Neoadjuvant Immunotherapy and Chemotherapy for Locally Advanced Esophagogastric Junction and Gastric Cancer Trial

Efficacy and Safety of Neoadjuvant Immunotherapy and Chemotherapy for Locally Advanced Esophagogastric Junction and Gastric Cancer : a Open-label, Phase 2 Randomised Controlled Trial (NICE Trial)

For locally advanced esophagogastric junction and gastric cancer (cT3-4aNxM0 or cT2N+M0), neoadjuvant chemotherapy can downstage T and N stage,treated distant micrometastases early before local therapy has begun, and finally improve the long-term survival. Combination of perioperative PD-1 antibody and chemotherapy for locally advanced esophagogastric junction and gastric cancer could be a novel therapy to increase response rate and reduce recurrence rate. JS001 in this study is a Chinese anti-PD-1 monoclonal antibody for injection which has been approved for melanoma. This study is a multi-center, open-label, randomized phase II clinical trial to evaluate safety and efficacy of JS001 in combination with perioperative chemotherapy in locally advanced esophagogastric junction and gastric cancer. Differences in gut microbiome and tumor immune microenvironment were detected to screen people who were more sensitive to immunotherapy.

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide and a substantial global health burden. Surgery is the only possible way to cure gastric cancer, however, more than 80% of the Chinese patients are diagnosed at advanced stages. Locally advanced esophagogastric junction and gastric cancer (cT3-4aNxM0 or cT2N+M0) could be cured by multi-disciplinary therapies including surgery, chemotherapy and radiotherapy. Neoadjuvant chemotherapy can downstage T and N stage, treated distant micrometastases early before local therapy has begun, and finally improve the long-term survival. However, the therapeutic effects remain unsatisfactory. PD-1 antibody has demonstrated its efficacy in metastatic gastric cancer and has been proved to be effective in neoadjuvant setting in lung cancer and melanoma. Combination of perioperative PD-1 antibody and chemotherapy for locally advanced esophagogastric junction and gastric cancer could be a novel therapy to increase response rate and reduce recurrence rate. JS001 in this study is a Chinese anti-PD-1 monoclonal antibody for injection which has been approved for melanoma. This study is a multi-center, open-label, randomized phase II clinical trial to evaluate safety and efficacy of JS001 in combination with perioperative chemotherapy in locally advanced esophagogastric junction and gastric cancer. Differences in gut microbiome and tumor immune microenvironment were detected to screen people who were more sensitive to immunotherapy.

Inclusion Criteria:

1. Written (signed) informed consent;

2. Age ≥ 18 years and ≤75 years.

3. Confirmed gastric and gastroesophageal junction adenocarcinoma by Gastroscopic biopsy histopathological examination.

4. Imaging (CT/MRI) and diagnostic laparoscopy confirmed at the stage of cT3/4a Nx or T2 N+, M0(AJCC 8th) before randomization.

5. confirmed by immunohistochemistry (IHC) staining or genetic and transcriptional profiling detection to meet one of the following conditions:

   1. Combined positive score (CPS) of PD-L1 protein expression ≥5.
   2. Epstein-Barr virus-positive (EBV(+)).
   3. mismatch repair-deficient (dMMR).
   4. Microsatellite instability-high (MSI-H)

6. The Eastern Cooperative Oncology Group Performance status (ECOG PS) 0-1

7. Expected survival period ≥ 12 weeks

8. 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×l09/L
   3. Platelet (PLT) ≥100×109/L
   4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level ≤2.5×ULN
   5. Alkaline phosphatase(ALP)level ≤2.5×ULN
   6. Serum creatinine (Cr) level ≤1.5×ULN and creatinine clearance ≥60 ml/min
   7. Thyroid stimulating hormone (TSH) level ≤1×ULN (if abnormal, should require normal serum free thyroid hormone (T4) and Normal serum free triiodothyronine (T3))

Exclusion Criteria:

1. Confirmed at stage IV (AJCC 8th) or unresectable by investigator before randomization.

2. Prior chemotherapy, radiotherapy, surgery immunotherapy or molecular targeted therapy for gastric cancer;

3. Patients who have HER2 positive confiemed with IHC3+ or IHC2+ and FISH positive

4. Patients are allergic to study medication and its ingredients

5. Patients with a history of following treatments:

   1. Prior therapy with a PD-1, anti-PD-Ligand 1 (PD-L1) or CTLA-4 agent
   2. Prior therapy with tyrosine kinase inhibitor within 2 weeks.
   3. Patients who have participated in other clinical trials of anti-tumor drugs within four weeks
   4. Have vaccination with attenuated live vaccines within 4 weeks prior to initiation of the study treatment or plan to vaccinate during the study;
   5. Concurrent medical condition requiring the use of cortisol (>10mg/day Prednisone or equivalent dose) or other systematic immunosuppressive medications within 14 days before the study treatment. Except: inhalation or topical corticosteroids. Doses > 10 mg/day prednisone or equivalent for replacement therapy

6. Patients have experienced or currently has other malignancies within 5 years.

7. Patients have an active or history of autoimmune disease that may recur or require immunosuppressive drugs within 2 weeks or less or during the study. Or have a history of immunodeficiency, including HIV-positive or other acquired, congenital immunodeficiency disease, or a history of organ transplantation

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. Within 2 weeks or 2 weeks before randomization, patients have an active or uncontrollable infection that requires systemic antibiotic treatment

10. Diagnosed with interstitial pneumonia, non-infectious pneumonia, pulmonary fibrosis, acute lung disease;

11. Patients with active tuberculosis or receiving previous anti-tuberculosis therapy within one year

12. Women who are pregnant, breast-feeding or planning to become pregnant during treatment or within 6 months after treatment ends.

13. Patients have a history of psychotropic substance abuse and are unable to quit or have a mental disorder