study.

Note: Injectable inactivated seasonal influenza vaccines are permitted; however, live attenuated influenza vaccines are not permitted.

• Patients requiring long-term systemic corticosteroid therapy or receiving any other form of immunosuppressive therapy within 7 days before randomization.

Note: Intranasal, inhaled, or other topical corticosteroids; systemic corticosteroids at physiological doses (≤10 mg/day of prednisone or equivalent); or corticosteroids administered as premedication (e.g., for prevention of contrast media hypersensitivity) are permitted.

• History of noninfectious pneumonitis requiring corticosteroid treatment within 1 year before randomization or current interstitial lung disease.

• Active autoimmune disease requiring systemic treatment (e.g., disease-modifying agents, corticosteroids, or immunosuppressants) within 2 years before randomization, including but not limited to inflammatory bowel disease, such as ulcerative colitis or Crohn's disease; diverticulitis; celiac disease; systemic lupus erythematosus; sarcoidosis; Wegener's syndrome (granulomatosis with polyangiitis); Graves' disease; rheumatoid arthritis; multiple sclerosis; vasculitis; glomerulonephritis; antiphospholipid syndrome; hypophysitis; or uveitis.

• Replacement therapy (e.g., thyroxine, insulin, or physiological doses of corticosteroids for adrenal or pituitary insufficiency) is not considered systemic treatment. Patients with positive autoimmune antibodies may be enrolled only after investigator assessment confirms the absence of an autoimmune disease requiring systemic treatment.

• Primary immunodeficiency disorder.

• History of or current myocarditis.

• Failure to adequately recover from toxicities and/or complications caused by any intervention before randomization (i.e., toxicity of Grade >1 or failure to recover to the baseline level required by the protocol).

• Peripheral neuropathy of Grade ≥2.

• Hereditary bleeding tendency or coagulation disorder, or a history of thrombosis: any arterial thrombosis, embolism, or ischemic event within 6 months before randomization, such as myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, or pulmonary embolism. History of deep vein thrombosis or any other serious thromboembolic event within 3 months before randomization. Thrombosis associated with an implanted venous access port or catheter, or superficial venous thrombosis, is not considered a serious thromboembolic event.

• Uncontrolled hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg); history of hypertensive crisis or hypertensive encephalopathy; or uncontrolled hyperglycemia (fasting blood glucose >8.9 mmol/L).

• Patients with non-squamous NSCLC who are unable or unwilling to receive folic acid or vitamin B12 supplementation.

• Any unstable systemic disease or concomitant medical condition, including but not limited to:

  1. Active infection (requiring anti-infective treatment or receipt of systemic anti-infective medication within 1 week before randomization).
  2. Congestive heart failure [New York Heart Association (NYHA) functional class ≥II].
  3. Severe arrhythmia requiring medication, or severe hepatic, renal, or metabolic disease.

• Untreated coronary artery disease.

• History of gastrointestinal perforation and/or fistula, intestinal obstruction, extensive bowel resection, or long-term chronic diarrhea within 6 months before randomization.

• History of solid organ or hematopoietic transplantation.

• Known history of human immunodeficiency virus (HIV) infection (i.e., positive HIV-1/2 antibodies) or known active syphilis.

• Active tuberculosis, including but not limited to pulmonary tuberculosis, or tuberculosis currently requiring medical intervention.

• Active hepatitis B.

  1. Patients with hepatitis B who meet the following criteria are eligible for enrollment: hepatitis B surface antigen (HBsAg)-positive or hepatitis B core antibody (anti-HBc)-positive, with an HBV viral load <1,000 copies/mL, <200 IU/mL, or below the lower limit of detection before randomization.
  2. HBsAg-positive patients must receive anti-HBV treatment throughout the study drug treatment period to prevent HBV reactivation.
  3. For patients who are anti-HBc-positive, HBsAg-negative, hepatitis B surface antibody (anti-HBs)-negative, and HBV DNA-negative, prophylactic anti-HBV treatment is not required; however, close monitoring for viral reactivation is necessary.

• Active hepatitis C (positive hepatitis C virus [HCV] antibody and HCV RNA level above the lower limit of detection).

• History of a confirmed malignancy other than NSCLC within 5 years before randomization, except for adequately treated carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin, localized prostate cancer after curative surgery, ductal carcinoma in situ after curative surgery, or papillary thyroid carcinoma after curative surgery.

• Known hypersensitivity to the active ingredients and/or any excipients of the PD-1 monoclonal antibody, ipilimumab N01, and/or the selected chemotherapy regimen (pemetrexed plus carboplatin/cisplatin for non-squamous NSCLC; nab-paclitaxel plus carboplatin/cisplatin for squamous NSCLC).

• Female patients who are pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study.

• Known psychiatric disorders or substance abuse that may affect compliance with study requirements, or a history of alcohol abuse.

• Any medical history, disease, treatment, or laboratory abnormality that may interfere with study results, prevent the patient from participating in the study throughout its duration, or, in the investigator's opinion, make study participation inconsistent with the patient's best interests.

• Any localized or systemic disease unrelated to malignancy, or any secondary reaction to cancer, that may result in increased medical risk and/or uncertainty in survival assessment.