The Effect of Toripalimab Plus Radiotherapy in Patients With Operable Stage II-IIIA (N+) Non Small Cell Lung Cancer

Exploratory Phase II Clinical Study of Toripalimab Plus Radiotherapy Versus Toripalimab Plus Chemotherapy for the Neoadjuvant Treatment of Operable Stage II-IIIA (N+) Non-small Cell Lung Cancer (NSCLC)

This randomized phase II trial is to explore the clinical efficacy, safety and feasibility of neoadjuvant immunotherapy plus radiotherapy compared with neoadjuvant immunotherapy plus chemotherapy in operable stage II-IIIA (N+) non small cell lung cancer (NSCLC) and the optimal radiotherapy pattern.

In recent years, the survival rate after diagnosis of non small cell lung cancer (NSCLC) has improved with advances in treatment. In terms of 5-year average overall survival (OS) by stage at the time of diagnosis, OS decreases significantly from stage IB to IIIA NSCLC, with 68% for stage IB, 53-60% for stage II, and 36% for stage IIIA. How to optimize the perioperative treatment strategy to reduce postoperative recurrence and prolong the survival of patients has raised great concern in early and mid-stage NSCLC. Radiotherapy combined with immunotherapy is suggested for advanced NSCLC in preclinical basic studies and recent clinical trials. Stereotactic body radiation therapy (SBRT) at 8 Gy × 3 Fx plays an effective immunoregulated role and can further enhance the antitumor immune response promoted by immune checkpoint inhibitors (ICIs). Although little is known about the optimal SBRT dose and fraction pattern, 6 Gy × 5 Fx or 8-9 Gy × 3 Fx have shown effectiveness in clinical studies.

Inclusion Criteria:

1. Age 18 to 75 years old, gender is not limited.

2. ECOG performance status 0-1.

3. non-small cell lung cancer diagnosed by pathology.

4. sufficient tumor tissue available for biomarker analysis.

5. clinical staging of cT1-2N1-2M0 or T3N1M0, stage II-IIIA (8th UICC staging criteria).

6. Patients with distant metastases ruled out by CT or PET/CT and physically assessed as acceptable for radical lung cancer surgery.

7. histomolecular pathology confirming the absence of classic driver oncogene mutations in EGFR, ALK, or ROS1.

8. Basic normal function of all organs (laboratory test results within 1 week prior to enrollment).

   • Bone marrow function: absolute neutrophil count (ANC) ≥ 1.5x109 /L, platelet count ≥ 100x109 /L, hemoglobin ≥ 9g/dL.
   • Liver: serum total bilirubin ≤ 1.5 times the upper limit of normal; ALT and AST ≤ 2.5 times the upper limit of normal.
   • Kidney: blood creatinine level ≤ 1.5 times the upper limit of normal or creatinine clearance ≥ 60 ml/min and urea nitrogen ≤ 200 mg/L.
   • Urine protein <+, if urine protein + then total 24 hour protein must be <500mg.
   • Blood glucose: within normal range and/or with diabetic patients on treatment but with stable blood glucose control.
   • Pulmonary function: baseline FEV1 of at least 2L; if baseline FEV1 < 2L then FEV1 > 800ml is expected after surgery as assessed by a surgical specialist.
   • Cardiac function: no myocardial infarction within 1 year; no unstable angina; no symptomatic severe arrhythmia; no cardiac insufficiency.

9. Voluntarily participated in this study and signed the informed consent form by himself or his agent

Exclusion Criteria:

1. Pathology suggestive of compound small cell lung cancer, etc.

2. History of previous lobectomy, radiotherapy or chemotherapy.

3. Those with concurrent second primary carcinoma and a history of previous malignancy of less than 5 years (except for completely cured cervical carcinoma in situ or basal cell or squamous epithelial cell skin cancer).

4. Patients with any active autoimmune disease or a history of autoimmune disease (e.g., interstitial pneumonia, uveitis, enterocolitis, hepatitis, pituitary inflammation, vasculitis, myocarditis, nephritis, hyperthyroidism, hypothyroidism, etc.).

5. Have an active infection requiring systemic treatment or a history of active tuberculosis.

6. Known history of human immunodeficiency virus (HIV) or active chronic Hepatitis C or Hepatitis B virus infection or any uncontrolled active systemic infection requiring intravenous (iv) antimicrobial treatment.

7. Those with known presence or coexistence of other uncontrollable diseases that are not amenable to surgical treatment

8. Physical examination or clinical trial finds that, in the opinion of the investigator, may interfere with the results or place the patient at increased risk for treatment complications

9. Prior interstitial lung disease, drug-induced interstitial disease or any clinically evident active interstitial lung disease with idiopathic pulmonary fibrosis on baseline CT scan; uncontrolled massive pleural or pericardial effusion

10. Unstable systemic concomitant disease (active infection, moderate to severe chronic obstructive pulmonary disease, poorly controlled hypertensive disease, unstable angina pectoris, congestive heart failure, myocardial infarction occurring within 6 months, severe mental disorder requiring medication for control, liver, renal or other metabolic disease, neuropsychiatric pathology such as Alzheimer's disease)

11. History of congenital or acquired immunodeficiency disorders or organ transplantation

12. Received any of the following treatments:

    • Prior radiotherapy, treatment with anti PD-1, anti PD-L1 or anti PD-L2 drugs, or other drugs that synergistically inhibit T-cell receptors such as CTLA-4, OX-40, CD137.
    • Having received any investigational drug within 4 weeks
    • Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or an interventional clinical study follow-up
    • Persons who have received an antineoplastic vaccine or who have received a live vaccine within 4 weeks
    • Have undergone major surgery or had severe trauma within 4 weeks