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

Head and Neck Cancer, Locally Advanced Head and Neck Cancer, Neoadjuvant Therapy, Oral Squamous Cell Carcinoma

MRG003, Becotatug vedotin, Pucotenlimab, anti-PD-1, ADC, EGFR, neoadjuvant therapy, oral squamous cell carcinoma, OSCC, head and neck cancer

This is a phase 2, open-label, single-arm clinical trial evaluating neoadjuvant therapy with Becotatug vedotin (MRG003) combined with Pucotenlimab (HX008) in patients with previously untreated, resectable stage III-IVA oral cavity squamous cell carcinoma (OSCC) with a PD-L1 Combined Positive Score (CPS) of 1 or higher. Eligible participants will receive 3 cycles of neoadjuvant treatment (Becotatug vedotin 2.3 mg/kg plus Pucotenlimab 200 mg, intravenously, every 3 weeks), followed by radical surgery 2-3 weeks after the last cycle of neoadjuvant therapy. Postoperative adjuvant radiotherapy will be stratified based on pathological response and risk factors: patients achieving major pathological response (MPR, defined as ≤10% residual viable tumor) with negative margins and no extranodal extension (ENE) will receive de-escalated radiotherapy (50-54 Gy); patients not achieving MPR or with high-risk features will receive standard radiotherapy (60-66 Gy) with or without concurrent cisplatin chemotherapy. The primary endpoint is major pathological response (MPR). Secondary endpoints include objective response rate (ORR), pathological complete response (pCR), event-free survival (EFS), overall survival (OS), and safety profile. Exploratory biomarkers will be assessed in tumor tissue and peripheral blood. A total of 32-33 participants will be enrolled using a Simon two-stage optimal design (α=0.05, power=80%).

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.

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