PD-1 Antibody-based Therapy With Concurrent RT for Early-stage NKTCL

A Prospective Study to Evaluate the Efficacy and Safety of PD-1 Monoclonal Antibody-based Stratified Targeted Therapy Combined With Concurrent Radiotherapy for Patients With Treatment-naive Early-stage Nasal-type NK/T-cell Lymphoma

Natural killer/T-cell lymphoma (nasal type) is a mature T/NK-cell lymphoma closely associated with Epstein-Barr virus (EBV), with a high prevalence among populations in Asia and South America. It primarily occurs at extranodal sites, including the nasal/paranasal regions, skin, gastrointestinal tract, and other organs. This study focuses on previously untreated patients with early-stage NKTCL (nasal type), exploring a response-adapted comprehensive therapeutic strategy that combines PD-1 monoclonal antibody-based stratified targeted therapy with concurrent radiotherapy. The aim is to provide integrated management for early-stage extranodal NK/T-cell lymphoma (nasal type), and reduce toxicity while improving overall treatment outcomes for patients.

Inclusion Criteria:

• The subject has histopathologically confirmed extranodal NK/T-cell lymphoma, nasal type (according to the 2022 WHO classification).

• No prior history of anti-lymphoma therapy.

• Age ≥ 18 years.

• Life expectancy > 3 months.

• Ann Arbor stage I-II.

• At least one measurable/evaluable disease site confirmed by diagnostic biopsy prior to the initiation of treatment.

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2.

• Signed informed consent form (ICF).

• Willingness and ability to comply with the study protocol.

• Sufficient bone marrow, hepatic, and renal function, defined as:

  1. Absolute neutrophil count (ANC) > 1,000/μL
  2. Platelet count > 50,000/μL
  3. Hemoglobin > 9 g/dL
  4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3× upper limit of normal (ULN)
  5. Serum total bilirubin < 1.5 × ULN (patients with Gilbert's syndrome are eligible)
  6. Serum creatinine < 2 × ULN or creatinine clearance > 50 mL/min

• Availability of tumor tissue samples (preferably fresh tissue; archived tissue samples are acceptable).

• For women of childbearing potential, agreement to use adequate contraception to avoid pregnancy during the study treatment period.

• For male, agreement to remain abstinent or use a barrier method of contraception.

Exclusion Criteria:

• Advanced-stage disease (Ann Arbor Stage III-IV).
• Nonnasal-type NKTCL.
• A history of autoimmune disease requiring systemic treatment (i.e., with disease-modifying antirheumatic drugs, corticosteroids, or immunosuppressants) within the past 2 years, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody-associated vasculopathy, granulomatosis with polyangiitis (Wegener's), Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

The following conditions are permissible for enrollment: patients with autoimmune hypothyroidism or type 1 diabetes receiving stable treatment; hormone replacement therapy (e.g., levothyroxine, insulin, or supplementation with physiological hormones for adrenal or pituitary insufficiency) is not considered systemic therapy and is allowed.

• A history of other invasive malignancies within the past 3 years that has not been treated with curative intent or is currently receiving anticancer therapy (including hormonal therapy for breast or prostate cancer).

• A history of (non-infectious) pneumonia requiring corticosteroid therapy; or clinical evidence of interstitial lung disease or active, non-infectious pneumonia.

• Active infections requiring systemic treatment, including:

  1. A known history of active tuberculosis;
  2. Positive results for HBsAg, HCV, or HIV; HBV seropositivity is permitted only if HBV DNA < 1000 IU/mL;
  3. Active viral infections other than hepatitis B and C (e.g., herpes zoster).

• Severe cardiovascular disease, including myocardial infarction, unstable arrhythmia, or unstable angina occurring within the past 3 months.

• Prior treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 agents.

• Administration of live-attenuated vaccines within 4 weeks prior to the initiation of study treatment; patients are prohibited from receiving live-attenuated vaccines during the study period, including influenza vaccines.

• Use of systemic immunosuppressive agents within 2 weeks prior to the initiation of study treatment, or planned use of such agents during the study period, including cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) drugs.

• Evidence of central nervous system involvement.

• A history of allogeneic tissue/solid organ transplantation.

• A history of severe hypersensitivity reactions (Grade ≥ 3) to PD-1 monoclonal antibodies and/or their excipients, or to gorlitinib and/or its excipients.

• Any other factors judged by the investigator to potentially affect compliance with the study protocol.