Urothelial Carcinoma Associated 1 RNA, Human
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Brief summary
The purpose of this study is to determine the efficacy and safety of pembrolizumab (pembro, MK-3475) with or without chemotherapy versus chemotherapy alone in participants with advanced or metastatic urothelial carcinoma (bladder cancer). The primary hypotheses are that pembrolizumab plus chemotherapy is superior to chemotherapy alone with respect to Progression-free Survival (PFS) and Overall Survival (OS) in all participants, and that pembrolizumab alone is superior to chemotherapy alone with respect to OS in all participants and in participants with programmed cell death ligand 1 (PD-L1) positive tumors (Combined Positive Score \[CPS\] ≥10%).
Detailed description
As specified by the protocol, the study hypotheses will be evaluated by comparing the pembro combo arm or pembro arm separately to the chemo arm.
Interventions
BIOLOGICALPembrolizumab
IV infusion
DRUGCisplatin
IV infusion
DRUGCarboplatin
IV infusion
DRUGGemcitabine
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a histologically or cytologically confirmed diagnosis of advanced/unresectable (inoperable) or metastatic urothelial carcinoma of the renal pelvis, ureter \[upper urinary tract\], bladder, or urethra. Both transitional cell and mixed transitional/non- transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology. * Has measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment. * Has received no prior systemic chemotherapy for advanced or metastatic urothelial carcinoma, with the following exceptions: * Neoadjuvant platinum-based chemotherapy with recurrence \>12 months from completion of therapy is permitted. * Adjuvant platinum-based chemotherapy following radical cystectomy with recurrence \>12 months from completion of therapy is permitted. * Has provided tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated from a muscle invasive urothelial carcinoma or a metastatic biopsy, originally from the original tumor. * Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2. * Demonstrates adequate organ function. * Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of pembrolizumab or 180 days after chemotherapy treatment. * Male participants of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of pembrolizumab or 180 days after chemotherapy treatment.
Exclusion criteria
* Has disease that is suitable for local therapy administered with curative intent. * Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study drug. * Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization. * Has an active autoimmune disease that has required systemic treatment in the past 2 years. * Has had a prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastic treatment within 4 weeks prior to the first dose of study drug (6 weeks for nitrosoureas or mitomycin C) or who has not recovered (i.e., ≤ Grade 1 or at Baseline) from adverse events (AEs) due to mAbs administered more than 4 weeks earlier. * Has not recovered (i.e., AE ≤ Grade 1 or at Baseline) from AEs due to a previously administered agent. * Has a known additional malignancy that is progressing or requires active treatment within the past 5 years. * Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. * A history of prostate cancer that was identified incidentally following cystoprostatectomy for bladder cancer is acceptable, provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score ≤6; Prostate-specific Antigen (PSA) level undetectable. * Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. * Has a known history of active tuberculosis (TB). * Has an active infection requiring systemic therapy. * Has a history of severe hypersensitivity reaction (e.g. generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to pembrolizumab, gemcitabine, carboplatin, or cisplatin or their analogs and/or to any of their excipients. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is a known regular user (including recreational use) of any illicit drug(s) or had a recent history (within the last year) of drug or alcohol abuse. * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab or 180 days after the last dose of chemotherapy treatment. * Has received prior therapy with an anti-PD-1, or anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], OX-40, CD137). * Has a known history of human immunodeficiency virus (HIV). * Has known active hepatitis B or hepatitis C.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pembro Combo vs Chemo: Progression-free Survival (PFS) Using Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | Up to approximately 42 months | PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS in the pembro combo arm was compared to the chemo arm as a pre-specified primary analysis of the Intent-To-Treat (ITT) population (all randomized participants). PFS is reported here for all participants in the pembro combo arm and chemo arm. Per protocol, PFS was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record. |
| Pembro Combo vs Chemo: Overall Survival (OS) | Up to approximately 42 months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro combo arm was compared to the chemo arm as a pre-specified primary analysis of the ITT population (all randomized participants). OS is reported here for all participants in the pembro combo arm and chemo arm. Per protocol, OS was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record. |
| Pembro vs Chemo: OS in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10% | Up to approximately 42 months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the CPS ≥10% subset of the pembro arm was compared to OS in the CPS ≥10% subset of the chemo arm for this endpoint as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro arm and chemo arm who were PD-L1 CPS ≥10%. Per protocol, OS in the CPS ≥10% subset of the pembro combo arm was not a pre-specified analysis of the ITT population and is not presented. |
| Pembro vs Chemo: OS | Up to approximately 42 months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro arm was compared to the chemo arm as a pre-specified primary analysis of the ITT population (all randomized participants). OS is reported here for all participants in the pembro arm and chemo arm. Per protocol, OS was compared separately between all participants of the pembro combo arm and chemo arm and is presented earlier in the record. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pembro Combo vs Chemo: Duration of Response (DOR) Using RECIST 1.1 as Assessed by BICR | Up to approximately 42 months | For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based upon BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. DOR is reported here for all participants in the pembro combo arm and chemo arm who had CR or PR. Per protocol, DOR was assessed separately in responders of the pembro arm and chemo arm and is presented later in the record. |
| Pembro Combo vs Chemo: Disease Control Rate (DCR) Using RECIST 1.1 as Assessed by BICR | Up to approximately 42 months | DCR was defined as the percentage of participants who had a confirmed CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions), or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD \[at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD\]). Per protocol, DCR in the pembro combo arm was compared to the chemo arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced a confirmed CR, PR, or SD according to RECIST 1.1 as assessed by BICR was reported as the DCR for all participants in the pembro combo arm and chemo arm. Per protocol, DCR was compared separately between participants of the pembro arm and chemo arm and is presented later in the record. |
| Pembro vs Chemo: ORR Using RECIST 1.1 as Assessed by BICR | Up to approximately 42 months | ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, ORR in the pembro arm was compared to the chemo arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro arm and chemo arm. Per protocol, ORR was compared separately between participants of the pembro combo arm and chemo arm and is presented earlier in the record. |
| Pembro vs Chemo: DOR Using RECIST 1.1 as Assessed by BICR | Up to approximately 42 months | For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based upon BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. DOR is reported here for all participants in the pembro arm and chemo arm who had CR or PR. Per protocol, DOR was assessed separately in responders of the pembro combo arm and chemo arm and is presented earlier in the record. |
| Pembro vs Chemo: DCR Using RECIST 1.1 as Assessed by BICR | Up to approximately 42 months | DCR was defined as the percentage of participants who had a CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions), or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD \[at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD\]). Per protocol, DCR in the pembro arm was compared to the chemo arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced a confirmed CR, PR, or SD according to RECIST 1.1 as assessed by BICR was reported as the DCR for all participants in the pembro arm and chemo arm. Per protocol, DCR was compared separately between participants of the pembro combo arm and chemo arm and is presented earlier in the record. |
| PFS Using RECIST 1.1 as Assessed by BICR at 6 Months | 6 months | PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS was compared between arms as a pre-specified secondary analysis of the ITT population (all randomized participants). PFS is reported here for all participants at 6 months based on the product-limit (Kaplan-Meier) method for censored data. |
| Pembro vs Chemo: PFS Using RECIST 1.1 as Assessed by BICR | Up to approximately 42 months | PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS in the pembro arm was compared to the chemo arm as a pre-specified analysis of the ITT population (all randomized participants). PFS is reported here for all participants in the pembro arm and chemo arm. Per protocol, PFS was compared separately between all participants of the pembro combo arm and chemo arm and is presented earlier in the record. |
| PFS Using RECIST 1.1 as Assessed by BICR at 18 Months | 18 months | PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS was compared between arms as a pre-specified secondary analysis of the ITT population (all randomized participants). PFS is reported here for all participants at 18 months based on the product-limit (Kaplan-Meier) method for censored data. |
| Pembro Combo vs Chemo: Change From Baseline to Week 18 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score | Baseline, Week 18 | The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question How would you rate your overall health during the past week? (Item 29) and the Quality of Life (QoL) question How would you rate your overall quality of life during the past week? (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared between all participants of the pembro combo arm and the chemo arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record. |
| Pembro Combo vs Chemo: Time to Deterioration (TTD) in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score | Baseline up to approximately 25 months | EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the GHS question How would you rate your overall health during the past week? (Item 29) and the QoL question How would you rate your overall quality of life during the past week? (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD in GHS/QoL was defined as the time from first dose date to the first onset of a ≥10 point decrease from baseline in GHS/QoL combined score without confirmation. Per protocol, TTD in GHS/QoL combined score was compared between the pembro combo arm and chemo arm. TTD in GHS/QoL combined score was compared separately between the pembro arm and chemo arm and is presented later in the record. |
| Pembro vs Chemo: Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score | Baseline, Week 18 | The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question How would you rate your overall health during the past week? (Item 29) and the Quality of Life (QoL) question How would you rate your overall quality of life during the past week? (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared between all participants of the pembro arm and the chemo arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro combo arm and chemo arm and is presented earlier in the record. |
| Pembro vs Chemo: TTD in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score | Baseline up to approximately 25 months | EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the GHS question How would you rate your overall health during the past week? (Item 29) and the QoL question How would you rate your overall quality of life during the past week? (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD in GHS/QoL was defined as the time from first dose date to the first onset of a ≥10 point decrease from baseline in GHS/QoL combined score without confirmation. Per protocol, TTD in GHS/QoL combined score was compared between the pembro arm and chemo arm. TTD in GHS/QoL combined score was compared separately between the pembro combo arm and chemo arm and is presented earlier in the record. |
| PFS Using RECIST 1.1 as Assessed by BICR at 12 Months | 12 months | PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS was compared between arms as a pre-specified secondary analysis of the ITT population (all randomized participants). PFS is reported here for all participants at 12 months based on the product-limit (Kaplan-Meier) method for censored data. |
| Number of Participants Who Experience an Adverse Event (AE) | Up to approximately 55 months | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The number of participants that experienced at least one AE was reported for each treatment arm. |
| Number of Participants Who Discontinue Study Drug Due to an AE | Up to approximately 52 months | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The number of participants that discontinued any study drug due to an AE was reported for each treatment arm. |
| Pembro Combo vs Chemo: Objective Response Rate (ORR) Using RECIST 1.1 as Assessed by BICR | Up to approximately 42 months | ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, ORR in the pembro combo arm was compared to the chemo arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro combo arm and chemo arm. Per protocol, ORR was compared separately between participants of the pembro arm and chemo arm and is presented later in the record. |
Participant flow
Recruitment details
Participants with advanced or metastatic urothelial carcinoma were recruited to examine the efficacy and safety of pembrolizumab plus chemotherapy (pembro combo) versus pembrolizumab alone (pembro) or chemotherapy alone (chemo).
Pre-assignment details
1,010 participants were randomized 1:1:1 to receive pembrolizumab plus chemotherapy, pembrolizumab alone, or chemotherapy alone. Per protocol, response/progression or adverse events (AEs) that occurred during the second course were not counted towards efficacy outcome measures or safety outcome measures, respectively.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + ST Chemotherapy (Pembro Combo) Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m\^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m\^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m\^2 IV on Day 1 and Day 8 of each 3-week cycle. Eligible participants who stopped 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. | 351 |
| Pembrolizumab (Pembro) Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses. Eligible participants who stopped pembrolizumab with 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. | 307 |
| ST Chemotherapy (Chemo) Participants received ST chemotherapy with EITHER cisplatin 70 mg/m\^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m\^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m\^2 IV on Day 1 and Day 8 of each 3-week cycle. | 352 |
| Total | 1,010 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 287 | 249 | 300 |
| Overall Study | Did Not Continue on Extension Study | 16 | 20 | 24 |
| Overall Study | Transferred to Extension Study | 46 | 30 | 25 |
| Overall Study | Withdrawal by Subject | 2 | 8 | 3 |
Baseline characteristics
| Characteristic | Pembrolizumab + ST Chemotherapy (Pembro Combo) | Pembrolizumab (Pembro) | ST Chemotherapy (Chemo) | Total |
|---|---|---|---|---|
| Age, Continuous | 68.3 years STANDARD_DEVIATION 9.2 | 67.0 years STANDARD_DEVIATION 10.1 | 68.0 years STANDARD_DEVIATION 9.6 | 67.8 years STANDARD_DEVIATION 9.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants | 25 Participants | 32 Participants | 83 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 269 Participants | 231 Participants | 261 Participants | 761 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 56 Participants | 51 Participants | 59 Participants | 166 Participants |
| Investigator Choice of Cisplatin or Carboplatin - IVRS Carboplatin | 191 Participants | 169 Participants | 192 Participants | 552 Participants |
| Investigator Choice of Cisplatin or Carboplatin - IVRS Cisplatin | 160 Participants | 138 Participants | 160 Participants | 458 Participants |
| PD-L1 CPS Status-IVRS PD-L1 CPS<10 | 192 Participants | 148 Participants | 193 Participants | 533 Participants |
| PD-L1 CPS Status-IVRS PD-L1 CPS≥10 | 159 Participants | 159 Participants | 159 Participants | 477 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 64 Participants | 47 Participants | 70 Participants | 181 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 42 Participants | 42 Participants | 42 Participants | 126 Participants |
| Race (NIH/OMB) White | 243 Participants | 212 Participants | 235 Participants | 690 Participants |
| Sex: Female, Male Female | 79 Participants | 79 Participants | 90 Participants | 248 Participants |
| Sex: Female, Male Male | 272 Participants | 228 Participants | 262 Participants | 762 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 283 / 351 | 244 / 307 | 300 / 352 | 4 / 14 | 8 / 15 |
| other Total, other adverse events | 345 / 349 | 275 / 302 | 337 / 342 | 0 / 14 | 1 / 15 |
| serious Total, serious adverse events | 189 / 349 | 145 / 302 | 138 / 342 | 0 / 14 | 0 / 15 |
Outcome results
Primary
Pembro Combo vs Chemo: Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro combo arm was compared to the chemo arm as a pre-specified primary analysis of the ITT population (all randomized participants). OS is reported here for all participants in the pembro combo arm and chemo arm. Per protocol, OS was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record.
Time frame: Up to approximately 42 months
Population: All participants in the ITT population randomized to the pembro combo arm and chemo arm were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + ST Chemotherapy (Pembro Combo) | Pembro Combo vs Chemo: Overall Survival (OS) | 17.0 Months |
| ST Chemotherapy (Chemo) | Pembro Combo vs Chemo: Overall Survival (OS) | 14.3 Months |
Comparison: OS in all participants of the pembro combo arm was compared to OS in all participants of the chemo arm to address the second primary hypothesis (superiority to chemo). The HR and its 95% CI were estimated using a stratified Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS\<10 vs. CPS≥10) at baseline.p-value: 0.040795% CI: [0.72, 1.02]Stratified Log-Rank
Primary
Pembro Combo vs Chemo: Progression-free Survival (PFS) Using Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS in the pembro combo arm was compared to the chemo arm as a pre-specified primary analysis of the Intent-To-Treat (ITT) population (all randomized participants). PFS is reported here for all participants in the pembro combo arm and chemo arm. Per protocol, PFS was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record.
Time frame: Up to approximately 42 months
Population: All participants in the ITT population randomized to the pembro combo arm and chemo arm were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + ST Chemotherapy (Pembro Combo) | Pembro Combo vs Chemo: Progression-free Survival (PFS) Using Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 8.3 Months |
| ST Chemotherapy (Chemo) | Pembro Combo vs Chemo: Progression-free Survival (PFS) Using Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 7.1 Months |
Comparison: PFS in all participants of the pembro combo arm was compared to PFS in all participants of the chemo arm to address the first primary hypothesis (superiority to chemo). The hazard ratio (HR) and its 95% confidence interval (CI) were estimated using a stratified Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS\<10 vs. CPS≥10) at baseline.p-value: 0.003395% CI: [0.65, 0.93]Stratified Log-Rank
Primary
Pembro vs Chemo: OS
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro arm was compared to the chemo arm as a pre-specified primary analysis of the ITT population (all randomized participants). OS is reported here for all participants in the pembro arm and chemo arm. Per protocol, OS was compared separately between all participants of the pembro combo arm and chemo arm and is presented earlier in the record.
Time frame: Up to approximately 42 months
Population: All participants in the ITT population randomized to the pembro arm and chemo arm were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab (Pembro) | Pembro vs Chemo: OS | 15.6 Months |
| ST Chemotherapy (Chemo) | Pembro vs Chemo: OS | 14.3 Months |
Comparison: OS in all participants of the pembro arm was compared to OS in all participants of the chemo arm. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS\<10 vs. CPS≥10) at baseline.95% CI: [0.77, 1.11]
Primary
Pembro vs Chemo: OS in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10%
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the CPS ≥10% subset of the pembro arm was compared to OS in the CPS ≥10% subset of the chemo arm for this endpoint as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro arm and chemo arm who were PD-L1 CPS ≥10%. Per protocol, OS in the CPS ≥10% subset of the pembro combo arm was not a pre-specified analysis of the ITT population and is not presented.
Time frame: Up to approximately 42 months
Population: All participants in the ITT population randomized to the pembro arm and chemo arm who were PD-L1 CPS ≥10% were included in the analysis. Per protocol, the pembro combo arm was not pre-specified as part of this analysis and is not included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab (Pembro) | Pembro vs Chemo: OS in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10% | 16.1 Months |
| ST Chemotherapy (Chemo) | Pembro vs Chemo: OS in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10% | 15.2 Months |
Comparison: OS in CPS≥10 participants of the pembro arm was compared to OS in CPS≥10 participants of the chemo arm. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) at baseline.95% CI: [0.77, 1.32]
Secondary
Number of Participants Who Discontinue Study Drug Due to an AE
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The number of participants that discontinued any study drug due to an AE was reported for each treatment arm.
Time frame: Up to approximately 52 months
Population: All randomized participants who received at least 1 dose of trial treatment were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + ST Chemotherapy (Pembro Combo) | Number of Participants Who Discontinue Study Drug Due to an AE | 108 Participants |
| Pembrolizumab (Pembro) | Number of Participants Who Discontinue Study Drug Due to an AE | 48 Participants |
| ST Chemotherapy (Chemo) | Number of Participants Who Discontinue Study Drug Due to an AE | 62 Participants |
Secondary
Number of Participants Who Experience an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The number of participants that experienced at least one AE was reported for each treatment arm.
Time frame: Up to approximately 55 months
Population: All randomized participants who received at least 1 dose of trial treatment were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + ST Chemotherapy (Pembro Combo) | Number of Participants Who Experience an Adverse Event (AE) | 348 Participants |
| Pembrolizumab (Pembro) | Number of Participants Who Experience an Adverse Event (AE) | 289 Participants |
| ST Chemotherapy (Chemo) | Number of Participants Who Experience an Adverse Event (AE) | 341 Participants |
Secondary
Pembro Combo vs Chemo: Change From Baseline to Week 18 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score
The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question How would you rate your overall health during the past week? (Item 29) and the Quality of Life (QoL) question How would you rate your overall quality of life during the past week? (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared between all participants of the pembro combo arm and the chemo arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record.
Time frame: Baseline, Week 18
Population: All participants in the ITT population randomized to the pembro combo arm and chemo arm who received at least 1 dose of study drug and who completed at least 1 EORTC-QLQ-C30 assessment were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and is not included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pembrolizumab + ST Chemotherapy (Pembro Combo) | Pembro Combo vs Chemo: Change From Baseline to Week 18 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score | 2.54 Score on a Scale |
| ST Chemotherapy (Chemo) | Pembro Combo vs Chemo: Change From Baseline to Week 18 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score | -0.14 Score on a Scale |
Comparison: Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between all participants of the pembro combo arm and the chemo arm. Comparison based on constrained longitudinal data analysis (cLDA) model with GHS/QoL score as response variable, and with treatment by study visit interactions and stratification factors (investigator's choice of chemotherapy \[cisplatin or carboplatin\] and PD-L1 status \[CPS\<10 vs. CPS≥10\]) at baseline as covariates.95% CI: [-0.76, 6.12]
Secondary
Pembro Combo vs Chemo: Disease Control Rate (DCR) Using RECIST 1.1 as Assessed by BICR
DCR was defined as the percentage of participants who had a confirmed CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions), or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD \[at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD\]). Per protocol, DCR in the pembro combo arm was compared to the chemo arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced a confirmed CR, PR, or SD according to RECIST 1.1 as assessed by BICR was reported as the DCR for all participants in the pembro combo arm and chemo arm. Per protocol, DCR was compared separately between participants of the pembro arm and chemo arm and is presented later in the record.
Time frame: Up to approximately 42 months
Population: All participants in the ITT population randomized to the pembro combo arm and chemo arm were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + ST Chemotherapy (Pembro Combo) | Pembro Combo vs Chemo: Disease Control Rate (DCR) Using RECIST 1.1 as Assessed by BICR | 80.3 Percentage of Participants |
| ST Chemotherapy (Chemo) | Pembro Combo vs Chemo: Disease Control Rate (DCR) Using RECIST 1.1 as Assessed by BICR | 75.9 Percentage of Participants |
Comparison: DCR in participants of the pembro combo arm was compared to DCR in participants of the chemo arm based on the Miettinen \& Nurminen method stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS\<10 vs. CPS≥10) at baseline.95% CI: [-1.6, 10.6]
Secondary
Pembro Combo vs Chemo: Duration of Response (DOR) Using RECIST 1.1 as Assessed by BICR
For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based upon BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. DOR is reported here for all participants in the pembro combo arm and chemo arm who had CR or PR. Per protocol, DOR was assessed separately in responders of the pembro arm and chemo arm and is presented later in the record.
Time frame: Up to approximately 42 months
Population: All participants in the ITT population randomized to the pembro combo arm and chemo arm and who demonstrated a confirmed CR or PR were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + ST Chemotherapy (Pembro Combo) | Pembro Combo vs Chemo: Duration of Response (DOR) Using RECIST 1.1 as Assessed by BICR | 8.5 Months |
| ST Chemotherapy (Chemo) | Pembro Combo vs Chemo: Duration of Response (DOR) Using RECIST 1.1 as Assessed by BICR | 6.2 Months |
Secondary
Pembro Combo vs Chemo: Objective Response Rate (ORR) Using RECIST 1.1 as Assessed by BICR
ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, ORR in the pembro combo arm was compared to the chemo arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro combo arm and chemo arm. Per protocol, ORR was compared separately between participants of the pembro arm and chemo arm and is presented later in the record.
Time frame: Up to approximately 42 months
Population: All participants in the ITT population randomized to the pembro combo arm and chemo arm were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + ST Chemotherapy (Pembro Combo) | Pembro Combo vs Chemo: Objective Response Rate (ORR) Using RECIST 1.1 as Assessed by BICR | 54.7 Percentage of Participants |
| ST Chemotherapy (Chemo) | Pembro Combo vs Chemo: Objective Response Rate (ORR) Using RECIST 1.1 as Assessed by BICR | 44.9 Percentage of Participants |
Comparison: ORR in participants of the pembro combo arm was compared to ORR in participants of the chemo arm. The comparison was based on the Miettinen \& Nurminen method stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS\<10 vs. CPS≥10) at baseline.95% CI: [2.4, 17.1]
Secondary
Pembro Combo vs Chemo: Time to Deterioration (TTD) in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score
EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the GHS question How would you rate your overall health during the past week? (Item 29) and the QoL question How would you rate your overall quality of life during the past week? (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD in GHS/QoL was defined as the time from first dose date to the first onset of a ≥10 point decrease from baseline in GHS/QoL combined score without confirmation. Per protocol, TTD in GHS/QoL combined score was compared between the pembro combo arm and chemo arm. TTD in GHS/QoL combined score was compared separately between the pembro arm and chemo arm and is presented later in the record.
Time frame: Baseline up to approximately 25 months
Population: All participants in the ITT population randomized to the pembro combo arm and chemo arm who received at least 1 dose of study drug and who had an EORTC-QLQ-C30 assessment at baseline were included in the analysis. Per protocol, the pembro arm was compared to the chemo arm separately and is not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + ST Chemotherapy (Pembro Combo) | Pembro Combo vs Chemo: Time to Deterioration (TTD) in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score | 8.0 Months |
| ST Chemotherapy (Chemo) | Pembro Combo vs Chemo: Time to Deterioration (TTD) in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score | 4.5 Months |
Comparison: TTD in GHS/QoL combined score was compared between all participants of the pembro combo arm and the chemo arm. Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS\<10 vs. CPS≥10) at baseline.95% CI: [0.62, 1]
Secondary
Pembro vs Chemo: Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score
The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question How would you rate your overall health during the past week? (Item 29) and the Quality of Life (QoL) question How would you rate your overall quality of life during the past week? (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared between all participants of the pembro arm and the chemo arm as a pre-specified secondary analysis. As specified by the protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro combo arm and chemo arm and is presented earlier in the record.
Time frame: Baseline, Week 18
Population: All participants in the ITT population randomized to the pembro arm and chemo arm who received at least 1 dose of study drug and who completed at least 1 EORTC-QLQ-C30 assessment were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and is not included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Pembrolizumab (Pembro) | Pembro vs Chemo: Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score | -1.89 Score on a Scale |
| ST Chemotherapy (Chemo) | Pembro vs Chemo: Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score | -0.95 Score on a Scale |
Comparison: Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between all participants of the pembro arm and the chemo arm. Comparison based on cLDA model with GHS/QoL score as response variable, and with treatment by study visit interactions and stratification factors (investigator's choice of chemotherapy \[cisplatin or carboplatin\] and PD-L1 status \[CPS\<10 vs. CPS≥10\]) at baseline as covariates.95% CI: [-5.06, 3.18]
Secondary
Pembro vs Chemo: DCR Using RECIST 1.1 as Assessed by BICR
DCR was defined as the percentage of participants who had a CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions), or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD \[at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD\]). Per protocol, DCR in the pembro arm was compared to the chemo arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced a confirmed CR, PR, or SD according to RECIST 1.1 as assessed by BICR was reported as the DCR for all participants in the pembro arm and chemo arm. Per protocol, DCR was compared separately between participants of the pembro combo arm and chemo arm and is presented earlier in the record.
Time frame: Up to approximately 42 months
Population: All participants in the ITT population randomized to the pembro arm and chemo arm were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab (Pembro) | Pembro vs Chemo: DCR Using RECIST 1.1 as Assessed by BICR | 47.2 Percentage of Participants |
| ST Chemotherapy (Chemo) | Pembro vs Chemo: DCR Using RECIST 1.1 as Assessed by BICR | 75.9 Percentage of Participants |
Comparison: DCR in participants of the pembro arm was compared to DCR in participants of the chemo arm based on the Miettinen \& Nurminen method stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS\<10 vs. CPS≥10) at baseline.95% CI: [-35.9, -21.6]
Secondary
Pembro vs Chemo: DOR Using RECIST 1.1 as Assessed by BICR
For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based upon BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. DOR is reported here for all participants in the pembro arm and chemo arm who had CR or PR. Per protocol, DOR was assessed separately in responders of the pembro combo arm and chemo arm and is presented earlier in the record.
Time frame: Up to approximately 42 months
Population: All participants in the ITT population randomized to the pembro arm and chemo arm who demonstrated a confirmed CR or PR were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab (Pembro) | Pembro vs Chemo: DOR Using RECIST 1.1 as Assessed by BICR | 28.2 Months |
| ST Chemotherapy (Chemo) | Pembro vs Chemo: DOR Using RECIST 1.1 as Assessed by BICR | 6.2 Months |
Secondary
Pembro vs Chemo: ORR Using RECIST 1.1 as Assessed by BICR
ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, ORR in the pembro arm was compared to the chemo arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro arm and chemo arm. Per protocol, ORR was compared separately between participants of the pembro combo arm and chemo arm and is presented earlier in the record.
Time frame: Up to approximately 42 months
Population: All participants in the ITT population randomized to the pembro arm and chemo arm were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab (Pembro) | Pembro vs Chemo: ORR Using RECIST 1.1 as Assessed by BICR | 30.3 Percentage of Participants |
| ST Chemotherapy (Chemo) | Pembro vs Chemo: ORR Using RECIST 1.1 as Assessed by BICR | 44.9 Percentage of Participants |
Comparison: ORR in participants of the pembro arm was compared to ORR in participants of the chemo arm. The comparison was based on the Miettinen \& Nurminen method stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS\<10 vs. CPS≥10) at baseline.95% CI: [-22, -7.4]
Secondary
Pembro vs Chemo: PFS Using RECIST 1.1 as Assessed by BICR
PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS in the pembro arm was compared to the chemo arm as a pre-specified analysis of the ITT population (all randomized participants). PFS is reported here for all participants in the pembro arm and chemo arm. Per protocol, PFS was compared separately between all participants of the pembro combo arm and chemo arm and is presented earlier in the record.
Time frame: Up to approximately 42 months
Population: All participants in the ITT population randomized to the pembro arm and chemo arm were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab (Pembro) | Pembro vs Chemo: PFS Using RECIST 1.1 as Assessed by BICR | 3.9 Months |
| ST Chemotherapy (Chemo) | Pembro vs Chemo: PFS Using RECIST 1.1 as Assessed by BICR | 7.1 Months |
Comparison: PFS in all participants of the pembro arm was compared to PFS in all participants of the chemo arm. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS\<10 vs. CPS≥10) at baseline.95% CI: [1.09, 1.58]
Secondary
Pembro vs Chemo: TTD in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score
EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. Participant responses to the GHS question How would you rate your overall health during the past week? (Item 29) and the QoL question How would you rate your overall quality of life during the past week? (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD in GHS/QoL was defined as the time from first dose date to the first onset of a ≥10 point decrease from baseline in GHS/QoL combined score without confirmation. Per protocol, TTD in GHS/QoL combined score was compared between the pembro arm and chemo arm. TTD in GHS/QoL combined score was compared separately between the pembro combo arm and chemo arm and is presented earlier in the record.
Time frame: Baseline up to approximately 25 months
Population: All participants in the ITT population randomized to the pembro arm and chemo arm who received at least 1 dose of study drug and who had an EORTC-QLQ-C30 assessment at baseline were included in the analysis. Per protocol, the pembro combo arm was compared to the chemo arm separately and is not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab (Pembro) | Pembro vs Chemo: TTD in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score | 3.6 Months |
| ST Chemotherapy (Chemo) | Pembro vs Chemo: TTD in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score | 4.5 Months |
Comparison: TTD in GHS/QoL combined score was compared between all participants of the pembro arm and the chemo arm. Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator's choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS\<10 vs. CPS≥10) at baseline.95% CI: [0.93, 1.49]
Secondary
PFS Using RECIST 1.1 as Assessed by BICR at 12 Months
PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS was compared between arms as a pre-specified secondary analysis of the ITT population (all randomized participants). PFS is reported here for all participants at 12 months based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: 12 months
Population: All participants in the ITT population (all randomized) were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + ST Chemotherapy (Pembro Combo) | PFS Using RECIST 1.1 as Assessed by BICR at 12 Months | 33.7 Percentage of Participants |
| Pembrolizumab (Pembro) | PFS Using RECIST 1.1 as Assessed by BICR at 12 Months | 26.6 Percentage of Participants |
| ST Chemotherapy (Chemo) | PFS Using RECIST 1.1 as Assessed by BICR at 12 Months | 20.9 Percentage of Participants |
Secondary
PFS Using RECIST 1.1 as Assessed by BICR at 18 Months
PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS was compared between arms as a pre-specified secondary analysis of the ITT population (all randomized participants). PFS is reported here for all participants at 18 months based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: 18 months
Population: All participants in the ITT population (all randomized) were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + ST Chemotherapy (Pembro Combo) | PFS Using RECIST 1.1 as Assessed by BICR at 18 Months | 23.0 Percentage of Participants |
| Pembrolizumab (Pembro) | PFS Using RECIST 1.1 as Assessed by BICR at 18 Months | 19.1 Percentage of Participants |
| ST Chemotherapy (Chemo) | PFS Using RECIST 1.1 as Assessed by BICR at 18 Months | 13.5 Percentage of Participants |
Secondary
PFS Using RECIST 1.1 as Assessed by BICR at 6 Months
PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS was compared between arms as a pre-specified secondary analysis of the ITT population (all randomized participants). PFS is reported here for all participants at 6 months based on the product-limit (Kaplan-Meier) method for censored data.
Time frame: 6 months
Population: All participants in the ITT population (all randomized) were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + ST Chemotherapy (Pembro Combo) | PFS Using RECIST 1.1 as Assessed by BICR at 6 Months | 73.7 Percentage of Participants |
| Pembrolizumab (Pembro) | PFS Using RECIST 1.1 as Assessed by BICR at 6 Months | 43.6 Percentage of Participants |
| ST Chemotherapy (Chemo) | PFS Using RECIST 1.1 as Assessed by BICR at 6 Months | 70.3 Percentage of Participants |