Combination therapies for PD-1–resistant recurrent or metastatic nasopharyngeal cancer

Inclusion Criteria:

1. Histologically and/or cytologically confirmed recurrent or metastatic non-keratinizing nasopharyngeal carcinoma (either differentiated or undifferentiated subtype, corresponding to WHO type II or III).
2. Age between 18 and 70 years.
3. Performance Status (PS) score of 0 or 1.
4. Disease progression after prior platinum-based doublet chemotherapy.
5. Received at least one line of systemic therapy previously. (Progression occurring during or within 6 months after definitive concurrent chemoradiotherapy, neoadjuvant/adjuvant therapy, or treatment completion may be counted as first-line treatment.)
6. Resistance to anti-PD-1 antibody therapy (either combination or sequential), including primary or secondary resistance（PD-1 exposure must be at least 6 weeks.）
7. At least one measurable lesion according to RECIST 1.1 criteria.
8. All acute toxicities from prior anti-tumor therapies have resolved to grade ≤1 (per NCI-CTCAE v5.0) or meet the specified inclusion/exclusion thresholds. (Certain toxicities such as alopecia, hair color changes, nail changes, fatigue, etc., which do not pose safety risks, are exempt.)
9. Adequate organ function:

   Hematology: WBC ≥ 4000/μL, absolute neutrophil count ≥ 2000/μL, hemoglobin ≥ 9 g/dL, platelets ≥ 100,000/μL.

   Liver function: Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (patients with Gilbert's syndrome and bilirubin ≤ 3 × ULN are eligible); AST and ALT ≤ 3 × ULN; alkaline phosphatase ≤ 3 × ULN; albumin ≥ 3 g/dL.

   Coagulation: INR, prothrombin time (PT), or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.

   Renal function: Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min calculated by Cockcroft-Gault formula. Proteinuria: Urine protein/creatinine ratio (UPC) \< 1.0. For UPC ≤ 0.5, no further testing is required; for UPC \> 0.5, 24-hour urine protein must be \< 1000 mg for eligibility.
10. Estimated life expectancy of at least 3 months.
11. Signed informed consent and willingness and ability to comply with study visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

1. Locoregional recurrent lesions that are amenable to definitive (curative) treatment, such as surgery.
2. Prior treatment with any regimen included in the study protocol.
3. Prior use of agents targeting the VEGF or VEGFR pathway.
4. Diagnosis and/or treatment of another malignancy within the past 5 years, with the exception of adequately treated carcinoma in situ of the cervix, basal cell or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ.
5. Receipt of surgery, chemotherapy, radiotherapy, immunotherapy, any investigational agent, or other anti-cancer therapy within 4 weeks prior to enrollment (or within 2 weeks for palliative radiotherapy).
6. Tumor encasement of the internal carotid artery or evidence of nasopharyngeal necrosis observed on endoscopy prior to enrollment.
7. Any significant bleeding event (≥ Grade 2, CTCAE v5.0) within 4 weeks prior to enrollment, or visible hemoptysis defined as ≥ 1/2 teaspoon of fresh red blood or blood clots with little or no sputum. Recurrent positive fecal occult blood test (++ or more) during screening also leads to exclusion. (Patients with occasional blood-tinged sputum may be eligible.)
8. Active peptic ulcers or gastrointestinal surgery within 1 month prior to enrollment; history within 6 months of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, gastrointestinal hemorrhage, esophageal varices, or pathological fracture.
9. Uncontrolled hypertension (systolic \>140 mmHg or diastolic \>90 mmHg) despite antihypertensive therapy; coronary artery disease ≥ Grade II; or any of the following within 6 months prior to enrollment: myocardial infarction, severe or unstable angina, NYHA class II or higher heart failure, sustained arrhythmia ≥ Grade 2 (including QTc \>450 ms in males or \>470 ms in females), atrial fibrillation of any grade, coronary or peripheral artery bypass grafting, symptomatic congestive heart failure, or cerebrovascular events (e.g., TIA or symptomatic pulmonary embolism). History of arterial thromboembolism or venous thromboembolism \> Grade 3. (ST elevation ≥2 mm on ECG without clinical evidence of myocardial infarction or ischemia is not exclusionary.)
10. History of bleeding diathesis, hemorrhagic disorders, or coagulopathy; current use of anticoagulants or antiplatelet agents including warfarin, heparin, aspirin \>325 mg/day, ticlopidine, clopidogrel, or cilostazol, unless discontinued ≥10 days prior to first dose and coagulation parameters meet inclusion criteria.
11. Severe infection requiring intravenous antibiotics, antifungals, or antivirals within 4 weeks prior to the first dose, or unexplained fever \>38.5°C within 7 days prior to the first dose; baseline WBC \>15 × 10⁹/L.
12. Known hypersensitivity to study drugs or excipients, or a history of severe hypersensitivity reactions such as generalized rash/erythema, hypotension, bronchospasm, angioedema, or anaphylaxis.
13. Conditions that may affect oral drug absorption, including dysphagia, nausea/vomiting, chronic diarrhea, or bowel obstruction.
14. Ongoing treatment with immunosuppressants or systemic corticosteroids (\>10 mg/day prednisone or equivalent) within 2 weeks prior to the first dose.
15. Presence of any active autoimmune disease or a history of autoimmune diseases likely to recur (including but not limited to interstitial pneumonitis, uveitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, hypothyroidism). Exceptions include vitiligo and childhood asthma now in complete remission. Patients with asthma requiring bronchodilator therapy are excluded.
16. History of acute exacerbation of chronic obstructive pulmonary disease or other respiratory disease requiring hospitalization within 1 month prior to enrollment; patients with active tuberculosis or those who received anti-TB therapy within 1 year prior to screening.
17. HIV positive; or positive HBsAg with quantifiable HBV DNA ≥1000 cps/mL; or positive anti-HCV antibody.
18. Receipt of live vaccines within 4 weeks prior to first dose or anticipated during the study period.
19. Positive pregnancy test or currently breastfeeding.
20. Women of childbearing potential or sexually active men who are unwilling or unable to use medically accepted methods of contraception during the study period.
21. Any condition, as determined by the investigator, that may interfere with the study results or patient safety, such as substance abuse, serious physical or mental illness requiring concurrent treatment, significant laboratory abnormalities, or adverse social/family circumstances.