Neo-Sequence 1: Neoadjuvant Chemotherapy With or Without Antiangiogenesis and Sequential Immunotherapy for HER2-negative MMR-proficient Locally Advanced Gastric or Gastroesophageal Adenocarcinoma

This is a single-institution, prospective phase II trial designed to evaluate the efficacy of neoadjuvant chemotherapy and sequential immunotherapy in patients with locally advanced esophagogastric junction and gastric adenocarcinoma. Patients with Her-2 positive or dMMR tumors will be excluded from the study. Six cycles of nab-paclitaxel, oxaliplatin and S-1 with or without bevacizumab, followed by three circles of nab-paclitaxel, bevacizumab, with or without S-1 combined with two cycles of PD-1 monoclonal antibody, will be administered as neoadjuvant therapy. Patients will receive different adjuvant treatments depending on the degrees of surgical radicality and the pathological reactions of tumors.


Eligibility Criteria:
Inclusion Criteria:

1. Be willing and able to provide written (signed) informed consent;
2. Age ≥ 18 years and ≤75 years.
3. Has a pathologic diagnosis of gastroesophageal or gastric adenocarcinoma, mucinous adenocarcinoma or signet ring cell carcinoma.
4. Imaging (CT/ultrasonography of cervical lymph nodes and supraclavicular lymph nodes/ endoscopy and endoscopic ultrasound) confirmed at the stage of cT3/4a NanyM0(AJCC 8th).
5. Confirmed by immunohistochemistry (IHC) staining or genetic and transcriptional profiling detection to meet all of the following conditions:

   1. Her-2-negative was defined as IHC -, IHC 1+ or IHC 2+ and FISH negative;
   2. Mismatch repair-proficient (pMMR).
6. The Eastern Cooperative Oncology Group Performance status (ECOG PS) 0-1;
7. The main organ function meets the following criteria within 7 days before treatment:

   1. Hemoglobin (Hb) level ≥9.0 g/dl.
   2. Neutrophil count (ANC)≥1.5×10\^9/L.
   3. Platelet (PLT) ≥100×10\^9/L
   4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level ≤2.5×ULN.
   5. Serum creatinine (Cr) level ≤1.0×ULN and creatinine clearance ≥60 ml/min.
   6. Total bilirubin(TBIL) level ≤1.5×ULN.

Exclusion Criteria:

1. Confirmed at stage IV (AJCC 8th) or unresectable by investigator before enrolling.
2. Patienta have had prior chemotherapy, targeted small molecule therapy, or radiation therapy for the current diagnosis of EGJ cancer or gastric cancer.
3. Patients are allergic to study medication and its ingredients.
4. Patients have experienced or currently have other malignancies within 5 years.
5. Patients have an active infection requiring systemic therapy.
6. Women who are pregnant, breast-feeding or planning to become pregnant during treatment or within 6 months after treatment ends.
7. Patients have a history of psychotropic substance abuse and are unable to quit or have a mental disorder.
8. Patients with other severe acute or chronic conditions that may increase the risk of participation in the study and study treatment, or may interfere with interpretation of study results, and judged by the investigator as not suitable for participation in this clinical trial.
9. Diagnosis of immunodeficiency or active autoimmune disease, receiving or being treated with immunomodulators, systemic steroids or immunosuppressive drugs in the past two years.
10. Patients with gastrointestinal obstruction or uncontrolled bleeding undergo emergency surgery.
11. The proportion of other components in the pathology (such as squamous cell carcinoma, neuroendocrine carcinoma, etc.) exceeds 10%