Neoadjuvant Radio-immunotherapy Versus Immunotherapy Alone for Locally Advanced HNSCC (RAIN-HNSCC)

A Randomized, Controlled, Phase II Clinical Study of Neoadjuvant Radio-immunotherapy Versus Immunotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma

The purpose of this randomized Phase II study is to evaluate and compare the efficacy and safety of neoadjuvant radio-immunotherapy versus immunotherapy alone for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Participants will be randomly assigned to one of two groups. The experimental group will receive a combination of radiotherapy and Adebrelimab as neoadjuvant treatment, while the control group will receive Adebrelimab monotherapy. Following the neoadjuvant phase, all eligible patients will undergo surgical resection. The primary objective is to determine if the addition of radiotherapy improves the major pathological response (MPR) rate. Secondary objectives include pathological complete response (pCR) rate, objective response rate (ORR), and event-free survival (EFS).

Study Overview

• Status: Not yet recruiting
• Conditions: Head and Neck Squamous Cell Carcinoma; Locally Advanced Head and Neck Squamous Cell Carcinoma
• Intervention / Treatment: Drug: Adebrelimab; Radiation: radiotherapy

Detailed Description

This is a randomized, controlled, open-label, Phase II clinical trial designed to compare the efficacy and safety of neoadjuvant radiotherapy combined with Adebrelimab versus Adebrelimab monotherapy in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Experimental Arm (Radio-immunotherapy): Patients will receive neoadjuvant radiotherapy (SBRT 24 Gy in 3 fractions) followed by or concurrent with 2 cycles of Adebrelimab (1200mg, Q3W).

Control Arm (Immunotherapy alone): Patients will receive 2 cycles of Adebrelimab (1200mg, Q3W) as monotherapy.

Following the completion of neoadjuvant therapy, a multidisciplinary team (MDT) will evaluate the patients' response. Eligible patients will then undergo standard surgical resection of the primary tumor and neck dissection within 3 to 4 weeks after the last dose of immunotherapy.

The primary endpoint is the Major Pathological Response (MPR) rate, defined as less than or equal to 10% residual viable tumor in the resected specimen. Secondary endpoints include Pathological Complete Response (pCR) rate, Objective Response Rate (ORR) according to RECIST 1.1, Event-Free Survival (EFS), and the incidence of treatment-emergent adverse events (TEAEs) graded by CTCAE 5.0.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Anqi He, MB; Phone Number: +86-18025464619; Email: heaq@sysucc.org.cn
• Study Contact Backup: Name: Chunyan Chen, MD; Phone Number: +86-13826423812; Email: chenchuny@sysucc.org.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Sun Yat-sen University Cancer Center
      • Contact: Chunyan Chen, MD; Phone Number: +86-13826423812; Email: chenchuny@sysucc.org.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically confirmed, treatment-naive, resectable head and neck squamous cell carcinoma (HNSCC).
2. Clinical stage III to IVB (according to AJCC 8th edition), excluding HPV-positive oropharyngeal cancer.
3. PD-L1 expression with a Combined Positive Score (CPS) ≥ 1.
4. Karnofsky Performance Status (KPS) score ≥ 70.
5. Age between 18 and 70 years (inclusive).
6. Evaluated by a multidisciplinary team (MDT) as resectable or borderline resectable, and suitable for preoperative Stereotactic Body Radiotherapy (SBRT).
7. Adequate organ function within 7 days prior to enrollment, meeting laboratory criteria for hematology, liver, and renal function.
8. Anatomical requirements for SBRT: Lesions must be localized with adequate anatomical space for high-precision radiotherapy without exceeding safety limits for Organs at Risk (OARs).
9. Voluntary participation with a signed Informed Consent Form (ICF).

Exclusion Criteria:

1. Prior radical surgery, radiotherapy, or immunotherapy for head and neck malignancies.
2. Severe comorbidities that may interfere with study participation, such as uncontrolled cardiovascular disease or active infections.
3. Active Hepatitis B virus (HBV) infection (HBsAg positive and HBV DNA ≥ 500 IU/mL).
4. Pregnant or breastfeeding women.
5. Any other condition that, in the opinion of the investigator, makes the patient unsuitable for enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neoadjuvant Radio-immunotherapy (Adebrelimab + RT); Patients will receive 2 cycles of neoadjuvant Adebrelimab (1200 mg, IV, Q3W) combined with radiotherapy (SBRT), followed by surgical resection.	Drug: Adebrelimab; A humanized IgG4 monoclonal antibody against programmed cell death-ligand 1 (PD-L1). Dosage: 1200 mg administered via intravenous (IV) infusion on Day 1 of each 21-day cycle, for a total of 2 cycles in the neoadjuvant setting.; Radiation: radiotherapy; Neoadjuvant radiotherapy targeting the primary tumor and involved cervical lymph nodes. (SBRT with a total dose of [24] Gy in [3] fractions).
Active Comparator: Neoadjuvant Immunotherapy Monotherapy (Adebrelimab); Patients will receive 2 cycles of neoadjuvant Adebrelimab (1200 mg, IV, Q3W) monotherapy, followed by surgical resection.	Drug: Adebrelimab; A humanized IgG4 monoclonal antibody against programmed cell death-ligand 1 (PD-L1). Dosage: 1200 mg administered via intravenous (IV) infusion on Day 1 of each 21-day cycle, for a total of 2 cycles in the neoadjuvant setting.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Pathological Response (MPR) Rate	The percentage of participants with 10% or less residual viable tumor cells in the resected primary tumor and lymph nodes following neoadjuvant therapy. Assessment will be performed by independent pathologists.	At the time of surgery (approximately 6-8 weeks after the first dose of neoadjuvant therapy).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response (pCR) Rate	The percentage of participants with no residual viable tumor cells (0%) in the resected primary tumor and lymph nodes.	At the time of surgery.
Objective Response Rate (ORR)	The percentage of participants with a complete response (CR) or partial response (PR) based on RECIST v1.1 criteria as assessed by imaging (CT or MRI) prior to surgery.	From the first dose of neoadjuvant therapy until pre-operative clinical evaluation (approximately 6 weeks).
Incidence of Treatment-Emergent Adverse Events (TEAEs)	Percentage of participants with treatment-emergent adverse events (TEAEs) as defined by CTCAE v5.0. Adverse events include immune-related adverse events (irAEs) and radiation-related toxicities. Severity will be graded for each event according to CTCAE v5.0 criteria.	From the start of treatment up to 30 days after surgery.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Tumor Microenvironment (TME) Immune Cell Populations	Changes in the density of immune cell populations (including CD8+ T cells and M1/M2 macrophages) and PD-L1 expression in the tumor microenvironment. Each parameter will be reported as a percentage of total nucleated cells, comparing baseline biopsy specimens to surgical specimens.	Baseline (biopsy) and at the time of surgery (approximately 6 weeks).

Collaborators and Investigators

• Sponsor: Chen Chunyan
• Collaborators: Shanghai Shengdi Pharmaceutical Co., Ltd
• Investigators: Principal Investigator: Chunyan Chen, Sun Yat-sen University Cancer Center

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2029

Study Registration Dates

• First Submitted: April 16, 2026
• First Submitted That Met QC Criteria: April 23, 2026
• First Posted (Actual): April 28, 2026

Study Record Updates

• Last Update Posted (Actual): April 28, 2026
• Last Update Submitted That Met QC Criteria: April 23, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: SBRT; Neoadjuvant Therapy; PD-L1 Inhibitor; Adebrelimab; Radio-immunotherapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Therapeutics; Radiotherapy
• Other Study ID Numbers: B2026-158-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No