Inclusion Criteria:
* Written informed consent and HIPAA authorization for release of personal health information.
NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
* Histological or cytological confirmed locally advanced or metastatic EGA. Known HER2 status prior to treatment initiation required. Known PDL1 CPS status prior to treatment initiation.
* Measurable disease according to RECIST v1.1.
* No prior lines of systemic therapy for advanced disease.
* Participants who had received neoadjuvant or adjuvant therapy or definitive chemoradiation will be allowed to participate if recurrence occurred 6 months or longer from the completion of all prior treatments.
* Demonstrate adequate organ function as defined below; all screening labs to be obtained within 14 days prior to registration
* Absolute Neutrophil Count (ANC) ≥1,500 /μl without the use of hematopoietic growth factors
* Hemoglobin (Hgb) ≥8 g/dL (blood transfusions are permitted for participants with hemoglobin levels below 8 g/dL)
* Platelets ≥100,000 /μl
* Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl). CrCl calculation using the Cockcroft-Gault formula. ≥50 mL/min for participants with creatinine levels \> 1.5 X institutional ULN
* Bilirubin within normal range for the institution (biliary drainage is allowed for biliary obstruction)
* Aspartate aminotransferase (AST) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
* Alanine aminotransferase (ALT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
* International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
* Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
* Women of childbearing potential should have a negative urine or serum pregnancy test within 14 days of study registration. NOTE: Women are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
* Women of childbearing potential and males must be willing to abstain from heterosexual activity or to use a form of effective method of contraception from the time of informed consent until 30 days after treatment discontinuation.
* As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.
Exclusion Criteria:
* Known hypersensitivity to 5-FU, oxaliplatin or other platinum agents, or any of the components of nal-IRI and other liposomal products.
* Known dihydropyrimidine dehydrogenase (DPD) deficiency (testing not required prior to enrollment).
* Other active malignancy requiring treatment within the last 2 years. Exceptions include subjects with non-melanoma skin cancer, non-invasive/in situ cancer or low-risk prostate cancer requiring hormonal therapy only.
* Current therapy with other investigational agents or participation in another clinical study (supportive care and nontherapeutic trial participation allowed if not receiving an investigational drug). Participants may participate in prescreening for other therapeutic trials (prescreening of biologic sample for specific mutations, receptors, etc.)
* Major surgery within 28 days or minor surgery within 14 days of the start of the study treatment, except for tumor biopsy or placement of central infusion device (port placement).
* Radiotherapy less than 7 days prior to the start of the study treatment
* Participants who receive nivolumab or pembrolizumab in addition to chemotherapy should not have any contraindications to immune checkpoint inhibitors and should not have received immunotherapy agents for the treatment of EGA prior to study enrollment.
* Participants must not have active autoimmune disease that has required systemic treatment in the past 2 years. Participants are permitted to receive immunotherapy l if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event).
* Participants must not have a condition requiring systemic treatment with either corticosteroids (\>10 mg/day prednisone equivalents) or other immunosuppressive medications within 14 days of study immunotherapy administration. Inhaled or topical steroids and adrenal replacement doses (≤10 mg/day prednisone equivalent) are permitted. Participants with prior immune mediated adverse events related to immunotherapy that resulted in permanent treatment discontinuation with these agents.
* Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up schedule.
* Active infection requiring systemic therapy.
* Pregnant or breastfeeding.
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
* Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before inclusion.
* NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure.
* Known history of Human Immunodeficiency Virus (HIV).
