Because most patients with R/M NPC have received long-term maintenance of immunotherapy at the time of initial treatment and the first-line treatment, there are a large number of PD-1 inhibitor refractory patients. How to deal with the ICIs resistance is an urgent problem in clinical practice. Based on previous clinical trials, anti-angiogenic drugs combined with immunotherapy were found to be effective. Therefore, this study intends to preliminarily evaluate which treatment regimen can provide the most benefit to PD-1 inhibitor refractory patients by comparing the efficacy of VEGFR inhibitor or standard chemotherapy combined with PD-1 inhibitor.

Inclusion Criteria:

1. Male or female; 18-70 years of age;
2. Had histopathologically confirmed nonkeratinizing recurrent/metastatic NPC (AJCC, 8th; the metastatic tissue biopsy is preferred, not necessary).
3. ECOG performance status of 0 or 1.
4. Progression after previous treatment with platinum-based dual-drug chemotherapy.
5. Progression after previous treatment with PD-1 inhibitors.
6. Experieced at least 1 line systemic therapy.
7. Subjects enrolled must have measurable lesion(s) according to response evaluation criteria in solid (RECIST) v1.1.
8. Adequate organ function assessed by laboratory parameters during the screening period
9. Life expectancy more than 12 weeks.
10. Able to understand and sign an informed consent form (ICF).

Exclusion Criteria:

1. Recurrent lesions suitable for radical treatment (radiotherapy or surgery).
2. Previous treatment over 2 lines.
3. Patients who had previously received one of the three chemotherapy drugs and were randomly assigned to single-agent chemotherapy (control group) were not eligible to reuse the same treatment in this study. In addition, patients who had previously received all three chemotherapy agents for R/M lesions were excluded from the study.
4. Prior use of any anti-VEGF(R) agents.
5. Patients with other malignancies.
6. Patients with nasopharyngeal necrosis found by endoscope before enrollment or with a > 50% chance of nasopharyngeal necrosis according to the risk prediction model: ① Patients with recurrent stage T3-4 received two courses of radiotherapy before enrollment, or received nasopharyngeal radiotherapy within 1 year before enrollment; ② Patients with recurrent T1-2 stage had received two courses of radiotherapy and nasopharyngeal radiotherapy within 1 year before enrollment.
7. Patients with or previous with serious hemorrhage (bleeding >30 ml within 3 months), haemoptysis (> 5 ml within 4 weeks) of thromboembolic events within 12 months (including stroke events and/or transient ischemic attack).
8. Patients with hypertension who cannot be reduced to the normal range by antihypertensive drug treatment (systolic blood pressure > 140 mmHg/diastolic blood pressure > 90 mmHg), patients with ≥ grade II coronary heart disease, arrhythmia (including QTc interval prolongation > 450 ms in men and > 470 ms in women) and cardiac insufficiency.
9. Patients with known or suspected autoimmune diseases including dementia and seizures.
10. Multiple factors affecting the absorption of oral medications (e.g., dysphagia, chronic diarrhea, and bowel obstruction).
11. An excessive dose of glucocorticoids given within 4 weeks before enrollment.
12. Complications requiring long-term use of immunosuppressive drugs or systemic or local use of immunosuppressive-dose corticosteroids.
13. Patients with active pulmonary tuberculosis (TB) receiving anti-TB treatment or who have received anti-TB treatment within 1 year prior to screening.
14. HIV positive; HBsAg positive and HBV DNA copy number positive (quantitative detection ≥ 1000 cps/ml); chronic hepatitis C with blood screening positive (HCV antibody positive).
15. Any anti-infective vaccines such as influenza vaccine, varicella vaccine, etc., within 4 weeks before enrollment.
16. Women of childbearing age with a positive pregnancy test and lactating women.
17. Special attention: Patients with active bleeding, ulcers, and bowel perforations within 30 days after major surgery with tumors in close proximity to the internal carotid artery or other major vessels, and those at risk of major bleeding are prohibited.
18. Patients considered unsuitable for inclusion.