Neoadjuvant Presurgical Becotatug Vedotin (MRG003) Plus Pucotenlimab (HX008) in Oral Cavity Squamous Cell Carcinoma

Oral cavity squamous cell carcinoma (OSCC) accounts for approximately 42.5% of all head and neck cancers, with about 60% of patients presenting with locally advanced disease (stage III-IVA). Despite standard-of-care treatment consisting of radical surgery followed by radiotherapy or concurrent chemoradiotherapy, the 5-year overall survival rate remains below 50%, and approximately one-third of patients experience disease recurrence within one year.

The 2025 NCCN Guidelines recommend perioperative immune checkpoint inhibitor therapy for locally advanced OSCC patients with PD-L1 CPS ≥1, based on the results of the KEYNOTE-689 trial. However, neoadjuvant pembrolizumab monotherapy has demonstrated limited pathological responses, with pCR and MPR rates of only 3.0% and 9.8%, respectively. Combining immune checkpoint inhibitors with other therapeutic modalities has emerged as a promising strategy to enhance pathological response rates.

Becotatug vedotin (MRG003) is a novel anti-EGFR antibody-drug conjugate (ADC) that delivers the potent cytotoxic agent monomethyl auristatin E (MMAE) specifically to EGFR-expressing tumor cells. In a phase II study, MRG003 monotherapy achieved an objective response rate of 43% in patients with recurrent/metastatic HNSCC who had failed prior platinum-based chemotherapy and PD-1/L1 inhibitors, representing one of the highest ORRs reported for ADC monotherapy in HNSCC.

Pucotenlimab (HX008) is a humanized anti-PD-1 monoclonal antibody with an Fc-engineered modification that enhances binding affinity to the neonatal Fc receptor (FcRn), potentially extending serum half-life and providing more sustained PD-1 pathway blockade. It has demonstrated robust antitumor activity across multiple tumor types, with an ORR of 49.0% in MSI-H/dMMR solid tumors.

Preclinical and clinical evidence supports the synergistic mechanism of combining an EGFR-targeted ADC with a PD-1 inhibitor: ADC-mediated tumor cell killing promotes antigen release and T-cell infiltration, while PD-1 blockade reverses T-cell exhaustion, creating a "pro-immune activation and de-immunosuppression" synergistic effect. In a phase Ib/II study of this combination in recurrent/metastatic HNSCC, the ORR reached 60.0% with a manageable safety profile, providing the rationale for moving this combination forward to the neoadjuvant setting.

Study Design:

This is a multicenter, open-label, single-arm phase II trial. The study will enroll 32-33 patients with previously untreated, resectable stage III-IVA OSCC with PD-L1 CPS ≥1. The trial employs a Simon two-stage optimal design with the null hypothesis that the MPR rate is ≤10% and the alternative hypothesis that the MPR rate is ≥30%, with a one-sided alpha of 0.05 and 80% power.

Treatment Regimen:

Neoadjuvant phase: 3 cycles of Becotatug vedotin 2.3 mg/kg plus Pucotenlimab 200 mg, IV, Q3W Surgery: Radical tumor resection and neck dissection, performed 2-3 weeks after the last neoadjuvant cycle

Adjuvant phase (stratified by pathological response):

Group A (de-escalation layer): MPR (≤10% residual viable tumor) with negative margins and ENE-negative → de-escalated radiotherapy (50-54 Gy) Group B (standard layer): Not achieving MPR or presence of high-risk factors → standard radiotherapy (60-66 Gy) ± concurrent cisplatin chemotherapy

Study Endpoints:

Primary: Major pathological response (MPR) rate Secondary: ORR, pCR, pPR, EFS, OS, DCR, DoR, DFFS, LRFFS, safety/tolerability, and quality of life (EORTC QLQ-C30/H&N43, PRO-CTCAE) Exploratory: Dynamic changes in the tumor immune microenvironment, predictive value of PD-L1 and EGFR expression, and peripheral blood immune biomarkers

Sample Size:

Based on Simon's two-stage optimal design: 10 patients in stage I; if ≤1 response is observed, the trial will be terminated for futility; otherwise, an additional 19 patients will be enrolled, totaling 29 patients. Allowing for a 10% dropout rate, the sample size is expanded to 32-33 patients.

Inclusion criteria

• Voluntary participation with written informed consent, good compliance, and willingness to complete follow-up.
• Age ≥18 years and ≤70 years, regardless of gender.
• ECOG performance status score of 0 or 1.
• Histopathologically confirmed, previously untreated, primary oral cavity squamous cell carcinoma (OSCC); central laboratory-confirmed PD-L1 Combined Positive Score (CPS) ≥1; clinical stage III-IVA (AJCC 8th edition) with potential for curative surgical resection as assessed by the investigator; no evidence of definite locoregional residual or distant metastasis.
• Adequate organ function within 14 days prior to the first dose, without transfusion or hematopoietic growth factor support:
• Bone marrow: ANC ≥1.5×10^9/L; platelet count ≥100×10^9/L; hemoglobin ≥90 g/L.
• Liver: TBIL ≤1.5×ULN; AST/ALT ≤3.0×ULN; ALP ≤2.5×ULN; serum albumin ≥28 g/L.
• Kidney: creatinine clearance (Ccr) ≥40 mL/min (calculated by Cockcroft-Gault formula) or serum creatinine ≤1.5×ULN.
• Coagulation: INR ≤1.5×ULN and APTT ≤1.5×ULN (excluding patients receiving therapeutic anticoagulation).
• Cardiac: LVEF ≥50% with no significant cardiac dysfunction.
• Negative serum pregnancy test within 7 days prior to the first dose for women of childbearing potential; all fertile male and female participants must agree to use highly effective contraception from signing of informed consent through 1 year after the last dose of Pucotenlimab.

Exclusion criteria

• Age >70 years or <18 years.
• History of other malignancies within the past 5 years, except adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
• HIV infection.
• HBsAg positive with HBV DNA >200 IU/mL or 1000 copies/mL.
• HCV antibody positive.
• Severe concurrent diseases that may pose significant risks or affect trial compliance, including unstable cardiac disease, renal disease, chronic hepatitis, poorly controlled diabetes (fasting blood glucose >1.5×ULN), severe cognitive impairment, or psychiatric disorders.
• Active pulmonary tuberculosis infection within the past 1 year, or history of active tuberculosis >1 year ago unless documented prior standard anti-tuberculosis treatment.
• History of interstitial lung disease.
• Active, known, or suspected autoimmune disease. Exceptions: type I diabetes, hypothyroidism requiring only hormone replacement therapy, and skin conditions not requiring systemic treatment (e.g., vitiligo, psoriasis, alopecia).
• Systemic corticosteroids (>10 mg/day prednisone equivalent) or other immunosuppressive therapy within 28 days prior to signing informed consent. Patients receiving ≤10 mg/day prednisone equivalent or inhaled/topical corticosteroids are eligible.
• Live vaccination within 30 days prior to signing informed consent or planned during the study.
• Prior surgery, chemotherapy, radiotherapy, immunotherapy, or other anti-tumor therapy for head and neck cancer (excluding diagnostic procedures).
• Known hypersensitivity to macromolecular protein preparations, or any component of Becotatug vedotin, Pucotenlimab, or cisplatin.
• Pregnancy, lactation, or anticipated pregnancy during the study period.