This phase III trial compares the effect of modified fluorouracil, leucovorin calcium, oxaliplatin, and irinotecan (mFOLFIRINOX) to modified fluorouracil, leucovorin calcium, and oxaliplatin (mFOLFOX) for the treatment of advanced, unresectable, or metastatic HER2 negative esophageal, gastroesophageal junction, and gastric adenocarcinoma.

The usual approach for patients is treatment with 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) chemotherapy. Some patients receive an immunotherapy drug, either nivolumab or pembrolizumab, in addition to FOLFOX chemotherapy. Both of these regimens are approved by the United States Food and Drug Administration (FDA).

Chemotherapy drugs work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Fluorouracil stops cells from making DNA and it may kill tumor cells. Leucovorin is used with fluorouracil to enhance the effects of the drug. Oxaliplatin works by killing, stopping, or slowing the growth of tumor cells. Some patients also receive an immunotherapy drug, nivolumab, in addition to FOLFOX chemotherapy. Immunotherapy may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Irinotecan blocks certain enzymes needed for cell division and DNA repair, and it may kill tumor cells. Adding irinotecan to the FOLFOX regimen could shrink the cancer and extend the life of patients with advanced gastroesophageal cancers.

Participants will be randomized to receive one of two treatments. Randomization is like flipping a coin and there is a 50/50 chance of being assigned to either treatment arm. 

Arm I will receive mFOLFIRINOX plus nivolumab via intravenous (IV) infusions. Arm II will receive mFOLFOX and nivolumab via intravenous (IV) infusions.

All study participants will undergo MRI and a CT scan throughout the trial. Participants may also undergo blood sample collection.

Total study participation will last until disease progression or discontinuation of treatment for other reasons, such as adverse effects or patient withdrawal.