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Evaluating new treatments for advanced esophageal cancer after prior PD-1 therapy

A Phase 1/2 Open-Label, Umbrella Platform Design Study of Investigational Agents With or Without Pembrolizumab (MK-3475) and/or Chemotherapy in Participants With Advanced Esophageal Cancer Previously Exposed to PD-1/PD-L1 Treatment (KEYMAKER-U06): Substudy 06B

Phase1; Phase2 Interventional Merck Sharp & Dohme LLC · NCT05319730

This study is testing new treatment combinations for people with advanced esophageal cancer who didn't respond to previous PD-1 therapy to see if they can improve their outcomes.

Quick facts

PhasePhase1; Phase2
Study typeInterventional
Enrollment230 (estimated)
Ages18 Years and up
SexAll
SponsorMerck Sharp & Dohme LLC Industry-sponsored
Drugs / interventionspembrolizumab, chemotherapy, Lenvatinib
Locations57 sites (Tucson, Arizona and 56 other locations)
Trial IDNCT05319730 on ClinicalTrials.gov

What this trial studies

This Phase 1/2 multicenter, randomized, open-label study aims to assess the safety and efficacy of investigational agents, with or without pembrolizumab and/or chemotherapy, in patients with advanced esophageal squamous cell carcinoma (ESCC) who have previously received PD-1/PD-L1 treatment. Participants must have documented disease progression after one line of standard therapy that included a platinum agent. The study will analyze the effects of various treatment combinations on this patient population.

Who should consider this trial

Good fit: Ideal candidates include individuals with metastatic or locally advanced unresectable esophageal squamous cell carcinoma who have progressed on prior PD-1/PD-L1 therapy.

Not a fit: Patients who have not received prior PD-1/PD-L1 treatment or those with resectable disease may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could provide new treatment options for patients with advanced esophageal cancer who have limited alternatives after prior therapies.

How similar studies have performed: Other studies have shown promise in using combination therapies for advanced esophageal cancer, but this specific approach is still being evaluated.

Eligibility criteria

Show full inclusion / exclusion 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 esophageal squamous cell carcinoma (ESCC)
* Has experienced investigator documented radiographic or clinical disease progression on one prior line of standard therapy, that includes a platinum agent and previous exposure to an anti-programmed cell death 1 (PD1)/programmed cell death ligand 1 (PD-L1) based immune oncology (IO) therapy
* Has provided an archival or most recent tumor tissue sample obtained as part of clinical practice
* 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 history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing
* Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease
* Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
* 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
* Participants with human immunodeficiency virus (HIV) with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* History of allogenic tissue/solid organ transplant
* Clinically significant cardiovascular disease within 12 months from first dose of study intervention
* Has risk for significant gastrointestinal (GI) bleeding such as a serious nonhealing wound, peptic ulcer, or bone fracture within 28 days prior to allocation/randomization, significant bleeding disorders, vasculitis, or has had a significant bleeding episode from the GI tract within 12 weeks prior to allocation/randomization

Where this trial is running

Tucson, Arizona and 56 other locations

+7 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Esophageal Squamous Cell CarcinomaEsophageal cancerProgrammed Cell Death 1Programmed Cell Death 1 Ligand 1Programmed Cell Death 1 Ligand 2
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.