Conversion Therapy With Retlirafusp Alfa Plus Chemotherapy in Gastric or Gastroesophageal Junction Adenocarcinoma

Prior treatment

• Prior systemic therapy for advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.
• Use of traditional Chinese medicine with antitumor indication or systemic immunomodulatory drugs, including thymosin, interferon, or interleukin, within 2 weeks before the first dose, except for local use to control pleural effusion.
• Requirement for systemic corticosteroids equivalent to prednisone \>10 mg/day or other immunosuppressive therapy within 14 days before the first dose or during the study, except for topical or inhaled corticosteroids or adrenal replacement therapy at a dose equivalent to prednisone ≤10 mg/day in the absence of active autoimmune disease.
• Any active infection requiring systemic anti-infective therapy within 14 days before the first dose, except prophylactic antibiotics.
• Thrombotic events within 6 months before screening, including cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or pulmonary embolism, except catheter-related venous thrombosis that has resolved as judged by the investigator.
• Receipt of a live vaccine within 30 days before the first dose.

Other illness

• History of malignancy within 5 years or current presence of another malignancy.
• Active bleeding from the tumor as shown by endoscopy.
• Known hypersensitivity to SHR-1701 or active ingredients or excipients of the chemotherapy drugs used in this study.
• Known history of human immunodeficiency virus infection.
• Untreated active hepatitis B, defined as HBsAg positivity with HBV DNA above the upper limit of normal at the study site.
• Active pulmonary tuberculosis.
• Liver disease such as cirrhosis, decompensated liver disease, or acute or chronic active hepatitis.

Lab values

• Myocardial infarction or poorly controlled arrhythmia within 6 months before the first dose, including QTc interval ≥450 ms in males or ≥470 ms in females using Fridericia's formula.
• New York Heart Association class III or IV heart failure or left ventricular ejection fraction \<50% by echocardiography.
• Poorly controlled diabetes mellitus, defined as fasting blood glucose \>10 mmol/L.
• Any medical history, disease, treatment, laboratory abnormality, or other condition that may interfere with study results, prevent full participation in the study, or pose additional risk as judged by the investigator.

Other

• Macroscopically visible peritoneal metastasis or other unresectable distant metastasis.
• Clinically active diverticulitis, abdominal abscess, or gastrointestinal obstruction.

• Histologically confirmed gastric or gastroesophageal junction adenocarcinoma by gastroscopic biopsy.
• Potentially resectable gastric or gastroesophageal junction adenocarcinoma as judged by the investigator, including but not limited to: T4b disease or fixed/fused lymph nodes; single liver metastasis, limited para-aortic lymph node metastasis (No.16a2/b1), or CY1P0 disease; more than one liver metastasis or a liver metastasis larger than 5 cm adjacent to the hepatic vein or portal vein, extensive para-aortic lymph node metastasis (No.16a1/b2), or selected distant metastases such as Virchow lymph node or lung metastasis.
• HER2-low, HER2-intermediate, or HER2-negative disease, and PD-L1 CPS ≥1.
• Age 18 to 75 years.
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• No prior systemic therapy for advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.
• Adequate organ function, defined as: white blood cell count ≥3.0 × 10\^9/L; absolute neutrophil count ≥1.5 × 10\^9/L; platelet count ≥100 × 10\^9/L; total bilirubin ≤ upper limit of normal; AST and ALT ≤3 × upper limit of normal; serum creatinine ≤1.5 × upper limit of normal or creatinine clearance ≥50 mL/min; activated partial thromboplastin time and international normalized ratio ≤1.5 × upper limit of normal; cardiac enzymes within normal range; and normal thyroid function. Participants with abnormal baseline TSH may be eligible if total T3 or free T3 and free T4 are within the normal range.
• Female participants of childbearing potential must have a negative serum pregnancy test within 72 hours before the first dose and agree to use effective contraception during the study and for at least 3 months after the last dose. Male participants with partners of childbearing potential must be surgically sterilized or agree to use effective contraception during the study and for at least 3 months after the last dose.
• Good compliance and willingness to complete study follow-up.