Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/1325-MG/KEYNOTE-054)

Study Results

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Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Clinical Phase

PHASE3

Total Enrollment

1019 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-07-16

Study Completion Date

2026-11-01

Brief Summary

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This study will assess whether post-surgery therapy with pembrolizumab improves recurrence-free survival (RFS) as compared to placebo for high-risk participants with melanoma (Stage IIIA \[\> 1 mm metastasis\], IIIB and IIIC). The study will also assess whether pembrolizumab improves RFS versus placebo in the subgroup of participants with programmed cell death-ligand 1 (PD-L1)-positive tumor expression. Participants will be stratified for stage of disease and region and then will be randomly assigned to receive either pembrolizumab or placebo as post-surgery therapy in Part 1. In Part 2, participants who experience a disease recurrence are eligible for pembrolizumab treatment (if treated with placebo in Part 1) or pembrolizumab rechallenge (if treated with pembrolizumab in Part 1).

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Detailed Description

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As of Amendment 8, enrollment in Part 2 has closed, and an optional pembrolizumab extension study will not be available to participants after study closure.

Conditions

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Melanoma

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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Pembrolizumab

In Part 1, participants receive pembrolizumab 200 mg intravenously (IV) as post-surgery therapy every 3 weeks (Q3W) for up to 1 year. During Part 2, participants with documented recurrence may receive optional re-treatment with pembrolizumab Q3W for up to 2 years or disease progression.

Group Type EXPERIMENTAL

pembrolizumab

Intervention Type BIOLOGICAL

Pembrolizumab 200 mg administered intravenously (IV) on Day 1 of each 21-day cycle

Placebo

In Part 1, participants receive placebo IV as post-surgery therapy Q3W. During Part 2, participants with documented recurrence who received placebo in Part 1 may receive optional treatment with pembrolizumab Q3W for up to 2 years or disease progression.

Group Type PLACEBO_COMPARATOR

placebo

Intervention Type DRUG

Normal saline solution administered IV on Day 1 of each 21-day cycle

Interventions

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pembrolizumab

Pembrolizumab 200 mg administered intravenously (IV) on Day 1 of each 21-day cycle

Intervention Type BIOLOGICAL

placebo

Normal saline solution administered IV on Day 1 of each 21-day cycle

Intervention Type DRUG

Other Intervention Names

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KEYTRUDA® MK-3475 SCH 900475

Eligibility Criteria

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Inclusion Criteria

* Completely resected Stage III melanoma
* Tumor tissue available for evaluation of PD-L1 expression
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Adequate organ function
* No prior therapy for melanoma except surgery for primary melanoma lesions (or previously treated with interferon for thick primary melanomas without evidence of lymph node involvement are eligible)
* Female participants of childbearing potential should be willing to use adequate methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication
* Male participants should agree to use an adequate method of birth control starting with the first dose of study therapy through 120 days after the last dose of study medication

Exclusion Criteria

* Mucosal or ocular melanoma
* History of (non-infectious) pneumonitis that required steroids or current pneumonitis
* History of or current interstitial lung disease
* History of hematologic or primary solid tumor malignancy, unless no evidence of that disease for 5 years
* Active autoimmune disease that has required systemic treatment in past 2 years
* Active infection requiring therapy
* Unstable hyperthyroidism or hypothyroidism
* Diagnosis of immunodeficiency
* Systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
* Known history of human immunodeficiency virus (HIV), active Hepatitis B or C
* Treatment with live vaccine within 30 days prior to the first dose of study medication are not eligible
* Prior treatment with any anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibody or anti-programmed cell death receptor 1 (PD-1), anti-programmed cell death receptor ligand 1 (PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent, or prior participation in any Merck pembrolizumab clinical trial
* Currently participating and receiving study therapy, or participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study medication
* Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study medication
* Participant is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial without prospective Institutional Review Board approval (by chair or designee) is given

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

References

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Buhrer E, Kicinski M, Mandala M, Pe M, Long GV, Atkinson V, Blank CU, Haydon A, Dalle S, Khattak A, Carlino MS, Meshcheryakov A, Sandhu S, Puig S, Schadendorf D, Jamal R, Rutkowski P, van den Eertwegh AJM, Coens C, Grebennik D, Krepler C, Robert C, Eggermont AMM. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): long-term, health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2024 Sep;25(9):1202-1212. doi: 10.1016/S1470-2045(24)00338-3. Epub 2024 Aug 12.

Reference Type DERIVED

PMID: 39146951 (View on PubMed)

Eggermont AMM, Kicinski M, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Boers-Sonderen M, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Lorigan P, Grebennik D, Krepler C, Marreaud S, Suciu S, Robert C. Five-Year Analysis of Adjuvant Pembrolizumab or Placebo in Stage III Melanoma. NEJM Evid. 2022 Nov;1(11):EVIDoa2200214. doi: 10.1056/EVIDoa2200214. Epub 2022 Sep 10.

Reference Type DERIVED

PMID: 38319852 (View on PubMed)

Kennedy OJ, Kicinski M, Valpione S, Gandini S, Suciu S, Blank CU, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Robert C, Eggermont AMM, Lorigan P, Mandala M. Prognostic and predictive value of beta-blockers in the EORTC 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma. Eur J Cancer. 2022 Apr;165:97-112. doi: 10.1016/j.ejca.2022.01.017. Epub 2022 Feb 24.

Reference Type DERIVED

PMID: 35220182 (View on PubMed)

Bottomley A, Coens C, Mierzynska J, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Puig S, Ascierto PA, Larkin J, Lorigan PC, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C, Eggermont AMM; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):655-664. doi: 10.1016/S1470-2045(21)00081-4. Epub 2021 Apr 12.

Reference Type DERIVED

PMID: 33857414 (View on PubMed)

Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C; EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):643-654. doi: 10.1016/S1470-2045(21)00065-6. Epub 2021 Apr 12.

Reference Type DERIVED

PMID: 33857412 (View on PubMed)

Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C. Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. J Clin Oncol. 2020 Nov 20;38(33):3925-3936. doi: 10.1200/JCO.20.02110. Epub 2020 Sep 18.

Reference Type DERIVED

PMID: 32946353 (View on PubMed)

Eggermont AMM, Kicinski M, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, Krepler C, Ibrahim N, Marreaud S, van Akkooi A, Robert C, Suciu S. Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2020 Apr 1;6(4):519-527. doi: 10.1001/jamaoncol.2019.5570.

Reference Type DERIVED

PMID: 31895407 (View on PubMed)

van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T. Immunogenicity of pembrolizumab in patients with advanced tumors. J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.

Reference Type DERIVED

PMID: 31395089 (View on PubMed)

Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. doi: 10.1056/NEJMoa1802357. Epub 2018 Apr 15.

Reference Type DERIVED

PMID: 29658430 (View on PubMed)

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

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