Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor worldwide, with particularly high incidence in East Asian regions such as China, and is associated with poor patient prognosis. In recent years, immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 antibodies) combined with chemotherapy have become the standard first-line treatment for advanced ESCC. Multiple randomized controlled trials have confirmed that this combination significantly improves patient survival compared to chemotherapy alone. However, a subset of patients still exhibit poor response or develop resistance to the immunotherapy-chemotherapy regimen, necessitating the exploration of novel combination strategies to further enhance efficacy.

The epidermal growth factor receptor (EGFR) is frequently overexpressed in ESCC and is associated with tumor proliferation, metastasis, and poor prognosis, making it an important therapeutic target. Antibody-drug conjugates (ADCs) targeting EGFR achieve precise tumor killing by conjugating an anti-EGFR antibody to a potent cytotoxic payload. Preclinical studies have demonstrated significant antitumor activity of EGFR ADCs in ESCC models. Mechanistically, anti-EGFR therapy and immune checkpoint inhibitor therapy may exert synergistic effects through several avenues: enhancing tumor antigen presentation, remodeling the tumor microenvironment, and modulating PD-L1 expression. Therefore, this triple combination strategy holds promise for overcoming the limitations of monotherapies and providing a new treatment option for patients with ESCC.

Inclusion Criteria:

1. Age ≥ 18 years.

2. Male or non-pregnant, non-lactating female.

3. ECOG performance status of 0 or 1, with no deterioration within 7 days.

4. Histologically confirmed locally advanced or metastatic esophageal squamous cell carcinoma.

5. No prior systemic therapy for ESCC. Patients who have received neoadjuvant or adjuvant therapy must have experienced disease progression or recurrence more than 6 months after completion of that treatment.

6. Patients with metastatic disease must have at least one measurable lesion per RECIST 1.1 criteria; patients with disease after neoadjuvant therapy must have an evaluable lesion.

7. Adequate organ and bone marrow function, as demonstrated by the following laboratory values:

   1. Hemoglobin (HGB) ≥ 90 g/L.
   2. Absolute neutrophil count (NEUT) ≥ 1.5 × 10⁹/L.
   3. Platelet count (PLT) ≥ 80 × 10⁹/L.
   4. Total bilirubin (TBIL) ≤ 1.5 × the upper limit of normal (ULN).
   5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; for patients with liver metastases, ALT and AST ≤ 5 × ULN.
   6. Creatinine clearance ≥ 50 mL/min (calculated by the Cockcroft-Gault formula).
   7. Urine protein < (++) or 24-hour urinary protein < 1.0 g.

8. Normal coagulation function and no active bleeding:

   1. International Normalized Ratio (INR) ≤ 1.5.
   2. Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN.

9. For women of childbearing potential: negative pregnancy test (serum or urine) within 14 days prior to enrollment, and agreement to use adequate contraception during the study period and for 8 weeks after the last dose of study drug. For men: surgically sterile or agreement to use adequate contraception during the study period and for 8 weeks after the last dose of study drug.

10. Expected survival ≥ 6 months.

11. Patient voluntarily participates in the study and signs the informed consent form (ICF).

12. Patient is expected to be compliant and able to undergo follow-up for efficacy and adverse events as required by the protocol.

Exclusion Criteria:

Patients meeting any of the following criteria at screening will be excluded from the study:

1. Prior treatment with any anti-EGFR monoclonal antibody, or with anti-PD-1/PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody, CTLA-4 antibody, or any other drug/antibody targeting T-cell co-stimulation or checkpoint pathways.
2. Administration of a live vaccine within 4 weeks prior to enrollment or anticipated during the study period.
3. Active autoimmune disease or a history of autoimmune disease within 4 weeks prior to enrollment.
4. Prior allogeneic bone marrow transplantation or solid organ transplant.
5. Uncontrolled hypertension at enrollment, defined as: systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 90 mmHg.
6. Any disease or condition affecting drug absorption at enrollment.
7. Clinically significant cardiovascular disease, including but not limited to: acute myocardial infarction within 6 months prior to enrollment; severe/unstable angina or coronary artery bypass grafting; congestive heart failure > New York Heart Association (NYHA) Class 2; ventricular arrhythmias requiring medication; left ventricular ejection fraction (LVEF) < 50%.
8. Active or uncontrolled severe infection (≥ CTCAE v5.0 Grade 2 infection).
9. Known HIV infection. Known clinically significant liver disease, including viral hepatitis [known hepatitis B virus (HBV) carriers must be excluded if they have active HBV infection, i.e., HBV DNA positive (>1×10⁴ copies/mL or >2000 IU/mL); known hepatitis C virus (HCV) infection with HCV RNA positive (>1×10³ copies/mL)].
10. Any other disease, clinically significant metabolic abnormality, physical examination finding, or laboratory abnormality that, in the investigator's judgment, reasonably suggests the presence of a disease or condition that contraindicates the use of the investigational drug (e.g., a condition associated with seizures requiring treatment), would affect the interpretation of study results, or would place the patient at high risk.
11. Patients deemed by the investigator to be unsuitable for participation in this study.