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)

NCT02564263 | Completed Phase 3 Results DMC FDA Drug

• 5 other identifiers: 3475-181163145MK-3475-181KEYNOTE-1812015-002782-32
• Study Type: interventional
• Target: 628
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Esophageal Carcinoma; Esophagogastric Junction Carcinoma

Keywords

Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1); Programmed Death-Ligand 2 (PDL2, PD-L2); Gene expression profiling (GEP)

Outcome Measures

Primary Outcomes (3)

• Overall Survival (OS) in Participants With Squamous Cell Carcinoma (SCC) of the Esophagus

  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)

  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

  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 Outcomes (8)

• Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants

  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

  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

  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)

  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

  Through Final Analysis data cutoff date of 15-Oct-2018 (up to approximately 34 months)

Study Arms (2)

Pembrolizumab

EXPERIMENTAL

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

Chemotherapy

ACTIVE COMPARATOR

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; Drug: docetaxel; Drug: irinotecan

Interventions

pembrolizumab BIOLOGICAL

200 mg administered as IV infusion on Day 1 of every 21-day cycle

Also known as: KEYTRUDA®, MK-3475

Pembrolizumab

paclitaxel DRUG

80-100 mg/m\^2 administered as IV infusion on Days 1, 8, and 15 of each 28-day cycle

Also known as: TAXOL®

Chemotherapy

docetaxel DRUG

75 mg/m\^2 administered as IV infusion on Day 1 of every 21-day cycle

Also known as: TAXOTERE®

Chemotherapy

irinotecan DRUG

180 mg/m\^2 administered as IV infusion on Day 1 of every 14-day cycle

Also known as: CAMPTOSAR®

Chemotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (2)

• 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.

  PMID: 33026938 RESULT

• 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.

  PMID: 34730989 DERIVED

Related Links

• Merck Oncology Clinical Trial Information

MeSH Terms

Conditions

Esophageal Neoplasms; Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

pembrolizumab; Paclitaxel; Docetaxel; Irinotecan

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Camptothecin; Alkaloids; Heterocyclic Compounds

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 29, 2015
• First Posted: September 30, 2015
• Study Start: December 1, 2015
• Primary Completion: October 15, 2018
• Study Completion: March 14, 2022
• Last Updated: March 13, 2023
• Results First Posted: November 20, 2019

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will share