Inclusion Criteria:
1. Voluntarily sign the Informed Consent Form (ICF);
2. Aged ≥18 years at the time of ICF signing, regardless of gender;
3. Histologically or cytologically confirmed esophageal squamous cell carcinoma (ESCC) with unresectable locally advanced disease, local recurrence, or distant metastasis;
4. Subjects with disease progression or intolerance after at least one line of systemic therapy.
5. At least one evaluable lesion meeting the criteria of RECIST 1.1;
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
7. Expected survival≥3 months;
8. Major organ functions meeting the prespecified criteria within 3 days prior to randomization
9. Male participants and female participants of childbearing potential must agree to adopt effective contraceptive measures from the time of signing the ICF until 7 months after the last dose; during this period, female participants must not be breastfeeding and male participants must refrain from sperm donation. Female participants of childbearing potential must have a negative blood pregnancy test within 7 days prior to randomization.
Exclusion Criteria:
1. A past pathological diagnosis of esophageal cancer with adenocarcinoma, adenosquamous carcinoma, or other pathological types.
2. Active central nervous system (CNS) metastasis and/or meningeal metastasis. Subjects with supratentorial and/or cerebellar (i.e., no midbrain, pons, or medulla oblongata) metastasis who achieve stable disease for at least 4 weeks prior to randomization after local therapy (imaging shows no new brain metastases or no enlargement of existing brain metastatic lesions, and all neurological symptoms are stable or return to normal), and who do not require glucocorticoid therapy or are receiving a daily prednisone dose of ≤10 mg or an equivalent dose of other glucocorticoids, are eligible for the study.
3. Receipt of any anti-tumor therapy (including but not limited to chemotherapy, immunotherapy, radiotherapy, targeted therapy, etc.) within 4 weeks prior to randomization, with the exception of the following:
1. Receipt of oral chemotherapeutic agents or small-molecule targeted therapy agents within 2 weeks prior to randomization or within 5 half-lives of the drug (whichever is shorter);
2. Receipt of traditional Chinese medicine (TCM) or proprietary Chinese medicines with anti-tumor indications within 2 weeks prior to randomization;
3. Receipt of local palliative radiotherapy for the purpose of relieving bone metastasis pain within 2 weeks prior to randomization;
4. Receipt of major surgical treatment (excluding needle biopsy), participation in other clinical trials with study drug administration, or vaccination with live-attenuated vaccines within 4 weeks prior to randomization, or anticipated need for live-attenuated vaccine vaccination during the study period.
4. Known hypersensitivity to any component of SYS6010, or to humanized monoclonal antibody products; hypersensitivity or contraindication to irinotecan, paclitaxel, or docetaxel.
5. Prior receipt of treatment with irinotecan-containing drugs or topoisomerase Ⅰ inhibitor-toxin antibody-drug conjugate (ADC) products.
6. Body mass index (BMI) \< 16.0 kg/m\^2 or body weight \< 40 kg.
7. A history of any other active malignant tumor within 5 years (except for radically resected and non-recurrent basal cell carcinoma of the skin, cutaneous squamous cell carcinoma, superficial bladder cancer, localized prostate cancer, carcinoma in situ of the cervix, or other carcinomas in situ).
8. Presence of bleeding diathesis; active bleeding, hemoptysis, or a history of major bleeding within the past 6 months; imaging (CT or MRI) showing tumor invasion of major blood vessels, or the investigator judges that the tumor is highly likely to invade major blood vessels during the subsequent study period leading to fatal massive bleeding.
9. Presence of any severe and/or uncontrolled disease prior to randomization, including but not limited to:
1. Myocardial infarction, congestive heart failure (New York Heart Association \[NYHA\] class ≥ Ⅱ), unstable angina pectoris, coronary angioplasty, or bypass surgery within 6 months prior to randomization;
2. Left ventricular ejection fraction (LVEF) \< 50% as indicated by echocardiography during screening;
3. Arterial/deep venous thrombosis/cancer-associated thrombosis events (e.g., cerebrovascular accident including transient ischemic attack, cerebral hemorrhage, cerebral infarction, deep venous thrombosis, pulmonary embolism, etc.) within 6 months prior to randomization;
4. Uncontrolled serous cavity effusions requiring repeated drainage (e.g., pleural effusion, ascites, pericardial effusion, etc.);
5. Uncontrolled hypertension (defined as systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg with medical management) or a history of hypertensive crisis/hypertensive encephalopathy;
6. Corrected QT interval using Fridericia's formula (QTcF) ≥ 450 ms in males and QTcF ≥ 470 ms in females; or a diagnosis of congenital long QT syndrome, and/or known concomitant use of drugs that prolong the QT interval;
7. Severe cardiac rhythm or conduction abnormalities (e.g., ventricular arrhythmias requiring clinical intervention, third-degree atrioventricular block, etc.);
8. Clinically significant severe electrolyte abnormalities requiring medical treatment as judged by the investigator;
9. Poorly controlled diabetes mellitus (fasting blood glucose \> 10.0 mmol/L).
10. Active viral hepatitis (positive HBsAg with HBV-DNA ≥ 10\^4 cps/mL or ≥ 2000 IU/mL; positive HCV antibody with positive HCV viral titer); human immunodeficiency virus antibody (HIV-Ab) positive subjects; active syphilis infection (positive Treponema pallidum antibody with positive Rapid Plasma Reagin \[RPR\] or Toluidine Red Unheated Serum Test \[TRUST\]).
11. A past history of interstitial lung disease (ILD)/non-infectious pneumonia requiring glucocorticoid therapy, current ILD/non-infectious pneumonia, or inability to rule out ILD/non-infectious pneumonia by imaging examination during screening.
12. A history of abdominal fistula, tracheoesophageal fistula, gastrointestinal perforation, or abdominal abscess within 6 months prior to randomization; or obvious ulceration of the esophageal lesion, tumor invasion of adjacent tissues, or imaging evidence of a risk of tracheoesophageal fistula, and the investigator judges the subject to be unsuitable for anti-angiogenic drug therapy.
13. A past or current history of mental disorders or epilepsy requiring treatment.
14. Infection requiring systemic anti-infective therapy within 2 weeks prior to randomization (except for uncomplicated urinary tract infection or upper respiratory tract infection).
15. Presence of clinically significant gastrointestinal diseases during screening, including bleeding, inflammation, obstruction, intractable vomiting (defined as ≥ 3 episodes of vomiting within 24 hours), and diarrhea of grade \> 1.
16. Ingestion of strong CYP3A4 inducers or inhibitors, or OATP1B1/OATP1B3 inhibitors within 2 weeks prior to randomization, or anticipated need for the above drugs during the trial period.
17. Failure of adverse reactions from prior chemotherapy, surgery, radiotherapy, or other anti-tumor therapies to resolve to ≤ Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) Version 6.0 or baseline levels (except for toxicities with no safety risk as judged by the investigator, such as alopecia).
18. Presence of skin diseases requiring oral or intravenous drug therapy during screening, and the investigator judges the subject to be unsuitable for study drug administration.
19. Other conditions that the investigator deems unsuitable for participation in this clinical trial.
