Reduced-Dose vs Standard-Dose Thoracic Radiotherapy After Induction Chemoimmunotherapy in Older or Frail Stage III NSCLC

This is a multicenter, open-label, randomized phase III study in older or frail adults with unresectable stage III non-small cell lung cancer (NSCLC) who are considered unsuitable for concurrent chemoradiotherapy. All participants first receive standard induction chemotherapy plus immunotherapy (4-6 cycles), which is part of routine clinical care and not a study intervention. Patients whose cancer responds (complete response, partial response, or stable disease) may then sign informed consent and be randomly assigned 1:1 to receive either reduced-dose thoracic radiotherapy or standard-dose thoracic radiotherapy. After radiotherapy, both groups receive immune checkpoint inhibitor maintenance therapy for at least 6 months. The main goal is to find out whether reduced-dose radiotherapy is not unacceptably worse than standard-dose radiotherapy in controlling the cancer at 1 year, measured by the 1-year progression-free survival rate. The study will also compare side effects, overall survival, tumor response, and treatment completion. About 276 patients will be enrolled at Ruijin Hospital and six collaborating hospitals in China.

Inclusion Criteria: 1. Histologically confirmed unresectable stage III non-small cell lung cancer (NSCLC) according to AJCC 8th edition. 2. For non-squamous NSCLC: known EGFR-sensitizing mutations must be excluded. 3. Considered unsuitable for concurrent chemoradiotherapy by a multidisciplinary team, meeting at least one of the following: ECOG performance status 2; or Age ≥70 years; or Age 65-69 years with Charlson Comorbidity Index (CCI) ≥1; or Age 60-64 years with CCI ≥2. 4. Adequate bone marrow, hepatic, and renal function. 5. Expected survival of at least 3 months. 6. At least one measurable (RECIST 1.1) and irradiable thoracic lesion. 7. Adequate pulmonary function: FEV1 \>1 L or \>50% of predicted, and DLCO \>60% of predicted. 8. Completion of 4-6 cycles of induction chemotherapy plus immunotherapy. 9. Post-induction response of complete response (CR), partial response (PR), or stable disease (SD) according to RECIST 1.1. 10. Willingness to receive thoracic radiotherapy followed by sequential immune checkpoint inhibitor (ICI) maintenance therapy. 11. Provision of written informed consent. Exclusion Criteria: 1. Prior chemotherapy, immunotherapy, or radiotherapy for NSCLC. 2. Major surgery within the past 28 days. 3. History of allogeneic organ transplantation, autoimmune disease, immunodeficiency, hepatitis, or HIV infection. 4. Uncontrolled comorbid conditions. 5. Other active malignancy. 6. Leptomeningeal carcinomatosis. 7. Contraindication to the use of immunosuppressive drugs. 8. Pregnancy or breastfeeding.