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.
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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.
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.
Single group
Neoadjuvant and Adjuvant Immunotherapy
DrugNeoadjuvant therapy with Toripalimab (240mg, Day 1, Q3W, 2 cycles);Adjuvant immunotherapy with Toripalimab (240mg, Day 1, Q3W, for a total of 15 cycles).
Low-dose radiotherapy
RadiationLow-dose radiotherapy (1 Gy/fraction, on Days 1, 8, and 15 of each cycle, Q3W, for 2 cycles; total dose: 6 Gy in 6 fractions).
Surgery
Procedure/SurgeryRadical surgery performed 3-4 weeks after neoadjuvant therapy, following a re-evaluation of surgical indications by the surgeon.
Adjuvant Radiotherapy
RadiationLow-risk group: 60 Gy in 30 fractions, using intensity-modulated radiation therapy (IMRT); High-risk group: 66 Gy in 33 fractions, or 70 Gy in 35 fractions for residual lesions, using intensity-modulated radiation therapy (IMRT).
Adjuvant Cisplatin
DrugHigh-risk group：Cisplatin 100 mg/m² is administered via intravenous infusion on Day 1 of every 21-day cycle during radiotherapy, for a total of 3 cycles.
Main pathological response rate
The proportion of patients with residual living tumor cells in the tumor bed under microscopy after HE staining of the specimens organized is less than 10%.
Progression-free survival
From random grouping to the time interval until tumor progression or death for any reason, or until the last follow-up time if there is no tumor progression.
Pathological complete response rate
The proportion of patients with no residual live tumor cells under the microscope.
Objective response rate
Evaluate the proportion of patients with objective response (complete response and partial response) through imaging assessments such as MRI and CT.
Overall survival
The time interval from random grouping to the time of death for any reason, or to the last follow-up time if there is no death.
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Rui You
Lead sponsor
Fifth Affiliated Hospital, Sun Yat-Sen University
Sponsor institution