Head and Neck Squamous Cell Carcinoma, HNSCC
Conditions
Keywords
antibody-drug conjugate, Head and neck squamous cell carcinoma, HNSCC, Neoadjuvant combination therapy
Brief summary
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.
Detailed description
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.
Interventions
DRUGBecotatug Vedotin, Pucotenlimab, and Cisplatin
Becotatug vedotin is an EGFR-directed antibody-drug conjugate (ADC) comprising a humanized anti-EGFR monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable valine-citrulline linker. It binds to EGFR-overexpressing tumor cells, undergoes receptor-mediated internalization, and releases MMAE to inhibit microtubule polymerization, inducing cell cycle arrest and apoptosis. Pucotenlimab is a humanized anti-PD-1 monoclonal antibody that blocks the PD-1/PD-L1 interaction, restoring T-cell-mediated antitumor immune responses. Cisplatin is a platinum-based alkylating agent that forms DNA crosslinks, leading to cell death. These three agents are administered as sequential intravenous infusions on Day 1 of each 21-day cycle: pucotenlimab 200 mg, followed by beccotatug vedotin 2.0 mg/kg, and cisplatin 60 mg/m². The regimen is given for up to 3 neoadjuvant cycles prior to definitive local therapy.
Sponsors
Xuekui Liu
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate | After 3 cycles of neoadjuvant therapy (approximately 9 weeks) | Objective response rate defined as the proportion of patients achieving a confirmed complete response (CR) or partial response (PR) per RECIST v1.1 after neoadjuvant therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathological Response (MPR) | At the completion of definitive surgery | MPR is defined as the presence of ≤10% viable residual tumour cells in the surgical specimen after neoadjuvant therapy. |
| Pathological Complete Response (pCR) | At the completion of definitive surgery | pCR means the complete absence of invasive tumour cells in the resected primary tumour and all sampled regional lymph nodes (ypT0ypN0). |
| Disease Control Rate (DCR) | After 3 cycles of neoadjuvant therapy (approximately 9 weeks) | DCR is the proportion of patients who achieve a best overall response of complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1, maintained for a specified duration. |
| 2-Year Progression-Free Survival (PFS) | Up to 2 years | PFS is the time from treatment initiation (or randomisation) until the first occurrence of disease progression (per RECIST v1.1) or death from any cause. |
| 2-Year Overall Survival (OS) | Up to 2 years | Definition: OS is the time from treatment initiation to death from any cause. |
| Health-Related Quality of Life assessed by the EORTC QLQ-C30 | 2 years | Quality of life and functional status are assessed using the validated EORTC QLQ-C30 (version 3.0). All scores are linearly transformed to a 0-100 scale; higher scores indicate better global health status and functioning, but worse symptom burden. Administered per the standard EORTC scoring manual. |
| EORTC QLQ-H&N35 Module | 2 years | Head and neck cancer-specific quality of life is assessed using the validated EORTC QLQ-H\&N35 module. All item scores are linearly transformed to a 0-100 scale. For this module, higher scores indicate worse symptom burden and poorer quality of life. The questionnaire is administered per the standard EORTC manual. |
| Safety Endpoints (Safety Profiles) | 2 years | This includes the incidence, severity, and attribution of adverse events (AEs), serious adverse events (SAEs), treatment-related AEs, dose modifications, delays, and discontinuations. |
Countries
China
Contacts
CONTACTZhongyu Wang, MD
Outcome results
None listed