Efficacy and Safety of TPC Induction Chemotherapy Combined With Nimotuzumab and Toripalimab "Immune Sandwich" Regimen Versus Full-Course Immunotherapy for Locally Advanced Nasopharyngeal Carcinoma

Efficacy and Safety of TPC Induction Chemotherapy Combined With Nimotuzumab and Toripalimab "Immune Sandwich" Regimen Versus Full-Course Immunotherapy for Locally Advanced Nasopharyngeal Carcinoma: A Multicenter, Randomized, Open-Label, Non-Inferiority Phase III Clinical Study

Immunotherapy combined with chemoradiotherapy has become standard care for locally advanced nasopharyngeal carcinoma, yet radiotherapy-induced lymphopenia may impair the efficacy of concurrent PD-1 blockade. Existing evidence supports synergistic anti-tumor activity between the anti-EGFR antibody nimotuzumab and toripalimab. This multicenter, open-label, non-inferiority Phase III trial randomizes eligible stage III-IVA LA-NPC patients 1:1 to two arms. The experimental group receives an "immune sandwich" regimen: TPC induction plus nimotuzumab and toripalimab, concurrent radiotherapy with weekly nimotuzumab only, followed by toripalimab maintenance. The control arm adopts full-course toripalimab throughout induction, concurrent radiotherapy and adjuvant phases. The primary endpoint is 3-year event-free survival, with secondary endpoints covering overall survival, local/distant control rates, objective response rate and treatment-related toxicities. A total of 566 subjects will be enrolled to verify whether the simplified sandwich strategy delivers non-inferior survival with better safety profiles.

The survival outcomes of patients with locally advanced nasopharyngeal carcinoma (LA-NPC) have been greatly elevated with the combination of immunotherapy and targeted therapy. Numerous previous studies have confirmed that PD-1 immune checkpoint inhibitors exert prominent anti-tumor efficacy for locally advanced nasopharyngeal carcinoma. Large-scale Phase III trials including CONTINUUM, DIPPER and DIAMOND verified that adding anti-PD-1 agents to chemoradiotherapy remarkably extended event-free survival (EFS) of high-risk LA-NPC patients, with the 3-year EFS rate reaching up to 86%-88%. In addition, anti-EGFR targeted antibody nimotuzumab could boost radiotherapy sensitivity and further optimize long-term survival for LA-NPC patients when combined with comprehensive chemoradiotherapy. Mechanistic research revealed that EGFR pathway activation upregulates tumor PD-L1 expression, and the combination of nimotuzumab and toripalimab generates synergistic anti-tumor effects.

However, intensive full-course immunotherapy throughout induction, concurrent and adjuvant phases may lead to severe treatment-related lymphopenia during radiotherapy, which potentially weakens immunotherapeutic efficacy and increases adverse reaction risks. Our previous exploratory trial demonstrated an "immune sandwich" strategy (toripalimab only applied in induction and adjuvant stages without concurrent immunotherapy plus weekly nimotuzumab during radiation) achieved comparable survival benefits while reducing treatment toxicity.

This study aims to design a multicenter, randomized, open-label non-inferiority Phase III clinical trial to compare the efficacy and safety of the "immune sandwich" regimen (TPC induction chemotherapy plus nimotuzumab and toripalimab, concurrent nimotuzumab monotherapy radiotherapy followed by toripalimab maintenance) versus the full-course toripalimab combined regimen for patients with locally advanced nasopharyngeal carcinoma.

Inclusion Criteria:

• Aged between 18 and 70 years, regardless of gender
• Histologically or cytologically confirmed diagnosis of nasopharyngeal carcinoma
• Locoregionally advanced nasopharyngeal carcinoma classified as Stage III-IVA per the 8th AJCC staging system, excluding T3-4N0 and T3N1 disease
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Adequate organ and bone marrow function as demonstrated by laboratory test results obtained within 7 days prior to enrollment. No blood products, hematopoietic growth factors, albumin, or other intravenous/subcutaneous corrective medications are permitted within 14 days before laboratory testing. Specific criteria are listed below.Hematology: Absolute Neutrophil Count (ANC) ≥ 1.5 × 10⁹/L; Platelet (PLT) count ≥ 75 × 10⁹/L; Hemoglobin (HGB) ≥ 9.0 g/dL;Liver function: Total Bilirubin (TBIL) ≤ 2 × Upper Limit of Normal (ULN); Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 5 × ULN; serum albumin ≥ 28 g/L; Alkaline Phosphatase (ALP) ≤ 5 × ULN. Renal function: Serum Creatinine (Cr) ≤ 1.5 × ULN, or Creatinine Clearance (CCr) ≥ 50 mL/min (calculated via the Cockcroft-Gault formula). For patients with urine protein ≥ 2+ on routine urinalysis, a 24-hour urine collection is required, with total 24-hour urinary protein quantification < 1 g. Coagulation function: International Normalized Ratio (INR) ≤ 2.3, or prothrombin time (PT) prolongation ≤ 6 seconds
• Able to provide written informed consent and comply with all protocol-specified study visits and related procedures.

Exclusion Criteria:

• Diagnosis of another malignant tumor within 5 years prior to the first study drug administration, excluding radically treated basal cell carcinoma, squamous cell carcinoma of the skin, and/or radically resected carcinoma in situ
• Symptomatic congestive heart failure (New York Heart Association [NYHA] Class II-IV) or left ventricular ejection fraction (LVEF) <50% on echocardiography
• Patients with acute or chronically active hepatitis B or hepatitis C infection: HBV DNA >2000 IU/mL or 10⁴ copies/mL; HCV RNA >10³ copies/mL; concurrent positive hepatitis B surface antigen (HBsAg) and anti-HCV antibody. Subjects with viral loads below the above thresholds after nucleotide antiviral therapy are eligible for enrollment
• Past or current history of pulmonary diseases including pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-induced pneumonitis, or severely impaired pulmonary function
• Active tuberculosis (TB) receiving anti-tuberculosis treatment, or having received anti-tuberculosis therapy within 1 year before the first study drug dose.
• Human immunodeficiency virus (HIV) infection (positive HIV 1/2 antibody), or known syphilis infection requiring treatment
• Severe active or poorly controlled infections. Severe infection requiring hospitalization within 4 weeks before the first dose, including but not limited to complications from infection, bacteremia, or severe pneumonia
• History of active autoimmune diseases requiring systemic therapy (e.g., disease-modifying agents, corticosteroids, immunosuppressants) within 2 years prior to the first dose. Replacement therapies (e.g., thyroxine, insulin, physiological corticosteroids for adrenal or pituitary insufficiency) are permitted. Known history of primary immunodeficiency. Subjects with only positive autoantibodies will be assessed by the investigator to confirm the presence of autoimmune disease
• Female patients who are pregnant or breastfeeding
• Prior radiotherapy, chemotherapy, or surgery for nasopharyngeal and cervical lesions (excluding biopsy)
• History of hypersensitivity to any study drug or its components