Uterine Cervical Neoplasms
Conditions
Keywords
Programmed Cell Death Receptor 1 (PD-1, PD1), Programmed Cell Death Receptor Ligand 1 (PD-L1, PDL1), Programmed Cell Death Receptor Ligand 2 (PD-L2, PDL2)
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.
Interventions
BIOLOGICALPembrolizumab
IV infusion
IV infusion
DRUGCisplatin
IV infusion
RADIATIONExternal Beam Radiotherapy (EBRT)
Given as a total radiotherapy dose of 80 Gy for volume-directed and 75 Gy for point-directed
RADIATIONBrachytherapy
Given as a total radiotherapy dose of 80 Gy for volume-directed and 75 Gy for point-directed
Sponsors
Merck Sharp & Dohme LLC
GOG Foundation
European Network of Gynaecological Oncological Trial Groups (ENGOT)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by the Investigator | Up to approximately 55 months | 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. |
| Overall Survival (OS) | Up to approximately 55 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS Per RECIST 1.1 as Assessed by Blinded Independent Central Review (BICR) | Up to approximately 55 months | 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. |
| PFS Per RECIST 1.1 at Month 24 as Assessed by the Investigator | 24 months | 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. |
| PFS Per RECIST 1.1 at Month 24 as Assessed by BICR | 24 months | 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. |
| Overall Survival (OS) at Month 36 | 36 months | 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. |
| Complete Response (CR) Rate Per RECIST 1.1 at Week 12 as Assessed by the Investigator | 12 weeks | 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. |
| CR Rate Per RECIST 1.1 at Week 12 as Assessed by BICR | 12 weeks | 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. |
| Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by the Investigator | Up to approximately 55 months | 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. |
| ORR Per RECIST 1.1 as Assessed by BICR | Up to approximately 55 months | 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. |
| PFS Per RECIST 1.1 in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by the Investigator | Up to approximately 55 months | 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. |
| PFS Per RECIST 1.1 in PD-L1 Positive Participants as Assessed by BICR | Up to approximately 55 months | 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. |
| OS in PD-L1 Positive Participants | Up to approximately 55 months | 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. |
| PFS After Next-Line Treatment (PFS 2) Following Discontinuation of Study Treatment | Up to approximately 55 months | 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. |
| 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 | Baseline and week 36 | The EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Global scores are converted to a score of 0 to 100, with a higher score indicating improved health status. The change from baseline in EORTC QLQ-C30 score will be presented. |
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Function Score | Baseline and week 36 | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=not at all to 4=very much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in physical function (EORTC QLQ-C30 Items 1-5) score will be presented. |
| 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 | Baseline and Week 36 | The EORTC QLQ-CX24 is a questionnaire that rates the symptoms common to women with cervical cancer and evaluates the impact of disease and/or treatments. The 24 items use a 4-point scale (1=not at all to 4=very much) and are classified into 3 multi-item scales, 11 items with symptom experience, 3 items with body image, and 4 items with sexual/ vaginal functioning. The other items of the questionnaire are lymphedema, peripheral neuropathy, menopausal symptom, sexual worry, sexual activity, and sexual enjoyment. Total scores are linearly transformed and range from 0 (no symptoms) to 100 (most severe symptoms). The change from baseline in EORTC QLQ-CX24 score is presented, with negative scores representing an improvement from baseline and vice versa. |
| Number of Participants Who Experience One or More Adverse Events (AEs) | Up to 55 months | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. |
| Number of Participants Who Discontinue Study Treatment Due to an AE | Up to 32 months | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. |
Countries
Australia, Austria, Belgium, Brazil, Canada, Chile, China, Colombia, Czechia, France, Germany, Greece, Guatemala, Hungary, Ireland, Israel, Italy, Japan, Norway, Peru, Russia, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Recruitment details
The following participants were enrolled: had high-risk IB2-IIB (node-positive) or Stage III-IVA locally advanced cervical cancer (LACC); had histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix; had not previously received any definitive surgical, radiation, or systemic therapy for cervical cancer, including investigational agents, and was immunotherapy-naïve; had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Participants by arm
| Arm | Count |
|---|---|
| Chemoradiotherapy + Pembrolizumab Participants received 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 received 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). | 529 |
| Chemoradiotherapy + Placebo for Pembrolizumab Participants received 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 received 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). | 531 |
| Total | 1,060 |
Baseline characteristics
| Characteristic | Chemoradiotherapy + Pembrolizumab | Total | Chemoradiotherapy + Placebo for Pembrolizumab |
|---|---|---|---|
| Age, Continuous | 49.4 Years STANDARD_DEVIATION 11.9 | 49.8 Years STANDARD_DEVIATION 12.1 | 50.1 Years STANDARD_DEVIATION 12.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 161 Participants | 334 Participants | 173 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 363 Participants | 719 Participants | 356 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 7 Participants | 2 Participants |
| PDL-1 Status CPS<1 | 22 Participants | 50 Participants | 28 Participants |
| PDL-1 Status CPS>=1 | 502 Participants | 1000 Participants | 498 Participants |
| PDL-1 Status Missing | 5 Participants | 10 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 24 Participants | 46 Participants | 22 Participants |
| Race (NIH/OMB) Asian | 156 Participants | 304 Participants | 148 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 22 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 78 Participants | 164 Participants | 86 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 254 Participants | 518 Participants | 264 Participants |
| Sex: Female, Male Female | 529 Participants | 1060 Participants | 531 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 107 / 529 | 140 / 531 |
| other Total, other adverse events | 528 / 528 | 525 / 530 |
| serious Total, serious adverse events | 175 / 528 | 153 / 530 |
Outcome results
Primary
Overall Survival (OS)
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.
Time frame: Up to approximately 55 months
Population: All randomized participants analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | Overall Survival (OS) | NA Months |
| Chemoradiotherapy + Placebo for Pembrolizumab | Overall Survival (OS) | NA Months |
p-value: 0.007695% CI: [0.57, 0.94]Log Rank
Primary
Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by the Investigator
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.
Time frame: Up to approximately 55 months
Population: All randomized participants analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by the Investigator | 47.6 Months |
| Chemoradiotherapy + Placebo for Pembrolizumab | Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by the Investigator | 47.5 Months |
p-value: 0.000495% CI: [0.59, 0.87]Log Rank
Secondary
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
The EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Global scores are converted to a score of 0 to 100, with a higher score indicating improved health status. The change from baseline in EORTC QLQ-C30 score will be presented.
Time frame: Baseline and week 36
Population: Randomized participants who have at least 1 patient reported outcome (PRO) assessment for QLQ-C30 available and have received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | 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 | 7.51 Score on a scale |
| Chemoradiotherapy + Placebo for Pembrolizumab | 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 | 7.44 Score on a scale |
p-value: 0.959395% CI: [-2.66, 2.8]cLDA model
Secondary
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Function Score
The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=not at all to 4=very much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in physical function (EORTC QLQ-C30 Items 1-5) score will be presented.
Time frame: Baseline and week 36
Population: Randomized participants who have at least 1 PRO assessment for QLQ-C30 available and have received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Function Score | 2.74 Score on a scale |
| Chemoradiotherapy + Placebo for Pembrolizumab | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Function Score | 2.07 Score on a scale |
p-value: 0.514595% CI: [-1.36, 2.71]cLDA model
Secondary
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
The EORTC QLQ-CX24 is a questionnaire that rates the symptoms common to women with cervical cancer and evaluates the impact of disease and/or treatments. The 24 items use a 4-point scale (1=not at all to 4=very much) and are classified into 3 multi-item scales, 11 items with symptom experience, 3 items with body image, and 4 items with sexual/ vaginal functioning. The other items of the questionnaire are lymphedema, peripheral neuropathy, menopausal symptom, sexual worry, sexual activity, and sexual enjoyment. Total scores are linearly transformed and range from 0 (no symptoms) to 100 (most severe symptoms). The change from baseline in EORTC QLQ-CX24 score is presented, with negative scores representing an improvement from baseline and vice versa.
Time frame: Baseline and Week 36
Population: Randomized participants who have at least 1 PRO assessment for QLQ-CX24 available and have received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | 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 | -8.86 Score on a scale |
| Chemoradiotherapy + Placebo for Pembrolizumab | 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 | -9.60 Score on a scale |
p-value: 0.295395% CI: [-0.65, 2.15]cLDA model
Secondary
Complete Response (CR) Rate Per RECIST 1.1 at Week 12 as Assessed by the Investigator
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.
Time frame: 12 weeks
Population: All randomized participants analyzed in the treatment group to which they were randomized. Participants with measurable disease at baseline. As the BICR and Investigator each measure and collect results differently, this can result in different numbers of participants with measurable disease at baseline, and hence different numbers analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | Complete Response (CR) Rate Per RECIST 1.1 at Week 12 as Assessed by the Investigator | 36.9 Percentage of participants |
| Chemoradiotherapy + Placebo for Pembrolizumab | Complete Response (CR) Rate Per RECIST 1.1 at Week 12 as Assessed by the Investigator | 33.5 Percentage of participants |
p-value: 0.130795% CI: [-2.5, 9.1]One-sided p-value for testing
Secondary
CR Rate Per RECIST 1.1 at Week 12 as Assessed by BICR
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.
Time frame: 12 weeks
Population: All randomized participants analyzed in the treatment group to which they were randomized. Participants with measurable disease at baseline. As the BICR and Investigator each measure and collect results differently, this can result in different numbers of participants with measurable disease at baseline, and hence different numbers analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | CR Rate Per RECIST 1.1 at Week 12 as Assessed by BICR | 42.9 Percentage of participants |
| Chemoradiotherapy + Placebo for Pembrolizumab | CR Rate Per RECIST 1.1 at Week 12 as Assessed by BICR | 42.2 Percentage of participants |
p-value: 0.408295% CI: [-5.2, 6.7]One-sided p-value for testing
Secondary
Number of Participants Who Discontinue Study Treatment Due to an AE
An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment.
Time frame: Up to 32 months
Population: All randomized participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | Number of Participants Who Discontinue Study Treatment Due to an AE | 112 Participants |
| Chemoradiotherapy + Placebo for Pembrolizumab | Number of Participants Who Discontinue Study Treatment Due to an AE | 79 Participants |
Secondary
Number of Participants Who Experience One or More Adverse Events (AEs)
An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment.
Time frame: Up to 55 months
Population: All randomized participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | Number of Participants Who Experience One or More Adverse Events (AEs) | 528 Participants |
| Chemoradiotherapy + Placebo for Pembrolizumab | Number of Participants Who Experience One or More Adverse Events (AEs) | 526 Participants |
Secondary
Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by the Investigator
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.
Time frame: Up to approximately 55 months
Population: All randomized participants analyzed in the treatment group to which they were randomized. Participants with measurable disease at baseline. As the BICR and Investigator each measure and collect results differently, this can result in different numbers of participants with measurable disease at baseline, and hence different numbers analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by the Investigator | 87.3 Percentage of participants |
| Chemoradiotherapy + Placebo for Pembrolizumab | Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by the Investigator | 83.7 Percentage of participants |
p-value: 0.049695% CI: [-0.7, 7.9]One-sided p-value for testing.
Secondary
ORR Per RECIST 1.1 as Assessed by BICR
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.
Time frame: Up to approximately 55 months
Population: All randomized participants analyzed in the treatment group to which they were randomized. Participants with measurable disease at baseline. As the BICR and Investigator each measure and collect results differently, this can result in different numbers of participants with measurable disease at baseline, and hence different numbers analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | ORR Per RECIST 1.1 as Assessed by BICR | 90.5 Percentage of participants |
| Chemoradiotherapy + Placebo for Pembrolizumab | ORR Per RECIST 1.1 as Assessed by BICR | 88.3 Percentage of participants |
p-value: 0.124495% CI: [-1.5, 5.9]One-sided p-value for testing.
Secondary
OS in PD-L1 Positive Participants
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.
Time frame: Up to approximately 55 months
Population: All randomized participants analyzed in the treatment group to which they were randomized. PD-L1 positive participants were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | OS in PD-L1 Positive Participants | NA Months |
| Chemoradiotherapy + Placebo for Pembrolizumab | OS in PD-L1 Positive Participants | NA Months |
p-value: 0.008395% CI: [0.56, 0.95]Log Rank
Secondary
Overall Survival (OS) at Month 36
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.
Time frame: 36 months
Population: All randomized participants analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | Overall Survival (OS) at Month 36 | 81.8 Percentage of Participants |
| Chemoradiotherapy + Placebo for Pembrolizumab | Overall Survival (OS) at Month 36 | 74.4 Percentage of Participants |
95% CI: [2.3, 12.5]
Secondary
PFS After Next-Line Treatment (PFS 2) Following Discontinuation of Study Treatment
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.
Time frame: Up to approximately 55 months
Population: All randomized participants analyzed in the treatment group to which they were randomized
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | PFS After Next-Line Treatment (PFS 2) Following Discontinuation of Study Treatment | NA Months |
| Chemoradiotherapy + Placebo for Pembrolizumab | PFS After Next-Line Treatment (PFS 2) Following Discontinuation of Study Treatment | NA Months |
p-value: 0.001595% CI: [0.54, 0.88]Log Rank
Secondary
PFS Per RECIST 1.1 as Assessed by Blinded Independent Central Review (BICR)
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.
Time frame: Up to approximately 55 months
Population: All randomized participants analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | PFS Per RECIST 1.1 as Assessed by Blinded Independent Central Review (BICR) | 48.9 Months |
| Chemoradiotherapy + Placebo for Pembrolizumab | PFS Per RECIST 1.1 as Assessed by Blinded Independent Central Review (BICR) | NA Months |
p-value: 0.001195% CI: [0.58, 0.89]Log Rank
Secondary
PFS Per RECIST 1.1 at Month 24 as Assessed by BICR
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.
Time frame: 24 months
Population: All randomized participants analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | PFS Per RECIST 1.1 at Month 24 as Assessed by BICR | 76.0 Percentage of Participants |
| Chemoradiotherapy + Placebo for Pembrolizumab | PFS Per RECIST 1.1 at Month 24 as Assessed by BICR | 68.1 Percentage of Participants |
95% CI: [2.3, 13.5]
Secondary
PFS Per RECIST 1.1 at Month 24 as Assessed by the Investigator
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.
Time frame: 24 months
Population: All randomized participants analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | PFS Per RECIST 1.1 at Month 24 as Assessed by the Investigator | 70.6 Percentage of Participants |
| Chemoradiotherapy + Placebo for Pembrolizumab | PFS Per RECIST 1.1 at Month 24 as Assessed by the Investigator | 59.7 Percentage of Participants |
95% CI: [5.1, 16.7]
Secondary
PFS Per RECIST 1.1 in PD-L1 Positive Participants as Assessed by BICR
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.
Time frame: Up to approximately 55 months
Population: All randomized participants analyzed in the treatment group to which they were randomized. PD-L1 positive participants were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | PFS Per RECIST 1.1 in PD-L1 Positive Participants as Assessed by BICR | 48.9 Months |
| Chemoradiotherapy + Placebo for Pembrolizumab | PFS Per RECIST 1.1 in PD-L1 Positive Participants as Assessed by BICR | NA Months |
p-value: 0.001695% CI: [0.58, 0.9]Log Rank
Secondary
PFS Per RECIST 1.1 in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by the Investigator
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.
Time frame: Up to approximately 55 months
Population: All randomized participants analyzed in the treatment group to which they were randomized. PD-L1 positive participants were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemoradiotherapy + Pembrolizumab | PFS Per RECIST 1.1 in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by the Investigator | 47.6 Months |
| Chemoradiotherapy + Placebo for Pembrolizumab | PFS Per RECIST 1.1 in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by the Investigator | 47.5 Months |
p-value: 0.00195% CI: [0.59, 0.89]Log Rank