SYS6010 plus Enlonstobart for recurrent or metastatic nasopharyngeal cancer in patients who have not had prior systemic therapy

Inclusion Criteria:

1. Female participants aged ≥ 18 years (as of the date of signed informed consent).
2. Histologically confirmed recurrent or metastatic nasopharyngeal carcinoma, with no prior systemic therapy for recurrent or metastatic nasopharyngeal carcinoma.
3. For recurrent nasopharyngeal carcinoma: the disease is currently not eligible for local or curative-intent treatment, and the interval from completion of adjuvant/neoadjuvant therapy or concurrent chemoradiotherapy to disease recurrence must be more than 6 months. Metastatic nasopharyngeal carcinoma is defined as stage IV per AJCC 9.0 staging system.
4. Willing to provide tumor tissue samples for testing of EGFR protein and PD-L1 expression. If sample collection is not feasible for certain reasons, eligibility will be determined by joint assessment of the investigator and sponsor
5. At least one measurable lesion confirmed by CT or MRI per RECIST v1.1. The lesion has not received prior radiotherapy, or has demonstrated clear progression after prior radiotherapy.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
7. Expected survival of the participant is ≥ 3 months.
8. Major organ function must meet the following criteria within 7 days prior to enrollment:

   1. Complete blood count (no whole blood, red blood cell, or platelet transfusion, and no administration of hematopoietic growth factors \[G-CSF or GM-CSF\], erythropoietin \[EPO\], or thrombopoietin \[TPO\] to correct blood cell counts within 14 days before sampling):i. Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L;Platelet count (PLT) ≥ 100 × 10\^9/L;Hemoglobin (HGB) ≥ 90 g/L.
   2. Blood biochemistry: Serum creatinine: Creatinine clearance ≥ 60 mL/min, calculated using the Cockcroft-Gault formula.; Serum total bilirubin (TBIL) ≤ 1.5 × ULN (participants with Gilbert's syndrome may be allowed up to 3 × ULN);Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5.0 × ULN for participants with liver metastasis).

      3\) Coagulation function: i. Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5 × ULN (for participants not receiving anticoagulation therapy).
9. Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose. Participants must agree to use effective contraception from the time of signing the ICF until 7 months after the last study treatment dose (14 months after the last dose of cisplatin for female participants, and 11 months for male participants). Female participants shall not be breastfeeding during this period, and male participants must refrain from sperm donation
10. Provides voluntary written informed consent after adequate understanding of the clinical trial.

Exclusion Criteria:

1. Patients with leptomeningeal metastasis, brainstem metastasis, spinal cord metastasis and/or compression, or active CNS metastasis. Patients with supratentorial and/or cerebellar metastases (i.e., no midbrain, pons, or medulla oblongata involvement) may be enrolled if they have received local therapy, have achieved disease stability at least 2 weeks prior to the first dose of study intervention (no new brain metastases or enlargement of pre-existing brain metastatic lesions on imaging, all neurologic symptoms stabilized or returned to normal), and require no glucocorticoid treatment or receive prednisone at a daily dose ≤10 mg or equivalent doses of other glucocorticoids.
2. History of other malignant neoplasms within 3 years prior to the first dose of study intervention, except for the following: cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the prostate, carcinoma in situ of the cervix, etc.
3. Known hypersensitivity to study drugs, any components of PD-1 inhibitors/gemcitabine/cisplatin, or humanized monoclonal antibody products.
4. Prior treatment with antibody-drug conjugates (ADCs) carrying topoisomerase I inhibitor payloads.
5. Adverse events from prior anti-tumor therapy that have not recovered to Grade ≤1 per NCI-CTCAE v6.0 (except for toxicities judged by the investigator to pose no safety risk such as alopecia); patients who experienced Grade ≥3 immune-related adverse events (irAEs) during prior therapy, or who permanently discontinued treatment due to irAEs
6. Participants who fail to meet the required washout periods will be excluded.
7. History of severe cardiovascular and cerebrovascular diseases within 6 months prior to the first dose of study intervention, including but not limited to:

   1. Severe cardiac rhythm or conduction abnormalities, such as clinically significant ventricular arrhythmias requiring intervention, third-degree atrioventricular block, etc.; Fridericia-corrected QT interval \>470 ms (Fridericia formula: QTcF=QT/RR⁰·³³, RR=60/heart rate);
   2. History of myocardial infarction, unstable angina, aortic dissection, angioplasty, or coronary artery bypass graft surgery;
   3. New York Heart Association (NYHA) class Ⅱ or higher heart failure, or left ventricular ejection fraction \<50% on screening assessment;
   4. Stroke or other grade ≥3 cardiovascular or cerebrovascular events;
   5. Pulmonary embolism; known deep vein thrombosis requiring intervention as judged by the investigator.
8. Prior history of ILD / non-infectious pneumonitis requiring glucocorticoid treatment, current ILD / non-infectious pneumonitis, or ILD / non-infectious pneumonitis cannot be ruled out on screening imaging, or severe ventilatory dysfunction and/or impaired diffusion shown on pulmonary function test.
9. Severe infection within 4 weeks prior to the first dose of study intervention, including but not limited to bacteremia requiring hospitalization, severe pneumonia, active tuberculosis infection, etc.; active infection requiring systemic antibiotics within 2 weeks prior to the first dose of study intervention.
10. Prior interruption of EGFR-targeted therapy for ≥1 month or permanent discontinuation due to skin toxicity, or current skin disease requiring oral or intravenous treatment.
11. Participants with active autoimmune disease or history of autoimmune disease (e.g., ulcerative colitis, Crohn's disease, etc.). Participants with the following conditions may proceed for screening: well-controlled type 1 diabetes, well-controlled hypothyroidism requiring only hormone replacement therapy, skin disorders that do not require systemic treatment (such as vitiligo, psoriasis or alopecia), or participants whose disease is not expected to relapse in the absence of external triggers.
12. Pleural, peritoneal or pericardial effusion requiring clinical intervention within 2 weeks prior to the first dose of study intervention.
13. Active HBV or HCV infection (HBsAg positive with HBV-DNA ≥1×10⁴ copies/mL, or positive HCV antibody with HCV-RNA above the assay lower limit of detection), or HIV infection / diagnosed acquired immunodeficiency syndrome. Note: For HBsAg-positive subjects, antiviral therapy with nucleoside analogues such as entecavir or tenofovir disoproxil fumarate is recommended to be initiated before the first dose of study intervention.
14. History of immunodeficiency (including positive HIV test, other acquired or congenital immunodeficiency diseases), or history of allogeneic stem cell or solid organ transplantation.
15. Other conditions that, in the investigator's opinion, render the participant unsuitable for this clinical trial (e.g., psychiatric disorders, uncontrolled or poorly controlled hypertension and diabetes mellitus, etc.)