Local Consolidative Therapy Versus Maintenance Immunotherapy After First-Line Chemoimmunotherapy in Metastatic NSCLC

1. This study incorporates both a randomized controlled trial (RCT) cohort and a real-world study (RWS) cohort. RCT Cohort: A prospective, randomized, multicenter clinical study. The primary study population comprises patients with stage IV disease (9th edition TNM staging) who have received 4-6 cycles of first-line immunotherapy combined with platinum-based doublet chemotherapy, achieved at least partial response (PR) upon efficacy assessment, demonstrated metabolically active residual lesions on PET evaluation, and been clinically assessed by the multidisciplinary team (MDT) as amenable to individualized local therapy (e.g., ≤3 organs and ≤5 lesions, with feasibility for surgery/radiotherapy/ablation). Patients will be randomly assigned to: Local Therapy Arm: Receiving local treatment targeting residual lesions, followed by physician-assessed continuation of maintenance systemic therapy or surveillance monitoring; optional local treatment modalities include surgery, radiotherapy, and ablation. Assessment of residual lesions will be primarily based on imaging examinations including PET-CT and brain MRI. PET evaluation of residual lesions will primarily reference the PERCIST (PET Response Criteria in Solid Tumors) criteria. Compared with baseline imaging, lesions with metabolic activity exceeding that of the mediastinal blood pool or liver on PET evaluation will be considered potentially active residual lesions. The final determination shall be made through multidisciplinary assessment jointly by a radiologist or nuclear medicine physician with more than 10 years of clinical experience, together with thoracic surgeons, pulmonologists, and radiation oncologists. Systemic Therapy Arm: Continuation of systemic maintenance therapy until disease progression (PD) or intolerable toxicity; upon PD, patients may undergo MDT reassessment for potential local therapy opportunities. 2. Primary Endpoint: Progression-Free Survival (PFS): Time from randomization to first documented disease progression or death from any cause. 3. Secondary Endpoints: Overall Survival (OS): Time from randomization to death from any cause. Safety of local consolidative therapy. Impact of different local consolidative treatment modalities on prognosis. Time from local consolidative therapy to recurrence/progression of previously existing metastatic lesions. Time from local consolidative therapy to development of new metastatic lesions. 4. Exploratory Endpoints: Tumor Immune Microenvironment (TiME) and prognosis. Tumor dormancy characteristics. Clinical outcomes of different treatment choices after disease progression (PD) in the control arm. Correlation between ctDNA-based minimal residual disease (MRD) status before and after randomization and prognosis. 5. RCT Cohort: The time from randomization to disease progression (PD) or death in the control arm following induction therapy was 6 months. Assuming that the experimental arm combined with local therapy could be extended to 11 months (based on clinical experience and literature inference), with a one-sided α of 0.05, power of 80%, accrual period of 12 months, and a randomization ratio of 2:1, the total required sample size was calculated to be 105 patients (with a total of 76 required events), comprising 70 patients in the experimental arm and 35 patients in the control arm. Considering an 8%-10% dropout rate, a total of 117 patients are planned for enrollment. 6. RWS Cohort: This cohort does not prespecify statistical hypotheses. It is designed to observe patients who met the eligibility criteria during the RCT study period but were unable to be enrolled in the RCT for various reasons. This cohort will serve to supplement the safety and clinical benefit data of the experimental arm in the RCT cohort. Based on epidemiological projections from our center, approximately 50 patients are expected to be enrolled during this period.