A randomized, non-comparative, multicenter phase II trial of neoadjuvant becotatug vedotin alone or combined with immune checkpoint inhibitors (penpulimab/ivonescimab) in resectable locally advanced head and neck squamous cell carcinoma.

TPS6135 Background: The efficacy and safety of neoadjuvant therapy for resectable locally advanced head and neck squamous cell carcinoma (LAHNSCC) remain uncertain, and optimal treatment protocols needs further explored. Epidermal growth factor receptor (EGFR) is overexpressed in 90% of head and neck squamous cell cancers (HNSCC) and plays a critical role in tumor proliferation and survival. Antibody drug conjugates (ADCs) represent an emerging class of cancer therapeutics that combines several mechanisms of action to improve efficacy and reduce the systemic toxicity. Becotatug Vedotin is a novel ADC molecule of an anti-EGFR humanized immunoglobulin G1 (IgG1) monoclonal antibody conjugated with monomethyl auristatin E via a valine-citrulline linker. Studies have shown that combining immunotherapy with an Anti-EGFR monoclonal antibody may produces a synergistic anti-tumor effect. This study aims to assess the efficacy and safety of neoadjuvant Becotatug Vedotin, alone or in combination with immune checkpoint inhibitors Penpulimab, an anti-PD-1 monoclonal antibody, or Ivonescimab, a bispecific anti-PD-1/VEGF-A antibody, in patients with resectable LAHNSCC. Methods: This is a randomized, non-comparative, multicenter phase II clinical trial. Key eligible patients aged 18–70 years with previously untreated, pathologically confirmed LAHNSCC (oral, laryngeal, hypopharyngeal, and oropharyngeal carcinoma), resectable and ECOG 0–1 will be enrolled. Main exclusions include active autoimmune diseases, use of immunosuppressive drugs, or systemic corticosteroids. Patients will be allocated to 3 cohorts, and all will receive three preoperative cycles of Becotatug Vedotin(2.3 mg/kg, ivgtt, Q3W) with or without immune checkpoint inhibitors: Cohort 1 (monotherapy); Cohort 2 (combined with Penpulimab, 200 mg, ivgtt, Q3W); Cohort 3 (combined with Ivonescimab, 10 mg/kg, ivgtt, Q3W). Surgery will be scheduled 2 to 4 weeks after the completion of neoadjuvant therapy, followed by adjuvant radiotherapy or chemoradiotherapy based on risk factors. Subjects in Cohorts 2 and 3 will continue immune checkpoint inhibitor therapy for 14 cycles following the completion of radiotherapy. Dose adjustments are permitted based on toxicity. The primary endpoint is Pathologic Complete Response (PCR).Secondary endpoints include major Pathological Response (MPR), objective Response Rate (ORR), 1-year Event-Free Survival (EFS) Rate, 2-year Overall Survival (OS) Rate, treatment-related safety, and predictive biomarkers. Research Sponsor: Lepu Biopharma Co., Ltd. Clinical trial information: NCT07381075 .