This phase III randomized trial evaluates PD-1 inhibitor plus chemotherapy followed by immediate versus salvage locoregional radiotherapy in de novo metastatic nasopharyngeal carcinoma. The study aims to evaluate whether salvage locoregional radiotherapy is non-inferior to immediate radiotherapy following PD-1 inhibitor plus GP in de novo metastatic NPC, with potential for reduced toxicity.

Nasopharyngeal carcinoma (NPC) is highly prevalent in Southern China, with approximately 15% of patients presenting with distant metastases at diagnosis. A PD-1 inhibitor combined with gemcitabine and cisplatin (GP) has become the standard first-line therapy for metastatic NPC. However, the survival benefit of adding immediate locoregional radiotherapy to PD-1 inhibitor plus GP in de novo metastatic NPC remains uncertain. This phase III randomized trial is designed to compare immediate versus salvage locoregional radiotherapy following PD-1 inhibitor plus GP in de novo metastatic NPC, with the objective of determining whether salvage radiotherapy is non-inferior to immediate radiotherapy while offering reduced toxicity.

Inclusion Criteria:

1. Age 18-70 years, any gender.

2. Histologically confirmed differentiated non-keratinizing carcinoma or undifferentiated non-keratinizing carcinoma by tissue biopsy, with radiologically detectable metastatic lesions. Pathological confirmation of metastatic lesions is recommended but not mandatory.

3. ECOG performance status 0-1.

4. Stage IV NPC according to the 9th edition of the UICC/AJCC staging system.

5. No prior anti-tumor treatment for NPC (radiotherapy, chemotherapy, surgery, etc.).

6. Expected survival ≥ 3 months.

7. At least one measurable lesion per RECIST v1.1.

8. Achieved complete response (CR) or partial response (PR) after 4-6 cycles of chemotherapy plus PD-1 inhibitor therapy.

9. Adequate organ function within 14 days before first dose, defined as:

   Hematology：Hemoglobin ≥ 90 g/L，ANC ≥ 1.5 × 10⁹/L，Platelet count ≥ 100 × 10⁹/L Renal Function：Creatinine ≤ 1.5 × ULN, or creatinine clearance (CrCl) / eGFR ≥ 60 mL/min Liver Function：Total bilirubin ≤ 1.5 × ULN，AST and ALT ≤ 2.5 × ULN, or ≤ 5 × ULN in the presence of liver metastases

10. INR or PT ≤ 1.5 × ULN, unless on therapeutic anticoagulation and values within therapeutic range，aPTT ≤ 1.5 × ULN, unless on therapeutic anticoagulation and values within therapeutic range

Exclusion Criteria:

1. Prior anti-tumor therapy for nasopharyngeal carcinoma, including radiotherapy, chemotherapy, surgery, or immunotherapy.
2. Prior treatment with PD-1/PD-L1 or CTLA-4 inhibitors.
3. Presence of uncontrolled or symptomatic central nervous system (CNS) metastases.
4. History of other malignancies within the past 5 years, except adequately treated basal cell carcinoma, squamous cell skin cancer, or in-situ cervical cancer.
5. Active autoimmune disease or history of autoimmune disease requiring systemic treatment (e.g., corticosteroids, immunosuppressants) within the past 2 years, except for stable hypothyroidism, type 1 diabetes mellitus, or resolved childhood asthma/atopy.
6. Known history of active pulmonary tuberculosis (TB). Suspected active TB must be excluded by chest X-ray, sputum examination, and assessment of clinical signs and symptoms.
7. Hepatitis B: HBsAg positive with peripheral blood HBV DNA ≥ 1000 copies/mL
8. Hepatitis C: HCV antibody positive, eligible only if HCV RNA is negative
9. HIV infection
10. Clinically significant cardiovascular disease (e.g., uncontrolled hypertension, unstable angina, myocardial infarction within 6 months, congestive heart failure ≥ NYHA class II, or serious arrhythmia).
11. Interstitial lung disease, non-infectious pneumonitis, or history of ≥ grade 2 pneumonitis.
12. Major surgery within 4 weeks before enrollment, or unhealed surgical wound.
13. Pregnant or breastfeeding women, or those planning pregnancy during the study period.
14. Known allergy or hypersensitivity to study drugs or their excipients.
15. Any condition that, in the investigator's judgment, would interfere with trial participation or interpretation of results.