Chemoradiotherapy and SHR-1701 in Patients With Unresectable Gastric Cancer

The investigators are conducting a clinical research study to evaluate the efficacy and safety of radiotherapy combined with CAPOX and SHR-1701 for patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. The study hypothesizes that radiotherapy combined with CAPOX and SHR-1701, a PD-L1/TGF-β bispecific antibody, may improve clinical outcomes compared with the current standard first-line treatment. The primary objective is to evaluate progression-free survival (PFS). Secondary objectives include objective response rate (ORR), overall survival (OS), local control rate (LCR), R0 resection rate, pathological complete response (pCR), major pathological response (MPR), treatment-related adverse events, and quality of life. The trial will enroll 60 participants across multiple study centers. Eligible participants will receive radiotherapy combined with CAPOX and SHR-1701, followed by SHR-1701 maintenance therapy when appropriate. Exploratory analyses will evaluate potential biomarkers associated with treatment response and survival. This study aims to provide a safe and effective first-line treatment strategy for patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.

Inclusion criteria

• Male or female participants aged 18 to 75 years.
• Histologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.
• Unresectable locally advanced or metastatic gastric cancer, with primary and metastatic lesions amenable to radiotherapy (excluding patients with brain metastases or extensive metastatic disease).
• HER2-negative disease.
• ECOG performance status of 0-1.
• At least one measurable lesion according to RECIST version 1.1.
• Adequate organ function, including:

• Hemoglobin ≥90 g/L;
• White blood cell count ≥3.5 × 10⁹/L;
• Absolute neutrophil count ≥1.5 × 10⁹/L;
• Platelet count ≥100 × 10⁹/L;
• Serum creatinine ≤1.0 × upper limit of normal (ULN);
• Blood urea nitrogen (BUN) ≤1.0 × ULN;
• Alanine aminotransferase (ALT) ≤1.5 × ULN;
• Aspartate aminotransferase (AST) ≤1.5 × ULN;
• Alkaline phosphatase (ALP) ≤1.5 × ULN;
• Total bilirubin (TBIL) ≤1.5 × ULN;
• Negative urine protein;
• Normal coagulation function.
• No contraindications to immunotherapy.
• No history of hypersensitivity to fluoropyrimidines or platinum-based agents.
• No prior surgery, chemotherapy, immunotherapy, or other antitumor therapy for gastric or gastroesophageal junction cancer since diagnosis.
• No previous radiotherapy to the intended irradiation sites.
• Ability to understand and willingness to sign a written informed consent form.

Exclusion criteria

• Brain metastases or extensive metastatic disease.
• Prior treatment with PD-1, PD-L1, TGF-β, CTLA-4 inhibitors, or other investigational immunotherapies.
• Severe autoimmune diseases, including but not limited to active inflammatory bowel disease (Crohn's disease or ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, or autoimmune vasculitis (e.g., Wegener's granulomatosis).
• Symptomatic interstitial lung disease or active infectious/non-infectious pneumonitis.
• Conditions associated with an increased risk of gastrointestinal perforation, including active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, abdominal carcinomatosis, or other known risk factors.
• History of another malignancy, except adequately treated early-stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or carcinoma in situ of the cervix.
• Active infection, heart failure, myocardial infarction within 6 months, unstable angina, or unstable cardiac arrhythmia.
• Any physical examination findings, laboratory abnormalities, or uncontrolled medical conditions that, in the investigator's judgment, may interfere with study outcomes or increase the risk of treatment-related complications.
• Pregnant or breastfeeding women.
• Congenital or acquired immunodeficiency, including HIV infection, or a history of organ transplantation or allogeneic hematopoietic stem cell transplantation.
• Active hepatitis B infection (HBV DNA ≥2,000 IU/mL), active hepatitis C infection, or active tuberculosis.
• Receipt of any live or other prohibited vaccines within 4 weeks before study treatment. Seasonal inactivated influenza vaccines are permitted, whereas intranasal live attenuated influenza vaccines are not permitted.
• Concurrent treatment with other immunosuppressive agents, chemotherapy, investigational drugs, or long-term systemic corticosteroids.
• Psychiatric disorders, substance abuse, or social conditions that may compromise treatment compliance, as determined by the investigator.
• Known hypersensitivity or contraindication to any study treatment.