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

Clinical Efficacy of Pucotenlimab Combined With Lenvatinib and SOX Versus SOX Alone in Patients With HER2-Negative Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: A Single-Center Randomized Controlled Trial

The purpose of this study is to evaluate the objective response rate (ORR) of Pembrolizumab combined with Lenvatinib and SOX compared with SOX alone in the treatment of patients with HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma.

At present, for patients with advanced gastric cancer, palliative chemotherapy or the best supportive care is the main treatment approach, but the therapeutic effect is not satisfactory. The median survival time is around 10-16 months, and the survival rate of patients is very low. How to improve the treatment effect of advanced gastric cancer is an urgent problem to be solved. Currently, several studies on immunotherapy combined with chemotherapy for gastric cancer are underway. From the subgroup analyses of a series of studies ，it can be seen that the expression of PDL1 is increased, which provides a basis for the treatment of advanced tumors with immune checkpoint inhibitors. Studies have shown that the combination of Lenvatinib can reduce angiogenesis in mice, reprogram vascular structure, enhance the infiltration of CD8+ T cells, CD8+ TNFα+ T cells and CD8+ IFNγ+ T cells, and decrease the proportion of MDSCs and macrophages. This provides a basis for the combined use of Lenvatinib and immune checkpoint inhibitors in the treatment of advanced tumors. This study adopts a single-center, prospective research method, aiming to explore the clinical effectiveness and safety of Pucotenlimab combined with Lenvatinib and the SOX regimen in the treatment of patients with HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma.

Inclusion Criteria:

**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:

1. Haematology (obtained ≤ 14 days without transfusion):

   1. Hb ≥ 80 g/L
   2. WBC ≥ 3 × 10⁹/L
   3. ANC ≥ 1.5 × 10⁹/L
   4. PLT ≥ 100 × 10⁹/L

2. Biochemistry:

   1. Total bilirubin < 1.5 × upper limit of normal (ULN)

   2. ALT and AST < 2.5 × ULN; ALP ≤ 1.5 × ULN

   3. 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.

      Exclusion Criteria:

      Exclusion Criteria

      Subjects meeting any of the following conditions will be excluded from enrollment:

      1. Known or suspected hypersensitivity to the investigational drug or any drug of the same class.

      2. 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.

      3. Currently receiving treatment in another interventional clinical trial, or any systemic anti-gastric-cancer therapy within 4 weeks prior to the first dose.

      4. 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.

      5. 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.

      6. 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.

      7. 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.

      8. Prior allogeneic bone-marrow or solid-organ transplantation.

      9. Any condition that could impair drug absorption or inability to swallow oral medication.

      10. Uncontrolled hypertension despite optimal medical management:

          • SBP ≥ 150 mmHg or DBP ≥ 100 mmHg on a single antihypertensive, or requirement of ≥ 2 antihypertensive agents.

      11. Urinalysis showing proteinuria ≥ 2+ and 24-h urinary protein > 1.0 g.

      12. 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.

      13. 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.

      14. 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.

      15. Active or uncontrolled severe infection (≥ CTCAE grade 2).

      16. 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.

      17. Known dihydropyrimidine dehydrogenase (DPD) deficiency.

      18. Any condition that, in the opinion of the investigator, would compromise the subject's safety or interfere with study participation.