Low-Dose Radiotherapy and Anti-PD-1 Immunotherapy as Neoadjuvant Treatment for Resectable Locally Advanced Head and Neck Squamous Cell Carcinoma

A Single Arm, Phase II Clinical Study of Low-Dose Radiotherapy Combined With Anti-PD-1 Monoclonal Antibody Immunotherapy as Neoadjuvant Treatment for Surgically Resectable, Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC)

Over 60% of head and neck squamous cell carcinoma (HNSCC) patients are diagnosed at a locally advanced stage. While standard treatments involve surgery and chemoradiotherapy, prognosis remains poor, with 50-60% experiencing local recurrence within two years. Neoadjuvant therapy can potentially reduce tumor burden, preserve organs, and lower distant metastasis risk. Despite the KEYNOTE-689 trial showing that adjuvant two-cycle pembrolizumab increased major pathological response to 9.8% in stage III-IVB HNSCC, this result remains insufficient. More effective immunotherapy-based combinations are urgently needed to improve long-term survival after neoadjuvant treatment.

Preclinical and clinical evidence indicates that low-dose radiotherapy can activate the tumor immune microenvironment and synergize with immunotherapy. Based on this rationale, the present clinical trial will evaluate a neoadjuvant regimen combining LDRT with two cycles of an anti-PD-1 inhibitor in patients with surgically resectable, locally advanced HNSCC.

Inclusion Criteria:

• Voluntarily sign and date the informed consent form.
• Untreated, histologically confirmed squamous cell carcinoma of the head and neck (oral cavity, oropharynx, hypopharynx, or larynx) with CPS ≥1, classified as stage T3-4bN0M0 or T1-4bN1-3M0, corresponding to stage III-IVB according to the AJCC Staging System, 8th Edition.
• Deemed eligible for curative surgery based on surgeon's assessment.
• Age: 18 to 75 years.
• ECOG performance status of 0 or 1.
• Life expectancy greater than 6 months.
• At least one measurable lesion as per RECIST 1.1 criteria.
• Adequate organ function, defined as meeting all the following criteria (without receipt of blood products, colony-stimulating factors, or hematopoietic growth factors within 14 days prior to testing): Hemoglobin ≥ 90 g/L Absolute neutrophil count ≥ 1.5 × 10⁹/L Platelet count ≥ 100 × 10⁹/L Serum albumin ≥ 28 g/L Total bilirubin ≤ 1.5 × upper limit of normal (ULN) ALT and AST ≤ 2.5 × ULN Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min Activated partial thromboplastin time (aPTT) and international normalized ratio (INR) ≤ 1.5 × ULN (patients on a stable dose of anticoagulant therapy such as low molecular weight heparin or warfarin are eligible if INR is within the therapeutic range) Thyroid-stimulating hormone (TSH) ≤ ULN; if abnormal, T3 and T4 levels must be evaluated, and patients with normal T3 and T4 levels are eligible.
• Women of childbearing potential must agree to use effective contraception (e.g., intrauterine device, oral contraceptives, or condoms) during the treatment period and for 3 months after the last dose.
• Good compliance with the study protocol.

Exclusion Criteria:

• Pregnant or lactating women.
• History of allergy to PD-1 inhibitors.
• History of other malignancies within the past 5 years or at the time of enrollment, with the exception of cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, and papillary thyroid carcinoma.
• Uncontrolled cardiac clinical symptoms or diseases, such as: (1) heart failure of NYHA Class II or higher, (2) unstable angina, (3) myocardial infarction within the past year, and (4) patients with clinically significant ventricular or supraventricular arrhythmias requiring intervention.
• Any of the following prior treatments: ① Receipt of any investigational drug prior to the first dose of the current study drug. ② Concurrent participation in another clinical study, unless it is an observational (non-interventional) study or an interventional study during the follow-up phase. ③ Systemic treatment with corticosteroids (>10 mg prednisone daily or equivalent) or other immunosuppressive agents within 2 weeks prior to the first dose of the study drug, with the exception of topical corticosteroid use for local inflammation, prevention of allergic reactions, or management of nausea and vomiting. Inhaled or topical steroids and physiologic replacement doses of corticosteroids (≤10 mg prednisone equivalent daily) are permitted in the absence of active autoimmune disease. ④ Administration of live vaccines within 4 weeks prior to the first dose of the study drug. ⑤ Major surgery or severe trauma within 4 weeks prior to the first dose of the study drug.
• Severe infection (Grade >2 according to Common Terminology Criteria for Adverse Events), such as severe pneumonia, bacteremia, or complicating infections requiring hospitalization, occurring within 4 weeks prior to the first dose of the study drug; or active pulmonary inflammation or signs/symptoms of infection indicated by baseline chest imaging within 2 weeks prior to the first dose, or requiring oral or intravenous antibiotic treatment (excluding prophylactic antibiotics).
• History of active autoimmune diseases and syndromes (including but not limited to interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, and hypothyroidism). Patients with vitiligo not requiring intervention in adulthood, or childhood asthma/allergies that have resolved, are not excluded.
• History of immunodeficiency, including HIV positivity, other acquired or congenital immunodeficiency diseases, or history of organ or bone marrow transplantation.
• Patients with active tuberculosis infection based on medical history or CT findings, or a history of active tuberculosis infection within 1 year prior to enrollment, or a history of active tuberculosis infection more than 1 year ago without adequate course of anti-tuberculosis therapy.
• Active hepatitis B (HBV DNA ≥ 2,000 IU/mL or 10,000 copies/mL) or hepatitis C (positive HCV antibody test with HCV RNA above the lower limit of detection).
• Known history of substance abuse, alcohol abuse, or drug use.
• Considered ineligible for participation based on the investigator's judgment.