Zimberelimab + Domvanalimab in Gastroesophageal Adenocarcinoma

Inclusion Criteria:

* Participants must have histologically proven adenocarcinoma of the stomach or gastroesophageal junction (GEJ), including Siewert I-III adenocarcinomas of the GEJ
* Tumors must have a programmed death ligand-1 (PDL1) expression score of at least 1 or greater (≥1) by any testing method (any conventional immunohistochemistry assay and any calculation)
* Participants must be treatment naïve.
* Age ≥18 years.
* ECOG performance status ≤1
* Participants must have adequate organ and marrow function as defined below:

  * leukocytes ≥2,000/mcL
  * absolute neutrophil count ≥1,500/mcL
  * hemoglobin \> 9 g/dL
  * platelets ≥100,000/mcL
  * total bilirubin ≤ 1.5x institutional upper limit of normal (ULN) unless documented Gilbert's disease
  * AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN
  * Creatinine clearance ≥50 mL/min.
* For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
* Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
* Patients must have been deemed to have resectable disease by the medical oncology provider after reviewing with the multidisciplinary team including surgery. This must be documented in the medical record by the medical oncologist.
* Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation including six months after last study dose.
* Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of domvanalimab and/or zimberelimab administration. Males who have had a successful vasectomy (confirmed azoospermia, documentation needed) require no additional contraception.
* Ability to understand and the willingness to sign a written informed consent document.
* The participant is a non-smoker or light smoker who smokes no more than 10 cigarettes, 2 cigars, 2 pipes, or other nicotine equivalents (eg, vape, snuff, gum) of tobacco per day; willing to limit smoking during the treatment period to 4 cigarettes or 1 cigar per day.

Exclusion Criteria:

* Prior anti-PD-1/PD-L1/TIGIT treatment
* Participants who are receiving any other investigational agents or other anticancer therapies.
* Patients with brain metastases are excluded. Brain metastases constitute stage IVB disease and are not approached with curative intent and are therefore excluded.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to domvanalimab or zimberelimab
* Subjects with any condition requiring systemic treatment with either corticosteroids (\>2mg daily dexamethasone equivalent) or other immunosuppressive medications within 14 days of treatment. Premedication for hypersensitivity reactions (e.g. to contrast for CT or gadolinium for MRI) is allowed.
* History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), idiopathic pneumonitis, or clinical evidence of active pneumonitis. History of radiation pneumonitis/fibrosis in the radiation field is permitted.
* Participants with uncontrolled intercurrent illness that would interfere with ability to participate in the opinion of the treating investigator.
* Participants with psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant and/or nursing women are excluded from this study because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with domvanalimab or zimberelimab.
* Patients with a history of another primary malignancy that is currently clinically significant and has potential for metastases or currently requires active intervention (except for hormonal therapy for breast or prostate cancer).
* New York Heart Association \[NYHA\] Class III or IV (see Appendix D, New York Heart Association \[NYHA\] Classification) within the previous 2 months; if \>2 months, cardiac function must be within normal limits and the patient must be free of cardiac-related symptoms.
* HIV Infection: Participants with a known history of Human Immunodeficiency Virus (HIV) infection are excluded unless they meet all of the following criteria:

  * Stable antiretroviral therapy (ART) for at least 12 weeks prior to enrollment.
  * No history of AIDS-defining conditions.
  * CD4+ T-cell count ≥ 350 cells/mm³ at screening.
  * HIV viral load ≤ 50 copies/mL at screening.
  * No significant comorbidities associated with HIV infection that could interfere with the safety or efficacy of the investigational treatment.
  * No concurrent use of prohibited medications that may interfere with the study drug or cancer therapy.
* Fredericia's corrected QT interval (QTcF) ≥ 450 ms for men and ≥ 470 ms for women on ECG conducted during screening.
* Active systemic infection requiring intravenous antibiotics or intravenous monoclonal antibody treatments within 7 days of cycle 1 day 1.
* Use of any live vaccines against infectious diseases within 28 days of first dose of study drug.
* History of trauma or major surgery within 28 days prior to the first dose of study drug (placement of central venous access catheter \[eg, port or similar\] is not considered a major surgical procedure).
* Any active autoimmune disease or a documented history of autoimmune disease or syndrome that required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), except for vitiligo or resolved childhood asthma/atopy. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
* Any history of clinically significant pulmonary embolism within 30 days causing clinical symptoms including but not limited to shortness of breath, pleuritic chest pain, dyspnea on exertion and/or evidence of unresolved right heart strain on EKG or echocardiography.
* History of allogeneic stem cell or solid organ transplantation