NCT04221945 · CITED IN SOURCE DOCUMENTS

Study of Chemoradiotherapy With or Without Pembrolizumab (MK-3475) For The Treatment of Locally Advanced Cervical Cancer (MK-3475-A18/KEYNOTE-A18/ENGOT-cx11/GOG-3047)

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: COMPLETED
Registry last update: 2026-02-20

The purpose of this study is to evaluate the efficacy and safety of pembrolizumab plus concurrent chemoradiotherapy compared to placebo plus concurrent chemoradiotherapy in participants with locally advanced cervical cancer. The primary hypotheses are that pembrolizumab plus concurrent chemoradiotherapy is superior to placebo plus concurrent chemoradiotherapy with respect to progression-free survival and overall survival. Once the study objectives have been met or the study has ended, participants will be discontinued from this study and will be enrolled in an extension study to continue protocol-defined assessments and treatment.

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

Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by the Investigator

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outcome · POSTED

Overall Survival (OS)

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outcome · POSTED

PFS Per RECIST 1.1 as Assessed by Blinded Independent Central Review (BICR)

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outcome · POSTED

PFS Per RECIST 1.1 at Month 24 as Assessed by the Investigator

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outcome · POSTED

PFS Per RECIST 1.1 at Month 24 as Assessed by BICR

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outcome · POSTED

Overall Survival (OS) at Month 36

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outcome · POSTED

Complete Response (CR) Rate Per RECIST 1.1 at Week 12 as Assessed by the Investigator

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outcome · POSTED

CR Rate Per RECIST 1.1 at Week 12 as Assessed by BICR

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outcome · POSTED

Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by the Investigator

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outcome · POSTED

ORR Per RECIST 1.1 as Assessed by BICR

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outcome · POSTED

PFS Per RECIST 1.1 in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by the Investigator

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outcome · POSTED

PFS Per RECIST 1.1 in PD-L1 Positive Participants as Assessed by BICR

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outcome · POSTED

OS in PD-L1 Positive Participants

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outcome · POSTED

PFS After Next-Line Treatment (PFS 2) Following Discontinuation of Study Treatment

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outcome · POSTED

Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status Score

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outcome · POSTED

Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Function Score

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outcome · POSTED

Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Symptom Specific Scale for Cervical Cancer (EORTC QLQ-CX24) Score

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outcome · POSTED

Number of Participants Who Experience One or More Adverse Events (AEs)

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outcome · POSTED

Number of Participants Who Discontinue 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 Criteria: * Has high-risk locally advanced cervical cancer (LACC): The International Federation of Gynecology and Obstetrics (FIGO) 2014 Stage IB2-IIB (with node-positive disease) or FIGO 2014 Stages III-IVA * Has histologically-confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix * Has not previously received any definitive surgical, radiation, or systemic therapy for cervical cancer, including investigational agents, and is immunotherapy-naïve * Female participants must not be pregnant or breastfeeding and agree to use highly effective contraception during the treatment period and for at least 120 days after the last dose of pembrolizumab or placebo and 180 days following the end of chemoradiotherapy and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. * Female participants must abstain from breastfeeding during the study intervention period and for at least 120 days after the last dose of pembrolizumab or placebo and 180 days following the end of chemoradiotherapy * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days prior to the first dose of study treatment * Has provided a tissue sample from a core incisional or excisional biopsy of a tumor lesion * Has radiographically evaluable disease, either measurable or non-measurable per RECIST 1.1, as assessed by the local site investigator/radiology * Has adequate organ function within 7 days prior to the start of study treatment. Exclusion Criteria: * Has excluded subtypes of LACC * Has FIGO 2014 Stage IVB disease * Has undergone a previous hysterectomy defined as removal of the entire uterus or will have a hysterectomy as part of their initial cervical cancer therapy * Has bilateral hydronephrosis, unless at least one side has been stented or resolved by positioning of nephrostomy or considered mild and not clinically significant in the opinion of the investigator * Has anatomy or tumor geometry or any other reason or contraindication that cannot be treated with intracavitary brachytherapy or a combination of intracavitary and interstitial brachytherapy * Has received a live vaccine within 30 days prior to the first dose of study treatment * Has received treatment with systemic immunostimulatory agents, colony stimulating factors, interferons, interleukins and vaccine combinations within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1 * 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 co-inhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137) * Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization * 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 randomization * Has any contraindication to the use of cisplatin * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment * Has a known additional malignancy that is progressing or has required active treatment within the past 3 years * Has severe hypersensitivity to pembrolizumab and/or any of its excipients * Has an active autoimmune disease that has required systemic treatment in past 2 years * Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease * Has an active infection requiring systemic therapy * Has a known history of Human Immunodeficiency Virus (HIV) infection * Has a known history of Hepatitis B or known active Hepatitis C virus infection * Has a history or current evidence of any condition, therapy, lab abnormality, or other circumstance that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results, and in the judgment of the investigator or Sponsor, would make the participant inappropriate for entry into this study * 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 allogenic tissue/solid organ transplant * Has evidence of metastatic disease per RECIST 1.1 including lymph nodes above the first lumbar vertebra (L1) cephalad body, in the inguinal region
healthy Volunteers: false
minimum Age: 18 Years
sex: FEMALE
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for 5 cycles followed by pembrolizumab 400 mg IV on Day 1 of each 6-week cycle (Q6W) for an additional 15 cycles. During the Q3W dosing period of pembrolizumab, participants receive concurrent chemoradiotherapy. The standard of care chemoradiotherapy regimen includes cisplatin 40 mg/m\^2 IV once per week (QW) for 5 or 6 weeks plus external beam radiotherapy (EBRT) followed by brachytherapy with minimum total radiotherapy dose of 80 Gray Units (Gy) for volume-directed and 75 Gy for point-directed given with the total duration of radiation treatment not to exceed 50 days (with an extension to a maximum of 56 days for unforeseen delays).
intervention Names
Biological: Pembrolizumab
Drug: Cisplatin
Radiation: External Beam Radiotherapy (EBRT)
Radiation: Brachytherapy
label
chemoradiotherapy + pembrolizumab
type
EXPERIMENTAL
description
Participants receive placebo for pembrolizumab IV on Day 1 of each 3-week cycle (Q3W) for 5 cycles followed by placebo IV on Day 1 of each 6-week cycle (Q6W) for an additional 15 cycles. During the Q3W dosing period of placebo, participants receive concurrent chemoradiotherapy. The standard of care chemoradiotherapy regimen includes cisplatin 40 mg/m\^2 IV once per week (QW) for 5 or 6 weeks plus external beam radiotherapy (EBRT) followed by brachytherapy with minimum total radiotherapy dose of 80 Gray Units (Gy) for volume-directed and 75 Gy for point-directed given with the total duration of radiation treatment not to exceed 50 days (with an extension to a maximum of 56 days for unforeseen delays).
intervention Names
Drug: Placebo for pembrolizumab
Drug: Cisplatin
Radiation: External Beam Radiotherapy (EBRT)
Radiation: Brachytherapy
label
chemoradiotherapy + placebo for pembrolizumab
type
EXPERIMENTAL

interventions

arm Group Labels
chemoradiotherapy + pembrolizumab
description
IV infusion
name
Pembrolizumab
other Names
KEYTRUDA®
MK-3475
type
BIOLOGICAL
arm Group Labels
chemoradiotherapy + placebo for pembrolizumab
description
IV infusion
name
Placebo for pembrolizumab
type
DRUG
arm Group Labels
chemoradiotherapy + pembrolizumab
chemoradiotherapy + placebo for pembrolizumab
description
IV infusion
name
Cisplatin
other Names
Platinol®
Platinol®-AQ
type
DRUG
arm Group Labels
chemoradiotherapy + pembrolizumab
chemoradiotherapy + placebo for pembrolizumab
description
Given as a total radiotherapy dose of 80 Gy for volume-directed and 75 Gy for point-directed
name
External Beam Radiotherapy (EBRT)
type
RADIATION
arm Group Labels
chemoradiotherapy + pembrolizumab
chemoradiotherapy + placebo for pembrolizumab
description
Given as a total radiotherapy dose of 80 Gy for volume-directed and 75 Gy for point-directed
name
Brachytherapy
type
RADIATION

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: TRIPLE
who Masked: PARTICIPANT
INVESTIGATOR
OUTCOMES_ASSESSOR

primary Purpose

TREATMENT

Enrollment

count: 1060
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, or by histopathologic confirmation of suspected disease progression, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Unequivocal progression of non-target lesions is also considered PD. The Kaplan-Meier nonparametric product limit method for censored data was used to estimate PFS.
measure
Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by the Investigator
time Frame
Up to approximately 55 months
description
OS is the time from randomization to death due to any cause. The Kaplan-Meier nonparametric product limit method for censored data was used to estimate OS.
measure
Overall Survival (OS)
time Frame
Up to approximately 55 months

secondary Outcomes

description
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Unequivocal progression of non-target lesions is also considered PD. The Kaplan-Meier nonparametric product limit method for censored data was used to estimate PFS.
measure
PFS Per RECIST 1.1 as Assessed by Blinded Independent Central Review (BICR)
time Frame
Up to approximately 55 months
description
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, or by histopathologic confirmation of suspected disease progression, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Unequivocal progression of non-target lesions is also considered PD. The percentage of participants with PFS as assessed by the investigator is presented.
measure
PFS Per RECIST 1.1 at Month 24 as Assessed by the Investigator
time Frame
24 months
description
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Unequivocal progression of non-target lesions is also considered PD. The percentage of participants with PFS as assessed by BICR is presented.
measure
PFS Per RECIST 1.1 at Month 24 as Assessed by BICR
time Frame
24 months
description
OS is the time from randomization to death due to any cause. The analysis was performed via Kaplan-Meier approach to estimate the OS rate at Month 36. The percentage of participants with OS at Month 36 is presented.
measure
Overall Survival (OS) at Month 36
time Frame
36 months
description
For participants who demonstrated a confirmed Complete Response (CR: Disappearance of all target and non-target lesions and also includes reduction of all nodal lesions to \<10mm) per RECIST 1.1, CR rate is defined as the percentage of participants who experienced a CR. The percentage of participants with CR per RECIST 1.1 as assessed by the investigator at Week 12 is presented.
measure
Complete Response (CR) Rate Per RECIST 1.1 at Week 12 as Assessed by the Investigator
time Frame
12 weeks
description
For participants who demonstrated a confirmed CR: Disappearance of all target and non-target lesions and also includes reduction of all nodal lesions to \<10mm) per RECIST 1.1, CR rate is defined as the percentage of participants who experienced a CR. The percentage of participants with CR per RECIST 1.1 as assessed by BICR at Week 12 is presented.
measure
CR Rate Per RECIST 1.1 at Week 12 as Assessed by BICR
time Frame
12 weeks
description
ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target and non-target lesions and also includes reduction of all nodal lesions to \<10mm) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions and includes no unequivocal progression in non-target lesions) per RECIST 1.1.
measure
Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by the Investigator
time Frame
Up to approximately 55 months
description
ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target and non-target lesions and also includes reduction of all nodal lesions to \<10mm) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions and includes no unequivocal progression in non-target lesions) per RECIST 1.1.
measure
ORR Per RECIST 1.1 as Assessed by BICR
time Frame
Up to approximately 55 months
description
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, or by histopathologic confirmation of suspected disease progression, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Unequivocal progression of non-target lesions is also considered PD. PD-L1 positive participants have a combined positivity score (CPS) equal or greater than 1. The Kaplan-Meier nonparametric product limit method for censored data was used to estimate PFS.
measure
PFS Per RECIST 1.1 in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by the Investigator
time Frame
Up to approximately 55 months
description
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Unequivocal progression of non-target lesions is also considered PD. PD-L1 positive participants have a CPS equal or greater than 1. The Kaplan-Meier nonparametric product limit method for censored data was used to estimate PFS.
measure
PFS Per RECIST 1.1 in PD-L1 Positive Participants as Assessed by BICR
time Frame
Up to approximately 55 months
description
OS is the time from randomization to death due to any cause. PD-L1 positive participants have a CPS equal or greater than 1. The Kaplan-Meier nonparametric product limit method for censored data was used to estimate OS.
measure
OS in PD-L1 Positive Participants
time Frame
Up to approximately 55 months
description
PFS is defined as the time from randomization to the first documented progressive disease (PD) on next-line treatment or death due to any cause, whichever occurs first, as assessed by the investigator. PFS 2 is measured after next-line treatment following discontinuation of study treatment administration.
measure
PFS After Next-Line Treatment (PFS 2) Following Discontinuation of Study Treatment
time Frame
Up to approximately 55 months

Full study description

brief Summary: The purpose of this study is to evaluate the efficacy and safety of pembrolizumab plus concurrent chemoradiotherapy compared to placebo plus concurrent chemoradiotherapy in participants with locally advanced cervical cancer. The primary hypotheses are that pembrolizumab plus concurrent chemoradiotherapy is superior to placebo plus concurrent chemoradiotherapy with respect to progression-free survival and overall survival. Once the study objectives have been met or the study has ended, participants will be discontinued from this study and will be enrolled in an extension study to continue protocol-defined assessments and treatment.

Source references

references

citation
Lorusso D, Xiang Y, Hasegawa K, Scambia G, Leiva M, Ramos-Elias P, Acevedo A, Sukhin V, Cloven N, Pereira de Santana Gomes AJ, Contreras Mejia F, Reiss A, Ayhan A, Lee JY, Saevets V, Zagouri F, Gilbert L, Sehouli J, Tharavichitkul E, Lindemann K, Lazzari R, Chang CL, Lampe R, Zhu H, Oaknin A, Christiaens M, Polterauer S, Usami T, Li K, Yamada K, Toker S, Keefe SM, Pignata S, Duska LR; ENGOT-cx11/GOG-3047/KEYNOTE-A18 investigators. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. Lancet. 2024 Apr 6;403(10434):1341-1350. doi: 10.1016/S0140-6736(24)00317-9. Epub 2024 Mar 20.
pmid
38521086
type
RESULT
citation
Lorusso D, Xiang Y, Hasegawa K, Scambia G, Leiva M, Ramos-Elias P, Acevedo A, Cvek J, Randall L, Pereira de Santana Gomes AJ, Contreras Mejia F, Helpman L, Akilli H, Lee JY, Saevets V, Zagouri F, Gilbert L, Sehouli J, Tharavichitkul E, Lindemann K, Colombo N, Chang CL, Bednarikova M, Zhu H, Oaknin A, Christiaens M, Petru E, Usami T, Liu P, Yamada K, Toker S, Keefe SM, Pignata S, Duska LR; ENGOT-cx11/GOG-3047/KEYNOTE-A18 investigators. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024 Oct 5;404(10460):1321-1332. doi: 10.1016/S0140-6736(24)01808-7. Epub 2024 Sep 14.
pmid
39288779
type
RESULT
citation
Randall L, Xiang Y, Matsumoto T, Giannarelli D, Milla DP, Lopez KA, Acevedo A, Vizkeleti J, Salani R, Nogueira-Rodrigues A, Mejia FC, Korach J, Akilli H, Lee JY, Saevets VV, Samouelian V, Sehouli J, Tharavichikul E, Sukhin V, Colombo N, Chang CL, Cueva JF, Lalondrelle S, Petru E, Szamreta E, Nguyen AM, Yamada K, Li K, Pignata S, Lorusso D. Patient-reported outcomes from the phase 3, randomized, double-blind, placebo-controlled ENGOT-cx11/GOG-3047/KEYNOTE-A18 study of pembrolizumab plus concurrent chemoradiotherapy in participants with high-risk locally advanced cervical cancer. Gynecol Oncol. 2025 Aug;199:88-95. doi: 10.1016/j.ygyno.2025.06.003. Epub 2025 Jun 30.
pmid
40592026
type
DERIVED