MRG003 Plus Toripalimab Versus Toripalimab as Neoadjuvant Therapy for PD-L1-Positive, Resectable, Locally Advanced Head and Neck Squamous Cell Carcinoma

MRG003 (Becotatug Vedotin) Plus Toripalimab Versus Toripalimab as Neoadjuvant Therapy for PD-L1-Positive, Resectable, Locally Advanced Head and Neck Squamous Cell Carcinoma: A Multicenter, Prospective, Randomized, Controlled Phase II Trial

This is a multicenter, randomized, open-label, controlled Phase 2 trial evaluating neoadjuvant MRG003 (anti-EGFR ADC) plus toripalimab versus toripalimab alone in PD-L1-positive (CPS ≥ 1), resectable, locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Patients are randomized 2:1 to receive 2 cycles of MRG003 2.0 mg/kg IV plus toripalimab 240 mg IV Q3W (n=43) or toripalimab 240 mg IV Q3W alone (n=22), followed by surgery and risk-adapted adjuvant therapy including radiotherapy and toripalimab maintenance. The primary endpoint is Major Pathological Response (MPR) rate. Secondary endpoints include pCR, ORR, EFS, R0 resection rate, surgical down-staging, and safety. Enrolling 65 participants across 11 centers in China.

Study Overview

• Status: Not yet recruiting
• Conditions: Head and Neck Squamous Cell Carcinoma
• Intervention / Treatment: Drug: MRG003 and Toripalimab; Drug: Toripalimab

Detailed Description

This is a multicenter, prospective, randomized, open-label, controlled Phase 2 trial evaluating neoadjuvant MRG003 (Vebecototagene Autoteucovaline), an anti-EGFR antibody-drug conjugate, combined with toripalimab (anti-PD-1) versus toripalimab alone in 65 patients with PD-L1-positive (CPS ≥ 1), resectable, locally advanced head and neck squamous cell carcinoma (LA-HNSCC) across 11 centers in China. Based on the rationale that KEYNOTE-689 showed limited MPR (9.8%) with PD-1 monotherapy and that ADC plus immunotherapy demonstrates synergistic antitumor activity, this study hypothesizes that combining MRG003 with toripalimab will significantly improve the primary endpoint of Major Pathologic Response (MPR) rate compared to toripalimab alone. Patients are stratified by tumor stage and PD-L1 CPS, then randomized 2:1 to receive 2 cycles of MRG003 2.0 mg/kg IV plus toripalimab 240 mg IV Q3W (experimental arm, n=43) or toripalimab 240 mg IV Q3W alone (control arm, n=22), followed by radical surgery and risk-adapted adjuvant therapy (radiotherapy ± concurrent cisplatin + toripalimab maintenance up to 12 cycles). Secondary endpoints include pCR rate, ORR per RECIST 1.1, EFS, R0 resection rate, surgical down-staging rate, on-time surgery rate, and safety (CTCAE v5.0). With an assumed MPR of 45% in the experimental arm versus 9.8% in controls (one-sided α=0.025, 80% power, ~10% dropout), enrollment of 65 patients is planned from 2026 to 2029.

• Study Type: Interventional
• Enrollment (Estimated): 65
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Liji Jiang, Master; Phone Number: 0769-28637916; Email: keynotejiang@163.com

Study Locations

• China
  • Guangdong
    • Dongguan, Guangdong, China, 523059
      • The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital)
      • Contact: Liji Jiang, Master; Phone Number: 0769-28637916; Email: keynotejiang@163.com

Participation Criteria

Eligibility Criteria

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

Description

1. Histologically or cytologically confirmed head and neck squamous cell carcinoma (HNSCC), PD-L1 positive (CPS ≥ 1)
2. Treatment-naïve, pathologically confirmed stage III-IVA resectable non-oropharyngeal HNSCC (oral cavity, larynx, hypopharynx) OR HPV-negative oropharyngeal SCC, OR HPV-positive stage III T4N0-2 resectable oropharyngeal cancer (AJCC 8th edition)
3. No prior antitumor treatment (radiotherapy, chemotherapy, targeted therapy, or immunotherapy)
4. Age 18 to 70 years
5. ECOG performance status 0 or 1

6. Adequate organ function within 14 days before first dose (no blood products or growth factors within 14 days):

   • ANC ≥ 1.0 × 10⁹/L, Hb ≥ 90 g/L, PLT ≥ 75 × 10⁹/L
   • ALT/AST ≤ 1.5 × ULN, total bilirubin ≤ 1.5 × ULN, ALP < 2.5 × ULN
   • CrCl ≥ 50 mL/min (Cockcroft-Gault)
   • APTT and INR ≤ 1.5 × ULN
7. At least one measurable lesion per RECIST 1.1
8. Life expectancy ≥ 12 weeks
9. Female subjects of childbearing potential and male subjects with reproductive potential must use medically accepted contraception during treatment and for 3 months after last dose
10. Voluntary signed informed consent, good compliance, willing to undergo follow-up

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: MRG003 + Toripalimab; Two cycles of neoadjuvant MRG003 (Vebecototagene Autoteucovaline) 2.0 mg/kg intravenous infusion on Day 1 plus Toripalimab 240 mg intravenous infusion on Day 1 of each 21-day cycle, followed by radical surgery and risk-adapted adjuvant therapy (radiotherapy ± concurrent cisplatin + Toripalimab maintenance up to 12 cycles).	Drug: MRG003 and Toripalimab; Neoadjuvant MRG003 (2.0 mg/kg IV Q3W) plus Toripalimab (240 mg IV Q3W for 2 cycles), followed by radical surgery and risk-adapted adjuvant therapy.; Drug: Toripalimab; Neoadjuvant Toripalimab (240 mg IV Q3W for 2 cycles), followed by radical surgery and risk-adapted adjuvant therapy.
Active Comparator: Toripalimab Monotherapy; Two cycles of neoadjuvant Toripalimab 240 mg intravenous infusion on Day 1 of each 21-day cycle (monotherapy), followed by radical surgery and risk-adapted adjuvant therapy (radiotherapy ± concurrent cisplatin + Toripalimab maintenance up to 12 cycles). During adjuvant radiotherapy, 3 cycles of concurrent Toripalimab 240 mg Q3W are given.	Drug: Toripalimab; Neoadjuvant Toripalimab (240 mg IV Q3W for 2 cycles), followed by radical surgery and risk-adapted adjuvant therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Pathological Response (MPR) rate	Proportion of patients with major pathological response, defined as ≤ 10% residual viable tumor in the primary tumor and all sampled lymph nodes after completion of neoadjuvant therapy.	At the time of surgical specimen evaluation (approximately 6-8 weeks after initiation of neoadjuvant therapy)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free Survival (EFS)	Time from randomization to first documented radiographic progression, progression leading to inoperability, or death from any cause.	From randomization up to approximately 36 months
Pathologic Complete Response (pCR) Rate	Proportion of subjects with no residual viable tumor cells in the primary tumor bed or resected lymph nodes after neoadjuvant therapy.	At definitive surgery (approximately Week 6-8 after randomization)
Objective Response Rate (ORR) per RECIST 1.1	Proportion of subjects achieving complete response (CR) or partial response (PR) according to RECIST 1.1 after 2 cycles of neoadjuvant therapy.	After completion of 2 cycles of neoadjuvant therapy (approximately Week 6)
Safety: Incidence of Adverse Events and Serious Adverse Events	Incidence, severity, and relationship of adverse events (AEs) and serious adverse events (SAEs) graded by CTCAE v5.0.	From first dose of study drug through 90 days after last dose or 30 days after surgery, whichever occurs later
On-Time Surgery Rate	Proportion of subjects who undergo radical surgery within 49 days after Cycle 2 Day 1 of neoadjuvant therapy.	Within 49 days after Cycle 2 Day 1（ (each cycle is 21 days)）
R0 Resection Rate	Proportion of subjects who achieve complete (microscopically margin-negative) resection at definitive surgery.	At definitive surgery (approximately Week 6-8 after randomization)

Collaborators and Investigators

• Sponsor: Dongguan People's Hospital
• Collaborators: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University; Shenzhen People's Hospital; Peking University Shenzhen Hospital; Huizhou Municipal Central Hospital; The University of Hong Kong-Shenzhen Hospital; Sun Yat-Sen University Cancer Center
• Investigators: Study Chair: Zhigang Liu, MD, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital)

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): January 30, 2029
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: June 23, 2026
• First Submitted That Met QC Criteria: June 28, 2026
• First Posted (Actual): June 30, 2026

Study Record Updates

• Last Update Posted (Actual): June 30, 2026
• Last Update Submitted That Met QC Criteria: June 28, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Neoadjuvant Therapy; Toripalimab; MRG003; Vebecototagene Autoleucovorin
• 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; toripalimab
• Other Study ID Numbers: IIT-2026-008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: This study does not currently have a plan to share individual participant data. The research team will not provide access to the raw data set.

Drug and device information, study documents

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