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.

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.

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

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.