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 .

Study Overview

• Status: Recruiting
• Conditions: Locally Advanced Head and Neck Squamous Cell Carcinoma
• Intervention / Treatment: Procedure: Surgery; Drug: Adjuvant Cisplatin; Drug: Neoadjuvant and Adjuvant Becotatug Vedotin; Drug: Neoadjuvant and Adjuvant Immunotherapy; Radiation: Adjuvant Radiotherapy

• Study Type: Interventional
• Enrollment (Estimated): 430
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Mingyuan Chen; Phone Number: +86 18124188280; Email: chmingy@mail.sysu.edu.cn
• Study Contact Backup: Name: Rui You; Phone Number: +86 13580439820; Email: your5@mail.sysu.edu.cn

Study Locations

• China
  • Guangdong
    • Zhuhai, Guangdong, China, 519099
      • Recruiting
      • The Fifth Affiliated Hospital,Sun Yat-sen University
      • Contact: Rui You; Phone Number: 13580439820; Email: your5@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Becotatug vedotin plus pucotenlimab arm; Patients receive Becotatug vedotin combined with pucotenlimab as neoadjuvant treatment prior to surgical resection and as adjuvant treatment after radiotherapy.	Procedure: Surgery; Radical surgery performed 3-4 weeks after neoadjuvant therapy, following a re-evaluation of surgical indications by the surgeon.; Drug: Adjuvant Cisplatin; High-risk group：Cisplatin 100 mg/m² is administered via intravenous infusion on Day 1 of every 21-day cycle during radiotherapy, for a total of 3 cycles.; Drug: Neoadjuvant and Adjuvant Becotatug Vedotin; Neoadjuvant therapy with Becotatug Vedotin (Day 1, Q3W, 2 cycles); Adjuvant therapy after radiotherapy with Becotatug Vedotin ( Day 1, Q3W, for a total of 12 cycles).; Drug: Neoadjuvant and Adjuvant Immunotherapy; Neoadjuvant immunotherapy with pucotenlimab (200mg, Day 1, Q3W, 2 cycles); Adjuvant immunotherapy duiring and after radiotherapy with pucotenlimab (200mg, Day 1, Q3W, for a total of 15 cycles).; Radiation: Adjuvant Radiotherapy; Radiotherapy is initiated 4-6 weeks after surgery. For the low-risk group, a total dose of 60 Gy in 30 fractions is delivered using intensity-modulated radiation therapy (IMRT). For the high-risk group, 66 Gy in 33 fractions is prescribed, or 70 Gy in 35 fractions for residual lesions, also using IMRT.
Active Comparator: pucotenlimab arm; Patients receive pucotenlimab as neoadjuvant treatment prior to surgical resection and as adjuvant duiring and after radiotherapy.	Procedure: Surgery; Radical surgery performed 3-4 weeks after neoadjuvant therapy, following a re-evaluation of surgical indications by the surgeon.; Drug: Adjuvant Cisplatin; High-risk group：Cisplatin 100 mg/m² is administered via intravenous infusion on Day 1 of every 21-day cycle during radiotherapy, for a total of 3 cycles.; Drug: Neoadjuvant and Adjuvant Immunotherapy; Neoadjuvant immunotherapy with pucotenlimab (200mg, Day 1, Q3W, 2 cycles); Adjuvant immunotherapy duiring and after radiotherapy with pucotenlimab (200mg, Day 1, Q3W, for a total of 15 cycles).; Radiation: Adjuvant Radiotherapy; Radiotherapy is initiated 4-6 weeks after surgery. For the low-risk group, a total dose of 60 Gy in 30 fractions is delivered using intensity-modulated radiation therapy (IMRT). For the high-risk group, 66 Gy in 33 fractions is prescribed, or 70 Gy in 35 fractions for residual lesions, also using IMRT.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free Survival Rate (EFS)	Defined as the time from randomization to the first occurrence of disease progression, relapse, or death from any cause.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Defined as the time interval from randomization to death due to any cause.	3 years
Distant Metastasis-Free Survival (DMFS)	Defined as the time interval from randomisation to the date of first distant metastases.	3 years
Locoregional Relapse-Free Survival (LRRFS)	Defined as the time from randomisation to the date of first locoregional relapse.	3 years
Incidence of treatment related late complications	The proportion of patients with treatment related late complications according to NCI-CTC5.0 criteria and RTOG criteria.	up to 3 years
Objective Response Rate (ORR)	The proportion of patients achieving an objective response (complete response and partial response) by imaging assessment after the completion of neoadjuvant therapy, prior to surgery.	After the completion of neoadjuvant therapy, prior to surgery.
Disease Control Rate (DCR)	The proportion of patients achieving predefined efficacy evaluation criteria (complete response, partial response, and stable disease) by imaging assessment after the completion of neoadjuvant therapy, prior to surgery.	After the completion of neoadjuvant therapy, prior to surgery.
Major Pathologic Response Rate (mPR):	The proportion of patients with less than 10% residual viable tumor cells in the tumor bed, assessed at 1 week post-surgery.	1 week post-surgery
Pathologic Complete Response Rate (pCR)	The proportion of patients with no microscopic residual viable tumor cells, assessed at 1 week post-surgery.	1 week post-surgery
Incidence of treatment related acute complications	The proportion of patients with treatment related acute complications according to NCI-CTC5.0 criteria and RTOG criteria.	up to 1 year
Non-Surgery Delay Rate	The proportion of patients whose surgery is delayed by more than 4 weeks from the planned date, assessed at 8 weeks after two cycles of neoadjuvant therapy.	8 weeks after two cycles of neoadjuvant therapy
R0 Resection Rate	The proportion of patients undergoing surgical resection who achieve R0 resection (complete tumor resection with negative histopathological margins), assessed at 1 week post-surgery.	1 week post-surgery.
General Quality of Life	Changes from baseline in general patient-reported quality of life were assessed using the EORTC QLQ-C30 . The scores range from 0 to 100, with higher scores indicating a better quality of life outcome and lower scores indicating worse symptoms or functions.	Baseline, week 4 (post-neoadjuvant), week 6 (preoperative), week 8 (postoperative), week 10 (pre-radiotherapy), week 17 (post-radiotherapy), every 2 cycles of adjuvant therapy (each cycle is 21 days), and at each follow-up, up to 3 years
Head and Neck Cancer-Specific Quality of Life	Changes from baseline in head and neck cancer-specific quality of life assessed by EORTC QLQ-H&N35. The scores range from 0 to 100, with higher scores indicating a better quality of life outcome and lower scores indicating worse symptoms or functions.	Baseline, week 4 (post-neoadjuvant), week 6 (preoperative), week 8 (postoperative), week 10 (pre-radiotherapy), week 17 (post-radiotherapy), every 2 cycles of adjuvant therapy (each cycle is 21 days), and at each follow-up, up to 3 years.

Collaborators and Investigators

• Sponsor: Ming-Yuan Chen

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2026
• Primary Completion (Estimated): February 28, 2031
• Study Completion (Estimated): February 28, 2032

Study Registration Dates

• First Submitted: March 28, 2026
• First Submitted That Met QC Criteria: April 6, 2026
• First Posted (Actual): April 13, 2026

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 6, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Becotatug Vedotin; Resectabl locally advanced head and neck squamous cell carcinoma; perioperative neoadjuvant and adjuvant therapy
• Additional Relevant MeSH Terms: Therapeutics; Radiotherapy; Combined Modality Therapy; Surgical Procedures, Operative; Neoadjuvant Therapy; Radiotherapy, Adjuvant
• Other Study ID Numbers: ZDWY.FSZLK.006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No