GAPP Induction and Concurrent Chemoradiotherapy for High-risk Locoregionally Advanced NPC.

The investigators have designed a multicenter, open-label, randomized controlled phase III clinical study of GAPP (gemcitabine + anlotinib + cisplatin + toripalimab) induction therapy followed by concurrent chemoradiotherapy (cisplatin) and toripalimab maintenance therapy for high-risk locoregionally advanced nasopharyngeal carcinoma (stage III, AJCC 9th edition). The aim is to obtain high-level, high-quality evidence-based data to clarify the efficacy and safety of combining chemoradiotherapy with PD-1 antibody and anlotinib, thereby providing a new treatment strategy to improve the prognosis of patients with high-risk locoregionally advanced nasopharyngeal carcinoma. In this study, GPP (gemcitabine + cisplatin + toripalimab) induction chemotherapy followed by concurrent chemoradiotherapy (cisplatin) and toripalimab maintenance therapy is selected as the control group. This regimen is currently the standard treatment recommended by guidelines for high-risk locoregionally advanced nasopharyngeal carcinoma, with well-established efficacy and broad clinical application. It provides a reliable benchmark for comparing the efficacy and safety of the experimental group, meets ethical requirements, and has mature clinical operational procedures.

Inclusion criteria

• Voluntary participation and signed informed consent.
• Age 18-65 years, male or non-pregnant female.
• Pathologically confirmed non-keratinizing nasopharyngeal carcinoma (differentiated or undifferentiated type, i.e., WHO type II or III).
• Previously untreated patients with no history of other malignancies; initial treatment for nasopharyngeal carcinoma.
• Stage III: TanyN3M0 / T4N0-2M0 (9th AJCC/UICC staging system).
• ECOG performance status 0-1, with no severe dysfunction of vital organs (heart, lung, liver, kidney, etc.).
• Hemoglobin (HGB) ≥90 g/L, white blood cell count (WBC) ≥4.0×10^9 /L, platelet count (PLT) ≥100×10^9/L.
• Liver function: ALT and AST <2.5× upper limit of normal (ULN); total bilirubin <2.0×ULN.
• Renal function: serum creatinine <1.5×ULN.

Exclusion criteria

• Patients with recurrent or distant metastatic nasopharyngeal carcinoma.
• Pathologically confirmed keratinizing squamous cell carcinoma (WHO type I).
• Receipt of systemic or topical glucocorticoid therapy within 4 weeks prior to enrollment.
• Participation in another clinical trial of an investigational drug within 3 months prior to treatment.
• Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
• Patients with idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans), radiation pneumonitis that is clinically symptomatic or requires steroid therapy, active pneumonitis, or other moderate-to-severe pulmonary diseases that significantly affect lung function.
• Comorbidities requiring long-term immunosuppressive medication or systemic/topical corticosteroids at immunosuppressive doses.
• Prior use of anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibodies (or any other antibodies targeting T-cell co-stimulatory or checkpoint pathways) with documented disease progression at the time of study entry.
• Presence of any active autoimmune disease or history of autoimmune disease (including but not limited to: interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, nephritis). Patients with vitiligo or childhood asthma that has completely resolved and requires no intervention in adulthood may be included; patients requiring bronchodilators for medical management of asthma are excluded.
• HIV-positive; HBsAg-positive with detectable HBV DNA copy number (quantitative detection ≥1000 cps/mL); positive hepatitis C antibody (HCV Ab) with detectable HCV RNA.
• Receipt of any anti-infective vaccine (e.g., influenza vaccine, varicella vaccine) within 4 weeks prior to enrollment.
• Positive pregnancy test in women of childbearing potential, or lactating women.
• Inability to comply with scheduled follow-up due to psychological, social, family, or geographical reasons.