Inclusion Criteria:
1. Age ≥ 18 years at diagnosis, regardless of sex.
2. Previously untreated nasopharyngeal carcinoma histologically confirmed as non-keratinizing carcinoma according to the World Health Organization (WHO) classification.
3. Locoregionally advanced nasopharyngeal carcinoma classified as stage II or III, excluding T3N0-1 disease, according to the 9th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) clinical staging system.
4. Positive plasma Epstein-Barr virus (EBV) DNA before initiation of treatment (\> 0 copies/mL).
5. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
6. Willing to provide an archived tumor tissue specimen from the primary or metastatic lesion obtained within the previous 2 years or a fresh tumor tissue specimen. Participants who are unable to provide a tumor tissue specimen may still be enrolled at the investigator's discretion, provided all other eligibility criteria are met.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days before the first dose of study treatment.
8. Adequate organ function meeting the following criteria, without blood transfusion, any hematopoietic growth factor, and/or thrombopoietic agent within the 4 weeks before the screening assessments:
1. Hematology: Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; white blood cell count \> 4 × 10⁹/L; hemoglobin \> 90 g/L; and platelet count \> 100 × 10⁹/L.
2. Hepatic and renal function: Serum total bilirubin (TBIL) ≤ 1.5 × the upper limit of normal (ULN); aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 × ULN; alkaline phosphatase (ALP) ≤ 2.5 × ULN; creatinine clearance ≥ 60 mL/min; and urinary protein ≤ 2+ or ≤ 1,000 mg/24 hours.
3. Coagulation: International normalized ratio (INR) ≤ 1.5 × ULN and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN. Stable low-dose anticoagulant therapy, such as aspirin 100 mg/day, is permitted.
9. Normal results for thyroid function, serum amylase and lipase, pituitary function, inflammatory and infectious markers, cardiac enzymes, and electrocardiography (ECG):
1. Patients aged \> 50 years with a smoking history must have normal pulmonary function test results.
2. Patients with ECG abnormalities or a history of cardiovascular disease that does not meet any condition listed in Exclusion Criterion 5 must additionally undergo myocardial function testing and echocardiography, with normal results required for enrollment.
10. Patients must provide written informed consent and be willing and able to comply with all protocol-specified follow-up visits, treatments, laboratory assessments, and other study requirements.
11. Male patients with reproductive potential and women of childbearing potential must agree to use effective contraception from the time of signing the informed consent form through 6 months after the last dose of study drug. Women of childbearing potential include premenopausal women and women who have been postmenopausal for less than 2 years. Women of childbearing potential must have a negative serum pregnancy test within 7 days before the first dose of study drug.
Exclusion Criteria:
Patients meeting any of the following criteria will be excluded from the study:
1. Current or previous history of another malignancy within the past 5 years, except for cured cervical carcinoma in situ, papillary thyroid carcinoma, or basal cell carcinoma of the skin.
2. Negative plasma Epstein-Barr virus (EBV) DNA before initiation of treatment (= 0 copies/mL) or absence of pretreatment plasma EBV DNA testing.
3. Prior receipt of any antitumor therapy for nasopharyngeal carcinoma or any of the following treatments:
1. Any antibody-drug conjugate (ADC) containing a monomethyl auristatin E (MMAE) payload within 3 months before the first dose of study treatment.
2. Any investigational drug from another clinical trial within 28 days before the first dose of study treatment.
3. Major surgery within 28 days before the first dose of study treatment without complete recovery, or planned major surgery within the first 12 weeks after initiation of study treatment.
4. Positive human immunodeficiency virus antibody (HIV-Ab); active tuberculosis; active hepatitis B virus infection (HBV DNA \> 1 × 10³ copies/mL); or positive hepatitis C virus antibody.
5. History of primary immunodeficiency or active autoimmune disease requiring immunosuppressive agents or systemic corticosteroid therapy at a dose of ≥ 10 mg/day of prednisone or an equivalent corticosteroid within 2 weeks before enrollment. The following conditions or treatments are permitted: type 1 diabetes mellitus; hypothyroidism, including hypothyroidism caused by autoimmune thyroid disease, that is stable on hormone replacement therapy; psoriasis, vitiligo, or alopecia not requiring systemic treatment; topical or inhaled corticosteroids; or short-term systemic corticosteroid therapy lasting ≤ 7 days for the prevention or treatment of non-autoimmune, non-recurrent allergic conditions.
6. Uncontrolled cardiac disease, including any of the following:
1. Heart failure of New York Heart Association (NYHA) Class ≥ II.
2. Unstable angina.
3. Myocardial infarction within the past year.
4. Prolonged QT interval, defined as QTc \> 450 msec in males or \> 470 msec in females; complete left bundle branch block; third-degree atrioventricular block; or supraventricular or ventricular arrhythmia requiring treatment or intervention.
7. Hypertension inadequately controlled with two antihypertensive agents, defined as systolic blood pressure \> 150 mmHg or diastolic blood pressure \> 100 mmHg.
8. Poorly controlled blood glucose, defined as either of the following, or concurrent diabetic gangrene:
1. Fasting blood glucose \> 10 mmol/L on two occasions.
2. Glycated hemoglobin (HbA1c) \> 8%.
9. History of noninfectious interstitial lung disease (ILD) or pneumonitis requiring corticosteroid treatment, including pulmonary fibrosis or radiation pneumonitis; current ILD or pneumonitis; or imaging findings at screening that cannot exclude suspected ILD or pneumonitis.
10. Concurrent pulmonary disease causing clinically severe respiratory impairment, including but not limited to:
1. Any underlying pulmonary disease, such as pulmonary embolism, severe asthma, or severe chronic obstructive pulmonary disease (COPD), occurring within 3 months before screening.
2. Restrictive lung disease.
3. History of or concurrent interstitial pneumonitis, radiation pneumonitis, severe COPD, severe pulmonary insufficiency, symptomatic bronchospasm, or a similar pulmonary condition.
11. Unstable thrombotic events requiring therapeutic intervention within 6 months before screening, including deep vein thrombosis, arterial thrombosis, or pulmonary embolism. Infusion catheter-related thrombosis is exempt.
12. Pregnant or breastfeeding women. Pregnancy testing should be considered for sexually active women of childbearing potential.
13. Known hypersensitivity to any component of pucotenlimab or becotatug vedotin (MRG003), including histidine, histidine hydrochloride, sucrose, mannitol, or polysorbate 80; or a history of a Grade ≥ 3 hypersensitivity reaction to any macromolecular protein preparation or monoclonal antibody.
14. Serious infection of Common Terminology Criteria for Adverse Events (CTCAE) Grade \> 2 within 4 weeks before the first dose of study treatment, including but not limited to severe pneumonia, bacteremia, sepsis, or tuberculosis.
15. Peripheral neuropathy of Grade \> 1.
16. Receipt of a live vaccine within 30 days before the first dose of becotatug vedotin (MRG003).
17. Prior solid organ transplantation or allogeneic hematopoietic stem cell transplantation (allo-HSCT).
18. Any other condition judged by the investigator to potentially compromise patient safety or compliance, including but not limited to a serious medical condition requiring prompt treatment, including a psychiatric disorder; markedly abnormal laboratory findings; or other psychological, familial, or social high-risk factors.
