Becotatug Vedotin (MRG003) in Combination With PD-1 Inhibitor Versus PD-1 Inhibitor for the Treatment of EGFR-positive, CPS≥1 Resectable Locally Advanced Head and Neck Squamous Cell Carcinoma

A Phase III Study of Becotatug Vedotin (MRG003) in Combination With PD-1 Inhibitor Versus PD-1 Inhibitor for the Treatment of EGFR-positive, CPS≥1 Resectable Locally Advanced Head and Neck Squamous Cell Carcinoma： a Multicenter, Randomized Controlled Trial

This study is a randomized, open-label, multicenter phase III trial designed to systematically evaluate the efficacy and safety of perioperative neoadjuvant and adjuvant therapy with Becotatug vedotin in combination with PD-1 inhibitor versus PD-1 inhibitor alone in patients with EGFR-positive, CPS ≥ 1 resectable locally advanced head and neck squamous cell carcinoma .

Inclusion Criteria:

1. Voluntarily sign the informed consent form;
2. Untreated, histologically confirmed head and neck squamous cell carcinoma (oral cavity, oropharynx, hypopharynx, or larynx), EGFR-positive, CPS ≥ 1, with clinical stage (AJCC 8th edition): p16-positive oropharynx: Stage III (T4N0-2M0); p16-negative oropharynx: Stage III or IVA; larynx/hypopharynx/oral cavity: Stage III or IVA;
3. Eligible for curative-intent surgery as determined by the surgeon;
4. Age: 18 to 75 years;
5. ECOG performance status 0-1;
6. Life expectancy greater than 6 months;
7. At least one measurable lesion per RECIST 1.1;
8. Adequate organ function, based on meeting all of the following criteria (no receipt of blood components or hematopoietic growth factors within 14 days prior to testing): hemoglobin ≥ 90 g/L; absolute neutrophil count ≥ 1.5 × 10⁹/L; platelet count ≥ 100 × 10⁹/L; serum albumin ≥ 28 g/L; total bilirubin ≤ 1.5 × upper limit of normal (ULN); ALT and AST ≤ 2.5 × ULN; serum creatinine ≤ 1.5 × ULN, with creatinine clearance ≥ 50 mL/min; activated partial thromboplastin time and international normalized ratio (INR) ≤ 1.5 × ULN (patients receiving a stable dose of anticoagulant therapy, such as low molecular weight heparin or warfarin, may be enrolled if INR is within the expected therapeutic range for the anticoagulant). Thyroid-stimulating hormone (TSH) ≤ ULN; if abnormal, T3 and T4 levels should be assessed, and patients with normal T3 and T4 levels may be enrolled;
9. Baseline left ventricular ejection fraction (LVEF) ≥ 50% as measured by multigated acquisition (MUGA) scan or echocardiography (ECHO);
10. Women of childbearing potential must agree to use contraception (e.g., intrauterine device, contraceptive pill, or condom) during the treatment period and for 3 months after the last dose;
11. Good compliance.

Exclusion Criteria:

1. Pregnant or breastfeeding women.

2. History of allergy to PD-1 inhibitors.

3. History of other malignancies within the past 5 years or at enrollment, with the exception of cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, and thyroid papillary tumors.

4. Residual toxicity from prior anti-tumor therapy (including immunotherapy, targeted therapy, chemotherapy, or radiotherapy, etc.) other than alopecia, fatigue, and grade 2 hypothyroidism, or clinically significant laboratory abnormalities greater than grade 1 (CTCAE v5.0).

5. Uncontrolled cardiac conditions or diseases, such as: ① NYHA Class II or greater heart failure, ② unstable angina, ③ myocardial infarction within 1 year, and ④ patients with clinically significant ventricular arrhythmias requiring intervention.

6. Grade ≥ 2 peripheral neuropathy (per CTCAE v5.0).

7. Pulmonary embolism or deep vein thrombosis within 3 months prior to enrollment (excluding catheter-related thrombosis from infusion ports or PICC lines).

8. Active bleeding, history of coagulation disorders, or patients receiving coumarin anticoagulant therapy.

9. Known hypersensitivity to any component or excipient of vibecotamab (citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, sodium chloride, and polysorbate 80), or known grade ≥ 3 hypersensitivity reaction to other prior anti-EGFR agents (including investigational drugs) or other monoclonal antibodies.

10. Receipt of any of the following treatments:

    ① Any investigational drug prior to the first dose of the current study drug.

    ② Concurrent participation in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period.

    ③ Use of systemic corticosteroids (more than 10 mg of prednisone or equivalent per day) or other immunosuppressive agents within 2 weeks prior to the first dose of study drug, except for the use of corticosteroids for localized inflammation, prevention of allergies, or nausea and vomiting. In the absence of active autoimmune disease, inhaled or topical steroids and adrenal corticosteroid replacement doses greater than 10 mg prednisone equivalent per day are permitted.

    ④ Administration of live vaccines within 4 weeks prior to the first dose of study drug.

    ⑤ Major surgery or severe trauma within 4 weeks prior to the first dose of study drug.

11. Severe infection (greater than grade 2 per CTCAE), such as severe pneumonia requiring hospitalization, bacteremia, or infectious complications, occurring within 4 weeks prior to the first dose of study drug; baseline chest imaging indicating active pulmonary inflammation or signs and symptoms of infection within 2 weeks prior to the first dose of study drug, or indicating the need for oral or intravenous antibiotic therapy (excluding prophylactic antibiotic use).

12. History of or concurrent severe chronic obstructive pulmonary disease with respiratory failure, severe pulmonary insufficiency, symptomatic bronchospasm, etc.

13. History of active autoimmune diseases or syndromes (including but not limited to interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, and hypothyroidism). Patients with vitiligo that did not require any intervention in adulthood, or childhood asthma/allergy that has resolved, are not excluded.

14. History of immunodeficiency, including HIV-positive status or other acquired/congenital immunodeficiency diseases, or history of organ transplantation or bone marrow transplantation.

15. Patients with active tuberculosis infection by history or CT findings, or history of active tuberculosis infection within 1 year prior to enrollment, or history of active tuberculosis infection more than 1 year prior without receiving formal treatment.

16. Active hepatitis B (HBV DNA ≥ 2,000 IU/mL or 10,000 copies/mL) or hepatitis C (positive HCV antibody test with HCV RNA above the lower limit of detection).

17. Uncontrolled pleural, peritoneal, pelvic, or pericardial effusion requiring drainage ≥ 1 time per month.

18. Known history of substance abuse, alcoholism, or drug use.

19. Inappropriate for inclusion based on the investigator's judgment.