De-Escalation Surgery After Immunotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma (Neo-Margin)

Shanghai Jiao Tong University

Status and phase: Not yet enrolling; Phase 3

Conditions: Squamous Cell Carcinoma of the Head and Neck

Treatments: Radiation: radiotherapy; Procedure: De-escalation surgery; Procedure: Standard Surgery; Drug: adjuvant immunotherapy

Study type: Interventional

Funder types: Other

Identifiers

NCT07320690

NCRCO2025ZD-01 (Other Grant/Funding Number)

JYKQ-2025-057

Details and patient eligibility

About

This is a multicenter, randomized, open-label, non-inferiority clinical trial designed to evaluate whether downgraded surgery-guided by post-immunotherapy tumor boundaries-can achieve comparable 3-year overall survival (OS) to standard surgery in patients with Stage III-IVa locally advanced head and neck squamous cell carcinoma (HNSCC) who have responded to neoadjuvant immunotherapy. A total of 356 patients will be randomized 1:1 to receive either downgraded or standard surgery, followed by risk-adapted adjuvant therapy. The primary endpoint is 3-year OS, with secondary endpoints including disease-free survival, quality of life, complication rates, and cost-effectiveness. The study hypothesizes that downgraded surgery will preserve organ function and quality of life without compromising survival outcomes.

Enrollment: 356 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Age between 18 and 75 years inclusive, with no restriction on gender.
2. Histologically confirmed primary squamous cell carcinoma of the head and neck (excluding nasopharyngeal carcinoma).
3. Clinical stage III-IVa according to the AJCC 8th edition TNM staging system prior to immunotherapy; specifically, stage III-IVa for oropharyngeal squamous cell carcinoma (p16-negative) or stage III for oropharyngeal squamous cell carcinoma (p16-positive).
4. ECOG performance status of 0 or 1.
5. Life expectancy of ≥6 months.
6. Received preoperative immune checkpoint inhibitor therapy, primarily with anti-PD-1 monoclonal antibodies or bispecific antibodies containing an anti-PD-1 arm, regardless of brand, with or without concurrent chemotherapy or targeted therapy, for no more than six cycles.
7. Achieved complete response (CR) or partial response (PR) on imaging assessment after preoperative therapy, according to RECIST 1.1 criteria.
8. Assessed as eligible for de-escalation surgery based on clinical evaluation by the surgeon. Examples include omission of surgery on the primary lesion; preservation of critical structures or functions, such as retaining the mandible initially planned for resection; avoidance of flap reconstruction; or limitation of tongue resection to less than half when hemi-glossectomy was initially indicated.
9. No prior curative surgery or radiotherapy for the current tumor.
10. Willing to undergo surgical treatment.
11. No significant contraindications to surgery.
12. Voluntary participation in the study, signed informed consent, good compliance, and willingness to cooperate with follow-up visits.

Exclusion criteria

1. Severe underlying diseases making the patient unable to tolerate surgery.
2. Current tumor is recurrent.
3. Myocardial infarction, severe/unstable angina, NYHA class II or higher heart failure, or symptomatic congestive heart failure within 6 months before randomization.
4. History of psychiatric drug abuse or drug addiction.
5. Pregnant or breastfeeding women.
6. Diagnosis of other malignancies within 5 years prior to study entry, except for locally treated and cured basal cell carcinoma or squamous cell carcinoma of the skin, superficial bladder carcinoma, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, and papillary thyroid carcinoma.
7. Any other severe physical or mental illness, or laboratory abnormalities that might increase the risk associated with participation or interfere with the study results, or any other conditions deemed unsuitable for participation by the investigator.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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356 participants in 2 patient groups

De-escalation surgery

Experimental group

Description:

The surgical procedure should be designed and performed based on the tumor boundaries following neoadjuvant therapy.

Treatment:

Drug: adjuvant immunotherapy

Procedure: De-escalation surgery

Radiation: radiotherapy

Standard Surgery

Active Comparator group

Description:

The surgical procedure should be designed and performed based on the tumor boundaries prior to neoadjuvant therapy.

Treatment:

Drug: adjuvant immunotherapy

Procedure: Standard Surgery

Radiation: radiotherapy