Trastuzumab Deruxtecan Plus Nivolumab Plus Capecitabine Plus Oxaliplatin for HER2 Low Gastric and Gastroesophageal Junction Adenocarcinoma

Prior treatment

• Has a prior chemotherapy for unresectable advanced or recurrent gastric/esophagogastric junction/esophageal adenocarcinoma. (Note: Patients are eligible if they have received prior preoperative or postoperative adjuvant therapy. However, treatment must have been completed at least 6 months prior to enrollment and progression must have occurred at least 6 months after completion of treatment).
• Grade 1 or residual adverse effects of prior therapy that have not resolved to baseline (excluding hair loss).
  • Note:Participants with Grade2 chronic toxicity (Defined as no worse than Grade 2 for at least 3 months prior to enrollment and manageable with standard therapy) who are considered by the investigator to have treatment-related toxicity are eligible for enrollment.
  • Chemotherapy-Induced Neuropathy
  • Malaise
• Has history of gastrointestinal perforation and/or gastrointestinal fistula within 6 months before enrollment.
• Has any of the following infections:
  • HBs antigen positive
  • HBs antibody or HBc antibody and HBV-DNA positive
  • Active hepatitis C (e.g., if HCV RNA is detected qualitatively) Patients who are HBsAg positive but who have achieved HBV DNA level \< 1.3 log IU/mL (2.1 log copies/mL) after treatment with antiviral drugs such as NAs, are eligible for the study.
• Lung diseases are defined as:
  • Has a history of non-infectious interstitial lung disease or pneumonitis that required treatment, has interstitial lung disease or pneumonitis, or these lung diseases cannot be ruled out by radiographic examination before enrollment.
  • Severe pulmonary impairment (e.g., pulmonary embolism within 3 months prior to enrollment, serious bronchial asthma, severe COPD, restrictive pulmonary disease, or pleural effusion).
  • Lung-related autoimmune or connective tissue or inflammatory diseases (e.g., rheumatoid arthritis, Sjogren's syndrome, or sarcoidosis) with clinically severe pulmonary risks.
  • Has history of pneumonectomy.
• Has history of concomitant autoimmune disease or chronic or recurrent autoimmune disease.
• Administration of systemic adrenocortical hormones (except prophylactic administration for tests or allergic reactions, and temporary use for the purpose of reducing edema associated with radiotherapy) or immunosuppressants is required, or has received these treatments within 14 days before enrollment in the study.
• If you have received a live attenuated vaccine (mRNA vaccine or replication-defective adenovirus vaccine is not regarded as live attenuated vaccine) within 30 days before the initial administration.

Other illness

• Active cancer that requires aggressive treatment, such as chemotherapy or operation
• Has serious (hospitalized) complications (intestinal palsy, intestinal obstruction, pulmonary fibrosis, diabetes mellitus that is difficult to control, heart failure, myocardial infarction, unstable angina, renal failure, liver failure, psychiatric disorders, cerebrovascular disorders, etc.)
• HIV infection has been documented.
• If you have uncontrolled acute systemic infection that requires Infusion intravenous antibiotic, antiviral, or antifungal drug.
• Severe hypersensitivity to the active ingredient or additive of the study drug has been confirmed.
• Has history/complications of severe hypersensitivity reactions to other monoclonal antibodies.

Lab values

• Has a medical history of myocardial infarction or congestive heart failure (New York Heart Association Classes II-IV) within 6 months before enrollment, corresponding to the \*\*troponin levels diagnosed as myocardial infarction as defined by the \*manufacturer within 28 days before enrollment (allowed on the same day), unstable angina, or any serious arrhythmia requiring treatment.
  • \*: Manufacturer refers to a testing company used by a study implementation institution.
  • \*\*: Enrollment is allowed if a subject exceeds ULN, if the subject is examined and myocardial infarction can be excluded.

Other

• Metastases to the central nervous system have been identified. (Only if CNS involvement is clinically suspected, cerebral CT scanning or MRI confirmation is mandatory at the time of screening.).
• Has unhealed wounds, ulcers, or fractures.
• If patients are a pregnancy or breastfeeding patient.
• Patients who do not take appropriate contraceptive measures during the study and contraceptive period
• Unwilling or unable to comply with any of implementation matters stipulated in the study implementation protocol or any of the instructions of the physician.
• The investigator or sub investigator considered it ineligible for the study.

• Historical confirmation of adenocarcinoma of the gastric, gastroesophageal junction, or esophagus is considered by the investigator or subinvestigator to be unresectable advanced or recurrent.
• HER2 low expression: IHC1+, or IHC2+ and ISH negative \[FISH or DISH method\] in HER2 test of the primary lesion or metastatic lesion.
• Having one or more measurable disease as specified in RECIST Guideline version 1.1.
• Systemic treatment is untreated (local radiation and surgical treatment is acceptable).
• Age at the date of informed consent is 20 years or older.
• ECOG Performance status (PS) of 0 or 1.
• Has LVEF \>= 50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before enrollment.
• Has a corrected QT interval (QTc) =\< 470 ms in females, or QTc =\< 450 ms in males based on a 12-lead ECG screening within 28 days before enrollment (allowed on the same day of the week). \[Fridericia's correction is recommended\]
• The most recent laboratory value within 14 days before enrollment meets all of the following. (Examinations on the same day of the week 2 weeks prior to the date of enrollment are allowed.) (1)Absolute Neutrophil count =\< 1,500/mm3 (2)Hemoglobin =\< 9.0 g/dL (3)Platelet count =\< 100,000/mm3 (4)Total bilirubin =\< 1.5 mg/dL (5)AST(GOT) =\< 100 IU/L =\< 200 IU/L in the presence of hepatic involvement (6)ALT(GPT) =\< 100 IU/L =\< 200 IU/L in the presence of hepatic involvement (7)Creatinine =\< 1.5 mg/dL (8)PT(INR) \< 1.8 and aPTT \< 60 seconds
• Has adequate treatment washout period before enrollment (allowed on the same day of the week), defined as:
  • Surgery with general anesthesia: \>= 4 weeks ii. Radiotherapy: \>= 4 weeks (including palliative stereotactic body radiation therapy to the chest; palliative stereotactic body radiation therapy to other than the chest \>= 2 weeks; abdominal vertebral bodies should be included in the abdomen).
  • Chloroquine and hydroxychloroquine: \>= 15 days
• No blood transfusion was performed within 7 days before registration. (Transfusions on the same day of the week prior to the day of enrollment are allowed.)
• Female of childbearing potential have a negative pregnancy test within 7 days before enrollment (allowed on the same day of the week). Male and Female of childbearing potential agree to contraception for a period (4 months for male and 7 months for Female) from informed consent to the last dose of study drug.
• Written informed consent of participation in the study has been obtained from the patient.