Circulating Tumor DNA MRD-Guided Adjuvant Therapy for Curatively Resected Locally Advanced Esophageal Squamous Cell Carcinoma

Inclusion Criteria: * 1\. Be willing and able to provide written informed consent. 2. Be ≥19 years of age on the day of signing the informed consent form. 3. Have ECOG performance status of 0 or 1 (Appendix 1). 4. Have a histologically confirmed diagnosis of squamous cell carcinoma of the esophagus * Patients with tumors of mixed histology (i.e., squamous and non-squamous) are eligible if the predominant histological component is squamous, except when small cell or neuroendocrine elements are present. 5\. Must have completed surgical resection for localized disease, either with prior neoadjuvant chemoradiotherapy or without prior neoadjuvant therapy (i.e., upfront surgery), in accordance with the 8th edition of the AJCC staging system (Appendix 2). Exceptionally, cases with supraclavicular lymph node metastasis as the only M1 lesion are also eligible if the lymph node has been surgically removed. 6\. Must have undergone curative surgery (R0 resection) with negative margins on the resected specimen. 7\. Complete resection must have been performed within 4-16 weeks before randomization. 8\. Must have a documented disease-free status based on a complete physical examination and imaging studies within 4 weeks before randomization. Imaging studies must include CT scans (or MRI) of the chest, abdomen, and pelvis. 9\. Must provide tumor tissue from pre-treatment biopsy (i.e., a biopsy obtained prior to neoadjuvant therapy in cases where neoadjuvant therapy is followed by surgery) or from surgical specimens and baseline blood samples for post-surgery ctDNA-MRD measurement and biomarker analyses. * For patients who underwent upfront surgery, surgical tissue is preferred. For those who received neoadjuvant therapy followed by surgery, pre-treatment biopsy tissue is preferred. * A FFPE tumor specimen in a paraffin block or 20 (at least 10, with a thickness of 10 µm) freshly cut unstained FFPE slides, along with one H\&E-stained slide with tumor-area marking, must be submitted with the associated pathology report. If an insufficient number of slides is available, the decision on patient enrollment can be made in consultation with the Study Sponsor. * Peripheral blood of 20 mL must be collected between 3 to 12 weeks after curative surgery for ctDNA testing. 10\. Must be confirmed to have MRD-positive status via postoperative baseline ctDNA testing. 11\. Must have adequate major organ functions as demonstrated by the following laboratory results obtained within 14 days before randomization (these criteria must also be met within 7 days before initiating study treatment in the adjuvant therapy arm): * Adequate bone marrow function defined by: * Absolute neutrophil count (ANC) ≥ 1,500/μL without granulocyte colony-stimulating factor support within 7 days before laboratory testing * Platelet count ≥ 100 ×103/μL without transfusion within 7 days before laboratory testing • Adequate renal function defined by: * Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 50 mL/minute, calculated using the Cockcroft-Gault formula (Appendix 3) or measured by a 24-hour urine collection • Adequate hepatic function defined by: * ALT and AST ≤ 2.5 × ULN * Total bilirubin ≤ 1.5 × ULN, except for subjects with Gilbert syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who must have a total bilirubin level ≤ 3 × ULN 12. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 14 days prior to randomization. If the urine test is positive or inconclusive, a serum pregnancy test will be required. 13\. Female subjects of childbearing potential randomized to the adjuvant therapy arm must agree to use an adequate method of contraception for the duration of study treatment and for 90 days after the last dose of study treatment. 14\. Non-sterile male subjects randomized to the adjuvant therapy arm with female sexual partner(s) of childbearing potential must agree to use an adequate method of contraception for the duration of study treatment and for 90 days after the last dose of study treatment. Exclusion Criteria: * 1\. Documented recurrence of esophageal cancer before randomization following curative resection. 2\. Receipt of any treatment aimed at the resected esophageal cancer after curative surgery, including chemotherapy, targeted therapy, immunotherapy, radiotherapy, biologic therapy, investigational agent, or local therapies, except for procedures intended for palliative care (e.g., stent insertion, balloon dilatation, or feeding enterostomy). 3\. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitor, or any other drug targeting T-cell co-stimulation or checkpoint pathways. 4\. Active autoimmune disease requiring systemic treatment within the 2 years prior to study entry (i.e., using disease-modifying agents, corticosteroids, or immunosuppressive drugs). • Replacement therapy (e.g., thyroxine for autoimmune-related hypothyroidism, insulin for type 1 diabetes mellitus, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. 5\. Condition requiring systemic treatment with corticosteroids (\>10 mg daily prednisone or equivalent) or any other form of immunosuppressive therapy within 14 days prior to study entry. • Use of topical, ocular, intra-articular, intranasal, and inhaled corticosteroids is permitted if there is no active autoimmune disease. * A short course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergens) is permitted. 6\. Receipt of a live vaccine within 28 days prior to study entry. * COVID-19 vaccines are allowed except for any live vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. 7\. Active infection requiring systemic therapy within 14 days prior to study entry. 8\. History of severe hypersensitivity to paclitaxel, carboplatin, or any antibody products. 9\. Known history of, or any evidence of, interstitial lung disease, non-infectious pneumonitis, or pulmonary fibrosis diagnosed based on imaging or clinical findings. * Subjects with radiation pneumonitis may be enrolled if radiation pneumonitis is stable (beyond the acute phase) and unlikely to recur. 10\. History of allogeneic stem cell or solid organ transplantation. 11. Malignancies other than esophageal cancer within the 3 years prior to study entry, except for malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate \>90%), such as adequately treated non-melanoma skin cancer, superficial bladder cancer, or carcinoma in situ (e.g., cervix, breast, or prostate). * Subjects who received endoscopic mucosal resection or dissection for superficial mucosal cancers within the past 3 years are eligible. 12\. Subjects with toxicities attributed to prior anti-cancer therapy, except alopecia, anorexia, fatigue, and hearing loss, that have not resolved to Grade 1 (NCI CTCAE v5.0) or baseline before randomization will be excluded. 13\. Significant cardiovascular impairment within 6 months prior to study entry, including a history of congestive heart failure (New York Heart Association Class III or IV), unstable angina, myocardial infarction, cerebrovascular accident, or cardiac arrhythmia associated with hemodynamic instability. 14\. Any serious or uncontrolled medical disorder that, in the investigator's opinion, may increase the risk associated with study participation or study treatment administration, or compromise the subject's ability to receive protocol therapy. 15\. History or current evidence of any condition, therapy, or laboratory abnormality that could confound trial results, interfere with the subject's participation for the full trial duration, or is not in the best interest of the subject to participate, in the investigator's opinion. 16\. Medical or psychiatric conditions that impair the subject's ability to give informed consent or complete the protocol, or a history of non-compliance. 17\. Known history of Human Immunodeficiency Virus (HIV) infection. 18. Untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers with HBV DNA ≥500 IU/mL (or 2,500 copies/mL), or active hepatitis C virus (HCV) infection: * Subjects with chronic hepatitis B (HBV DNA \< 500 IU/mL or \< 2,500 copies/mL) who are receiving antiviral therapy can be enrolled. Patients with detectable HBsAg or detectable HBV DNA should be managed according to institutional guidelines. * Patients with a negative HCV antibody test result at screening or a positive HCV antibody test followed by a negative HCV RNA test result at screening are eligible. 19\. Pregnant or breastfeeding women 20. Any condition requiring treatment with prohibited or restricted concomitant medication or therapy as described in Section 6.2.2