This is a clinical trial for adults with metastatic squamous cell carcinoma of the esophagus.
   
The purpose of this study is to test two treatment regimens in people with advanced esophageal cancer to see how well they work to stop the cancer as well as to determine whether one treatment regimen is more effective than the other. The two treatment regimens being evaluated are lenvatinib + pembrolizumab with chemotherapy followed by lenvatinib + pembrolizumab compared to pembrolizumab with chemotherapy.
   
The study drugs lenvatinib (E7080/MK‑7902), also called LENVIMA®, and pembrolizumab (MK‑3475), also called KEYTRUDA® or pembro have been approved by the U.S. Food and Drug Administration (FDA) to treat various cancers but may not be approved for this type of cancer. Getting pembrolizumab + lenvatinib with chemotherapy is considered experimental as the combination is not approved by the FDA.

Participants will be randomized into one of the study groups. Randomization is like flipping a coin and there is a 50/50 chance of being assigned to either group. The first group will receive
lenvatinib + pembrolizumab with chemotherapy and the second group will receive pembrolizumab with chemotherapy and no Lenvatinib.

Pembrolizumab is given by intravenous (IV) infusion about every 6 weeks. Lenvatinib is taken orally, as a capsule, once daily. Several different chemotherapy regimens are used in this trial and will be discussed with the study team.

Participants will be in the study for approximately 2-3 years.