NCT03553836 · CITED IN SOURCE DOCUMENTS

Safety and Efficacy of Pembrolizumab Compared to Placebo in Resected High-risk Stage II Melanoma (MK-3475-716/KEYNOTE-716)

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: ACTIVE NOT RECRUITING
Registry last update: 2024-11-29

This 2-part study will evaluate the safety and efficacy of pembrolizumab (MK-3475) compared to placebo in participants with surgically resected high-risk Stage II melanoma. Participants in Part 1 will receive either pembrolizumab or placebo in a double-blind design every 3 weeks (Q3W) for up to 17 cycles/\~1 year (each cycle = 21 days). Participants who complete the initial treatment of 17 cycles of pembrolizumab in Part 1 and experience disease recurrence may be eligible for re-challenge with pembrolizumab at the same dose and schedule of 200 mg Q3W (21-day cycles) for up to 35 cycles (up to \~2 years) in Part 2 in an open label design. Participants who complete the initial treatment of placebo and experience disease recurrence may be eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35 cycles (up to \~2 years) in Part 2 in an open label design. The primary hypothesis of this study is that pembrolizumab increases recurrence-free survival (RFS) compared to placebo. Per protocol, response/ progression or adverse events (AEs) during re-challenge/switch-over in Part 2 will not be counted towards the RFS outcome measure or safety outcome measures respectively.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Recurrence-free Survival (RFS)

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outcome · NOT POSTED

Distant Metastasis-free Survival (DMFS)

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outcome · NOT POSTED

Overall Survival (OS)

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outcome · POSTED

Number of Participants Who Experienced at Least One Adverse Event (AE)

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outcome · POSTED

Number of Participants Who Discontinued Study Treatment Due to an AE

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Inclusion: * Has surgically resected and histologically/pathologically confirmed new diagnosis of Stage IIB or IIC cutaneous melanoma per American Joint Committee on Cancer (AJCC) 8th edition guidelines * Has not been previously treated for melanoma beyond complete surgical resection * Has ≤12 weeks between final surgical resection and randomization * Has no evidence of metastatic disease on imaging as determined by investigator * Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale or Lansky Play-Performance Scale (LPS) score ≥50 for participants ≤16 years old, or a Karnofsky Performance Scale (KPS) score ≥50 for participants \>16 and \<18 years old * Has recovered adequately from toxicity and/or complications from surgery prior to study start * Female participants must not be pregnant or breastfeeding, and must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment if they are women of childbearing potential (WOCBP) Exclusion: * Has a known additional malignancy that is progressing or has required active antineoplastic therapy (including hormonal) within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment * WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Has received prior therapy with an 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 with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], OX-40, CD137) * Has received prior systemic anti-cancer therapy for melanoma including investigational agents * Has received a live vaccine within 30 days prior to the first dose of study treatment * Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment * Has severe hypersensitivity (≥Grade 3) to any excipients of pembrolizumab * Has an active autoimmune disease that has required systemic treatment in the past 2 years * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis * Has an active infection requiring systemic therapy * Has a known history of human immunodeficiency virus (HIV) infection * Has a known history of hepatitis B (defined as hepatitis B surface antigen reactive) or known active hepatitis C virus (defined as hepatitis C virus ribonucleic acid \[RNA\] \[qualitative\] is detected) infection * Has a history of active tuberculosis (Bacillus tuberculosis) * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator * Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study * Has had an allogeneic tissue/solid organ transplant
healthy Volunteers: false
minimum Age: 12 Years
sex: ALL
std Ages: CHILD
ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
Participants receive 200 mg pembrolizumab (2 mg/kg for a maximum of 200 mg in pediatric participants) by intravenous (IV) infusion once every 3 weeks (Q3W; 21-day cycles) for up to 17 cycles (up to \~1 year) in Part 1. Participants who complete the initial treatment of 17 cycles of pembrolizumab and experience disease recurrence may be eligible for re-challenge with pembrolizumab at the same dose and schedule of 200 mg Q3W (21-day cycles) for up to 35 cycles (up to \~2 years) in Part 2.
intervention Names
Biological: Pembrolizumab
label
Pembrolizumab
type
EXPERIMENTAL
description
Participants receive saline placebo by IV infusion Q3W (21-day cycles) for up to 17 cycles (up to \~1 year) in Part 1. Participants who complete the initial treatment of 17 cycles of placebo and experience disease recurrence may be eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35 cycles (up to \~2 years) in Part 2.
intervention Names
Biological: Pembrolizumab
Other: Placebo
label
Placebo
type
PLACEBO_COMPARATOR

interventions

arm Group Labels
Pembrolizumab
Placebo
description
Administered as an intravenous (IV) infusion every 3 weeks (Q3W)
name
Pembrolizumab
other Names
KEYTRUDA®
MK-3475
type
BIOLOGICAL
arm Group Labels
Placebo
description
Administered as an IV infusion every 3 weeks (Q3W)
name
Placebo
type
OTHER

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: DOUBLE
masking Description: Participants and Investigators will be blinded in Part 1 and unblinded in Part 2, if done.
who Masked: PARTICIPANT
INVESTIGATOR

primary Purpose

TREATMENT

Enrollment

count: 976
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
RFS was defined as the time from randomization to any of the following events: recurrence of melanoma at any site (local, in-transit or regional lymph nodes or distant recurrence) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or death due to any cause, whichever occurs first. Per protocol, final analysis for this primary outcome measure was performed using the initial pembrolizumab or placebo treatment with a protocol-specified analysis data cut-off date of June-21-2021.
measure
Recurrence-free Survival (RFS)
time Frame
Up to ~32.7 months

secondary Outcomes

description
DMFS will be defined as the time from randomization to the first diagnosis of a distant metastasis per RECIST 1.1. Distant metastasis will refer to cancer that has spread from the original (primary) tumor and beyond local tissues and lymph nodes to distant organs or distant lymph nodes. DMFS will be reported for randomized participants.
measure
Distant Metastasis-free Survival (DMFS)
time Frame
Up to ~9 years
description
OS will be defined as the time from randomization to death due to any cause. OS will be reported for randomized participants.
measure
Overall Survival (OS)
time Frame
Up to ~15 years
description
An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, analysis for this outcome measure was performed using the initial pembrolizumab or placebo treatment.
measure
Number of Participants Who Experienced at Least One Adverse Event (AE)
time Frame
Up to ~19.3 months
description
An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, analysis for this outcome measure was performed using the initial pembrolizumab or placebo treatment.
measure
Number of Participants Who Discontinued Study Treatment Due to an AE
time Frame
Up to ~19.3 months

Full study description

brief Summary: This 2-part study will evaluate the safety and efficacy of pembrolizumab (MK-3475) compared to placebo in participants with surgically resected high-risk Stage II melanoma. Participants in Part 1 will receive either pembrolizumab or placebo in a double-blind design every 3 weeks (Q3W) for up to 17 cycles/\~1 year (each cycle = 21 days). Participants who complete the initial treatment of 17 cycles of pembrolizumab in Part 1 and experience disease recurrence may be eligible for re-challenge with pembrolizumab at the same dose and schedule of 200 mg Q3W (21-day cycles) for up to 35 cycles (up to \~2 years) in Part 2 in an open label design. Participants who complete the initial treatment of placebo and experience disease recurrence may be eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35 cycles (up to \~2 years) in Part 2 in an open label design. The primary hypothesis of this study is that pembrolizumab increases recurrence-free survival (RFS) compared to placebo. Per protocol, response/ progression or adverse events (AEs) during re-challenge/switch-over in Part 2 will not be counted towards the RFS outcome measure or safety outcome measures respectively.

Source references

references

citation
Luke JJ, Ascierto PA, Khattak MA, de la Cruz Merino L, Del Vecchio M, Rutkowski P, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Kirkwood JM, Robert C, Grob JJ, de Galitiis F, Schadendorf D, Carlino MS, Wu XL, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Long GV. Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study. J Clin Oncol. 2024 May 10;42(14):1619-1624. doi: 10.1200/JCO.23.02355. Epub 2024 Mar 7.
pmid
38452313
type
RESULT
citation
Leachman SA, Luke JJ, Ascierto PA, Long GV, Khattak MA, Rutkowski P, Xu ZJ, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, Schadendorf D. Adjuvant Pembrolizumab for Stage IIB or IIC Melanoma: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2026 Feb 2;9(2):e2559603. doi: 10.1001/jamanetworkopen.2025.59603.
pmid
41701495
type
DERIVED
citation
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pmid
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type
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citation
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pmid
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type
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citation
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pmid
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type
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citation
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pmid
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type
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citation
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pmid
36265502
type
DERIVED
citation
Luke JJ, Rutkowski P, Queirolo P, Del Vecchio M, Mackiewicz J, Chiarion-Sileni V, de la Cruz Merino L, Khattak MA, Schadendorf D, Long GV, Ascierto PA, Mandala M, De Galitiis F, Haydon A, Dummer R, Grob JJ, Robert C, Carlino MS, Mohr P, Poklepovic A, Sondak VK, Scolyer RA, Kirkwood JM, Chen K, Diede SJ, Ahsan S, Ibrahim N, Eggermont AMM; KEYNOTE-716 Investigators. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022 Apr 30;399(10336):1718-1729. doi: 10.1016/S0140-6736(22)00562-1. Epub 2022 Apr 1.
pmid
35367007
type
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citation
Luke JJ, Ascierto PA, Carlino MS, Gershenwald JE, Grob JJ, Hauschild A, Kirkwood JM, Long GV, Mohr P, Robert C, Ross M, Scolyer RA, Yoon CH, Poklepovic A, Rutkowski P, Anderson JR, Ahsan S, Ibrahim N, M Eggermont AM. KEYNOTE-716: Phase III study of adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma. Future Oncol. 2020 Jan;16(3):4429-4438. doi: 10.2217/fon-2019-0666. Epub 2019 Dec 24.
pmid
31870188
type
DERIVED