This study is a domestic, multicenter, single-arm clinical trial designed to evaluate the efficacy and safety of heterogeneous radiotherapy (high and low dose) sequenced with iparomlimab and tuvonralimab plus SOX as a first-line treatment for unresectable locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma.

Inclusion Criteria:

• Age 18-75 years, male or female.
• Histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma.
• Patients with no prior systemic therapy for locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. For patients who received neoadjuvant or adjuvant chemotherapy or chemoradiotherapy with curative intent, the interval from the last treatment to disease progression must be at least 6 months.
• HER-2 negative (IHC 1+ or IHC 2+/FISH-negative).
• Presence of radiation-eligible tumor lesions.
• No anticipated need for tumor resection during the study treatment period.
• ECOG performance status 0-1.
• At least one measurable lesion per RECIST v1.1. Lesions that have received prior radiotherapy cannot be selected as target lesions unless they are the only measurable lesions and show unequivocal progression on imaging, in which case they may be considered as target lesions.
• Expected overall survival ≥ 3 months.
• Adequate function of major organs.

Exclusion Criteria:

• Presence of other histologic components confirmed by histopathology or cytology, such as squamous cell carcinoma, undifferentiated carcinoma, neuroendocrine carcinoma, etc.

• Prior treatment with any tumor immunotherapy, including immune checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies), immune checkpoint agonists (e.g., antibodies targeting ICOS, CD40, CD137, GITR, OX40), or immune cell therapy (e.g., CAR-T cells).

• Palliative local therapy to non-target lesions within 2 weeks before the first dose; or systemic non-specific immunomodulatory therapy (e.g., interleukin, interferon, thymosin) within 2 weeks before the first dose.

• Clinically significant pleural effusion, pericardial effusion, or ascites requiring frequent drainage (≥ 1 time per month).

• Known active or untreated brain metastasis, meningeal metastasis, spinal cord compression, or leptomeningeal disease. Patients with measurable lesions outside the central nervous system may be eligible if: they are asymptomatic after treatment, radiologically stable for at least 4 weeks before study treatment (no new or enlarging brain metastases), and have discontinued systemic corticosteroids and anticonvulsants for at least 2 weeks.

• Gastrointestinal perforation, gastrointestinal fistula, or intra-abdominal abscess within 6 months before the first dose.

• Clinically significant bleeding or definite bleeding diathesis within 6 months before the first dose, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, or vasculitis, excluding asymptomatic positive fecal occult blood.

• Arterial or venous thromboembolism within 6 months before the first dose, including cerebrovascular accident (transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, pulmonary embolism, etc. Superficial venous thrombosis is permitted.

• Clinically active hemoptysis or active diverticulitis.

• Major surgery other than for gastric cancer diagnosis within 28 days before the first dose, or anticipated major surgery during the study period.

• Severe infection (CTCAE grade > 2) within 4 weeks before the first dose, such as severe pneumonia, bacteremia, infectious complications requiring hospitalization; active lung inflammation on baseline chest imaging; or signs/symptoms of infection or oral/intravenous antibiotic therapy within 14 days before the first dose, excluding prophylactic antibiotics.

• Any active or history of autoimmune disease, including but not limited to: interstitial lung disease, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism. Hypothyroidism may be allowed if controlled by hormone replacement. Patients with fully resolved psoriasis or childhood asthma/allergies requiring no intervention in adulthood may be included; those requiring medical intervention with bronchodilators are excluded.

• History of immunodeficiency, including positive HIV test, other acquired or congenital immunodeficiency diseases, organ transplantation, or allogeneic bone marrow transplantation.

• Uncontrolled cardiac conditions, including but not limited to:

  1. NYHA class ≥ II heart failure;
  2. unstable angina;
  3. myocardial infarction within 1 year;
  4. clinically significant supraventricular or ventricular arrhythmia uncontrolled or poorly controlled despite intervention;
  5. QTc > 450 ms (male); QTc > 470 ms (female).

• Active tuberculosis confirmed by medical history or CT scan, active tuberculosis within 1 year before screening, or history of active tuberculosis > 1 year without standard treatment.

• Active hepatitis: HBsAg positive with HBV DNA ≥ 2000 IU/mL; HCV antibody positive with HCV viral load above the upper limit of normal.

• Diagnosis of another malignancy within 5 years before the first dose, except malignancies with low risk of metastasis or death (5-year survival > 90%), such as adequately treated basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.

• Administration of live attenuated vaccine within 4 weeks before the first dose. If enrolled, patients must not receive live vaccines during the study or within 120 days after the last dose of iparomlimab and tuvonralimab.

• Known hypersensitivity or intolerance to any study drug(s) and/or their components.

• Toxicity from prior anti-tumor therapy that has not resolved to NCI-CTCAE v5.0 grade 0 or 1, or to the level specified in the inclusion/exclusion criteria, except alopecia or pigmentation.

• Pregnant or lactating female.

• Participation in another clinical study, unless it is an observational, non-interventional study or the follow-up period of an interventional study.

• Any other conditions judged by the investigator that may result in premature discontinuation from the study, including other severe diseases (including psychiatric disorders) requiring concurrent treatment, alcoholism, drug abuse, family or social factors that may affect patient safety or compliance.