This trial aims to study the role of Ivonescimab combined with chemoradiotherapy in high-Risk locoregionally advanced nasopharyngeal carcinoma.

The trial plans to enroll patients with T3N2M0+ Stage III (AJCC 9th) locoregionally advanced nasopharyngeal carcinoma (LANPC). Patients will receive 3 cycles of induction chemotherapy with gemcitabine and cisplatin combined with ivonescimab, followed by concurrent chemoradiotherapy with cisplatin, and then 9 cycles of adjuvant ivonescimab. Ivonescimab will be administered every 3 weeks starting from day 1 of induction therapy and continued through the adjuvant phase.

Inclusion Criteria:

1. Age between 18 and 65 years.
2. Histologically confirmed non-keratinizing carcinoma (according to WHO classification).
3. ECOG performance status of 0 or 1.
4. Previously untreated nasopharyngeal carcinoma staged as T3N2M0 or Stage III according to the AJCC 9th edition.
5. Adequate bone marrow function, defined as white blood cell count > 4×10⁹/L, hemoglobin > 90 g/L, and platelet count > 100×10⁹/L.
6. Adequate liver and renal function, defined as total bilirubin ≤ 1.5 × ULN; AST and/or ALT ≤ 2.5 × ULN; alkaline phosphatase ≤ 2.5 × ULN; and creatinine clearance ≥ 60 mL/min.
7. Normal thyroid function, amylase, lipase, pituitary function, inflammatory markers, myocardial enzymes, and ECG. For patients over 50 years old with a smoking history, pulmonary function test results must be normal. For patients with ECG abnormalities or a cardiovascular history not meeting exclusion criteria #8, echocardiography and cardiac function tests must be normal.
8. Signed informed consent and willingness to comply with all scheduled visits, treatment procedures, laboratory tests, and other study-related requirements.
9. Female participants of childbearing potential and male participants with female partners of childbearing potential must agree to use reliable contraception from screening until 1 year after completion of treatment.

Exclusion Criteria:

1. Tumor invasion of major blood vessels or significant recent (within 1 month) nasopharyngeal or nasal bleeding (>5 mL).
2. HBsAg positive with HBV DNA > 1×10³ copies/mL, or anti-HCV antibody positive.
3. HIV antibody positive or diagnosed with AIDS.
4. Active tuberculosis or history of active tuberculosis within the past year, unless adequately treated.
5. Active, known, or suspected autoimmune disease, including but not limited to uveitis, colitis, hepatitis, hypophysitis, nephritis, vasculitis, hyperthyroidism, hypothyroidism, or asthma requiring bronchodilator therapy; exceptions include type 1 diabetes, hypothyroidism requiring hormone replacement, and localized skin conditions not requiring systemic therapy (e.g., vitiligo, psoriasis, or alopecia).
6. History of interstitial lung disease or pneumonitis requiring corticosteroid treatment within the past year.
7. Chronic systemic corticosteroid therapy (≥10 mg/day prednisone or equivalent) or use of other immunosuppressive therapy; inhaled or topical corticosteroids are allowed.
8. Uncontrolled cardiovascular disease, including NYHA Class ≥ 2 heart failure, unstable angina, myocardial infarction within 1 year, or supraventricular/ventricular arrhythmias requiring intervention.
9. Pregnant or breastfeeding women; pregnancy testing is required for women of childbearing potential.
10. History or presence of other malignancies, except adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, or papillary thyroid carcinoma.
11. Known hypersensitivity to monoclonal antibodies or any component of ivonescimab.
12. Active systemic infection requiring treatment within 1 week before study treatment.
13. Receipt of live vaccine within 30 days prior to the first dose of ivonescimab.
14. History of organ transplantation.
15. History of psychiatric illness, substance abuse, alcohol or drug dependence.
16. Any other condition which, in the opinion of the investigator, could compromise patient safety or compliance with the study protocol, including severe uncontrolled comorbidities, serious abnormal lab findings, or psychosocial risk factors.

Complete de-identified patient data set will be submitted onto an online platform.