Prospective Phase II Study of Concurrent Radiotherapy Combined With Full-Course Immunotherapy or Consolidation Immunotherapy for Locally Advanced NSCLC

This is a prospective, randomized phase II study evaluating concurrent chemoradiotherapy combined with full-course immunotherapy or consolidative immunotherapy in unresectable, locally advanced non-small cell lung cancer. Patients are randomized in a 1:1 ratio to experimental group and control group. The experimental group will receive induction chemoimmunotherapy, concurrent chemoradiotherapy, and full-course immunotherapy during the chemoradiotherapy phase and consolidation phase. Patients in the control group will receive concurrent chemoradiotherapy and consolidative immunotherapy.

• Induction chemoimmunotherapy (Drug): Nab-paclitaxel 260 mg/m² + cisplatin 75 mg/m² + tislelizumab 200 mg on day 1, Q3W，3 cycles.
• radiotherapy (Radiation): Thoracic radiotherapy at a definitive dose using intensity-modulated radiation therapy or Volumetric Modulated Arc Therapy.
• Concurrent Chemotherapy (Drug): Nab-paclitaxel 50 mg/m² + cisplatin 25 mg/m² on day 1, weekly.
• consolidation immunotherapy (Drug): Tislelizumab 200 mg on day 1, every 3 weeks.
• full-course immunotherapy (Drug): Immunotherapy (Tislelizumab 200 mg d1) will be administered during the concurrent chemoradiotherapy phase and consolidation phase, but not on radiotherapy days.

Primary outcomes

• Progression free survival rate [18 months]: From the first day of treatment to the day of progression or the day of death.

Secondary outcomes

• Overall survival [18 months]: It was calculated from the first day of treatment to the day of death.
• Objective response rate [1 year]: The proportion of patients evaluated as CR or PR
• Incidence of Treatment-related Adverse Events [1 year]: Adverse effects are graded according to the CTCAE 5.0 version.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Male or female patients aged 18-75 years ;
* Histologically or cytologically confirmed, locally advanced, unresectable stage III non-small cell lung cancer (NSCLC);
* Wild-type EGFR, ALK, and ROS1;
* No prior chemotherapy, radiotherapy, surgery, targeted therapy, or immunotherapy;
* Availability of unstained archival tumor tissue samples sufficient for analysis;
* Life expectancy of ≥12 weeks;
* World Health Organization (WHO) performance status of 0 or 1;
* Female patients must not be breastfeeding;
* Adequate organ and bone marrow function, meeting all of the following criteria: Forced expiratory volume in 1 second (FEV1) ≥800 mL; Absolute neutrophil count ≥1.5 × 10⁹/L; Platelet count ≥100 × 10⁹/L; Hemoglobin ≥9.0 g/dL; Creatinine clearance ≥50 mL/min, calculated using the Cockcroft-Gault formula (Cockcroft and Gault, 1976); Serum bilirubin ≤1.5 times the upper limit of normal (ULN); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times ULN.

Exclusion Criteria:

Exclusion Criteria for Induction Therapy:

Patients meeting any of the following criteria will not receive induction therapy:

* Concurrent participation in another clinical study, unless it is an observational, non-interventional study;
* Mixed small cell and non-small cell lung cancer histology;
* Prior treatment with any anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody;
* Major surgery within 4 weeks before study entry, excluding procedures for vascular access;
* Active autoimmune disease or a history of autoimmune disease within the past 2 years;
* Active inflammatory bowel disease or a history of inflammatory bowel disease, such as Crohn's disease or ulcerative colitis;
* History of primary immunodeficiency;
* History of organ transplantation requiring immunosuppressive therapy;
* Uncontrolled intercurrent illness, including but not limited to ongoing or active infection, symptomatic congestive heart failure, poorly controlled hypertension, unstable angina, cardiac arrhythmia, active peptic ulcer disease or gastritis, or active bleeding disorders; known hepatitis B surface antigen (HBsAg) positivity with HBV DNA >500 IU/mL, hepatitis C, or human immunodeficiency virus (HIV) infection; or psychiatric illness or social circumstances that would limit compliance with study requirements or impair the ability to provide written informed consent;
* Known history of tuberculosis, except for old, inactive pulmonary tuberculosis;
* History of another primary malignancy within the past 5 years, except adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix;
* Pregnancy or breastfeeding; or male or female patients of reproductive potential who are not using effective contraception.

Exclusion Criteria for Concurrent Chemoradiotherapy After Induction Therapy:

* Patients meeting any of the following criteria will not proceed to concurrent chemoradiotherapy:
* Development of distant metastases;
* Locoregional disease progression that, in the judgment of the radiation oncologist, precludes definitive chemoradiotherapy because normal tissue dose constraints cannot be met;
* WHO performance status of 2-4;
* Any of the following organ or bone marrow impairments: FEV1 <800 mL; Absolute neutrophil count <1.5 × 10⁹/L; Platelet count <100 × 10⁹/L; Hemoglobin <9.0 g/dL; Creatinine clearance <50 mL/min, calculated using the Cockcroft-Gault formula (Cockcroft and Gault, 1976); Serum bilirubin >1.5 times ULN; AST and ALT >2.5 times ULN.

Exclusion Criteria for Consolidation Immunotherapy After Concurrent Chemoradiotherapy:

* Patients meeting any of the following criteria will not proceed to consolidation immunotherapy:
* Disease progression during concurrent chemoradiotherapy;
* Use of immunosuppressive medication within 28 days before the first dose of dual immunotherapy, except for intranasal or inhaled corticosteroids at physiological doses, or systemic corticosteroids at doses not exceeding 10 mg/day of prednisone or equivalent. Corticosteroids used to manage chemoradiotherapy-related toxicity are permitted;
* Unresolved toxicity of CTCAE grade >2 from prior chemoradiotherapy;
* Grade ≥2 pneumonitis resulting from prior chemoradiotherapy;
* Any previous grade ≥3 immune-related adverse event (irAE), or any unresolved irAE of grade >1.

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• Hui Liu, Principal investigator, Sun Yat-Sen University Cancer Center