Neoadjuvant SF-SBRT Plus Toripalimab and Chemotherapy in Resectable Stage II-III NSCLC.

A Randomized, Controlled, Multicenter Phase III Clinical Study of Spatially Fractionated Stereotactic Body Radiotherapy Plus Toripalimab and Chemotherapy Versus Toripalimab Plus Chemotherapy in Patients With Resectable or Potentially Resectable Stage II-III Non-Small Cell Lung Cancer

This is an open-label, randomized, controlled, multicenter phase III clinical trial designed to evaluate the efficacy and safety of spatially fractionated stereotactic body radiotherapy (SF-SBRT) combined with toripalimab and platinum-based chemotherapy versus toripalimab combined with platinum-based chemotherapy in patients with resectable or potentially resectable stage II-III non-small cell lung cancer (NSCLC). Eligible participants will be randomized 2:1 to receive either neoadjuvant SF-SBRT followed by toripalimab and platinum-based chemotherapy for two cycles, or toripalimab and platinum-based chemotherapy for three cycles. Randomization will be stratified by disease stage and histological subtype. Surgery is planned 4-6 weeks after completion of neoadjuvant treatment, and postoperative adjuvant therapy will be determined by the investigator. The primary endpoint is the 2-year event-free survival rate. Secondary endpoints include pathological complete response rate, major pathological response rate, objective response rate, R0 resection rate, event-free survival, overall survival, and safety. Adverse events will be assessed according to NCI CTCAE version 5.0 or later.

Inclusion Criteria:

• Male or female participants aged 18 to 75 years;
• Eastern Cooperative Oncology Group performance status of 0 or 1;
• Previously untreated, pathologically confirmed, resectable or potentially -resectable stage II, IIIA, or IIIB (N2) non-small cell lung cancer according to the 8th edition of the American Joint Committee on Cancer staging system;
• At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1;
• Adequate pulmonary function, as assessed by the surgeon, to tolerate the planned lung resection;
• Absence of sensitizing EGFR mutations or ALK rearrangements confirmed by tissue-based molecular pathological testing;
• Adequate organ function, defined as follows:

Bone marrow function: absolute neutrophil count ≥1.5 × 10^9/L, platelet count ≥80 × 10^9/L, and hemoglobin ≥9 g/dL; Liver function: total serum bilirubin ≤1.5 × upper limit of normal; alanine aminotransferase and aspartate aminotransferase ≤1.5 × upper limit of normal; Renal function: serum creatinine ≤1.5 × upper limit of normal or creatinine clearance ≥60 mL/min, and blood urea nitrogen ≤200 mg/L;

• Participants must be fully informed about the study and voluntarily sign the written informed consent form.
• Male participants with reproductive potential or female participants of childbearing potential must agree to use effective contraception during the study, such as oral contraceptives, an intrauterine device, or a barrier method combined with spermicide, and continue contraception for 6 months after completion of treatment.

Exclusion Criteria:

• Locally advanced unresectable or metastatic disease. Unresectable disease is defined according to the multidisciplinary consensus for stage III non-small cell lung cancer (2019 edition), including some stage IIIA, stage IIIB, and all stage IIIC disease. This usually includes N2 disease with a single-station mediastinal lymph node with a short-axis diameter ≥3 cm, or multistation lymph node fusion/conglomeration with lymph nodes having a short-axis diameter ≥2 cm on CT; T4 disease invading the esophagus, heart, aorta, or pulmonary veins; and all N3 disease;
• Non-small cell lung cancer involving the superior sulcus, large-cell neuroendocrine carcinoma, or sarcomatoid carcinoma;
• Known sensitizing EGFR mutation or ALK rearrangement. For participants with non-squamous histology, EGFR and ALK mutation status must be confirmed;
• Prior treatment with PD-1 or PD-L1 inhibitors, or agents targeting another T-cell receptor pathway, such as CTLA-4 or OX-40;
• Active or suspected active autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. Exceptions include type 1 diabetes mellitus or hypothyroidism controlled with stable replacement therapy, and dermatologic conditions not requiring systemic treatment, such as psoriasis or vitiligo;
• History of interstitial lung disease of grade 2 or higher;
• Use of systemic corticosteroids, defined as prednisone >10 mg/day or equivalent, or other immunosuppressive medications within 14 days before the first dose of study treatment;
• History of immunodeficiency, including acquired or congenital immunodeficiency disorders, history of organ transplantation, or prior allogeneic hematopoietic stem cell transplantation or solid organ transplantation;
• Receipt of a live vaccine within 4 weeks before the first dose of study treatment;
• Severe cardiovascular or cerebrovascular disease, including:

Poorly controlled hypertension or pulmonary hypertension;

• Unstable angina, myocardial infarction, coronary artery bypass grafting, or coronary stent implantation within 6 months before study treatment;
• Chronic heart failure with New York Heart Association class II or higher cardiac function;
• Left ventricular ejection fraction <50%;
• Severe arrhythmias requiring medical treatment, except atrial fibrillation or paroxysmal supraventricular tachycardia. Examples include QTcF >450 msec in males or >470 msec in females, complete left bundle branch block, or third-degree atrioventricular block;
• Cerebrovascular accident or transient ischemic attack within 6 months before study treatment;
• Uncontrolled or severe underlying medical conditions, including but not limited to active infection requiring systemic antibiotic therapy;
• Positive human immunodeficiency virus antibody test, active hepatitis B, or active hepatitis C. The following participants may be eligible:
• Participants positive for hepatitis B core antibody or hepatitis B surface antigen may be enrolled if HBV DNA is below the lower limit of detection at the study site, or <500 IU/mL, and active infection is excluded by the investigator based on clinical treatment history and clinical manifestations;
• Participants positive for hepatitis C antibody may be enrolled if HCV RNA is below the lower limit of detection at the study site;
• Known active pulmonary tuberculosis. Participants suspected of having active tuberculosis must undergo chest X-ray, sputum examination, and assessment of clinical symptoms and signs to exclude active tuberculosis;
• History of any active malignancy other than the study disease within 2 years before enrollment, except malignancies expected to be cured after treatment, including but not limited to adequately treated thyroid cancer, carcinoma in situ of the cervix, basal cell or squamous cell skin cancer, or ductal carcinoma in situ of the breast treated with curative surgery;
• History of psychotropic drug abuse that cannot be discontinued, or history of psychiatric disorder;
• Pregnant or breastfeeding women;
• Any other severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that, in the investigator's judgment, may increase the risk associated with study participation or may interfere with interpretation of the study results.