A Prospective, Exploratory Study of Becotatug Vedotin Plus Putlimab for Neoadjuvant Therapy and Adjuvant Radiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma

Neoadjuvant Phase (3-week cycle, 2 cycles):

Putlimab (HX008): 200 mg, Q3W, D1, IV infusion (60 ± 15 min, first cycle ≥ 60 min), for 2 cycles Becotatug vedotin (MRG003): 2.0 mg/kg, Q3W, D1, IV infusion (60 ± 10 min, first cycle ≥ 60 min), administered at least 30 min after completion of putlimab infusion, for 2 cycles For subjects unable to tolerate 60-min infusion, the infusion time may be extended to 120 min. Efficacy assessment will be performed every cycle until completion of 2 cycles followed by surgical resection or occurrence of discontinuation events (clinical progression, investigator-confirmed radiographic progression per RECIST 1.1, unacceptable toxicity, withdrawal of informed consent, or meeting criteria for intervention discontinuation).

Adjuvant/Maintenance Phase (3-week cycle):

Surgical resection within 2-4 weeks post-neoadjuvant; surgical approach at investigator discretion. Postoperative pathological response (pCR and MPR) will be determined based on the percentage of residual visible tumor relative to total tumor bed area on H&E-stained slides. Postoperative maintenance treatment will be administered in 3-week cycles. Adjuvant treatment will be selected based on pathological response: Group A (postoperative pCR); Group B (postoperative MPR); Group C (postoperative partial response/no response), further stratified into low/intermediate-risk (no extracapsular nodal extension [ENE] and negative margins) and high-risk (ENE and/or positive margins). All patients will receive putlimab (PD-1) maintenance therapy for a total duration of up to 1 year.

Post-discontinuation Standard Therapy:

Subjects unable to tolerate or unwilling to receive the study-specified adjuvant treatment after surgery will be withdrawn from the study and return to standard clinical chemoradiotherapy. Only neoadjuvant treatment data and postoperative assessment results will be retained for these patients.

Group A (Postoperative pCR):

Putlimab (HX008): 200 mg, Q3W, D1, IV infusion (60 ± 15 min, first cycle ≥ 60 min), up to 1 year Adjuvant RT: 40 Gy/5 weeks. RT timing, field, and fractionation may be adjusted by investigators based on individual disease status

Group B (Postoperative MPR):

Putlimab (HX008): 200 mg, Q3W, D1, IV infusion (60 ± 15 min, first cycle ≥ 60 min), up to 1 year Adjuvant RT: 50 Gy/5 weeks. RT timing, field, and fractionation may be adjusted by investigators based on individual disease status

Group C (Postoperative Partial Response/No Response):

Low/Intermediate-Risk (no ENE and negative margins):

Putlimab (HX008): 200 mg, Q3W, D1, IV infusion (60 ± 15 min, first cycle ≥ 60 min), up to 1 year Adjuvant RT: 60 Gy/6 weeks. RT timing, field, and fractionation may be adjusted by investigators based on individual disease status

High-Risk (ENE and/or positive margins):

Putlimab (HX008): 200 mg, Q3W, D1, IV infusion (60 ± 15 min, first cycle ≥ 60 min), up to 1 year Adjuvant RT: 60-66 Gy/6-6.6 weeks. RT timing, field, and fractionation may be adjusted by investigators based on individual disease status Cisplatin: 60 mg/m², Q3W, D1, IV infusion, administered at least 30 min after completion of putlimab infusion, for 2 cycles

Imaging Assessment:

Imaging assessments will be performed every 2 cycles (±7 days) from treatment initiation until disease recurrence, initiation of new anti-tumor therapy, withdrawal of informed consent, death, or up to 21 cycles, whichever occurs first. Additional imaging may be performed at any time if clinically indicated. Subjects must complete safety assessments and imaging evaluation at the end of treatment, followed by a safety follow-up visit 30 days after the last dose. Survival follow-up will then be conducted every 90 days (±7 days) to collect and record survival status and subsequent anti-tumor therapy.

Endpoints:

The primary endpoint is the postoperative pathological complete response (pCR) rate. Secondary endpoints include the major pathological response (MPR) rate, objective response rate (ORR), disease control rate (DCR), median event-free survival (mEFS), median overall survival (mOS), 1-year/2-year EFS/OS rates, and adverse event rates per NCI-CTCAE v6.0.

Study Size and Duration:

The study plans to enroll 35 subjects and is expected to be completed within 3 years.

Inclusion criteria

• Diagnosis of any malignancy other than gastric cancer within 5 years prior to the first dose, with the exception of adequately treated cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, and/or radically resected carcinoma in situ;
• Known endoscopic evidence of active bleeding in the target lesion;
• Concurrent participation in another interventional clinical study, or receipt of any investigational medicinal product or use of investigational device within 4 weeks prior to the first dose;
• Prior exposure to any of the following therapies: anti-PD-1, anti-PD-L1, or anti-PD-L2 agents; agents targeting other stimulatory or co-inhibitory T-cell receptors (including but not limited to CTLA-4, OX-40, and CD137); or antibody-drug conjugates (ADCs) with MMAE or MMAF payloads;
• Systemic administration of Chinese proprietary medicines with anti-tumor indications or immunomodulatory agents (including thymosin, interferon, and interleukins, except for local administration to control pleural effusion) within 2 weeks prior to the first dose;
• Active autoimmune disease requiring systemic therapy (e.g., disease-modifying antirheumatic drugs, corticosteroids, or immunosuppressants) within 2 years prior to the first dose. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) is not considered systemic therapy;
• Receipt of systemic corticosteroid therapy (excluding intranasal, inhaled, or other topical corticosteroids) or any other form of immunosuppressive therapy within 7 days prior to the first dose; *Note: Physiologic doses of corticosteroids (prednisone ≤10 mg/day or equivalent) are permitted;*
• History of allogeneic organ transplantation (corneal transplantation excluded) or allogeneic hematopoietic stem cell transplantation;
• Known hypersensitivity to pucotenlimab, MRG003, or any of their excipients;
• Failure to recover adequately from toxicities and/or complications of prior interventions (i.e., to Grade ≤1 or to baseline, excluding fatigue and alopecia) prior to initiation of study treatment;
• Known history of human immunodeficiency virus (HIV) infection (HIV-1/2 antibody positive);
• Untreated active hepatitis B infection (defined as HBsAg positivity with HBV-DNA copy number above the upper limit of normal of the local laboratory); *Note: Subjects with hepatitis B may be enrolled if they meet the following criteria:* 1) HBV viral load <1,000 copies/mL (200 IU/mL) prior to the first dose; subjects must receive prophylactic anti-HBV therapy throughout the study treatment period to prevent viral reactivation; 2) Subjects with anti-HBc (+), HBsAg (-), anti-HBs (-), and undetectable HBV viral load are not required to receive prophylactic anti-HBV therapy but require close monitoring for viral reactivation;
• Active hepatitis C infection (HCV antibody positive with HCV-RNA level above the lower limit of quantification);
• Receipt of a live vaccine within 30 days prior to Cycle 1 Day 1; *Note: Inactivated injectable influenza vaccines for seasonal influenza are permitted within 30 days prior to the first dose; intranasal live-attenuated influenza vaccines are not permitted;*
• Pregnancy or breastfeeding;
• Presence of any serious or uncontrolled systemic condition, including but not limited to:

• Resting ECG demonstrating significant, symptomatic, and poorly controlled abnormalities in rhythm, conduction, or morphology, including complete left bundle branch block, second-degree or higher atrioventricular block, ventricular arrhythmias, or atrial fibrillation; 2) Unstable angina pectoris, congestive heart failure, or chronic heart failure of New York Heart Association (NYHA) Class ≥2; 3) Any arterial thrombosis, embolism, or ischemic event (e.g., myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack) within 6 months prior to enrollment; 4) Inadequately controlled hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg); 5) History of non-infectious pneumonitis requiring corticosteroid therapy within 1 year prior to the first dose, or currently clinically active interstitial lung disease; 6) Active pulmonary tuberculosis; 7) Active or uncontrolled infection requiring systemic antimicrobial therapy; 8) Clinically active diverticulitis, intra-abdominal abscess, or gastrointestinal obstruction; 9) Hepatic conditions including cirrhosis, decompensated liver disease, or acute or chronic active hepatitis; 10) Poorly controlled diabetes mellitus (fasting blood glucose >10 mmol/L); 11) Urinalysis demonstrating urine protein ≥2+ with confirmed 24-hour urine protein >1.0 g; 12) Psychiatric disorder that would preclude compliance with study requirements;

• Any medical condition, laboratory abnormality, or concurrent therapy that, in the Investigator's opinion, may interfere with study assessments, compromise subject safety, or render the subject unsuitable for study participation.

Exclusion criteria

• Presence of distant metastatic lesions;
• History of Grade ≥3 immune-related adverse events or treatment-related adverse events that have not recovered to Grade ≤1;
• Receipt of surgery, chemotherapy, targeted small molecule therapy, or radiotherapy for another invasive malignancy within the past 5 years;
• Autoimmune disease requiring systemic corticosteroid therapy within the past 3 months, history of clinically significant autoimmune disease, or syndrome requiring systemic corticosteroid therapy;
• Active infection requiring systemic treatment;
• Prior receipt of any form of anti-tumor therapy for the primary tumor or metastatic lymph nodes, including chemotherapy, radiotherapy, targeted therapy, anti-PD-1 or anti-PD-L1 therapy, or surgery (biopsy excluded);
• History of other malignancies;
• History of organ transplantation;
• History of autoimmune disease, or other conditions requiring long-term systemic corticosteroid or immunosuppressive therapy;
• Positive for human immunodeficiency virus (HIV);
• Active hepatitis B or hepatitis C infection (HBV DNA or HCV RNA above the upper limit of normal);
• Total white blood cell count <3.5×10⁹/L, absolute lymphocyte count <0.8×10⁹/L, neutrophil count <1.5×10⁹/L, platelet count <100×10⁹/L, or hemoglobin <90 g/L; total bilirubin >1.5× upper limit of normal (ULN), transaminases (AST, ALT) >3× ULN (>5× ULN if hepatic metastases present), serum creatinine >1.5× ULN; coagulation abnormalities with international normalized ratio (INR) or prothrombin time (PT) >1.5× ULN;
• Serious cardiovascular, respiratory, or major immune system comorbidities; including urinary tract obstruction, myocardial infarction, arrhythmia, obstructive or restrictive lung disease, or other conditions that the Investigator considers may increase subject risk;
• Pregnant or lactating women;
• Refusal to use effective contraception during the treatment period and for 3 months thereafter;
• Concurrent participation in another clinical study;
• Critically ill patients unable to complete the study assessments;
• History of psychiatric disorders (e.g., schizophrenia, mania, anxiety disorder, depression, phobia, etc.) or subjects/spouses diagnosed with psychiatric illness at the time of study enrollment;
• Subjects or spouses with communication barriers or inability to provide normal responses due to altered consciousness, aphasia, intellectual disability, or other causes;
• Any other condition that the Investigator considers renders the subject unsuitable for enrollment or may interfere with subject participation or completion of the study.