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.

Study Overview

• Status: Recruiting
• Conditions: Nasopharyngeal Carcinoma (NPC)
• Intervention / Treatment: Drug: Toripalimab combined with Nimotuzumab; Drug: Nimotuzumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 566
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Liu Guoying; Phone Number: 18127919832; Email: liugy0109@163.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Recruiting
      • Sun Yat-sen Memorial Hospital, Sun Yat-sen University
      • Contact: Liu Guoying; Phone Number: 18127919832; Email: liugy0109@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Full-Course Immunotherapy Group; Induction Chemotherapy Phase：TPC chemotherapy+ Toripalimab + Nimotuzumab； Concurrent Radiotherapy Phase：Nimotuzumab + Toripalimab； Adjuvant Treatment Phase：Toripalimab	Drug: Toripalimab combined with Nimotuzumab; Induction Chemotherapy Phase： TPC chemotherapy regimen: Nab-paclitaxel: 200 mg/m², intravenous infusion on Day 1；Cisplatin: 60 mg/m², intravenous infusion on Day 1；Capecitabine: 1000 mg/m² orally twice daily on Days 1-14；Each cycle lasts 21 days, for a total of 3 cycles. Toripalimab: 240 mg toripalimab injection, intravenous infusion on Day 0; 21-day cycles for 3 cycles total. Nimotuzumab: 400 mg nimotuzumab, intravenous infusion on Days 0 and 8; 21-day cycles for 3 cycles total. Concurrent Radiotherapy Phase： Toripalimab: 240 mg toripalimab injection via intravenous infusion starting on the first day of radiotherapy, administered every 21 days for 3 cycles. Nimotuzumab: 200 mg nimotuzumab via intravenous infusion once weekly for 6 consecutive weeks, starting on the first day of radiotherapy. Adjuvant Phase： Toripalimab injection 240 mg is administered via intravenous infusion once every 21 days per cycle.
Experimental: Concurrent Immunotherapy-Omitted Group; Induction Chemotherapy Phase：TPC chemotherapy+ Toripalimab + Nimotuzumab； Concurrent Radiotherapy Phase：Nimotuzumab； Adjuvant Treatment Phase：Toripalimab	Drug: Nimotuzumab; Induction Chemotherapy Phase： TPC chemotherapy regimen: Nab-paclitaxel: 200 mg/m², intravenous infusion on Day 1；Cisplatin: 60 mg/m², intravenous infusion on Day 1；Capecitabine: 1000 mg/m² orally twice daily on Days 1-14；Each cycle lasts 21 days, for a total of 3 cycles. Toripalimab: 240 mg toripalimab injection, intravenous infusion on Day 0; 21-day cycles for 3 cycles total. Nimotuzumab: 400 mg nimotuzumab, intravenous infusion on Days 0 and 8; 21-day cycles for 3 cycles total. Concurrent Radiotherapy Phase： Nimotuzumab: 200 mg nimotuzumab via intravenous infusion once weekly for 6 consecutive weeks, starting on the first day of radiotherapy. Adjuvant Phase： Toripalimab injection 240 mg is administered via intravenous infusion once every 21 days per cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free Survival	Defined as the time from the date of randomization to the first documented tumor progression (assessed per RECIST Version 1.1, regardless of continued study treatment) or death from any cause, whichever occurs first.	From randomization to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Defined as the time from randomization to death from any cause.	From randomization to 3 years and 5 years
Locoregional Recurrence-Free Survival	Defined as the time from randomization to the first documented locoregional tumor recurrence.	From randomization to 3 years
Distant Metastasis-Free Survival	Defined as the time from randomization to the first documentation of distant tumor metastasis.	From randomization to 3 years
Objective Response Rate	The proportion of subjects achieving complete response (CR) or partial response (PR) assessed per RECIST Version 1.1 at the completion of radiotherapy in the analysis population.	9 weeks and 3 months
Incidence of Treatment-Emergent Adverse Events	Acute toxicities will be evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0). Late radiation toxicities will be assessed via the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) Late Radiation Morbidity Scoring Schema.	Through treatment completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Study record dates

Study Major Dates

• Study Start (Estimated): July 20, 2026
• Primary Completion (Estimated): July 20, 2030
• Study Completion (Estimated): July 20, 2033

Study Registration Dates

• First Submitted: July 6, 2026
• First Submitted That Met QC Criteria: July 15, 2026
• First Posted (Actual): July 16, 2026

Study Record Updates

• Last Update Posted (Actual): July 16, 2026
• Last Update Submitted That Met QC Criteria: July 15, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Stomatognathic Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Otorhinolaryngologic Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Nasopharyngeal Neoplasms; Nasopharyngeal Carcinoma; nimotuzumab
• Other Study ID Numbers: SYSKY-2026-425-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No