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

This study builds upon the limitations of neoadjuvant immunotherapy monotherapy (e.g., KEYNOTE-689), which showed a low MPR rate (9.8% overall, 13.7% in CPS>10) and a 25.6% progression rate, by exploring the synergistic combination of the EGFR-targeting antibody-drug conjugate MRG (Becotatug vedotin) with the PD-1 inhibitor Toripalimab. Eligible patients are treatment-naïve, PD-L1 positive (CPS ≥1), stage III-IVA resectable non-oropharyngeal, HPV-negative oropharyngeal, or specific HPV-positive oropharyngeal HNSCC, ECOG PS 0-1, aged 18-70. In the neoadjuvant phase, the experimental group receives MRG (Becotatug vedotin) 2.0 mg/kg (based on actual body weight) intravenously without prophylactic premedication, followed by Toripalimab 240 mg intravenously over 30-60 minutes on Day 1 of each 3-week cycle for 2 cycles; infusion reactions are monitored for at least 120 minutes after the first dose and 60 minutes thereafter. Dose reduction of MRG (Becotatug vedotin) to 1.5 mg/kg is permitted for toxicity, with permanent discontinuation if intolerance persists; Toripalimab dose modification is not allowed. The control group receives Toripalimab 240 mg alone on the same schedule. Three to four weeks after Cycle 2 Day 1, both arms undergo radical tumor resection; surgery is performed even if radiological progression occurs during neoadjuvant therapy, provided surgical criteria are met. Postoperatively, patients are stratified by pathology: those with extranodal extension or positive/inadequate margins receive adjuvant chemoradiotherapy (cisplatin 100 mg/m² every 3 weeks for 3 cycles plus radiotherapy at 60-70 Gy depending on risk), while those without receive adjuvant radiotherapy alone (same doses). During adjuvant radiotherapy, both arms concurrently receive 3 cycles of Toripalimab 240 mg every 3 weeks. After completing radiotherapy, all patients receive 12 cycles of adjuvant Toripalimab 240 mg every 3 weeks as maintenance. Secondary endpoints include event-free survival, pathologic complete response rate, objective response rate, R0 resection rate, surgical down-staging rate, safety (CTCAE v6.0), and quality of life; exploratory endpoints include overall survival and biomarker analysis. The MPR rate is compared using the exact test, assuming 45% in the experimental arm versus approximately 9.8% in the historical control, with a one-sided alpha of 0.025, 80% power, and 10% dropout, yielding the required sample size of 65. The full analysis set is the primary analysis population.

• Histologically or cytologically confirmed head and neck squamous cell carcinoma (HNSCC), PD-L1 positive (CPS ≥ 1)
• 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)
• No prior antitumor treatment (radiotherapy, chemotherapy, targeted therapy, or immunotherapy)
• Age 18 to 70 years
• ECOG performance status 0 or 1
• 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
• At least one measurable lesion per RECIST 1.1
• Life expectancy ≥ 12 weeks
• 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
• Voluntary signed informed consent, good compliance, willing to undergo follow-up