A Study of Combination Therapies With or Without Pembrolizumab (MK-3475) and/or Chemotherapy in Participants With Advanced Esophageal Cancer (MK-3475-06A)

This is a phase I/II multicenter, open-label umbrella platform study that will evaluate the safety and efficacy of investigational agents with pembrolizumab, plus chemotherapy or lenvatinib, for the treatment of participants with advanced esophageal cancer who have failed 1 prior line of therapy and have not been previously exposed to programmed cell death 1 protein (PD-1)/ programmed cell death ligand 1 (PD-L1) based treatment.

With protocol amendment 5 (effective: 17-November-2023), enrollment in study arms "Pembrolizumab plus MK-4830 plus Chemotherapy" and "Pembrolizumab plus MK-4830 plus lenvatinib" is discontinued.

The master protocol is MK-3475-U06.

Eligibility Criteria:
The main inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of metastatic or locally advanced unresectable ESCC
* Has experienced investigator documented radiographic or clinical disease progression on one prior line of standard therapy.
* Has an evaluable baseline tumor sample (newly obtained or archival) for analysis
* Has adequately controlled blood pressure (BP) with or without antihypertensive medications
* Participants who have adverse events (AEs) due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have ≤Grade 2 neuropathy are eligible

Exclusion Criteria:

* Direct invasion into adjacent organs such as the aorta or trachea
* Has experienced weight loss \>10% over approximately 2 months prior to first dose of study therapy
* Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
* Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
* Known additional malignancy that is progressing or has required active treatment within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that has undergone potentially curative therapy
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Active autoimmune disease that has required systemic treatment in past 2 years
* History of human immunodeficiency virus (HIV) infection
* History of Hepatitis B or known active Hepatitis C virus infection
* History of allogenic tissue/solid organ transplant
* Clinically significant cardiovascular disease within 12 months from first dose of study intervention
* Participants with known gastrointestinal (GI) malabsorption or any other condition that may affect the absorption of lenvatinib
* Has risk for significant GI bleeding, such as:
* Has had a serious nonhealing wound, peptic ulcer, or bone fracture within 28 days prior to allocation/randomization
* Has significant bleeding disorders, vasculitis, or has had a significant bleeding episode from the GI tract within 12 weeks prior to allocation/randomization