Vebrekotuzumab with or without anti-PD-1 for previously treated advanced esophageal squamous cell carcinoma

An Open-Label, Randomized Phase II Study of Vebrekotuzumab With or Without PD-1 Inhibitor Immunotherapy in Patients With Advanced Esophageal Squamous Cell Carcinoma Refractory to First-Line Therapy

This trial will test whether the EGFR-targeted antibody-drug conjugate vebrekotuzumab, alone or with an anti-PD-1 drug, helps people with advanced esophageal squamous cell carcinoma whose disease progressed after prior treatment.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 104 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Fudan University (other)
• Drugs / interventions: vebrekotuzumab, radiation, prednisone, chemotherapy
• Locations: 1 site (Shanghai)
• Trial ID: NCT07403136 on ClinicalTrials.gov

What this trial studies

This is a phase 2 interventional study enrolling adults with recurrent or metastatic esophageal squamous cell carcinoma that expresses EGFR and has progressed after at least one prior systemic therapy including a PD-1 inhibitor. Participants will receive vebrekotuzumab either alone or in combination with a PD-1 antibody, with treatment continued while they benefit and can tolerate therapy. The study will monitor tumor response, duration of control, safety, and tolerability. Tumor tissue testing for EGFR by IHC and routine clinical and imaging assessments will be used to guide enrollment and measure outcomes.

Who should consider this trial

Good fit: Adults (≥18 years) with histologically confirmed recurrent or metastatic ESCC that is EGFR IHC-positive, who have progressed after at least one prior systemic therapy including an immune checkpoint inhibitor, and who can provide a tumor sample are eligible.

Not a fit: Patients whose tumors lack EGFR expression, who are medically unfit for treatment, or who have very limited life expectancy are unlikely to benefit from this approach.

Why it matters

Potential benefit: If successful, the treatment may provide longer tumor control and better clinical outcomes than current second-line options for EGFR-positive ESCC after prior PD-1 therapy.

How similar studies have performed: Previous EGFR-targeting agents have not improved survival in ESCC, making this ADC approach comparatively novel, though ADCs and combinations with PD-1 inhibitors have shown benefit in other cancer types.

Eligibility criteria

Inclusion Criteria:

1. Willing to voluntarily sign the informed consent form and comply with the protocol requirements.
2. Age ≥18 years on the day of signing the informed consent form, regardless of gender.
3. Life expectancy ≥12 weeks.
4. Patients with histologically confirmed advanced recurrent or metastatic esophageal squamous cell carcinoma (ESCC) and immunohistochemistry (IHC) confirmed positive epidermal growth factor receptor (EGFR) expression (IHC 1+, 2+, or 3+).
5. Have experienced disease progression or intolerability after receiving at least one prior line of systemic therapy, which must have included an immune checkpoint inhibitor (e.g., anti-PD-1/PD-L1 antibody).
6. The patient must be able to provide a tumor tissue sample (paraffin block, paraffin-embedded sections, or fresh tissue sections) from the primary or metastatic site for pathological testing. Archived tumor tissue from the most recent treatment should be used. If archived tissue is unavailable, a new biopsy must be performed.
7. Must have radiographic evidence of disease progression confirmed by the investigator during or after the last treatment regimen. At baseline, there must be at least one measurable extracranial lesion per RECIST 1.1 criteria (longest diameter ≥10 mm on CT scan, or for lymph nodes, short axis ≥15 mm). The measurable lesion should not have been previously irradiated, unless it is within a prior radiation field or was previously treated locally and has documented progression.
8. All adverse events (AEs) from prior anti-tumor therapy have resolved to ≤ Grade 1 per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 (except for alopecia, non-clinically significant or asymptomatic laboratory abnormalities).
9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 days prior to the first dose.
10. No serious cardiac dysfunction, with left ventricular ejection fraction (LVEF) ≥50% confirmed by echocardiography or MUGA scan within 28 days prior to the first dose.
11. Adequate organ function within 7 days prior to the first dose, as defined by:

    * Bone marrow: Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L; platelet count ≥100 × 10⁹/L; hemoglobin ≥90 g/L. Patient must not have received any blood transfusion or blood component therapy within 14 days prior to the first dose, nor any biologic response modifiers (e.g., G-CSF, erythropoietin) within 7 days prior to the first dose.
    * Liver: For patients without liver metastases: total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN. For patients with liver metastases: TBIL ≤1.5 × ULN; ALT and AST ≤5 × ULN.
    * Kidney: Serum creatinine (Cr) ≤1.5 × ULN, or calculated creatinine clearance (Cockcroft-Gault formula) ≥50 mL/min.
    * Coagulation: International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) ≤1.5 × ULN (unless the patient is receiving therapeutic anticoagulation).
12. Male patients with reproductive potential and female patients of childbearing potential must be willing to use effective contraception from signing the ICF until 6 months after the last dose of the study drug. Women of childbearing potential include premenopausal women and women within 2 years of menopause onset. A negative serum pregnancy test result must be confirmed for women of childbearing potential within ≤7 days prior to the first study drug dose.

Exclusion Criteria:

1. History of other primary malignancies. Note: Except for adequately treated basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix; or patients with other malignancies who have undergone curative treatment and have been disease-free for ≥5 years may be enrolled.
2. Untreated or unstable parenchymal brain metastases, spinal cord compression, carcinomatous meningitis, or leptomeningeal disease.

   Note: Patients who have received local therapy for brain metastases may be enrolled if brain imaging shows stability for at least 28 days prior to the first dose, with no evidence of cerebral edema, and no requirement for corticosteroid therapy.
3. Presence of uncontrolled third-space fluid (e.g., significant ascites, pleural effusion, or pericardial effusion) that cannot be managed by drainage or other methods. Patients who required drainage to control third-space fluid within 14 days prior to the first dose are excluded.
4. Any severe or uncontrolled systemic disease, in the investigator's judgment, including poorly controlled hypertension (systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg), poorly controlled diabetes mellitus, or active bleeding signs, etc.
5. Poorly controlled cardiac disease, including heart failure of New York Heart Association (NYHA) class ≥II, unstable angina, myocardial infarction within the past year, clinically significant supraventricular or ventricular arrhythmia requiring treatment, or long QT syndrome, e.g., QTcF \>450 ms (male) or QTcF \>470 ms (female).
6. Evidence of active infection, including Hepatitis B (HBsAg positive AND HBV DNA ≥2000 IU/mL, excluding drug-induced or other causes of hepatitis), Hepatitis C (anti-HCV antibody positive AND HCV RNA above the lower limit of detection), or human immunodeficiency virus (HIV) infection; or uncontrolled active bacterial, viral, fungal, rickettsial, or parasitic infections, unless treated and resolved prior to study drug administration.
7. History of hypersensitivity to any component of vebrekotuzumab (histidine, histidine hydrochloride, sucrose, mannitol, polysorbate 80) OR history of ≥Grade 3 hypersensitivity reactions to macromolecular protein agents/monoclonal antibodies.
8. History of primary immunodeficiency or active autoimmune disease requiring systemic immunosuppressive therapy or systemic corticosteroid therapy (at doses ≥10 mg/day prednisone or equivalent) within 2 weeks prior to enrollment.

   Note: Patients with type I diabetes mellitus, hypothyroidism managed with stable hormone replacement therapy (including that caused by autoimmune thyroid disease), psoriasis not requiring systemic therapy, or vitiligo may be enrolled.
9. History of or concurrent interstitial lung disease, radiation pneumonitis, severe chronic obstructive pulmonary disease, severe pulmonary insufficiency, symptomatic bronchospasm, etc.
10. Female patients who are pregnant (positive serum pregnancy test), breastfeeding, or unwilling to use adequate contraception during the study period and for 6 months after the last dose of study drug.
11. Any other condition that, in the investigator's opinion, would make the patient unsuitable for participation in this clinical trial.

Where this trial is running

Shanghai

• Fudan University Shanghai Cancer Center — Shanghai, China (RECRUITING)

Study contacts

• Study coordinator: Kuaile Zhao, M.D.

Conditions: Esophageal Squamous Cell Carcinoma, Antibody-drug conjugate, Second-line