Study of Pembrolizumab (MK-3475) in Participants With Advanced Urothelial Cancer (MK-3475-052/KEYNOTE-052)

• ClinicalTrials.gov Identifier: NCT02335424
• Recruitment Status: Completed
• First Posted: January 9, 2015
• Results First Posted: July 5, 2019
• Last Update Posted: March 2, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: January 7, 2015
• First Posted Date: January 9, 2015
• Results First Submitted Date: May 29, 2019
• Results First Posted Date: July 5, 2019
• Last Update Posted Date: March 2, 2023
• Actual Study Start Date: February 24, 2015
• Actual Primary Completion Date: June 19, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 2, 2023)

• Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants [ Time Frame: Up to approximately 80.5 months ]
  ORR was determined in all participants and was defined as the percentage of participants who had a confirmed 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) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). Participants with missing data were considered non-responders. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1% [ Time Frame: Up to approximately 80.5 months ]
  ORR was determined in participants who had a PD-L1 CPS of ≥1% as measured by immunohistochemistry assay. ORR was defined as the percentage of participants who had a confirmed 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) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). Participants with missing data were considered non-responders. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10% [ Time Frame: Up to approximately 80.5 months ]
  ORR was determined in participants who had a PD-L1 CPS of ≥10% as measured by immunohistochemistry assay. ORR was defined as the percentage of participants who had a confirmed 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) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). Participants with missing data were considered non-responders. Per protocol, only data generated during the initial course of treatment contributed to the analysis.

• Original Primary Outcome Measures (submitted: January 8, 2015): overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1) for Participants with PD-L1-dependent Tumors (Independent Radiology Review) [ Time Frame: Up to 3 years ]

Current Secondary Outcome Measures (submitted: February 2, 2023)

• Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants [ Time Frame: Up to approximately 80.5 months ]
  DOR was determined in participants who demonstrated a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death and was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants who had not progressed or died at the time of analysis were censored at the date of their last tumor assessment. Per RECIST 1.1, PD was a ≥20% increase in the sum of diameters of target lesions plus an absolute increase of ≥5 mm in the sum, or the appearance of ≥1 new lesions. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1% [ Time Frame: Up to approximately 80.5 months ]
  DOR was determined in participants who had a PD-L1 CPS of ≥1%, as measured by immunohistochemistry assay, and had a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death and was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants who had not progressed or died at the time of analysis were censored at the date of their last tumor assessment. Per RECIST 1.1, PD was a ≥20% increase in the sum of diameters of target lesions plus an absolute increase of ≥5 mm in the sum, or the appearance of ≥1 new lesions. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10% [ Time Frame: Up to approximately 80.5 months ]
  DOR was determined in participants who had a PD-L1 CPS of ≥10%, as measured by immunohistochemistry assay, and had a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death and was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants who had not progressed or died at the time of analysis were censored at the date of their last tumor assessment. Per RECIST 1.1, PD was a ≥20% increase in the sum of diameters of target lesions plus an absolute increase of ≥5 mm in the sum, or the appearance of ≥1 new lesions. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants [ Time Frame: Up to approximately 80.5 months ]
  PFS was determined 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 occurred first, per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). Per RECIST 1.1, PD was a ≥20% increase in the sum of diameters of target lesions plus an absolute increase of ≥5 mm in the sum, or the appearance of ≥1 new lesions. Time to scheduled tumor assessment visit rather than the actual tumor assessment visit was used in the analysis. PFS was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1% [ Time Frame: Up to approximately 80.5 months ]
  PFS was determined in participants who had a PD-L1 CPS of ≥1% as measured by immunohistochemistry assay. PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). Per RECIST 1.1, PD was a ≥20% increase in the sum of diameters of target lesions plus an absolute increase of ≥5 mm in the sum, or the appearance of ≥1 new lesions. Time to scheduled tumor assessment visit rather than the actual tumor assessment visit was used in the analysis. PFS was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10% [ Time Frame: Up to approximately 80.5 months ]
  PFS was determined in participants who had a PD-L1 CPS of ≥10% as measured by immunohistochemistry assay. PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). Per RECIST 1.1, PD was a ≥20% increase in the sum of diameters of target lesions plus an absolute increase of ≥5 mm in the sum, or the appearance of ≥1 new lesions. Time to scheduled tumor assessment visit rather than the actual tumor assessment visit was used in the analysis. PFS was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Overall Survival (OS) in All Participants [ Time Frame: Up to approximately 80.5 months ]
  OS was determined for all participants and was defined as the time from randomization to death due to any cause. OS was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Overall Survival (OS) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1% [ Time Frame: Up to approximately 80.5 months ]
  OS was determined in participants who had a PD-L1 CPS of ≥1%, as measured by immunohistochemistry assay. OS was defined as the time from randomization to death due to any cause. OS was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Overall Survival (OS) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10% [ Time Frame: Up to approximately 80.5 months ]
  OS was determined in participants who had a PD-L1 CPS of ≥10% as measured by immunohistochemistry assay. OS was defined as the time from randomization to death due to any cause. OS was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Progression Free Survival Rate (PFS Rate) at Month 6 in All Participants [ Time Frame: Month 6 ]
  The PFS rate was determined in all participants at Month 6. PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR). Per RECIST 1.1, PD was a ≥20% increase in the sum of diameters of target lesions plus an absolute increase of ≥5 mm in the sum, or the appearance of ≥1 new lesions. Time to scheduled tumor assessment visit rather than the actual tumor assessment visit was used in the analysis. PFS at Month 6 was calculated using product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Progression Free Survival Rate (PFS Rate) at Month 6 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1% [ Time Frame: Month 6 ]
  The PFS rate was determined in participants who had a PD-L1 CPS of ≥1%, as measured by immunohistochemistry assay, at Month 6. PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR). Per RECIST 1.1, PD was a ≥20% increase in the sum of diameters of target lesions plus an absolute increase of ≥5 mm in the sum, or the appearance of ≥1 new lesions. Time to scheduled tumor assessment visit rather than the actual tumor assessment visit was used in the analysis. PFS at Month 6 was calculated using product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Progression Free Survival Rate (PFS Rate) at Month 6 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10% [ Time Frame: Month 6 ]
  The PFS rate was determined in participants who had a PD-L1 CPS of ≥10%, as measured by immunohistochemistry assay, at Month 6. PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR). Per RECIST 1.1, PD was a ≥20% increase in the sum of diameters of target lesions plus an absolute increase of ≥5 mm in the sum, or the appearance of ≥1 new lesions. Time to scheduled tumor assessment visit rather than the actual tumor assessment visit was used in the analysis. PFS at Month 6 was calculated using product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Progression Free Survival Rate (PFS Rate) at Month 12 in All Participants [ Time Frame: Month 12 ]
  The PFS rate was determined in all participants at Month 12. PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR). Per RECIST 1.1, PD was a ≥20% increase in the sum of diameters of target lesions plus an absolute increase of ≥5 mm in the sum, or the appearance of ≥1 new lesions. Time to scheduled tumor assessment visit rather than the actual tumor assessment visit was used in the analysis. PFS at Month 12 was calculated using product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Progression Free Survival Rate (PFS Rate) at Month 12 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1% [ Time Frame: Month 12 ]
  The PFS rate was determined in participants who had a PD-L1 CPS of ≥1%, as measured by immunohistochemistry assay, at Month 12. PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR). Per RECIST 1.1, PD was a ≥20% increase in the sum of diameters of target lesions plus an absolute increase of ≥5 mm in the sum, or the appearance of ≥1 new lesions. Time to scheduled tumor assessment visit rather than the actual tumor assessment visit was used in the analysis. PFS at Month 12 was calculated using product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Progression Free Survival Rate (PFS Rate) at Month 12 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10% [ Time Frame: Month 12 ]
  The PFS rate was determined in participants who had a PD-L1 CPS of ≥10%, as measured by immunohistochemistry assay, at Month 12. PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR). Per RECIST 1.1, PD was a ≥20% increase in the sum of diameters of target lesions plus an absolute increase of ≥5 mm in the sum, or the appearance of ≥1 new lesions. Time to scheduled tumor assessment visit rather than the actual tumor assessment visit was used in the analysis. PFS at Month 12 was calculated using product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Overall Survival Rate (OS Rate) at Month 6 in All Participants [ Time Frame: Month 6 ]
  The OS rate was determined for all participants at Month 6 and was defined as the time from randomization to death due to any cause. OS at Month 6 was calculated using product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Overall Survival Rate (OS Rate) at Month 6 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1% [ Time Frame: Month 6 ]
  The OS rate was determined in participants who had a PD-L1 CPS of ≥1%, as measured by immunohistochemistry assay, at Month 6. OS was defined as the time from randomization to death due to any cause. OS at Month 6 was calculated using product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Overall Survival Rate (OS Rate) at Month 6 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10% [ Time Frame: Month 6 ]
  The OS rate was determined in participants who had a PD-L1 CPS of ≥10%, as measured by immunohistochemistry assay, at Month 6. OS was defined as the time from randomization to death due to any cause. OS at Month 6 was calculated using product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Overall Survival Rate (OS Rate) at Month 12 in All Participants [ Time Frame: Month 12 ]
  The OS rate was determined for all participants at Month 12 and was defined as the time from randomization to death due to any cause. OS at Month 12 was calculated using product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Overall Survival Rate (OS Rate) at Month 12 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1% [ Time Frame: Month 12 ]
  The OS rate was determined in participants who had a PD-L1 CPS of ≥1%, as measured by immunohistochemistry assay, at Month 12. OS was defined as the time from randomization to death due to any cause. OS at Month 12 was calculated using product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Overall Survival Rate (OS Rate) at Month 12 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10% [ Time Frame: Month 12 ]
  The OS rate was determined in participants who had a PD-L1 CPS of ≥10%, as measured by immunohistochemistry assay, at Month 12. OS was defined as the time from randomization to death due to any cause. OS at Month 12 was calculated using product-limit (Kaplan-Meier) method for censored data. Participants were censored at the date of their last assessment. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Programmed Cell Death Ligand 1 (PD-L1) Expression Status [ Time Frame: Day 1 ]
  PD-L1 expression status was determined as the percent of disease tumor cells, from newly obtained tumor biopsies, demonstrating plasma membrane PD-L1 staining of any intensity using an immunohistochemistry (IHC) assay. The assay uses a Combined Positive Score (CPS) as a measure of PD-L1 positivity. The CPS is calculated as the number of PD-L1-positive cells divided by the number of viable tumor cells analyzed multiplied by 100. A CPS of <1% = negative; ≥1% = positive; and ≥10% = strongly positive. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Number of Participants Who Experienced At Least One Adverse Event (AE) [ Time Frame: Up to approximately 80.5 months ]
  An AE was defined as any untoward medical occurrence in a participant administered a study treatment and did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 26 months ]
  An AE was defined as any untoward medical occurrence in a participant administered a study treatment and did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. Per protocol, only data generated during the initial course of treatment contributed to the analysis.

Original Secondary Outcome Measures (submitted: January 8, 2015)

• ORR by RECIST 1.1 for All Participants (Independent Radiology Review) [ Time Frame: Up to 3 years ]
• ORR by Modified RECIST1.1 in Participants with PD-L1-dependent Tumors (Independent Radiology Review) [ Time Frame: Up to 3 years ]
• ORR by Modified RECIST1.1 in All Participants (Independent Radiology Review) [ Time Frame: Up to 3 years ]
• ORR by RECIST 1.1 for Participants with PD-L1-dependent Tumors (Site Radiology Review) [ Time Frame: Up to 3 years ]
• ORR by RECIST 1.1 for All Participants (Site Radiology Review) [ Time Frame: Up to 3 years ]

Current Other Pre-specified Outcome Measures (submitted: February 2, 2023)

• Objective Response Rate (ORR) Per Modified Response Evaluation Criteria in Solid Tumors (Modified RECIST) in All Participants [ Time Frame: Up to approximately 80.5 months ]
  ORR was determined in all participants and was defined as the percentage of participants who had a confirmed Complete Response (CR: complete disappearance of all lesions and no new lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per modified RECIST as assessed by Blinded Independent Central Review (BICR). Modified RECIST differs from RECIST 1.1 in that progressive disease requires confirmation by a repeat radiological assessment no less than 4 weeks from the date of first documented progressive disease. Participants with missing data were considered non-responders. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Objective Response Rate (ORR) Per Modified Response Evaluation Criteria in Solid Tumors (Modified RECIST) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1% [ Time Frame: Up to approximately 80.5 months ]
  ORR was determined in participants who had a PD-L1 CPS of ≥1% as measured by immunohistochemistry assay. ORR was defined as the percentage of participants who had a confirmed Complete Response (CR: complete disappearance of all lesions and no new lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per modified RECIST as assessed by Blinded Independent Central Review (BICR). Modified RECIST differs from RECIST 1.1 in that progressive disease requires confirmation by a repeat radiological assessment no less than 4 weeks from the date of first documented progressive disease. Participants with missing data were considered non-responders. Per protocol, only data generated during the initial course of treatment contributed to the analysis.
• Objective Response Rate (ORR) Per Modified Response Evaluation Criteria in Solid Tumors (Modified RECIST) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10% [ Time Frame: Up to approximately 80.5 months ]
  ORR was determined in participants who had a PD-L1 CPS of ≥10% as measured by immunohistochemistry assay. ORR was defined as the percentage of participants who had a confirmed Complete Response (CR: complete disappearance of all lesions and no new lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per modified RECIST as assessed by Blinded Independent Central Review (BICR). Modified RECIST differs from RECIST 1.1 in that progressive disease requires confirmation by a repeat radiological assessment no less than 4 weeks from the date of first documented progressive disease. Participants with missing data were considered non-responders. Per protocol, only data generated during the initial course of treatment contributed to the analysis.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Pembrolizumab (MK-3475) in Participants With Advanced Urothelial Cancer (MK-3475-052/KEYNOTE-052)
• Official Title: A Phase II Clinical Trial of Pembrolizumab (MK-3475) in Subjects With Advanced/Unresectable or Metastatic Urothelial Cancer

Brief Summary

This is a study using pembrolizumab (MK-3475, KEYTRUDA®) for first-line treatment of participants with advanced/unresectable (inoperable) or metastatic urothelial cancer who are ineligible for cisplatin-based therapy. The primary study objective is to determine the objective response rate (ORR) in all participants and by programmed cell death ligand 1 (PD-L1) status.

With Amendment 4, once a participant has achieved the study objective or the study has ended, the participant will be discontinued from this study and will be enrolled in an extension study to continue protocol-defined assessments and treatment.

• Detailed Description: Participants receiving pembrolizumab who attain a complete response (CR) may consider stopping trial treatment if they meet criteria for holding therapy. Participants who stop trial treatment after receiving 24 months of trial treatment for reasons other than progressive disease (PD) or intolerability, or participants who attain a CR and stop trial treatment may be eligible for up to one year of retreatment upon experiencing PD.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Urothelial Cancer

Intervention

Biological: pembrolizumab

IV infusion

Other Names:

• MK-3475
• KEYTRUDA®

Study Arms

Experimental: Pembrolizumab

Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 2 years. Eligible participants who stopped the initial course of pembrolizumab due to complete response (CR) or completed initial course of pembrolizumab and had stable disease but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion for up to an additional year.

Intervention: Biological: pembrolizumab

Publications *

• Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. doi: 10.1016/S1470-2045(17)30616-2. Epub 2017 Sep 26.
• Vuky J, Balar AV, Castellano D, O'Donnell PH, Grivas P, Bellmunt J, Powles T, Bajorin D, Hahn NM, Savage MJ, Fang X, Godwin JL, Frenkl TL, Homet Moreno B, de Wit R, Plimack ER. Long-Term Outcomes in KEYNOTE-052: Phase II Study Investigating First-Line Pembrolizumab in Cisplatin-Ineligible Patients With Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2020 Aug 10;38(23):2658-2666. doi: 10.1200/JCO.19.01213. Epub 2020 Jun 17.
• Bellmunt J, de Wit R, Fradet Y, Climent MA, Petrylak DP, Lee JL, Fong L, Necchi A, Sternberg CN, O'Donnell PH, Powles T, Plimack ER, Bajorin DF, Balar AV, Castellano D, Choueiri TK, Culine S, Gerritsen W, Gurney H, Quinn DI, Vuky J, Vogelzang NJ, Cristescu R, Lunceford J, Saadatpour A, Loboda A, Ma J, Rajasagi M, Godwin JL, Homet Moreno B, Grivas P. Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer: Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials. Clin Cancer Res. 2022 May 13;28(10):2050-2060. doi: 10.1158/1078-0432.CCR-21-3089.
• van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T. Immunogenicity of pembrolizumab in patients with advanced tumors. J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 18, 2017): 374
• Original Estimated Enrollment (submitted: January 8, 2015): 350
• Actual Study Completion Date: February 18, 2022
• Actual Primary Completion Date: June 19, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically- or cytologically-confirmed diagnosis of advanced/unresectable (inoperable) or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra (transitional cell and mixed transitional/non-transitional cell histologies)
• Ineligible for cisplatin therapy
• No prior systemic chemotherapy for metastatic disease (adjuvant or neoadjuvant platinum-based chemotherapy with recurrence >12 months since completion of therapy is allowed)
• Available tissue from a newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
• Measurable disease
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Adequate organ function
• Female participants of childbearing potential have a negative urine or serum pregnancy test; surgically sterile, or willing to use 2 acceptable methods of birth control, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study treatment
• Male participants must be willing to use an adequate method of contraception starting with the first dose of study medication through 120 days after the last dose of study treatment

Exclusion Criteria:

• Disease that is suitable for local therapy administered with curative intent
• Currently participating or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study treatment
• Prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastic treatment within 4 weeks prior to study Day 1 or who has not recovered from adverse events due to agents administered more than 4 weeks earlier
• Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or not recovered from AEs due to a previously administered agent
• Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cancer
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Active autoimmune disease that has required systemic treatment in past 2 years
• Evidence of interstitial lung disease or active non-infectious pneumonitis
• Active infection requiring systemic therapy
• Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study treatment
• Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another co-inhibitory T-cell receptor
• Known human immunodeficiency virus (HIV)
• Known active Hepatitis B or C
• Received a live virus vaccine within 30 days of planned start of study treatment

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided
• Removed Location Countries: Australia, Canada, Denmark, Guatemala, Hungary, Ireland, Israel, Italy, Korea, Republic of, Malaysia, Netherlands, Puerto Rico, Singapore, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT02335424
• Other Study ID Numbers: 3475-052; MK-3475-052 ( Other Identifier: Merck Protocol Number ); KEYNOTE-052 ( Other Identifier: Merck ); 2014-002206-20 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: February 2023