Clinical Efficacy of Pucotenlimab Combined With Lenvatinib and SOX Versus SOX Alone in Patients With HER2-Negative Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

Prior treatment

• Known or suspected hypersensitivity to the investigational drug or any drug of the same class.
• Currently receiving treatment in another interventional clinical trial, or any systemic anti-gastric-cancer therapy within 4 weeks prior to the first dose.
• Systemic Chinese patent medicines with anti-tumor indications or immunomodulatory agents (e.g., thymosin, interferon, interleukins; local intrapleural use for effusion control is permitted) received within 2 weeks before the first dose.
• Prior exposure to: anti-PD-1, anti-PD-L1, anti-PD-L2, or any agent targeting other T-cell co-stimulatory or co-inhibitory pathways (including but not limited to CTLA-4, OX-40, CD137); or prior chemotherapy including S-1.
• Live-vaccine administration within 4 weeks before enrollment or planned during the study.
  • Note: Inactivated seasonal influenza vaccine by injection is allowed within 4 weeks; intranasal live-attenuated influenza vaccine is prohibited.
• Prior allogeneic bone-marrow or solid-organ transplantation.
• Significant bleeding tendency within 3 months before enrollment: overt bleeding \> 30 mL, hematemesis, melena, hematochezia; hemoptysis (\> 5 mL fresh blood within 4 weeks); or thrombo-embolic event (including stroke/TIA) within 12 months.

Other illness

• Subjects meeting any of the following conditions will be excluded from enrollment:
• Other malignancies within the past 5 years, except adequately treated basal-cell or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix.
• Active autoimmune disease requiring systemic therapy (e.g., immunosuppressants, corticosteroids, or disease-modifying agents) within 2 years before the first dose. Replacement therapy (thyroxine, insulin, physiologic glucocorticoids for adrenal or pituitary insufficiency) is not considered systemic therapy.
• Any condition that could impair drug absorption or inability to swallow oral medication.
• Uncontrolled hypertension despite optimal medical management:
  • SBP ≥ 150 mmHg or DBP ≥ 100 mmHg on a single antihypertensive, or requirement of ≥ 2 antihypertensive agents.
• Active gastro-duodenal ulcer, ulcerative colitis, or other gastrointestinal disorders with bleeding risk; un-resected tumors with active hemorrhage; or any other condition judged by the investigator to predispose to GI bleeding or perforation.
• Active or uncontrolled severe infection (≥ CTCAE grade 2).
• Any condition that, in the opinion of the investigator, would compromise the subject's safety or interfere with study participation.

Lab values

• Clinically significant cardiovascular disease:
  • Acute MI, unstable/severe angina, or CABG within 6 months before enrollment;
  • NYHA class \> II congestive heart failure;
  • Ventricular arrhythmia requiring therapy;
  • QTc ≥ 480 ms on baseline ECG.
• Known HIV infection; clinically significant hepatic disorders:
  • Chronic hepatitis B with active replication (HBV DNA \> 1 × 10⁴ copies/mL or \> 2000 IU/mL);
  • Hepatitis C with detectable HCV RNA (\> 1 × 10³ copies/mL);
  • Other hepatitis or cirrhosis.

Other

• Urinalysis showing proteinuria ≥ 2+ and 24-h urinary protein \> 1.0 g.
• Known dihydropyrimidine dehydrogenase (DPD) deficiency.

• \*\*Inclusion Criteria\*\* 1. Age 18-75 years (inclusive). 2. Histologically or cytologically confirmed unresectable, locally advanced or metastatic HER2-negative adenocarcinoma of the stomach or gastro-oesophageal junction (GEJ).
• 3\. No prior systemic chemotherapy, radiotherapy, targeted therapy, or immunotherapy for advanced disease. Subjects who have received prior (neo)adjuvant chemotherapy and/or radiotherapy are eligible provided the last dose was completed ≥ 6 months before randomisation.
• 4\. At least one measurable lesion per RECIST 1.1 (see Appendix 2). 5. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 (see Appendix 4).
• 6\. Estimated life expectancy \> 3 months. 7. Adequate major organ function defined as:
• Haematology (obtained ≤ 14 days without transfusion):
  • Hb ≥ 80 g/L
  • WBC ≥ 3 × 10⁹/L
  • ANC ≥ 1.5 × 10⁹/L
  • PLT ≥ 100 × 10⁹/L
• Biochemistry:
  • Total bilirubin \< 1.5 × upper limit of normal (ULN)
  • ALT and AST \< 2.5 × ULN; ALP ≤ 1.5 × ULN
  • Serum creatinine ≤ 1 × ULN and calculated creatinine clearance ≥ 60 mL/min (Cockcroft-Gault formula) 8. Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to enrolment and must use highly effective contraception from screening until 8 weeks after the last dose of study drug. Men must be surgically sterile or agree to use effective contraception during the same period.
  • 9\. No participation in any other interventional clinical trial during the pre-treatment or on-treatment phases of this study.
  • 10\. Voluntary written informed consent obtained; willing and able to comply with study procedures and follow-up.