EBV Lytic Reactivation Therapy Combined With PD-1 Antibody in Recurrent/Metastatic Nasopharyngeal Carcinoma

Efficacy and Safety of EBV Lytic Reactivation Therapy Combined With PD-1 Antibody in Recurrent/Metastatic Nasopharyngeal Carcinoma: a Single-center, Single-arm Phase II Trial

Nearly all undifferentiated nasopharyngeal carcinoma (NPC) are associated with the Epstein-Barr Virus (EBV), which typically remains in a latent, non-immunogenic state within tumor cells. By combining EBV lytic induction strategy with standard chemo-immunotherapy, this study aims to create a synergistic anti-tumor effect and improve clinical outcomes for patients with recurrent/metastatic NPC (r/m NPC). This is a phase II, single-center, single-arm clinical trial designed to evaluate the efficacy and safety of a novel combination therapy in patients with r/m EBV-positive NPC.

Rationale: Epstein-Barr virus (EBV) is clonally present in nearly all undifferentiated nasopharyngeal carcinoma (NPC) tumor cells, particularly in endemic regions. In most cases, EBV remains in a latent state, expressing only a limited set of non-immunogenic proteins, which facilitates immune evasion by tumor cells. Chemotherapeutic agents such as gemcitabine and cisplatin can induce the EBV lytic cycle, activate valganciclovir hydrochloride, thereby enabling the selective killing of EBV-infected tumor cells. This strategy may act synergistically with immunotherapy. Early-phase clinical studies have demonstrated the safety and potential efficacy of this approach; however, larger-scale studies are required to confirm these findings.

Study Objectives: The primary objectives of this clinical trial are: 1.To assess the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS) in patients receiving chemotherapy combined with valganciclovir hydrochloride and PD-1 antibody. 2.To evaluate the safety profile, including acute and chronic toxicities.

Study Design and Treatment Regimen: Patients with histologically confirmed EBV-positive, recurrent or metastatic NPC will be enrolled. Patients will receive 4 to 6 cycles of gemcitabine, cisplatin, and PD-1 antibody, with oral administration of valganciclovir hydrochloride tablets during the first 3 cycles. Following completion of the 4 to 6 cycles, patients will continue PD-1 antibody maintenance therapy for up to two years or until disease progression, unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of informed consent, or death.

Inclusion Criteria:

• Patients must voluntarily participate and provide written informed consent.
• Histologically or cytologically confirmed recurrent or metastatic nasopharyngeal carcinoma (NPC) at enrollment, with positive EBERs by pathological immunohistochemistry.
• Metastatic NPC includes both newly diagnosed metastatic disease and metastatic disease after failure of first-line therapy, as well as recurrent NPC not amenable to local regional treatment, with confirmed metastatic or recurrent disease and no prior treatment after diagnosis.
• Age ≥ 18 years and ≤ 75 years, of any sex.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Expected survival time ≥ 3 months.
• Baseline plasma EBV DNA > 0 copies/mL.
• Adequate organ function confirmed by the following criteria (no blood component transfusions or use of hematopoietic growth factors within 2 weeks prior to study treatment initiation):
• Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; platelet count ≥ 100 × 10^9/L; hemoglobin ≥ 90 g/L. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or calculated creatinine clearance (CrCl) ≥ 60 mL/min . Total bilirubin (TBil) ≤ 1.5 × ULN; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (for patients with liver metastases, TBil ≤ 3 × ULN; AST and ALT ≤ 5 × ULN). Serum albumin ≥ 28 g/L.

Exclusion Criteria:

• History of severe hypersensitivity reactions to other monoclonal antibodies or to any component of PD-1 inhibitors.
• Receipt of radiotherapy, biological therapy (e.g., tumor vaccines, cytokines, or growth factors), or other immunotherapy (excluding PD-1 and PD-L1 inhibitors), or any other anti-tumor treatment within 28 days or 5 half-lives prior to the first dose of study drug, whichever is shorter.
• Prior treatment targeting Epstein-Barr virus (EBV) specifically.
• History of any Grade ≥3 bleeding event, as defined by CTCAE v5.0, within 4 weeks prior to screening, or patients deemed at high risk of bleeding by the investigator.
• Presence of necrotic lesions within 4 weeks prior to screening, with high risk of major hemorrhage as judged by the investigator.
• Known congenital or acquired immunodeficiency (e.g., HIV-positive individuals).
• Requirement for systemic corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive agents within 14 days prior to initiation of study treatment.
• History of active tuberculosis (TB). Suspected active TB must be excluded through chest X-ray, sputum examination, and clinical assessment of signs and symptoms.
• Patients with HBV DNA ≥1000 copies/mL. Patients with positive hepatitis C antibody results may only be enrolled if polymerase chain reaction (PCR) testing confirms HCV RNA negativity.
• Pregnant or breastfeeding women, or women of childbearing potential not using effective contraception.
• History of other malignancies, except for adequately treated basal cell carcinoma or carcinoma in situ of the cervix.
• Uncontrolled cardiovascular conditions, including but not limited to: Heart failure with NYHA classification ≥2; Unstable angina; Myocardial infarction within the past year; Supraventricular or ventricular arrhythmias requiring treatment or intervention.
• Significant impairment of cardiac, hepatic, pulmonary, renal, or bone marrow function.
• Severe and uncontrolled medical illnesses or infections.
• Concurrent participation in another clinical trial or use of another investigational agent.
• Refusal or inability to sign informed consent.
• Any other contraindications to study treatment as determined by the investigator.
• Individuals with personality disorders or psychiatric conditions, and those lacking or having limited legal capacity to provide consent.