This is a multicenter, randomized, controlled, Phase II clinical study designed to evaluate the efficacy and safety of neoadjuvant and adjuvant therapy with vebikotamab combined with Pucotenlimab compared to standard treatment in patients with locally recurrent resectable head and neck squamous cell carcinoma (HNSCC).

Investigational Arm:

The dosing regimen for the investigational arm is as follows:

Pucotenlimab: 200 mg per dose, administered intravenously (IV) every 3 weeks (Q3W). No dose adjustments are permitted; however, dosing delays are allowed up to a maximum of 12 weeks from the date of the previous dose. This is administered for two preoperative cycles.

Becotatug Vedotin: 2.3 mg/kg, administered IV Q3W for two preoperative cycles.

Following neoadjuvant therapy, patients will undergo surgery at 4 weeks ± 7 days. Postoperatively (at 6 weeks ± 3 weeks), patients will be stratified for adjuvant therapy based on pathological response:

Patients who achieve a major pathological response (MPR) and have no high-risk factors will receive 6 cycles of single-agent adjuvant Pucotenlimab (200 mg/dose, Q3W).

Patients who do not achieve MPR or who present with high-risk factors will receive standard postoperative adjuvant therapy.

Control Arm:

Patients in the control arm will undergo upfront surgery followed by standard adjuvant therapy.

Head and neck cancer is the sixth most common cancer worldwide, with over 550,000 new cases and more than 300,000 deaths annually. Over 95% of head and neck cancers are squamous cell carcinomas. Head and neck squamous cell carcinoma (HNSCC) severely impairs patients' physical appearance and basic physiological, sensory, and speech functions, thereby profoundly affecting their quality of life [1]. Due to difficulties in early detection, over 60% of HNSCC patients present with locally advanced disease at diagnosis. Locally advanced head and neck cancer carries a poor prognosis, with up to 60% of patients experiencing local recurrence or distant metastasis [2].

Currently, salvage surgery remains the preferred treatment for patients with resectable, locally recurrent HNSCC, with postoperative locoregional radiotherapy decisions based on pathology, staging, and prior radiation history [3]. However, despite aggressive treatment, at least 20% of head and neck cancer patients still experience local recurrence or distant metastasis. Previous studies have reported 5-year survival rates ranging from 11% to 40% for patients with resectable, locally recurrent HNSCC who underwent salvage surgery [4]. Improving outcomes for this high-risk patient population remains an urgent unmet clinical need.

The discovery that modulating the immune system can induce solid tumor regression has revolutionized our understanding and treatment of cancer [5]. In particular, the successful development of programmed death receptor-1 (PD-1) immune checkpoint inhibitors has significantly transformed the management of HNSCC [6]. In platinum-refractory, unresectable recurrent or metastatic HNSCC, the KEYNOTE-040 trial compared pembrolizumab with investigator's choice of therapy (docetaxel, methotrexate, or cetuximab). The study narrowly missed its primary endpoint of overall survival (OS) improvement in the intention-to-treat population (pembrolizumab OS: 8.4 months [95% CI, 6.4-9.4] vs. standard of care: 6.9 months [95% CI, 5.9-8.0]; Hazard Ratio [HR] for death, 0.80; 95% CI, 0.65-0.98; P=0.02) [7]. In the CheckMate 141 trial, previously platinum-treated patients were randomized 2:1 to receive nivolumab or investigator's choice of therapy. Nivolumab significantly improved OS (7.5 months [95% CI, 5.5-9.1] vs. 5.1 months [95% CI, 4.0-6.0]; HR for death, 0.70; 97.73% CI, 0.51-0.96; P=0.01), objective response rate (ORR; 13.3% vs. 5.8%), and 6-month progression-free survival (PFS) rate (19.7% vs. 9.9%), while reducing the incidence of grade ≥3 adverse events (13.1% vs. 35.1%). After over 2 years of follow-up, the survival benefit persisted (HR for death, 0.68; 95% CI, 0.54-0.86; 24-month OS rate, 16.9% vs. 6.0%) [8]. Due to durable responses and improved survival, the U.S. Food and Drug Administration (FDA) approved both agents for second-line treatment of advanced HNSCC in 2016. In the KEYNOTE-048 study, 882 treatment-naïve patients with recurrent or metastatic HNSCC were randomized to receive pembrolizumab monotherapy, pembrolizumab plus chemotherapy (fluorouracil and platinum), or the EXTREME regimen (fluorouracil, platinum, and cetuximab). Pembrolizumab plus chemotherapy demonstrated superior OS in the total population, and pembrolizumab monotherapy showed significant OS benefits in patients with CPS ≥1 compared to the EXTREME regimen. Consequently, the FDA approved pembrolizumab as first-line treatment for advanced HNSCC in 2019 [9].

Neoadjuvant therapy is a viable strategy to reduce tumor burden, increase R0 resection rates, decrease the need for adjuvant therapy, and eradicate potential minimal residual disease, thereby offering curative surgical opportunities for potentially resectable patients. Prior to resection, tumors possess high tumor burdens and abundant neoantigens. Introducing immune checkpoint inhibitors during the neoadjuvant phase may elicit a more robust immune response and anti-tumor effect, further reducing tumor burden and eradicating occult lesions. Currently, neoadjuvant immunotherapy for resectable advanced HNSCC is under active investigation. H. M. Knochelmann [10] and R. Uppaluri [11] pioneered reports on the safety of single-agent PD-1 inhibitor neoadjuvant therapy for resectable HNSCC, achieving pathological response rates of approximately 33%-44.4%. A Phase II study evaluating camrelizumab combined with nab-paclitaxel and cisplatin as neoadjuvant therapy for resectable and potentially resectable HNSCC achieved a pathological complete response (pCR) rate of 55% and a major pathological response (MPR) rate of 63% [12], bolstering confidence in combination immunotherapy for HNSCC neoadjuvant treatment. Furthermore, long-term follow-up data from non-small cell lung cancer (NSCLC) neoadjuvant immunotherapy trials indicate that patients with favorable pathological responses exhibit prolonged PFS and OS [13].

To further enhance pathological response rates and extend survival benefits in neoadjuvant immunotherapy for surgically resectable, locally recurrent HNSCC, researchers have extensively explored various combination regimens. Epithelial growth factor receptor (EGFR) is overexpressed in 90% of HNSCCs. High EGFR protein expression and gene copy number amplification are strongly correlated with poor prognosis, shorter survival, and increased metastatic risk in HNSCC [14]. Cetuximab, a chimeric EGFR-blocking monoclonal antibody (trade name Erbitux™), is FDA-approved for first- and second-line treatment of recurrent/metastatic, unresectable HNSCC. Compared to chemotherapy alone, it significantly improves long-term survival in this setting [15]. In the 2021 CSCO guidelines, cetuximab is recommended as a Grade I expert option combined with chemotherapy for first-line treatment of recurrent/metastatic HNSCC without surgical or radiotherapy indications (Category 1A evidence), and as a Grade II expert option as monotherapy for second-line or salvage treatment in similar settings (Category 2A evidence) [16]. Several studies have investigated combining immunotherapy with EGFR-targeted therapy. The rationale lies in their distinct yet complementary immunological and oncological mechanisms enhancing anti-tumor activity. Anti-PD-1 therapy enhances cytotoxic T lymphocyte function, promoting tumor regression and immune rejection. Conversely, anti-EGFR antibodies induce antibody-dependent cellular cytotoxicity (ADCC) and facilitate interactions between immune cells, including natural killer (NK) cells and dendritic cells. This crosstalk stimulates tumor antigen-specific cellular immunity and generates antigen-specific T-cell responses [17]. Therefore, these two classes of drugs may exert synergistic anti-tumor effects. In an open-label, multicenter, multi-cohort Phase II trial involving 33 patients with unresectable recurrent/metastatic HNSCC naïve to pembrolizumab and cetuximab, the combination achieved a 6-month ORR of 45%, with a median duration of response of 13.3 months among responders. Two additional cohorts are currently enrolling, but preliminary results highlight promising prospects for combining immunotherapy and EGFR-targeted therapy in recurrent/metastatic HNSCC [18].

Antibody-drug conjugates (ADCs) are complex biologics comprising a target-specific monoclonal antibody covalently linked via a chemical linker to a highly potent cytotoxic payload. ADCs are designed to achieve targeted delivery, thereby enhancing anti-tumor efficacy while minimizing systemic toxicity [19]. The mechanism of action involves a highly coordinated, multistep process: First, the antibody moiety specifically recognizes and binds to the target antigen on the tumor cell surface. Following binding, the ADC-antigen complex is internalized via clathrin-mediated endocytosis into early endosomes, which mature into late endosomes and ultimately fuse with lysosomes. Within the acidic environment of the lysosome and in the presence of specific enzymes (e.g., cathepsin B), the linker undergoes cleavage, releasing the free, biologically active cytotoxic payload, which subsequently induces tumor cell apoptosis [20]. Vicobitamab is a novel EGFR-targeted ADC consisting of three components: 1) JMT101, an anti-EGFR monoclonal antibody; 2) MMAE, a potent cytotoxic small molecule; and 3) a protease-cleavable valine-citrulline (vc) linker. Preclinical studies demonstrate that vicobitamab possesses a favorable safety profile and exhibits significantly greater anti-tumor efficacy compared to the EGFR-targeted monoclonal antibody cetuximab (Erbitux®) [21].

Based on previously reported data supporting the combination of EGFR-targeted therapy and immunotherapy in unresectable recurrent/metastatic HNSCC, as well as preliminary findings from dual-immunotherapy neoadjuvant treatment using PD-1 and KIR inhibitors in patients with resectable, locally recurrent HNSCC, we hypothesize that administering an EGFR ADC combined with immunotherapy prior to salvage surgery will improve outcomes for this high-risk population. Accordingly, we propose a prospective, randomized, controlled, multicenter Phase II clinical study evaluating vicobitamab combined with putulimab as neoadjuvant therapy for patients with resectable, locally recurrent HNSCC. As the first domestic clinical trial investigating an EGFR ADC combined with a PD-1 inhibitor in the neoadjuvant setting for resectable, locally recurrent HNSCC, this study explores urgently needed novel combination therapies and new treatment paradigms for this high-risk patient population, laying the foundation for future research and holding significant scientific and clinical value.

Inclusion Criteria:

• Age between 18 and 75 years, inclusive, regardless of sex; Histologically or cytologically confirmed locally recurrent head and neck squamous cell carcinoma (HNSCC) that is amenable to curative surgical resection. Patients must not have received any prior systemic antineoplastic therapy for the recurrent disease. (Note: Prior systemic therapy as part of a multimodality treatment for locally advanced disease is permitted, provided that ≥6 months have elapsed from the completion of such therapy to the signing of the informed consent form); Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; Estimated life expectancy ≥12 weeks; At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Previously irradiated lesions may be considered measurable if disease progression has been documented at the site; Availability of tumor tissue for PD-L1 testing (paraffin-embedded specimens collected within 2 years or fresh tumor tissue);

Adequate organ function, defined as follows (assessed within 14 days prior to the first dose of the investigational product):

Bone Marrow: Absolute neutrophil count (ANC) ≥1.5×10⁹/L, platelets (PLT) ≥100×10⁹/L, hemoglobin (HB) ≥9 g/dL (no blood transfusions or blood component therapy within 14 days prior to screening); Liver & Kidney: Serum total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN (if hepatic metastasis is present, AST and ALT ≤5 × ULN are allowed). Serum creatinine ≤1.5 × ULN and calculated creatinine clearance ≥50 mL/min (using the Cockcroft-Gault formula); Coagulation: International Normalized Ratio (INR) and activated partial thromboplastin time (APTT) ≤1.5 × ULN (applies only to patients not receiving anticoagulant therapy; patients on anticoagulants must be within the therapeutic range); Thyroid Function: Thyroid-stimulating hormone (TSH) ≤1 × ULN (if TSH is abnormal, free triiodothyronine [FT3] and free thyroxine [FT4] levels must be evaluated; enrollment is permitted if FT3 and FT4 are within normal limits); Urinary Protein: Urine dipstick protein ≤1+. If urine dipstick protein is >1+, a 24-hour urine collection is required, and the total protein must be ≤1 g/day; Cardiac Function: Normal cardiac function, defined as a normal electrocardiogram (ECG) or ECG abnormalities with no clinical significance, and left ventricular ejection fraction (LVEF) >50% as determined by echocardiography.

Women of childbearing potential must have a negative serum pregnancy test prior to the first dose of the investigational product; Sexually active men and women of childbearing potential must use highly effective contraception (e.g., oral contraceptives, intrauterine devices, sexual abstinence, or barrier methods combined with spermicides) throughout the entire study period and for 90 days after the end of treatment; The patient voluntarily agrees to participate in the study, signs the informed consent form, demonstrates good compliance, and agrees to cooperate with follow-up visits.

Exclusion Criteria:

• Presence of distant metastases or local lesions without surgical indications (Stage IVb or IVc); Disease progression occurring within 6 months following systemic therapy for locally advanced HNSCC; Re-irradiation to the head and neck region (including cervical, supraclavicular, and infraclavicular lymph nodes) within 6 months prior to enrollment; Prior treatment with PD-1/PD-L1/PD-L2/CTLA-4 antibodies, or agents targeting activating or inhibitory receptors on T cells (e.g., OX40, CD137); Prior treatment with antibody-drug conjugates (ADCs) bearing an MMAE payload; Participation in any other drug/treatment clinical trial within 4 weeks prior to the first dose of the investigational product, or currently participating in another trial; major surgery, unresolving adverse effects from prior surgery, live vaccines, or immunotherapy within 4 weeks prior to the first dose; radiotherapy within 2 weeks prior to the first dose; concurrent receipt of any other antineoplastic therapy; Any active autoimmune disease or history of autoimmune disease (including but not limited to: autoimmune hepatitis, interstitial pneumonitis, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism). Exceptions: Vitiligo not requiring systemic therapy is permitted; childhood asthma that has completely resolved and requires no intervention in adulthood is permitted. Asthma requiring medical intervention with bronchodilators is not permitted; Current use of immunosuppressants or systemic corticosteroids for immunosuppressive purposes (at doses >10 mg/day prednisone equivalent or equivalent efficacy) that are still being used within 2 weeks prior to enrollment; History of other malignancies within the past 5 years, except for adequately treated basal cell carcinoma of the skin, cutaneous squamous cell carcinoma, early-stage prostate cancer, and carcinoma in situ of the cervix; Active pulmonary diseases (interstitial pneumonitis, pneumonia, obstructive pulmonary disease, asthma) or a history of active pulmonary tuberculosis;

Any uncontrolled clinical conditions, including but not limited to:

Persistent or active (severe) infections; Poorly controlled hypertension (persistent blood pressure >150/90 mmHg); Poorly controlled diabetes mellitus; Cardiac diseases (New York Heart Association [NYHA] Class III/IV congestive heart failure or cardiac conduction blocks); Occurrence of any of the following within 6 months prior to the first dose: deep vein thrombosis (DVT) or pulmonary embolism (PE); myocardial infarction; severe or unstable arrhythmias or angina; percutaneous coronary intervention (PCI), acute coronary syndrome (ACS), or coronary artery bypass grafting (CABG); cerebrovascular accident (CVA), transient ischemic attack (TIA), or cerebral embolism; History of psychoactive substance abuse that cannot be discontinued, or a history of psychiatric disorders; Any other severe, acute, or chronic medical condition, or laboratory abnormalities that, in the investigator's judgment, may increase the risks associated with study participation or interfere with the interpretation of study results; Poor compliance, or any other circumstances that, in the investigator's judgment, render the patient unsuitable for participation in this trial.