Cervical Cancer
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)
Brief summary
The purpose of this study is to assess the efficacy and safety of pembrolizumab (MK-3475) plus one of four platinum-based chemotherapy regimens compared to the efficacy and safety of placebo plus one of four platinum-based chemotherapy regimens in the treatment of adult women with persistent, recurrent, or metastatic cervical cancer. Possible chemotherapy regimens include: paclitaxel plus cisplatin with or without bevacizumab and paclitaxel plus carboplatin with or without bevacizumab. The primary study hypotheses are that the combination of pembrolizumab plus chemotherapy is superior to placebo plus chemotherapy with respect to: 1) Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by the Investigator, or, 2) Overall Survival (OS).
Interventions
BIOLOGICALPembrolizumab
IV infusion
DRUGPaclitaxel
IV infusion
DRUGCisplatin
IV infusion
DRUGCarboplatin
IV infusion
BIOLOGICALBevacizumab
IV infusion
IV infusion
Sponsors
Merck Sharp & Dohme LLC
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 persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix which has not been treated with systemic chemotherapy and is not amenable to curative treatment (such as with surgery and/or radiation). Prior chemotherapy utilized as a radiosensitizing agent and completed at least 2 weeks prior to randomization with resolution of all treatment-related toxicities is allowed. AEs due to previous treatments should be resolved to ≤ Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are eligible. * Not pregnant or breastfeeding, and at least one of the following conditions applies: a.) Not a woman of childbearing potential (WOCBP), b.) A WOCBP must agree to use effective contraception during the treatment period and for at least 120 days after the last dose of pembrolizumab/placebo and 210 days after the last dose of chemotherapy/bevacizumab * Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology * Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated for prospective determination of Programmed Cell Death-Ligand 1 (PD-L1) status prior to randomization * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 14 days prior to randomization * Has adequate organ function
Exclusion criteria
* A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with known brain metastases may participate provided that the brain metastases have been previously treated (except with chemotherapy) and are radiographically stable. * Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, transitional cell carcinoma of urothelial cancer, or carcinoma in situ (e.g. breast cancer) that have undergone potentially curative therapy are not excluded. * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization * Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed * 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 or known active Hepatitis C virus infection * Has a known history of active tuberculosis (TB; Bacillus tuberculosis) * Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], OX 40, CD137) * Has received prior systemic chemotherapy for treatment of cervical cancer. * Has not recovered adequately from toxicity and/or complications from major surgery prior to randomization * Has received prior radiotherapy within 2 weeks prior to randomization. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. * Has received a live vaccine within 30 days prior to randomization * Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. * Has a contraindication or hypersensitivity to any component of cisplatin, carboplatin, paclitaxel, or bevacizumab * 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 * Is pregnant or breastfeeding or expecting to conceive within the projected duration of the study, starting with the screening visit through 120 days following last dose of pembrolizumab/placebo and 210 days following last dose of chemotherapy/bevacizumab * Has had an allogeneic tissue/solid organ transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFS Per RECIST 1.1 as Assessed by Investigator in Participants With PD-L1 CPS ≥10 | Up to approximately 46 months | PFS was 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 was defined as ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 as assessed by Investigator for all randomized participants with PD-L1 CPS ≥10 is presented. |
| Overall Survival (OS) in Participants With PD-L1 CPS ≥1 | Up to approximately 46 months | OS was defined as the time from randomization to death due to any cause. The OS for all randomized participants with PD-L1 CPS ≥1 is presented. |
| OS in All Participants | Up to approximately 46 months | OS was defined as the time from randomization to death due to any cause. The OS for all randomized participants is presented. |
| OS in Participants With PD-L1 CPS ≥10 | Up to approximately 46 months | OS was defined as the time from randomization to death due to any cause. The OS for all randomized participants with PD-L1 CPS ≥10 is presented. |
| Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants With Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | Up to approximately 46 months | PFS was 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 was defined as ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 as assessed by Investigator for all randomized participants with PD-L1 CPS ≥1 is presented. |
| PFS Per RECIST 1.1 as Assessed by Investigator in All Participants | Up to approximately 46 months | PFS was 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 was defined as ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 as assessed by Investigator for all randomized participants is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced an Immune-related AE (irAE) | Up to approximately 66 months | AEs associated with pembrolizumab exposure may be a result of an immune response. These irAEs may occur shortly after the first dose or several months after the last dose of pembrolizumab treatment and may affect more than one body system simultaneously. For this study irAEs included, but were not limited to: -Pneumonitis; * Diarrhea/Colitis; * Aspartate transaminase (AST)/Alanine transaminase (ALT) elevation or Increased bilirubin; * Type 1 diabetes mellitus or Hyperglycemia; * Hypophysitis; * Hyperthyroidism; * Hypothyroidism; * Nephritis and Renal dysfunction; and * Myocarditis. The number of participants who experienced an irAE is presented. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to approximately 63 months | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinued study treatment due to an AE is presented. |
| Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by Investigator | Up to approximately 46 months | ORR was defined as the percentage of the participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters). The ORR per RECIST 1.1 as assessed by Investigator is presented. |
| Number of Participants With a 10-point Change From Baseline in Quality of Life (QoL) Based on the European Organisation for the Research & Treatment of Cancer (EORTC) QoL Questionnaire-30 (QLQ-C30) Combined Global Score | Baseline (Cycle 1 Day 1: Predose) and up to approximately 46 months | The EORTC QLQ-C30 is a questionnaire to assess the quality of life of cancer patients. Participant responses to "How would you rate your overall health during the past week?" (Item 29) and "How would you rate your overall quality of life during the past week?" (Item 30) are scored on a 7-point scale (1= Very poor to 7=Excellent). Raw scores are standardized with linear transformation so that scores range from 0-100. A higher combined score indicates a better overall health status. Participant post-baseline scores were classified based on change from baseline, "Improved": a ≥10-point improvement in score and confirmed by the next visit; "Stable": a ≥10-point increase or \<10-point change in score OR a \<10-point change in score and a ≥10-point increase in score at the next visit; or "Deteriorated": a ≥10-point deterioration in score when the criteria for improvement/stability weren't met. Participants who didn't meet "Improved", "Stable", or "Deteriorated" criteria reported as "Other". |
| Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator | Up to approximately 46 months | For participants who demonstrate CR or PR, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. The DOR per RECIST 1.1 as assessed by Investigator is presented. |
| Percentage of Participants That Were PFS Event-Free (PFS Rate) at Month 12 Per RECIST 1.1 as Assessed by Investigator | 12 months | PFS was 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 was defined as ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. PFS Rate was defined as the percentage of participants that were PFS event-free at Month 12. The PFS Rate per RECIST 1.1 as assessed by Investigator at Month 12 is presented. |
| PFS Per RECIST 1.1 as Assessed by Blinded Independent Central Review (BICR) | Up to approximately 46 months | PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 as assessed by BICR is presented. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 66 months | An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experienced an AE is presented. |
| Number of Participants Who Experienced a Serious AE (SAE) | Up to approximately 66 months | An SAE was defined as any untoward medical occurrence that, at any dose: a.) Resulted in death; b.) Was life-threatening; c.) Required inpatient hospitalization or prolongation of existing hospitalization; d.) Resulted in persistent or significant disability/incapacity; e.) Was a congenital anomaly/birth defect; f.) Other important medical events; h.) Was a new cancer (that is not a condition of the study) or i.) Was associated with an overdose. The number of participants who experienced an SAE is presented. |
Countries
Argentina, Australia, Canada, Chile, Colombia, France, Germany, Israel, Italy, Japan, Mexico, Peru, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), Ukraine, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Recruitment details
883 participants were screened and 617 participants were randomized to receive either Pembrolizumab+Chemotherapy or Placebo+Chemotherapy.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab+Chemotherapy On Day 1 of each 21-day cycle, participants received an intravenous (IV) infusion of pembrolizumab 200 mg for up to 35 cycles (up to approximately 2 years) PLUS Investigator choice of chemotherapy for up to 6 cycles (paclitaxel 175 mg/m\^2 PLUS cisplatin 50 mg/m\^2 WITH or WITHOUT bevacizumab 15 mg/kg per local label OR paclitaxel 175 mg/m\^2 PLUS carboplatin Area Under the Curve (AUC) 5 for up to 6 cycles, WITH or WITHOUT bevacizumab 15 mg/kg per local label). All treatments were administered until disease progression or toxicity. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion. | 308 |
| Placebo+Chemotherapy On Day 1 of each 21-day cycle, participants received an IV infusion of placebo (Normal Saline or Dextrose solution) for up to 35 cycles (up to approximately 2 years) PLUS Investigator choice of chemotherapy for up to 6 cycles (paclitaxel 175 mg/m\^2 PLUS cisplatin 50 mg/m\^2 WITH or WITHOUT bevacizumab 15 mg/kg per local label OR paclitaxel 175 mg/m\^2 PLUS carboplatin AUC 5 for up to 6 cycles, WITH or WITHOUT bevacizumab 15 mg/kg per local label). All treatments were administered until disease progression or toxicity. | 309 |
| Total | 617 |
Baseline characteristics
| Characteristic | Pembrolizumab+Chemotherapy | Placebo+Chemotherapy | Total |
|---|---|---|---|
| Age, Continuous | 51.7 Years STANDARD_DEVIATION 11.9 | 50.7 Years STANDARD_DEVIATION 12.7 | 51.2 Years STANDARD_DEVIATION 12.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 109 Participants | 121 Participants | 230 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 193 Participants | 184 Participants | 377 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 4 Participants | 10 Participants |
| Investigator Choice to Use Bevacizumab No | 112 Participants | 116 Participants | 228 Participants |
| Investigator Choice to Use Bevacizumab Yes | 196 Participants | 193 Participants | 389 Participants |
| Metastatic at Initial Diagnosis No | 214 Participants | 213 Participants | 427 Participants |
| Metastatic at Initial Diagnosis Yes | 94 Participants | 96 Participants | 190 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) Status 1≤ PD-L1 CPS<10 | 115 Participants | 116 Participants | 231 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) Status PD-L1 CPS<1 | 35 Participants | 34 Participants | 69 Participants |
| Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) Status PD-L1 CPS≥10 | 158 Participants | 159 Participants | 317 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 18 Participants | 21 Participants | 39 Participants |
| Race (NIH/OMB) Asian | 65 Participants | 45 Participants | 110 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 32 Participants | 34 Participants | 66 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 19 Participants | 17 Participants | 36 Participants |
| Race (NIH/OMB) White | 170 Participants | 190 Participants | 360 Participants |
| Sex: Female, Male Female | 308 Participants | 309 Participants | 617 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 195 / 308 | 241 / 309 | 4 / 12 |
| other Total, other adverse events | 298 / 307 | 299 / 309 | 8 / 12 |
| serious Total, serious adverse events | 157 / 307 | 132 / 309 | 4 / 12 |
Outcome results
Primary
OS in All Participants
OS was defined as the time from randomization to death due to any cause. The OS for all randomized participants is presented.
Time frame: Up to approximately 46 months
Population: All randomized participants based on the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Chemotherapy | OS in All Participants | 26.4 Months |
| Placebo+Chemotherapy | OS in All Participants | 16.8 Months |
Comparison: Treatment comparison (HR) was based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by metastatic at initial diagnosis (FIGO \[2009\] stage IVB) (yes or no), bevacizumab use (yes or no), and PD-L1 status (CPS\<1, CPS 1 to \<10, or CPS ≥10).p-value: <0.000195% CI: [0.52, 0.77]Stratified Log-Rank
Primary
OS in Participants With PD-L1 CPS ≥10
OS was defined as the time from randomization to death due to any cause. The OS for all randomized participants with PD-L1 CPS ≥10 is presented.
Time frame: Up to approximately 46 months
Population: All randomized participants with PD-L1 CPS ≥10 based on the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Chemotherapy | OS in Participants With PD-L1 CPS ≥10 | 29.6 Months |
| Placebo+Chemotherapy | OS in Participants With PD-L1 CPS ≥10 | 17.4 Months |
Comparison: Treatment comparison (HR) was based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by metastatic at initial diagnosis (FIGO \[2009\] stage IVB) (yes or no), bevacizumab use (yes or no), and PD-L1 status (CPS\<1, CPS 1 to \<10, or CPS ≥10).p-value: <0.000195% CI: [0.44, 0.78]Stratified Log-Rank
Primary
Overall Survival (OS) in Participants With PD-L1 CPS ≥1
OS was defined as the time from randomization to death due to any cause. The OS for all randomized participants with PD-L1 CPS ≥1 is presented.
Time frame: Up to approximately 46 months
Population: All randomized participants with PD-L1 CPS ≥1 based on the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Chemotherapy | Overall Survival (OS) in Participants With PD-L1 CPS ≥1 | 28.6 Months |
| Placebo+Chemotherapy | Overall Survival (OS) in Participants With PD-L1 CPS ≥1 | 16.5 Months |
Comparison: Treatment comparison (HR) was based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by metastatic at initial diagnosis (FIGO \[2009\] stage IVB) (yes or no), bevacizumab use (yes or no), and PD-L1 status (CPS\<1, CPS 1 to \<10, or CPS ≥10).p-value: <0.000195% CI: [0.49, 0.74]Stratified Log-Rank
Primary
PFS Per RECIST 1.1 as Assessed by Investigator in All Participants
PFS was 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 was defined as ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 as assessed by Investigator for all randomized participants is presented.
Time frame: Up to approximately 46 months
Population: All randomized participants based on the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Chemotherapy | PFS Per RECIST 1.1 as Assessed by Investigator in All Participants | 10.4 Months |
| Placebo+Chemotherapy | PFS Per RECIST 1.1 as Assessed by Investigator in All Participants | 8.2 Months |
Comparison: Treatment comparison (HR) was based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by metastatic at initial diagnosis (FIGO \[2009\] stage IVB) (yes or no), bevacizumab use (yes or no), and PD-L1 status (CPS\<1, CPS 1 to \<10, or CPS ≥10).p-value: <0.000195% CI: [0.5, 0.74]Stratified Log-Rank
Primary
PFS Per RECIST 1.1 as Assessed by Investigator in Participants With PD-L1 CPS ≥10
PFS was 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 was defined as ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 as assessed by Investigator for all randomized participants with PD-L1 CPS ≥10 is presented.
Time frame: Up to approximately 46 months
Population: All randomized participants with PD-L1 CPS ≥10 based on the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Chemotherapy | PFS Per RECIST 1.1 as Assessed by Investigator in Participants With PD-L1 CPS ≥10 | 10.4 Months |
| Placebo+Chemotherapy | PFS Per RECIST 1.1 as Assessed by Investigator in Participants With PD-L1 CPS ≥10 | 8.1 Months |
Comparison: Treatment comparison (HR) was based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by metastatic at initial diagnosis (FIGO \[2009\] stage IVB) (yes or no), bevacizumab use (yes or no), and PD-L1 status (CPS\<1, CPS 1 to \<10, or CPS ≥10).p-value: <0.000195% CI: [0.4, 0.68]Stratified Log-Rank
Primary
Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants With Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1
PFS was 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 was defined as ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 as assessed by Investigator for all randomized participants with PD-L1 CPS ≥1 is presented.
Time frame: Up to approximately 46 months
Population: All randomized participants with PD-L1 CPS ≥1 based on the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Chemotherapy | Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants With Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | 10.5 Months |
| Placebo+Chemotherapy | Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants With Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | 8.2 Months |
Comparison: Treatment comparison (hazard ratio \[HR\]) was based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by metastatic at initial diagnosis (FIGO \[2009\] stage IVB) (yes or no), bevacizumab use (yes or no), and PD-L1 status (CPS\<1, CPS 1 to \<10, or CPS ≥10).p-value: <0.000195% CI: [0.47, 0.71]Stratified Log-Rank
Secondary
Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator
For participants who demonstrate CR or PR, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. The DOR per RECIST 1.1 as assessed by Investigator is presented.
Time frame: Up to approximately 46 months
Population: All randomized participants based on the treatment group to which they were randomized who demonstrated CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Chemotherapy | Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator | 18.0 Months |
| Placebo+Chemotherapy | Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator | 10.4 Months |
Secondary
Number of Participants Who Discontinued Study Treatment Due to an AE
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinued study treatment due to an AE is presented.
Time frame: Up to approximately 63 months
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab+Chemotherapy | Number of Participants Who Discontinued Study Treatment Due to an AE | 126 Number of Participants |
| Placebo+Chemotherapy | Number of Participants Who Discontinued Study Treatment Due to an AE | 92 Number of Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experienced an AE is presented.
Time frame: Up to approximately 66 months
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab+Chemotherapy | Number of Participants Who Experienced an Adverse Event (AE) | 305 Number of participants |
| Placebo+Chemotherapy | Number of Participants Who Experienced an Adverse Event (AE) | 307 Number of participants |
Secondary
Number of Participants Who Experienced an Immune-related AE (irAE)
AEs associated with pembrolizumab exposure may be a result of an immune response. These irAEs may occur shortly after the first dose or several months after the last dose of pembrolizumab treatment and may affect more than one body system simultaneously. For this study irAEs included, but were not limited to: -Pneumonitis; * Diarrhea/Colitis; * Aspartate transaminase (AST)/Alanine transaminase (ALT) elevation or Increased bilirubin; * Type 1 diabetes mellitus or Hyperglycemia; * Hypophysitis; * Hyperthyroidism; * Hypothyroidism; * Nephritis and Renal dysfunction; and * Myocarditis. The number of participants who experienced an irAE is presented.
Time frame: Up to approximately 66 months
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab+Chemotherapy | Number of Participants Who Experienced an Immune-related AE (irAE) | 134 Number of Participants |
| Placebo+Chemotherapy | Number of Participants Who Experienced an Immune-related AE (irAE) | 92 Number of Participants |
Secondary
Number of Participants Who Experienced a Serious AE (SAE)
An SAE was defined as any untoward medical occurrence that, at any dose: a.) Resulted in death; b.) Was life-threatening; c.) Required inpatient hospitalization or prolongation of existing hospitalization; d.) Resulted in persistent or significant disability/incapacity; e.) Was a congenital anomaly/birth defect; f.) Other important medical events; h.) Was a new cancer (that is not a condition of the study) or i.) Was associated with an overdose. The number of participants who experienced an SAE is presented.
Time frame: Up to approximately 66 months
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab+Chemotherapy | Number of Participants Who Experienced a Serious AE (SAE) | 157 Number of Participants |
| Placebo+Chemotherapy | Number of Participants Who Experienced a Serious AE (SAE) | 132 Number of Participants |
Secondary
Number of Participants With a 10-point Change From Baseline in Quality of Life (QoL) Based on the European Organisation for the Research & Treatment of Cancer (EORTC) QoL Questionnaire-30 (QLQ-C30) Combined Global Score
The EORTC QLQ-C30 is a questionnaire to assess the quality of life of cancer patients. Participant responses to How would you rate your overall health during the past week? (Item 29) and How would you rate your overall quality of life during the past week? (Item 30) are scored on a 7-point scale (1= Very poor to 7=Excellent). Raw scores are standardized with linear transformation so that scores range from 0-100. A higher combined score indicates a better overall health status. Participant post-baseline scores were classified based on change from baseline, Improved: a ≥10-point improvement in score and confirmed by the next visit; Stable: a ≥10-point increase or \<10-point change in score OR a \<10-point change in score and a ≥10-point increase in score at the next visit; or Deteriorated: a ≥10-point deterioration in score when the criteria for improvement/stability weren't met. Participants who didn't meet Improved, Stable, or Deteriorated criteria reported as Other.
Time frame: Baseline (Cycle 1 Day 1: Predose) and up to approximately 46 months
Population: Per protocol, all randomized participants who received at least one dose of study treatment and completed at least one EORTC QLQ-C30 assessment were analyzed. Participants with no EORTC QLQ-C30 assessment were not included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pembrolizumab+Chemotherapy | Number of Participants With a 10-point Change From Baseline in Quality of Life (QoL) Based on the European Organisation for the Research & Treatment of Cancer (EORTC) QoL Questionnaire-30 (QLQ-C30) Combined Global Score | Stable | 106 Number of Participants |
| Pembrolizumab+Chemotherapy | Number of Participants With a 10-point Change From Baseline in Quality of Life (QoL) Based on the European Organisation for the Research & Treatment of Cancer (EORTC) QoL Questionnaire-30 (QLQ-C30) Combined Global Score | Deteriorated | 42 Number of Participants |
| Pembrolizumab+Chemotherapy | Number of Participants With a 10-point Change From Baseline in Quality of Life (QoL) Based on the European Organisation for the Research & Treatment of Cancer (EORTC) QoL Questionnaire-30 (QLQ-C30) Combined Global Score | Other | 9 Number of Participants |
| Pembrolizumab+Chemotherapy | Number of Participants With a 10-point Change From Baseline in Quality of Life (QoL) Based on the European Organisation for the Research & Treatment of Cancer (EORTC) QoL Questionnaire-30 (QLQ-C30) Combined Global Score | Improved | 122 Number of Participants |
| Placebo+Chemotherapy | Number of Participants With a 10-point Change From Baseline in Quality of Life (QoL) Based on the European Organisation for the Research & Treatment of Cancer (EORTC) QoL Questionnaire-30 (QLQ-C30) Combined Global Score | Other | 9 Number of Participants |
| Placebo+Chemotherapy | Number of Participants With a 10-point Change From Baseline in Quality of Life (QoL) Based on the European Organisation for the Research & Treatment of Cancer (EORTC) QoL Questionnaire-30 (QLQ-C30) Combined Global Score | Deteriorated | 48 Number of Participants |
| Placebo+Chemotherapy | Number of Participants With a 10-point Change From Baseline in Quality of Life (QoL) Based on the European Organisation for the Research & Treatment of Cancer (EORTC) QoL Questionnaire-30 (QLQ-C30) Combined Global Score | Stable | 139 Number of Participants |
| Placebo+Chemotherapy | Number of Participants With a 10-point Change From Baseline in Quality of Life (QoL) Based on the European Organisation for the Research & Treatment of Cancer (EORTC) QoL Questionnaire-30 (QLQ-C30) Combined Global Score | Improved | 86 Number of Participants |
Secondary
Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by Investigator
ORR was defined as the percentage of the participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters). The ORR per RECIST 1.1 as assessed by Investigator is presented.
Time frame: Up to approximately 46 months
Population: All randomized participants based on the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab+Chemotherapy | Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by Investigator | 66.2 Percentage of Participants |
| Placebo+Chemotherapy | Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by Investigator | 51.5 Percentage of Participants |
Comparison: Treatment comparison was based on Miettinen \& Nurminen method stratified by metastatic at initial diagnosis (FIGO \[2009\] stage IVB) (yes or no), bevacizumab use (yes or no), and PD-L1 status (CPS\<1, CPS 1 to \<10, or CPS ≥10).p-value: 0.000195% CI: [7.4, 22.3]Miettinen & Nurminen method
Secondary
Percentage of Participants That Were PFS Event-Free (PFS Rate) at Month 12 Per RECIST 1.1 as Assessed by Investigator
PFS was 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 was defined as ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. PFS Rate was defined as the percentage of participants that were PFS event-free at Month 12. The PFS Rate per RECIST 1.1 as assessed by Investigator at Month 12 is presented.
Time frame: 12 months
Population: All randomized participants based on the treatment group to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab+Chemotherapy | Percentage of Participants That Were PFS Event-Free (PFS Rate) at Month 12 Per RECIST 1.1 as Assessed by Investigator | 44.7 Percentage of Participants |
| Placebo+Chemotherapy | Percentage of Participants That Were PFS Event-Free (PFS Rate) at Month 12 Per RECIST 1.1 as Assessed by Investigator | 33.1 Percentage of Participants |
Secondary
PFS Per RECIST 1.1 as Assessed by Blinded Independent Central Review (BICR)
PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 as assessed by BICR is presented.
Time frame: Up to approximately 46 months
Population: All randomized participants based on the treatment group to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab+Chemotherapy | PFS Per RECIST 1.1 as Assessed by Blinded Independent Central Review (BICR) | 12.3 Months |
| Placebo+Chemotherapy | PFS Per RECIST 1.1 as Assessed by Blinded Independent Central Review (BICR) | 8.3 Months |
Comparison: Treatment comparison (HR) was based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by metastatic at initial diagnosis (FIGO \[2009\] stage IVB) (yes or no), bevacizumab use (yes or no), and PD-L1 status (CPS\<1, CPS 1 to \<10, or CPS ≥10).p-value: <0.000195% CI: [0.49, 0.74]Stratified Log-Rank