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.
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);
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;
Parallel
Becotatug Vedotin combined with Pucotenlimab
Drugpatients received 2 cycles of Pucotenlimab(200 mg per dose, q3w) and Becotatug Vedotin (2.3 mg/kg, Q3W) in the neoadjuvant stage, then 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.
surgery
Procedure/SurgeryPatients in the control arm will undergo upfront surgery followed by standard adjuvant therapy.
1 year events free survival rate
the percentage of participants documented PD per RECIST 1.1 from enrollment in the neoadjuvant stage, or recurrent or death due to any cause, whichever occurred first.
Progression Free Survival Per RECIST 1.1
PFS was defined as the time from enrollment to the first documented PD per RECIST 1.1, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD
MPR rate
the percentage of participants viable tumour cells remaining in the tumour bed after neoadjuvant therapy ≤10%, regardless of the presence or absence of viable tumour cells in the lymph nodes
Number of Participants Experiencing an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The number of participants that experienced at least one AE was reported for each treatment arm.
overall survival
OS was defined as the time from enrollment to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up.
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