Immunotherapy Combined With ADC (MRG003) for Induction Conversion Therapy to Downstage Primary Stage IVB Oral/Oropharyngeal Squamous Cell Carcinoma：An Exploratory Two-Arm Randomized Controlled Trial (Transforming Trial)

More than 60% of patients with head and neck squamous cell carcinoma (HNSCC) have locally advanced disease at initial diagnosis, often presenting with a large primary tumor accompanied by marked local invasion and/or regional lymph-node metastasis. In patients with clinical stage IVB oral squamous cell carcinoma (OSCC), tumors frequently invade the masticator space, pterygoid plates, or skull base and/or encase the internal carotid artery; and in patients with clinical stage IVB oropharyngeal squamous cell carcinoma (OPSCC), tumors frequently invade the lateral pterygoid muscle, pterygoid plates, lateral nasopharyngeal wall, or skull base, or encase the carotid artery. Because of extensive infiltration and involvement of critical anatomical structures, radical surgery faces two major challenges in this population: firstly, R0 resection is difficult to achieve, resulting in rapid postoperative recurrence; secondly, radical surgery inevitably causes disfiguring tissue defects and severe functional loss, leading to extremely poor quality of life. The 1- to 2-year overall survival rate for these patients ranges from 22% to 35%.

For the patients with unresectable primary stage IVB OSCC or human papillomavirus (HPV)-negative OPSCC, current standard treatment consists of platinum-based concurrent chemoradiotherapy or radiotherapy following platinum-based induction chemotherapy. Although these regimens are widely used, their efficacy remains unsatisfactory. In recent years, additional approaches have been developed and evaluated, including monoclonal antibodies targeting epidermal growth factor receptor (EGFR), novel radiotherapy fractionation schedules, and induction or neoadjuvant chemotherapy regimens; however, none has demonstrated a clear improvement over standard concurrent chemoradiotherapy. Standard concurrent chemoradiotherapy may also cause toxicities such as late-onset dysphagia and severe xerostomia. Accordingly, developing new therapeutic strategies to improve outcomes in this population has become a major focus in the field of HNSCC.

Neoadjuvant therapy refers to antitumor treatment administered before surgery with the aims of reducing tumor volume, increasing the likelihood of surgical resection, and decreasing the risk of postoperative recurrence; it may therefore improve outcomes in locally advanced malignancies. Given the close interaction between antibody-drug conjugate (ADC) and the host immune system, the combination of these two modalities may theoretically produce synergistic antitumor effects and improve treatment outcomes. Therefore, this prospective, exploratory, two-arm, randomized controlled clinical trial will compare becotatug vedotin, an EGFR-targeted ADC, plus pucotenlimab, an anti-PD-1 monoclonal antibody, with current standard therapy consisting of platinum-based induction chemotherapy or chemoradiotherapy. The investigational regimen is expected to induce deep tumor regression in patients with unresectable primary stage IVB OSCC/OPSCC, achieve tumor downstaging, convert unresectable lesions into lesions amenable to R0 resection, and allow evaluation of efficacy and safety, including potential survival benefits. The study may provide a new therapeutic strategy for patients with stage IVB HNSCC.