This study is to investigate the efficacy and safety of the induction chemotherapy + concurrent chemoradiotherapy（CCRT）combined with toripalimab and endostar treatment, in comparison with the induction chemotherapy + concurrent chemoradiotherapy（CCRT）, in treating locally advanced high-risk nasopharyngeal carcinoma

GP-induced chemotherapy combined with concurrent chemoradiotherapy is the standard treatment for the locally advanced nasopharyngeal carcinoma recommended by the guidelines. However, the prognosis for T4 and/or N3 nasopharyngeal carcinoma is still poor, with the 3-year PFS of about 70%. Therefore, it is of great importance to improve the prognosis of patients with locally advanced high-risk nasopharyngeal carcinoma. Immunotherapy has been an emerging treatment method for tumors in recent years. Compared with the chemotherapy, immunotherapy has less adverse reactions, and the effects could last longer, significantly improving the prognosis and patients' quality of life. Endostar, as a VEGFR inhibitor, has good safety in treating nasopharyngeal carcinoma. Related data have shown that PD-1 and Endostar exert synergistic antitumor effects in a mouse model of lung cancer. A Phase II multi-center clinical study from our center has shown that, for patients with locally advanced low-risk nasopharyngeal carcinoma, all the 3-year OS, PFS, and DMFS for the radiotherapy combined with Endostar group were superior to the concurrent chemoradiotherapy group, and the combination of radiotherapy and Endostar lead to significantly reduced adverse effects. In clinical studies concerning other solid tumors, it has also been observed that the PD-1 inhibitors combined with VEGFR inhibitors could significantly improve the efficacy, and achieve synergistic effects. Therefore, A Phase II，randomized, prospective, multicentric clinical trail was conducted to compare the efficacy and safety of induction chemotherapy and the concurrent chemoradiotherapy plus Endostar and PD-1, followed by PD-1 treatment for half a year compared with the induction chemotherapy and the concurrent chemoradiotherapy for the T4 and/or N3 nasopharyngeal carcinoma.

Inclusion Criteria:

1. With ECOG score 0-1.
2. Subjective aged 18-65 years, male or non-pregnant female.
3. Pathologically diagnosed as nasopharyngeal non-keratinizing carcinoma (differentiated or undifferentiated, i.e., the WHO type II or III).
4. Stage IVa (8th AJCC/UICC stage) T4 and/or N3, untreated patients with nasopharyngeal carcinoma.
5. Agreeing to provide previously stored tumor tissue samples or perform biopsy to collect tumor tissues, which were sent to the central laboratory for the PD-L1 IHC test.
6. Hematology: white blood cells ≥ 4000 /μL; neutrophils ≥ 2000 /μL; hemoglobin ≥ 9 g/dL; and platelets ≥ 100000 /μL.
7. Liver function: ALT and AST lower than the 1.5 times (1.5 × ) the upper limits of normal (ULN); and total bilirubin < 1.5 × ULN.
8. Renal function: serum creatinine < 1.5 × ULN.
9. Patients signing the informed consents, and willing and able to follow the study plan (visit and treatment plan), laboratory tests, and other research procedures.

Exclusion criteria:

1. Patients with nasopharyngeal carcinoma with recurrence and distant metastasis.
2. Pathologically diagnosed as keratinizing squamous cell carcinoma (WHO classification type I).
3. Patients who had undergone radiotherapy or systemic chemotherapy.
4. Pregnant or breastfeeding females, or females in fertility period while with no effective contraceptive measures.
5. Positive for HIV.
6. Having suffered from other malignant tumors (except for the cured basal cell carcinoma or cervical carcinoma in situ).
7. Having been treated with inhibitors of immune regulatory points (i.e., CTLA-4, PD-1, PD-L1, etc.).
8. With complications needing long-term application of immunosuppressive drugs, or systemic or local application of corticosteroids with immunosuppressive doses of comorbidities.
9. Patients with immunodeficiency diseases, or a history of organ transplantation (including but not limited to: interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation, nephritis, hyperthyroidism, hypothyroidism; patients suffering from vitiligo, or asthma in childhood completely relieved, with no need of any intervention after adulthood could be included; and patients with asthma requiring bronchodilators for medical intervention could not be included).
10. With excessive usage of glucocorticoids within 4 weeks.
11. Whose laboratory examination values that did not meet the relevant standards within 7 days before participating in the research.
12. Patients with markedly reduced heart, liver, lung, kidney and/or bone marrow functions.
13. With serious and uncontrolled medical diseases and infections.
14. Using other test drugs or in other clinical trials.
15. Refusing or failing to sign the informed consent to participate in the trial.
16. With other treatment contraindications.
17. With personality or mental illness, with no or limited civil capacity.
18. Positive for hepatitis B surface antigen (HBsAg), and peripheral blood hepatitis B virus deoxyribonucleic acid (HBV DNA) ≥ 1000 cps/mL.
19. Patients positive for the HCV antibody test could only be included in this study with the negative results from the HCV RNA polymerase chain reaction test.
20. Unable to cooperate with regular follow-up due to psychological, social, family and geographical reasons.