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

Overview

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.