Becotatug Vedotin in Combination With Immunotherapy and Multimodality Radiotherapy for Esophageal Squamous Cell Carcinoma in the Second-line or Later Setting

1. Patients voluntarily participated in the trial, fully informed consent, signed written informed consent, and had good compliance;
2. Age of 18-80 years old (including the cut-off value), male or female;
3. Recurrent/metastatic or unresectable advanced esophageal squamous cell carcinoma confirmed by pathology or histology;
4. Failure of at least one previous standard therapy (including chemotherapy, PD-1 or PD-L1 inhibitors, etc.);
5. At least one baseline extracranial measurable lesion, according to RECIST 1.1 criteria (≥10 mm in the greatest dimension on CT scan or ≥15 mm in the short dimension if the lesion is a lymph node), that had not received radiation therapy or had received previous local radiation therapy but was considered by the investigator to be reirradiated;
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1;
7. Expected survival time ≥12 weeks;
8. The expression of epidermal growth factor receptor (EGFR) was confirmed by immunohistochemistry (IHC 1+,2+,3+);
9. Previous antineoplastic treatment-related aes of NCI Common Terminology for Adverse Events version 5.0 (NCI CTCAE v5.0) ≤ grade 1 (except alopecia, non-clinically significant or asymptomatic laboratory abnormalities);
10. The organ and bone marrow are sufficiently functional to meet the following requirements (within 14 days before starting study treatment) : 1) Blood routine examination: no blood transfusion, no use of granulocyte colony-stimulating factor [G-CSF], and no drug correction within 14 days before screening: hemoglobin [HB] ≥90g/L; Absolute neutrophil count (ANC) ≥1.5×109/L; Platelet (PLT) ≥75×109/L; 2) Blood biochemical tests should meet the following criteria (no albumin transfusion within 14 days before screening) : serum total bilirubin (BIL) ≤2×ULN (Gilbert's syndrome patients ≤3×ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5.0×ULN; Serum creatinine [Cr] ≤1.5×ULN or endogenous creatinine clearance ≥50ml/min (Cockcroft-Gault formula) Male: Cr clearance =((140-age)× body weight)/(72× blood Cr) Female: Cr clearance =((140-age)× weight)/(72× blood Cr) × 0.85 (Body weight: kg; blood Cr: mg/mL). 3) Coagulation function: international normalized ratio (INR) ≤2 or prothrombin time (PT) exceeding the upper limit of normal range ≤6 seconds;
11. Female subjects of childbearing potential must take a urine or serum pregnancy test within 7 days before the first dose (if the urine pregnancy test result cannot be confirmed as negative, the serum pregnancy test should be taken, and the result is negative);
12. If a female subject of childbearing potential has sex with an unsterilized male partner, the subject must be using an acceptable contraceptive method from the time of screening and must agree to continue using the method for 180 days after the last dose of study drug;
13. If an unsterilized male subject has sex with a fertile female partner, the subject must use an effective method of contraception from the start of screening until 180 days after the last dose of medication; Discontinuation of contraception after this time point should be discussed with the investigator.
14. Participants are willing and able to comply with the scheduled visits, treatment protocols, laboratory tests, and other requirements of the study.

Exclusion Criteria:

1. The presence of symptomatic or untreated known brain metastases or other central nervous system metastases that were completely resected and/or demonstrated to be stable or improved after radiotherapy were not exclusion criteria, as long as they were stable on computed tomography (CT) for at least 4 weeks before screening, had no evidence of cerebral edema, and did not require glucocorticoids or anticonvulsants;
2. The subjects had a malignancy other than esophageal squamous cell carcinoma within 5 years before enrollment. Note: Skin basal cell carcinoma, superficial bladder cancer, skin squamous cell carcinoma, or cervical cancer in situ were excluded. Or patients who had received curative treatment and had not relapsed within 5 years could participate in the trial;
3. Known to be allergic to a drug or a drug component;
4. Previous treatment interruption due to severe and/or life-threatening immune-related toxicity;
5. NCI-CTCAE v5.0 grade of adverse events caused by previous antineoplastic therapy did not recover to ≤1 before enrollment (except alopecia or antineoplastic therapy-induced tolerable events according to investigator's opinion);
6. Have received or are receiving any of the following: a) being treated with an immunosuppressive drug or systemic hormone for immunosuppression (at a dose of >10 mg/ day of prednisone or equivalent) within 2 weeks before the first dose of the study drug; Use of inhaled or topical steroids and replacement adrenocortical hormones at a dose of more than 10 mg per day of prednisone or equivalent were allowed in the absence of active autoimmune disease. b) have received a live attenuated vaccine within 4 weeks before the first dose of study drug, or plan to receive a live or live attenuated vaccine during the study; c) major surgery or severe trauma within 4 weeks before the first dose of study drug;
7. Have any active autoimmune disease or history of autoimmune disease, including but not limited to: interstitial pneumonia, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism (may be considered after hormone replacement therapy); Patients with psoriasis or complete remission of childhood asthma/allergies without any intervention in adulthood were considered for inclusion, but patients requiring medical intervention with bronchodilators were not included.
8. A history of immunodeficiency, including HIV positivity, other acquired or congenital immunodeficiency disorders, or organ or allogeneic bone marrow transplantation;
9. Presence of uncontrolled cardiac symptoms or diseases, including but not limited to: heart failure above NYHA class Ⅱ, unstable angina pectoris, myocardial infarction within 1 year, and clinically significant supraventricular or ventricular arrhythmias without clinical intervention or poorly controlled after clinical intervention;
10. Severe infection (CTCAE > 2) occurred within 4 weeks before the first dose of study drug, such as severe pneumonia requiring hospitalization, bacteremia, infectious complications, etc. Patients who had active pulmonary inflammation on baseline chest imaging, had signs and symptoms of infection within 14 days before the first dose of the study drug, or required treatment with oral or intravenous antibiotics, except those who received prophylactic antibiotics;
11. Patients with active pulmonary tuberculosis infection detected by medical history or CT examination, or with a history of active pulmonary tuberculosis infection within 1 year before enrollment, or with a history of active pulmonary tuberculosis infection more than 1 year before enrollment but without regular treatment;
12. Presence of active hepatitis B (HBV DNA ≥ 2000 IU/mL or 104 copies/mL), hepatitis C (hepatitis C antibody positive and HCV RNA above the detection limit of the analytical method);
13. Patients with clinically significant bleeding symptoms or clear bleeding tendency within 3 months before enrollment, such as daily cough/hemoptysis 2.5 mL or more lower gastrointestinal bleeding, esophageal and gastric varices with bleeding risk, bleeding gastric ulcer or angiitis;
14. Arterial/venous thrombotic events occurred within 6 months before enrollment, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism;
15. Pregnant or lactating women;
16. According to the investigator's judgment, there are other factors that may lead to the forced termination of the study, such as other serious diseases (including mental diseases) requiring concomitant treatment, alcoholism, drug abuse, family or social factors, and factors that may affect the safety or compliance of the subjects;
17. Is participating in another clinical study, unless it is an observational (noninterventional) clinical study or an interventional study follow-up.