Study of Pembrolizumab (MK-3475) Versus Investigator's Choice Standard Therapy for Participants With Advanced Esophageal/ Esophagogastric Junction Carcinoma That Progressed After First-Line Therapy (MK-3475-181/KEYNOTE-181)

February 9, 2023 updated by: Merck Sharp & Dohme LLC

A Phase III Randomized Open-Label Study of Single Agent Pembrolizumab vs Physicians' Choice of Single Agent Docetaxel, Paclitaxel, or Irinotecan in Subjects With Advanced/Metastatic Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus That Have Progressed After First-Line Standard Therapy (KEYNOTE-181)

In this study, participants with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the esophagogastric junction (EGJ) that had progressed after first-line standard therapy were randomized to receive either pembrolizumab (MK-3475) OR the Investigator's choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan.

The primary study hypothesis was that treatment with pembrolizumab would prolong overall survival (OS) as compared to treatment with standard chemotherapy.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

628

Phase

  • Phase 3

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically- or cytologically-confirmed diagnosis of adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the EGJ
  • Metastatic disease or locally advanced, unresectable disease
  • Life expectancy of greater than 3 months
  • Measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
  • Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
  • Documented radiographic or clinical disease progression on no more or less than one previous line of standard therapy
  • Can provide either a newly obtained or archival tumor tissue sample for intra-tumoral immune-related testing and for anti-programmed cell death (PD)-1
  • Participants of reproductive potential must be willing to use adequate contraception for the course of the study through 120 days after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel, docetaxel or irinotecan
  • Adequate organ function

Exclusion Criteria:

  • Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study treatment
  • Active autoimmune disease that has required systemic treatment in past 2 years
  • Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
  • Known central nervous system (CNS) metastases and/or carcinomatous meningitis (includes past history or current metastasis)
  • Has received prior anti-cancer monoclonal antibody (mAb), chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or not recovered from adverse events due to a previously administered agent
  • Has had a severe hypersensitivity reaction to treatment with another mAb
  • Prior therapy with a PD-1, anti-PD-Ligand 1 (PD-L1), or anti-PD-L2 agent, or previously participated in Merck pembrolizumab (MK-3475) study
  • Has a known additional malignancy that has progressed or required active treatment within the last 5 years with the exception of curatively treated basal cell and squamous cell carcinoma of the skin and/or curatively resected in-situ cervical and/or breast cancers, and in-situ or intra-mucosal pharyngeal cancer
  • Received a live vaccine within 30 days of the first dose of study treatment
  • Known history of human immunodeficiency virus (HIV) infection
  • Known history of or is positive for hepatitis B or known active hepatitis C
  • History of non-infectious pneumonitis that required steroids or current pneumonitis
  • Active infection requiring systemic therapy
  • Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
  • Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study starting with the screening visit through 120 days after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel, docetaxel or irinotecan
  • Known allergy, hypersensitivity, or contraindication to paclitaxel, docetaxel, or irinotecan or any components used in their preparation
  • Experienced weight loss >10% over approximately 2 months prior to first dose of study treatment
  • Has ascites or pleural effusion by physical exam
  • Has experienced documented objective radiographic or clinical disease progression during or after receiving >1 line of therapy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pembrolizumab
Participants received pembrolizumab 200 mg, intravenously (IV) on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months).
Biological: pembrolizumab
200 mg administered as IV infusion on Day 1 of every 21-day cycle
Other Names:
  • MK-3475
  • KEYTRUDA®
Active Comparator: Chemotherapy
Participants received Investigator's choice of paclitaxel 80-100 mg/m^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).
Drug: paclitaxel
80-100 mg/m^2 administered as IV infusion on Days 1, 8, and 15 of each 28-day cycle
Other Names:
  • TAXOL®
Drug: docetaxel
75 mg/m^2 administered as IV infusion on Day 1 of every 21-day cycle
Other Names:
  • TAXOTERE®
Drug: irinotecan
180 mg/m^2 administered as IV infusion on Day 1 of every 14-day cycle
Other Names:
  • CAMPTOSAR®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival (OS) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
OS was defined as the time from randomization to death due to any cause. Median OS in participants with SCC of the esophagus is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
Overall Survival (OS) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
OS was defined as the time from randomization to death due to any cause. Median OS in participants with a PD-L1 CPS ≥10 is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
Overall Survival (OS) in All Participants
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
OS was defined as the time from randomization to death due to any cause. Median OS in all participants is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by blinded independent central review per RECIST 1.1 in all participants is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. The percentage of all participants who experienced a CR or PR is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by blinded independent central review per RECIST 1.1 is presented for participants with SCC of the esophagus.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. Median PFS as assessed by blinded independent central review per RECIST 1.1 is presented for participants with a PD-L1 CPS ≥10.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. The percentage of participants with SCC of the esophagus who experienced a CR or PR is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With Programmed Death-Ligand 1 Combined Positive Score ≥10 (PD-L1 CPS ≥10)
Time Frame: Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. The percentage of participants with a PD-L1 CPS ≥10 who experienced a CR or PR is presented.
Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)
Number of Participants Experiencing an Adverse Event (AE)
Time Frame: Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The number of participants who experienced ≥1 AE is presented.
Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)
Number of Participants Discontinuing Study Treatment Due an Adverse Event (AE)
Time Frame: Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The number of participants who discontinued study treatment due to an AE is presented.
Through End-of-Trial Analysis data cutoff date of 14-Mar-2022 (up to approximately 6 years)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Merck Sharp & Dohme LLC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 1, 2015

Primary Completion (Actual)

October 15, 2018

Study Completion (Actual)

March 14, 2022

Study Registration Dates

First Submitted

September 29, 2015

First Submitted That Met QC Criteria

September 29, 2015

First Posted (Estimate)

September 30, 2015

Study Record Updates

Last Update Posted (Actual)

March 13, 2023

Last Update Submitted That Met QC Criteria

February 9, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 3475-181
  • 163145 (Registry Identifier: JAPAN-CTI)
  • MK-3475-181 (Other Identifier: Merck)
  • KEYNOTE-181 (Other Identifier: Merck)
  • 2015-002782-32 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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