Becotatug Vedotin Plus Pucotenlimab and Platinum Chemotherapy in Locally Advanced Epidermal Growth Factor Receptor (EGFR)-Positive Head and Neck Squamous Cell Carcinoma

Becotatug Vedotin Plus Pucotenlimab and Platinum Chemotherapy in Locally Advanced Epidermal Growth Factor Receptor (EGFR)-Positive Head and Neck Squamous Cell Carcinoma: A Phase II Prospective Single-Arm Multicenter Trial

This prospective, single-arm, multicenter phase II trial aims to evaluate the efficacy and safety of neoadjuvant beccotatug vedotin combined with pucotenlimab and cisplatin in patients with locally advanced epidermal growth factor receptor (EGFR)-positive head and neck squamous cell carcinoma (HNSCC). A total of 40 treatment-naive patients aged 18-70 years with stage III-IV (AJCC 8th edition) EGFR-positive HNSCC will be enrolled. Participants will receive three 3-week cycles of the triple-drug regimen. Tumor response will be reassessed after cycle 3 using RECIST v1.1. Patients achieving a complete or partial response (CR/PR) may proceed to de-escalation surgery followed by definitive chemoradiotherapy, or to definitive chemoradiotherapy alone; non-responders will undergo radical surgery with or without radiotherapy/chemoradiotherapy, or definitive chemoradiotherapy, as determined by multidisciplinary team (MDT) discussion. The primary endpoint is objective response rate (ORR). Secondary endpoints include major pathological response (MPR), pathological complete response (pCR), disease control rate (DCR), 2-year progression-free survival (PFS), 2-year overall survival (OS), quality of life, and safety.

This study aims to provide preliminary evidence on the feasibility and activity of this novel triple combination in the neoadjuvant setting, potentially offering a new treatment paradigm to improve long-term outcomes and reduce recurrence.

This is a prospective, single-arm, multicenter phase II trial evaluating the efficacy and safety of neoadjuvant beccotatug vedotin combined with pucotenlimab and cisplatin in patients with locally advanced epidermal growth factor receptor (EGFR)-positive head and neck squamous cell carcinoma (HNSCC). A total of 40 treatment-naïve patients aged 18-70 years with stage III-IV (AJCC 8th edition) EGFR-positive (IHC) HNSCC will be enrolled. Participants receive 3 cycles (every 3 weeks) of beccotatug vedotin, pucotenlimab, and cisplatin. After 3 cycles, tumor response is reassessed by RECIST v1.1. Responders (CR/PR) may proceed to de-escalation surgery plus definitive chemoradiotherapy or definitive chemoradiotherapy alone, while non-responders undergo radical surgery ± radiotherapy/chemoradiotherapy or definitive chemoradiotherapy as per multidisciplinary team (MDT) discussion. The primary endpoint is objective response rate (ORR). Secondary endpoints include major pathological response (MPR), pathological complete response (pCR), disease control rate (DCR), 2-year progression-free survival (PFS), 2-year overall survival (OS), quality of life (EORTC QLQ-C30 and QLQ-H&N35), and safety (NCI-CTCAE v5.0).

This study aims to provide preliminary evidence on the feasibility and activity of this novel triple combination in the neoadjuvant setting, potentially offering a new treatment paradigm to improve long-term outcomes and reduce recurrence.

Inclusion Criteria:

Histologically and/or cytologically confirmed, previously untreated (excluding diagnostic procedures) head and neck squamous cell carcinoma (oral cavity, oropharynx, hypopharynx, or larynx) with EGFR protein expression confirmed by immunohistochemistry (IHC), and has not received targeted therapy against the EGFR signaling pathway within 6 months prior to enrollment.

Clinical stage T2N2-3M0 or T3-4N0-3M0 (stage III-IV) per AJCC 8th edition.

Age 18 to 70 years.

ECOG performance status 0 or 1.

Assessed by head and neck oncologist as locally advanced without distant metastasis.

At least one measurable lesion per RECIST v1.1.

Toxicity assessment per CTCAE v4.03 (for baseline evaluation).

Adequate organ function to tolerate surgery:

Hematologic: WBC ≥4,000/μL, ANC ≥2,000/μL, hemoglobin ≥9 g/dL, platelets ≥100,000/μL.

Hepatic: bilirubin ≤1.5×ULN (or ≤3×ULN if known Gilbert's syndrome), AST and ALT ≤3×ULN, alkaline phosphatase ≤3×ULN, albumin ≥3 g/dL.

Renal: serum creatinine ≤1.5×ULN or calculated creatinine clearance ≥60 mL/min (Cockcroft-Gault).

Willing to provide archived tumor tissue or undergo biopsy to submit at least 3 unstained FFPE sections (additional if needed) for central PD-L1 IHC testing; lesion used for biopsy cannot be a target lesion unless no other suitable lesion exists.

Signed informed consent and willingness to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

History of severe hypersensitivity to any component of other monoclonal antibodies, CTLA-4, or PD-1/PD-L1 inhibitors.

Known or suspected autoimmune disease, including dementia and seizure disorder.

Recurrent or metastatic disease, concurrent other malignancy, or judged inoperable by head and neck surgeon.

Coagulation abnormalities (PT >16 s, APTT >53 s, TT >21 s, Fib <1.5 g/L), bleeding tendency, or current thrombolytic/anticoagulant therapy.

Severe cardiac or pulmonary dysfunction less than grade 3 (including grade 3).

Laboratory values not meeting eligibility criteria within 7 days prior to enrollment.

Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibodies (or any other agents targeting T-cell co-stimulation or checkpoint pathways).

Comorbid conditions requiring chronic immunosuppressive therapy or systemic/local corticosteroids at immunosuppressive doses.

Positive HIV; HBsAg-positive with detectable HBV DNA (≥1000 copies/mL); positive HCV antibody with detectable HCV RNA (if tested).

Use of traditional herbal medicines with antitumor indications within 4 weeks prior to randomization.

Active or history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, chronic diarrhea).

Positive pregnancy test (for women of childbearing potential) or breastfeeding.

Known active tuberculosis (TB); suspected cases require clinical evaluation to rule out.

History of allogeneic organ or hematopoietic stem cell transplantation.

Severe infection within 4 weeks prior to first dose, including but not limited to complications requiring hospitalization, sepsis, or severe pneumonia.

Planned major surgery within 30 days after first dose (or not fully recovered from prior surgery), except for minor procedures (e.g., port placement, biopsy) if performed at least 24 hours before first dose.