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, prospective, randomized, controlled Phase II trial evaluating the safety and efficacy of MRG003 (Becotatug vedotin) combined with Toripalimab versus Toripalimab alone as neoadjuvant therapy for PD-L1-positive, resectable locally advanced head and neck squamous cell carcinoma. A total of 65 subjects are planned (43 experimental, 22 control). The experimental arm receives two cycles of MRG003 (Becotatug vedotin) 2.0 mg/kg intravenously on Day 1 followed by Toripalimab 240 mg intravenously on Day 1 every 3 weeks, while the control arm receives two cycles of Toripalimab 240 mg alone. After neoadjuvant therapy, both arms undergo radical surgery 3-4 weeks later, followed by risk-adapted adjuvant radiotherapy or chemoradiotherapy with concurrent Toripalimab (3 cycles) and then 12 cycles of adjuvant Toripalimab maintenance. The primary endpoint is the major pathological response rate.

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.

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