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)

• ClinicalTrials.gov Identifier: NCT02564263
• Recruitment Status: Completed
• First Posted: September 30, 2015
• Results First Posted: November 20, 2019
• Last Update Posted: March 13, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: September 29, 2015
• First Posted Date: September 30, 2015
• Results First Submitted Date: September 26, 2019
• Results First Posted Date: November 20, 2019
• Last Update Posted Date: March 13, 2023
• Actual Study Start Date: December 1, 2015
• Actual Primary Completion Date: October 15, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 1, 2019)

• 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.
• 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.
• 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.

Original Primary Outcome Measures (submitted: September 29, 2015)

• Progression-free Survival (PFS) [ Time Frame: Up to 3 years ]
• Overall Survival (OS) [ Time Frame: Up to 3 years ]

Current Secondary Outcome Measures (submitted: February 9, 2023)

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• Original Secondary Outcome Measures (submitted: September 29, 2015): Overall Response Rate (ORR) [ Time Frame: Up to 3 years ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official Title: 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)

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Esophageal Carcinoma
• Esophagogastric Junction Carcinoma

Intervention

• Biological: pembrolizumab
  200 mg administered as IV infusion on Day 1 of every 21-day cycle
  Other Names:

  • KEYTRUDA®
  • MK-3475
• Drug: paclitaxel
  80-100 mg/m^2 administered as IV infusion on Days 1, 8, and 15 of each 28-day cycle
  Other Name: TAXOL®
• Drug: docetaxel
  75 mg/m^2 administered as IV infusion on Day 1 of every 21-day cycle
  Other Name: TAXOTERE®
• Drug: irinotecan
  180 mg/m^2 administered as IV infusion on Day 1 of every 14-day cycle
  Other Name: CAMPTOSAR®

Study Arms

• 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).
  Intervention: Biological: pembrolizumab
• 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).
  Interventions:

  • Drug: paclitaxel
  • Drug: docetaxel
  • Drug: irinotecan

Publications *

• Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. doi: 10.1200/JCO.20.01888. Epub 2020 Oct 7.
• Adenis A, Kulkarni AS, Girotto GC, de la Fouchardiere C, Senellart H, van Laarhoven HWM, Mansoor W, Al-Rajabi R, Norquist J, Amonkar M, Suryawanshi S, Bhagia P, Metges JP. Impact of Pembrolizumab Versus Chemotherapy as Second-Line Therapy for Advanced Esophageal Cancer on Health-Related Quality of Life in KEYNOTE-181. J Clin Oncol. 2022 Feb 1;40(4):382-391. doi: 10.1200/JCO.21.00601. Epub 2021 Nov 3.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 12, 2019): 628
• Original Estimated Enrollment (submitted: September 29, 2015): 600
• Actual Study Completion Date: March 14, 2022
• Actual Primary Completion Date: October 15, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided
• Removed Location Countries: Argentina, Australia, Brazil, Canada, China, Colombia, Czech Republic, Czechia, Denmark, Estonia, Finland, France, Germany, Hong Kong, Ireland, Israel, Italy, Japan, Korea, Republic of, Malaysia, Mexico, Netherlands, Norway, Peru, Portugal, Russian Federation, Singapore, Spain, Sweden, Taiwan, Thailand, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT02564263
• 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 )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: February 2023