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Combination therapies for esophageal squamous cell carcinoma (KEYMAKER-U06 Substudy 06E)

A Phase 1/2 Open-Label, Umbrella Platform Design Study of Investigational Agents in Combination With Pembrolizumab (MK-3475) With or Without Chemotherapy in Participants With 1L Locally Advanced Unresectable/Metastatic Esophageal Cancer: KEYMAKER-U06 Substudy 06E

PHASE1; PHASE2 · Merck Sharp & Dohme LLC · NCT06780111

This trial will test pembrolizumab together with an investigational antibody-drug conjugate (I-DXd), with or without chemotherapy, as a first-line treatment for people with locally advanced unresectable or metastatic esophageal squamous cell carcinoma.

Quick facts

PhasePHASE1; PHASE2
Study typeInterventional
Enrollment298 (estimated)
Ages18 Years and up
SexAll
SponsorMerck Sharp & Dohme LLC (industry)
Drugs / interventionsradiation, prednisone, pembrolizumab, Ifinatamab, chemotherapy, immunotherapy
Locations42 sites (Pittsburgh, Pennsylvania and 41 other locations)
Trial IDNCT06780111 on ClinicalTrials.gov

What this trial studies

This Phase 1/2 substudy within the MK-3475-U06 master protocol tests pembrolizumab in combination with investigational agents including the ADC ifinatamab deruxtecan (I-DXd), with or without standard chemotherapy. The trial enrolls patients with measurable, locally advanced unresectable or metastatic esophageal squamous cell carcinoma in the first-line setting and uses RECIST 1.1 with central radiology review for response. Early phases focus on safety, tolerability, and dosing while expansion cohorts will collect preliminary anti-tumor activity and response rate data. The protocol is sponsored by Merck with collaborating partner Daiichi Sankyo and includes sites in the United States and Brazil.

Who should consider this trial

Good fit: Ideal candidates are people with treatment-naïve, locally advanced unresectable or metastatic esophageal squamous cell carcinoma who have measurable disease, ECOG performance status 0–1, and adequate organ function.

Not a fit: People with resectable disease, prior systemic therapy for advanced ESCC, poor performance status (ECOG >1), or significant uncontrolled medical problems are unlikely to qualify or benefit from this protocol.

Why it matters

Potential benefit: If successful, the combinations could produce higher tumor response rates, longer disease control, and potentially improved survival compared with current first-line options.

How similar studies have performed: Anti-PD-1 therapy plus chemotherapy has shown benefit in ESCC, while ADCs like I-DXd are investigational and have shown encouraging activity in other tumors, making this combination a promising but not yet proven approach.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria

The main inclusion criteria include but are not limited to the following:

* Has histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic squamous cell carcinoma of the esophagus in first-line (1L) setting.
* Has measurable disease per RECIST 1.1 as assessed by the local site. investigator or designee/radiology assessment and verified by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.
* Has AEs due to previous anticancer therapies of ≤Grade 1 or baseline (except alopecia and vitiligo). Endocrine-related AEs adequately treated with hormone replacement are acceptable.
* Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART).
* Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
* Has adequate organ function.

Exclusion Criteria

The main exclusion criteria include but are not limited to the following:

* Has had systemic anticancer therapy for locally advanced unresectable or metastatic esophageal cancer.
* Has tumor invasion into organs located adjacent to the esophageal disease site (eg, aorta or respiratory tract) at an increased risk of fistula.
* Has uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or medical intervention.
* Has clinically significant corneal disease, history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.
* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
* Has received prior therapy with an anti-programmed cell death 1 protein (PD-1), anti-programmed cell death ligand 1 (PD-L1), or anti-programmed cell death ligand 2 (PD-L2) agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor.
* Has received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention.
* Has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation-related toxicities, requiring corticosteroids.
* Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
* Has inadequate cardiac function assessed as: - corrected QT interval by Fredericia (QTcF) value \>470 msec.
* Has clinically significant cardiovascular disease within 6 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
* Has peripheral neuropathy ≥ Grade 2.
* Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.
* Has known additional malignancy that is progressing or has required active treatment within the past 3 years.
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
* Has active autoimmune disease that has required systemic treatment in the past 2 years.
* Has had (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease, and/or suspected interstitial lung disease (ILD)/pneumonitis that cannot be ruled out by imaging at Screening.
* Has active infection requiring systemic therapy.
* Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses, including, but not limited to, any underlying pulmonary disorder.

Where this trial is running

Pittsburgh, Pennsylvania and 41 other locations

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 →

Conditions: Esophageal Squamous Cell Carcinoma

Last reviewed 2026-05-15 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.