Adding targeted radiation to remaining lung tumors after chemo‑immunotherapy

Inclusion Criteria:

1. Voluntary signed written informed consent and compliance with protocol requirements;
2. Age ≥ 18 years;
3. Expected survival time ≥ 3 months;
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
5. Histologically or cytologically confirmed advanced non-small cell lung cancer;
6. After receiving 4-6 cycles of first-line platinum-based chemotherapy combined with immunotherapy, PET-CT evaluation shows no disease progression, with no more than 5 lesions not meeting criteria for complete metabolic response, involving no more than 3 organs;
7. All residual lesions can safely receive radiation therapy as assessed by radiation oncologists;
8. Patient can tolerate the radiotherapy process, such as maintaining fixed position;
9. At least one measurable lesion among the oligoresidual lesions according to RECIST v1.1;
10. Agreement to provide archived tumor tissue specimens from primary or metastatic sites, or fresh tissue samples; if unable to provide tumor tissue samples, subjects may be enrolled after investigator assessment if meeting other inclusion/exclusion criteria;
11. Toxicities from previous anti-tumor therapies recovered to ≤ grade 1 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0) (excluding alopecia, fatigue, pigmentation, hypothyroidism stable on hormone replacement therapy, grade 2 peripheral neuropathy after chemotherapy, and exceptions specified in other inclusion criteria);
12. Laboratory values at screening must meet the following criteria: a) Neutrophils ≥ 1.5×10\^9/L b) Platelets ≥ 100×10\^9/L c) Hemoglobin ≥ 90g/L (no blood transfusion within 14 days) d) Serum Cr ≤ 1×ULN, endogenous creatinine clearance \> 50ml/min (Cockcroft-Gault formula) e) AST ≤ 2.5×ULN; ALT ≤ 2.5×ULN; if liver metastases present, ALT and AST ≤ 5×ULN f) Total bilirubin ≤ 1.5×ULN (except for Gilbert's syndrome subjects, where total bilirubin must be \< 51.3μmol/L) g) Thyroid Stimulating Hormone (TSH), Free Triiodothyronine (FT3), Free Thyroxine (FT4) all within ±10% of normal range.

Exclusion Criteria:

1. Archived tumor tissue, pre-treatment tumor biopsy, or histological examination showing evidence of previous small cell or mixed small cell/non-small cell histology;
2. Previous tissue samples or peripheral blood genetic sequencing reports indicating EGFR sensitizing mutations, ALK fusion, or other gene variations that should receive standard first-line targeted therapy; squamous cell carcinoma without genetic testing is presumed negative;
3. Symptomatic brain metastases;
4. Leptomeningeal metastases;
5. Active, known, or suspected autoimmune disease (excluding vitiligo, type I diabetes, residual hypothyroidism due to autoimmune thyroiditis requiring only hormone replacement therapy, or conditions not expected to recur in the absence of external triggers);
6. Active tuberculosis (TB) infection as determined by chest X-ray, sputum examination, and clinical examination. Patients with a history of active pulmonary TB infection within the previous year, even if treated, will be excluded. Patients with a history of active pulmonary TB infection more than 1 year ago will also be excluded unless effective previous anti-TB treatment can be documented;
7. Comorbidities requiring immunosuppressive medication, or requiring systemic or local use of corticosteroids at immunosuppressive doses;
8. Pregnancy or breastfeeding;
9. Interstitial lung disease with symptomatic manifestations, or that may interfere with the detection or management of suspected drug-related pulmonary toxicity;
10. Positive for human immunodeficiency virus antibody (HIVAb), active hepatitis B virus infection (HBsAg positive and HBV-DNA \> 10\^3 copies/ml), or hepatitis C virus infection (HCV antibody positive and HCV-RNA \> lower limit of detection at the research center);
11. History of severe neurological or psychiatric disorders, including but not limited to: dementia, depression, seizures, bipolar disorder, etc.;
12. Receipt of other investigational drugs or treatments within 4 weeks prior to study randomization;
13. Use of any Chinese herbal medicines with anti-tumor activity within 2 weeks prior to study drug administration;
14. History of other malignancies (excluding non-melanoma skin cancer and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast), unless complete remission was achieved at least 2 years prior to study enrollment and no additional therapy is required or anticipated during the study period;
15. History of severe cardiac or cerebrovascular disease, e.g., New York Heart Association (NYHA) ≥ class 2 heart failure, acute coronary syndrome (such as myocardial infarction, unstable angina, etc.) within 6 months of screening, acute cerebrovascular disease (such as transient ischemic attack, cerebral infarction, cerebral hemorrhage, etc.) within 6 months of screening;
16. Thromboembolic events requiring therapeutic intervention within 6 months prior to screening, such as unstable deep vein thrombosis, arterial thrombosis, and pulmonary embolism; excluding infusion-related thrombosis;
17. Planned vaccination or vaccination with live vaccines within 28 days prior to study randomization;
18. Other conditions deemed unsuitable for participation in this clinical trial by the investigator due to comorbidities or other circumstances.