A Study of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel, or Vinflunine for Participants With Advanced Urothelial Cancer (MK-3475-045/KEYNOTE-045)

• ClinicalTrials.gov Identifier: NCT02256436
• Recruitment Status: Completed
• First Posted: October 3, 2014
• Results First Posted: August 31, 2017
• Last Update Posted: September 20, 2021
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Urothelial Cancer
• Interventions: Biological: pembrolizumab; Drug: paclitaxel; Drug: vinflunine; Drug: docetaxel
• Enrollment: 542

Participant Flow

Recruitment Details
Pre-assignment Details	Per protocol, 13 participants randomized to receive Control were switched over to receive Pembrolizumab. Per protocol, response/progression or adverse events that occurred during a non-randomized switch-over or second course of pembrolizumab were not counted towards efficacy or safety outcome measures, respectively. These results are for randomized treatment only.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Period Title: Overall Study
Started	272	270
Treated	255	266
Switched Over to Pembrolizumab	13	0
Completed	0	0
Not Completed	272	270
Reason Not Completed
Adverse Event	9	14
Death	216	208
Lost to Follow-up	1	2
Physician Decision	1	0
Protocol Violation	0	1
Withdrawal by Subject	26	10
Transferred to Extension Study	11	23
Did Not Continue on Extension Study	8	12

Baseline Characteristics

Arm/Group Title		Control	Pembrolizumab	Total
Arm/Group Description		Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).	Total of all reporting groups
Overall Number of Baseline Participants		272	270	542
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	272 participants	270 participants	542 participants
		65.1 (9.2)	66.0 (10.2)	65.5 (9.7)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	272 participants	270 participants	542 participants
	Female	70 25.7%	70 25.9%	140 25.8%
	Male	202 74.3%	200 74.1%	402 74.2%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - All Participants
Description	PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease (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 must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was assessed by blinded independent central review (BICR) in all participants up through the primary analysis database cut-off date of 07-Sep-2016.
Time Frame	Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	272	270
Median (95% Confidence Interval); Unit of Measure: Months
	3.3; (2.3 to 3.5)	2.1; (2.0 to 2.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	PFS - All Participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.41648
	Comments	One-sided p-value based on stratified log-rank test
	Method	Regression, Cox
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.19
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Overall Survival (OS) - All Participants
Description	OS was defined as the time from randomization to death due to any cause. The OS was assessed in all participants up through the primary analysis database cut-off date of 07-Sep-2016.
Time Frame	Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	272	270
Median (95% Confidence Interval); Unit of Measure: Months
	7.4; (6.1 to 8.3)	10.3; (8.0 to 11.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	OS - All Participants (Note: ECOG PS=Eastern Cooperative Oncology Group Performance Status)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.00224
	Comments	One-sided p-value based on stratified log-rank test
	Method	Regression, Cox
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.59 to 0.91
	Estimation Comments	[Not Specified]

3. Primary Outcome

Title	PFS Per RECIST 1.1 - Participants With Programmed Cell Death-Ligand (PD-L1) Positive Tumors
Description	PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. 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 must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. PFS per RECIST 1.1 was assessed by BICR in all participants who had PD-L1 positive tumors (combined positive score [CPS] ≥1%) up through the primary analysis database cut-off date of 07-Sep-2016.
Time Frame	Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	120	110
Median (95% Confidence Interval); Unit of Measure: Months
	3.2; (2.2 to 3.4)	2.1; (2.0 to 2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	PFS - PD-L1 positive participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.26443
	Comments	One-sided p-value based on stratified log-rank test
	Method	Regression, Cox
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.24
	Estimation Comments	[Not Specified]

4. Primary Outcome

Title	OS - Participants With PD-L1 Positive Tumors
Description	OS was defined as the time from randomization to death due to any cause. For the purposes of this study, participants with PD-L1 CPS ≥1% were considered to have a PD-L1 positive tumor status. OS was assessed in all participants who had PD-L1 positive tumors (CPS ≥1%) up through the primary analysis database cut-off date of 07-Sep-2016.
Time Frame	Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	120	110
Median (95% Confidence Interval); Unit of Measure: Months
	6.9; (4.7 to 8.8)	11.3; (7.7 to 16.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	OS - PD-L1 positive participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.00239
	Comments	One-sided p-value based on stratified log-rank test
	Method	Regression, Cox
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.43 to 0.86
	Estimation Comments	[Not Specified]

5. Primary Outcome

Title	PFS Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors
Description	PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. 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 must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. PFS per RECIST 1.1 was assessed by BICR in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) up through the primary analysis database cut-off date of 07-Sep-2016.
Time Frame	Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized strongly PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	90	74
Median (95% Confidence Interval); Unit of Measure: Months
	3.1; (2.2 to 3.4)	2.1; (1.9 to 2.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	PFS - Strongly PD-L1 positive participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.23958
	Comments	One-sided p-value based on stratified log-rank test
	Method	Regression, Cox
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.28
	Estimation Comments	[Not Specified]

6. Primary Outcome

Title	OS - Participants With Strongly PD-L1 Positive Tumors
Description	OS was defined as the time from randomization to death due to any cause. For the purposes of this study, participants with a PD-L1 CPS ≥10% were considered to have a strongly PD-L1 positive tumor status. The OS was assessed in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) up through the primary analysis database cut-off date of 07-Sep-2016.
Time Frame	Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized strongly PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	90	74
Median (95% Confidence Interval); Unit of Measure: Months
	5.2; (4.0 to 7.4)	8.0; (5.0 to 12.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	OS - Strongly PD-L1 positive participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.00483
	Comments	One-sided p-value based on stratified log-rank test
	Method	Regression, Cox
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.37 to 0.88
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Number of Participants Who Experienced an Adverse Event (AE)
Description	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. Participants were monitored for the occurrence nonserious AEs for up to 30 days after last dose of study treatment and for serious AEs for up to 90 days after last dose of study treatment. The number of participants who experienced an AE was reported for each arm.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received at least one dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	255	266
Measure Type: Number; Unit of Measure: Participants
	250	250

8. Secondary Outcome

Title	Number of Participants Who Discontinued Study Treatment Due to an AE
Description	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. Participants were monitored for the occurrence nonserious AEs for up to 30 days after last dose of study treatment and for serious AEs for up to 90 days after last dose of study treatment. The number of participants who discontinued study treatment due to an AE was reported for each arm.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who received at least one dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	255	266
Measure Type: Number; Unit of Measure: Participants
	36	28

9. Secondary Outcome

Title	Objective Response Rate (ORR) Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors
Description	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: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by BICR in participants with strongly PD-L1 positive tumors (CPS ≥10%) up through the final analysis database cut-off date of 26-Oct-2017.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized strongly PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	90	74
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	6.7; (2.5 to 13.9)	20.3; (11.8 to 31.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	ORR per RECIST 1.1 - Strongly PD-L1 Positive Participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.00061
	Comments	One-sided p-value for testing H0: difference in %=0; H1: difference in %>0
	Method	Miettinen & Nurminen method
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Difference in Percentages
	Estimated Value	17.2
	Confidence Interval	(2-Sided) 95%; 6.8 to 29.4
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	ORR Per RECIST 1.1 - Participants With PD-L1 Positive Tumors
Description	ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by BICR in participants with PD-L1 positive tumors (CPS ≥1%) up through the final analysis database cut-off date of 26-Oct-2017.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	120	110
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	8.3; (4.1 to 14.8)	22.7; (15.3 to 31.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	ORR per RECIST 1.1 - PD-L1 Positive Participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.00049
	Comments	One-sided p-value for testing H0: difference in %=0; H1: difference in %>0
	Method	Miettinen & Nurminen method
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Difference in Percentages
	Estimated Value	15.6
	Confidence Interval	(2-Sided) 95%; 6.5 to 25.7
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	ORR Per RECIST 1.1 - All Participants
Description	ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by BICR in all participants up through the final analysis database cut-off date of 26-Oct-2017.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	272	270
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	11.0; (7.6 to 15.4)	21.1; (16.4 to 26.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	ORR per RECIST 1.1 - All Participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.00068
	Comments	One-sided p-value for testing H0: difference in %=0; H1: difference in %>0
	Method	Miettinen & Nurminen method
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Difference in Percentages
	Estimated Value	10.0
	Confidence Interval	(2-Sided) 95%; 3.9 to 16.2
	Estimation Comments	[Not Specified]

12. Secondary Outcome

Title	PFS Per Modified RECIST (mRECIST) - Participants With Strongly PD-L1 Positive Tumors
Description	PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per mRECIST, PD was defined was defined as at least 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Per mRECIST, confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required for participants remaining on treatment following PD per RECIST 1.1. PFS per mRECIST was assessed by BICR in participants with strongly PD-L1 positive tumors (CPS ≥10%) up through the final analysis database cut-off date of 26-Oct-2017.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized strongly PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	90	74
Median (95% Confidence Interval); Unit of Measure: Months
	3.3; (2.4 to 3.7)	2.1; (2.0 to 3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	PFS per mRECIST - Strongly PD-L1 Positive Participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.07066
	Comments	One-sided p-value based on stratified log-rank test
	Method	Regression, Cox
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.53 to 1.11
	Estimation Comments	[Not Specified]

13. Secondary Outcome

Title	PFS Per mRECIST - Participants With PD-L1 Positive Tumors
Description	PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per mRECIST, PD was defined was defined as at least 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Per mRECIST, confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required for participants remaining on treatment following PD per RECIST 1.1. PFS per mRECIST was assessed by BICR in participants with PD-L1 positive tumors (CPS ≥1%) up through the final analysis database cut-off date of 26-Oct-2017.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	120	110
Median (95% Confidence Interval); Unit of Measure: Months
	3.3; (2.6 to 3.6)	2.1; (2.0 to 3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	PFS per mRECIST - PD-L1 Positive Participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.08745
	Comments	One-sided p-value based on stratified log-rank test
	Method	Regression, Cox
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.60 to 1.10
	Estimation Comments	[Not Specified]

14. Secondary Outcome

Title	PFS Per mRECIST - All Participants
Description	PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per mRECIST, PD was defined as at least 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Per mRECIST, confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required for participants remaining on treatment following PD per RECIST 1.1. PFS per mRECIST was assessed by BICR in all randomized participants up through the final analysis database cut-off date of 26-Oct-2017.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	272	270
Median (95% Confidence Interval); Unit of Measure: Months
	3.4; (3.1 to 3.8)	2.2; (2.1 to 3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	PFS per mRECIST - All Participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.05328
	Comments	One-sided p-value based on stratified log-rank test
	Method	Regression, Cox
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.04
	Estimation Comments	[Not Specified]

15. Secondary Outcome

Title	ORR Per mRECIST - Participants With Strongly PD-L1 Positive Tumors
Description	ORR per mRECIST was defined as the percentage of participants in the analysis population who had a CR (complete disappearance of all lesions (and no new lesions), with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented) or a PR (decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation). ORR per mRECIST was assessed by BICR in participants with strongly PD-L1 positive tumors (CPS ≥10%) up through the final analysis database cut-off date of 26-Oct-2017.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized strongly PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	90	74
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	7.8; (3.2 to 15.4)	24.3; (15.1 to 35.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	ORR per mRECIST - Strongly PD-L1 Positive Participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.00009
	Comments	One-sided p-value for testing H0: difference in %=0; H1: difference in %>0
	Method	Miettinen & Nurminen method
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Difference in Percentages
	Estimated Value	21.5
	Confidence Interval	(2-Sided) 95%; 10.1 to 34.2
	Estimation Comments	[Not Specified]

16. Secondary Outcome

Title	ORR Per mRECIST - Participants With PD-L1 Positive Tumors
Description	ORR per mRECIST was defined as the percentage of participants in the analysis population who had a CR (complete disappearance of all lesions (and no new lesions), with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented) or a PR (decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation). ORR per mRECIST was assessed by BICR in participants with PD-L1 positive tumors (CPS ≥1%) up through the final analysis database cut-off date of 26-Oct-2017.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	120	110
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	9.2; (4.7 to 15.8)	28.2; (20.0 to 37.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	ORR per mRECIST - PD-L1 Positive Participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.00002
	Comments	One-sided p-value for testing H0: difference in %=0; H1: difference in %>0
	Method	Miettinen & Nurminen method
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Difference in Percentages
	Estimated Value	21.0
	Confidence Interval	(2-Sided) 95%; 11.1 to 31.5
	Estimation Comments	[Not Specified]

17. Secondary Outcome

Title	ORR Per mRECIST - All Participants
Description	ORR per mRECIST was defined as the percentage of participants in the analysis population who had a CR (complete disappearance of all lesions (and no new lesions), with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented) or a PR (decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation). ORR per mRECIST was assessed by BICR in all participants up through the final analysis database cut-off date of 26-Oct-2017.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	272	270
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	11.4; (7.9 to 15.8)	25.2; (20.1 to 30.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	ORR per mRECIST - All Participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.00001
	Comments	One-sided p-value for testing H0: difference in %=0; H1: difference in %>0
	Method	Miettinen & Nurminen method
	Comments	Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
Method of Estimation	Estimation Parameter	Difference in Percentages
	Estimated Value	13.8
	Confidence Interval	(2-Sided) 95%; 7.4 to 20.3
	Estimation Comments	[Not Specified]

18. Secondary Outcome

Title	Duration of Response (DOR) Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors
Description	For participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. Per protocol, the DOR was to be censored at the date of the last tumor assessment for participants who had progressed or died after 2 or more missed visits, who had started a new anti-cancer treatment, who were lost to follow-up, or who had an ongoing response. DOR was assessed in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) based on BICR and was analyzed using the Kaplan-Meier method.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized strongly PD-L1 positive participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	6	15
Median (95% Confidence Interval); Unit of Measure: Months
	4.4 [1]; (2.8 to NA)	NA [2]; (8.2 to NA)

[1]

NA= DOR upper 95% confidence limit was undefined because the DOR rate was not low enough at the time of the cut-off date.

[2]

NA= Median DOR was not reached because there were not enough events, DOR upper 95% confidence limit was undefined because the DOR rate was not low enough at the time of the cut-off date.

19. Secondary Outcome

Title	DOR Per RECIST 1.1 - Participants With PD-L1 Positive Tumors
Description	For participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. Per protocol, the DOR was to be censored at the date of the last tumor assessment for participants who had progressed or died after 2 or more missed visits, who had started a new anti-cancer treatment, who were lost to follow-up, or who had an ongoing response. DOR was assessed in all participants who had PD-L1 positive tumors (CPS ≥1%) based on BICR and was analyzed using the Kaplan-Meier method.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized PD-L1 positive participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	10	25
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (2.8 to NA)	NA [1]; (21.8 to NA)

[1]

NA= Median DOR was not reached because there were not enough events, DOR upper 95% confidence limit was undefined because the DOR rate was not low enough at the time of the cut-off date.

20. Secondary Outcome

Title	DOR Per RECIST 1.1 - All Participants
Description	For participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. Per protocol, the DOR was to be censored at the date of the last tumor assessment for participants who had progressed or died after 2 or more missed visits, who had started a new anti-cancer treatment, who were lost to follow-up, or who had an ongoing response. DOR was assessed in all participants based on BICR and was analyzed using the Kaplan-Meier method.
Time Frame	Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all randomized participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Control	Pembrolizumab
Arm/Group Description:	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).	Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
Overall Number of Participants Analyzed	30	57
Median (95% Confidence Interval); Unit of Measure: Months
	4.4; (4.0 to 20.3)	NA [1]; (15.9 to NA)

[1]

NA = Median DOR was not reached because there were not enough events, DOR upper 95% confidence limit was undefined because the DOR rate was not low enough at the time of the cut-off date.

Adverse Events

Time Frame	Through end of trial analysis database cut-off date of 01-Oct-2020 (Up to approximately 71 months)
Adverse Event Reporting Description	All-Cause Mortality table includes all randomized participants. Serious and Other AEs include all treated participants according to treatment received. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" unrelated to drug excluded as AEs. Thirteen participants randomized to receive Control were switched over to pembrolizumab per protocol and were monitored for AEs separately.
Arm/Group Title	Control		Pembrolizumab		Control Switched Over to Pembrolizumab
Arm/Group Description	Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).		Participants received pembrolizumab 200 mg IV on Day 1 Q3W. 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 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).		Per protocol, participants originally randomized to the Control arm that experienced disease progression were switched over to receive pembrolizumab 200 mg IV on Day 1 Q3W.
All-Cause Mortality
	Control		Pembrolizumab		Control Switched Over to Pembrolizumab
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	230/272 (84.56%)		224/270 (82.96%)		9/13 (69.23%)
Serious Adverse Events
	Control		Pembrolizumab		Control Switched Over to Pembrolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	104/255 (40.78%)		107/266 (40.23%)		8/13 (61.54%)
Blood and lymphatic system disorders
Anaemia † 1	7/255 (2.75%)	8	6/266 (2.26%)	7	0/13 (0.00%)	0
Anaemia of malignant disease † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Febrile neutropenia † 1	16/255 (6.27%)	16	0/266 (0.00%)	0	0/13 (0.00%)	0
Leukopenia † 1	2/255 (0.78%)	5	0/266 (0.00%)	0	0/13 (0.00%)	0
Nephrogenic anaemia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Neutropenia † 1	5/255 (1.96%)	5	0/266 (0.00%)	0	0/13 (0.00%)	0
Normocytic anaemia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Pancytopenia † 1	2/255 (0.78%)	2	0/266 (0.00%)	0	0/13 (0.00%)	0
Thrombocytopenia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Cardiac disorders
Acute coronary syndrome † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Atrial fibrillation † 1	2/255 (0.78%)	2	0/266 (0.00%)	0	0/13 (0.00%)	0
Atrial flutter † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Atrioventricular block † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Myocardial infarction † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Pericardial effusion † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Sinus tachycardia † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Endocrine disorders
Adrenal insufficiency † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Hypercalcaemia of malignancy † 1	0/255 (0.00%)	0	2/266 (0.75%)	2	0/13 (0.00%)	0
Hyperthyroidism † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Hypophysitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Gastrointestinal disorders
Abdominal pain † 1	4/255 (1.57%)	4	1/266 (0.38%)	1	0/13 (0.00%)	0
Anal incontinence † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Colitis † 1	0/255 (0.00%)	0	5/266 (1.88%)	5	1/13 (7.69%)	2
Constipation † 1	7/255 (2.75%)	7	0/266 (0.00%)	0	0/13 (0.00%)	0
Diarrhoea † 1	2/255 (0.78%)	2	3/266 (1.13%)	4	0/13 (0.00%)	0
Enteritis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Enterocolitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Gastric ulcer † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Gastrointestinal haemorrhage † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Gastrointestinal perforation † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Ileus † 1	3/255 (1.18%)	4	0/266 (0.00%)	0	0/13 (0.00%)	0
Ileus paralytic † 1	2/255 (0.78%)	3	0/266 (0.00%)	0	0/13 (0.00%)	0
Intestinal obstruction † 1	8/255 (3.14%)	8	0/266 (0.00%)	0	2/13 (15.38%)	2
Intestinal perforation † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Intestinal pseudo-obstruction † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Large intestinal obstruction † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Nausea † 1	1/255 (0.39%)	1	1/266 (0.38%)	1	1/13 (7.69%)	1
Neutropenic colitis † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Retroperitoneal haemorrhage † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Small intestinal obstruction † 1	1/255 (0.39%)	1	1/266 (0.38%)	1	0/13 (0.00%)	0
Stomatitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Subileus † 1	2/255 (0.78%)	3	0/266 (0.00%)	0	0/13 (0.00%)	0
Upper gastrointestinal haemorrhage † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Vomiting † 1	1/255 (0.39%)	2	0/266 (0.00%)	0	1/13 (7.69%)	1
General disorders
Asthenia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Death † 1	5/255 (1.96%)	5	1/266 (0.38%)	1	0/13 (0.00%)	0
Fatigue † 1	1/255 (0.39%)	1	2/266 (0.75%)	2	0/13 (0.00%)	0
General physical health deterioration † 1	0/255 (0.00%)	0	3/266 (1.13%)	3	0/13 (0.00%)	0
Hyperthermia malignant † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Influenza like illness † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Malaise † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Mucosal inflammation † 1	2/255 (0.78%)	2	0/266 (0.00%)	0	0/13 (0.00%)	0
Pain † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Pyrexia † 1	5/255 (1.96%)	6	5/266 (1.88%)	5	2/13 (15.38%)	2
Hepatobiliary disorders
Hepatic pain † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Hyperbilirubinaemia † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Jaundice † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Infections and infestations
Abdominal abscess † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Anal abscess † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Atypical pneumonia † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Bacteraemia † 1	0/255 (0.00%)	0	2/266 (0.75%)	2	0/13 (0.00%)	0
Bronchitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Catheter site infection † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Cystitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Device related sepsis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Diverticulitis † 1	0/255 (0.00%)	0	0/266 (0.00%)	0	1/13 (7.69%)	1
Epididymitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Fournier's gangrene † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Gastroenteritis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Gastroenteritis viral † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Infective exacerbation of chronic obstructive airways disease † 1	1/255 (0.39%)	1	1/266 (0.38%)	2	0/13 (0.00%)	0
Influenza † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Lower respiratory tract infection † 1	0/255 (0.00%)	0	2/266 (0.75%)	2	0/13 (0.00%)	0
Nasopharyngitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Osteomyelitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Pelvic infection † 1	0/255 (0.00%)	0	1/266 (0.38%)	2	0/13 (0.00%)	0
Pneumocystis jirovecii infection † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Pneumonia † 1	8/255 (3.14%)	9	11/266 (4.14%)	11	1/13 (7.69%)	1
Post procedural infection † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Psoas abscess † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Pyelonephritis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Respiratory tract infection † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Respiratory tract infection viral † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Sepsis † 1	5/255 (1.96%)	6	0/266 (0.00%)	0	0/13 (0.00%)	0
Septic shock † 1	1/255 (0.39%)	1	1/266 (0.38%)	1	0/13 (0.00%)	0
Tooth abscess † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Upper respiratory tract infection † 1	1/255 (0.39%)	1	1/266 (0.38%)	1	0/13 (0.00%)	0
Urinary tract infection † 1	12/255 (4.71%)	13	12/266 (4.51%)	16	0/13 (0.00%)	0
Urosepsis † 1	1/255 (0.39%)	1	5/266 (1.88%)	5	0/13 (0.00%)	0
Vascular device infection † 1	0/255 (0.00%)	0	1/266 (0.38%)	2	0/13 (0.00%)	0
Injury, poisoning and procedural complications
Craniocerebral injury † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Fall † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Hip fracture † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Incisional hernia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Pelvic fracture † 1	1/255 (0.39%)	1	1/266 (0.38%)	1	0/13 (0.00%)	0
Post procedural haemorrhage † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Procedural pain † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Stoma site haemorrhage † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Thoracic vertebral fracture † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Toxicity to various agents † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Wrist fracture † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Investigations
Alanine aminotransferase increased † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	1/13 (7.69%)	1
Aspartate aminotransferase increased † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	1/13 (7.69%)	1
Bacterial test positive † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Blood calcium increased † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Blood creatinine increased † 1	2/255 (0.78%)	2	0/266 (0.00%)	0	0/13 (0.00%)	0
Lipase increased † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Neutrophil count decreased † 1	2/255 (0.78%)	2	0/266 (0.00%)	0	0/13 (0.00%)	0
Platelet count decreased † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Transaminases increased † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Metabolism and nutrition disorders
Cachexia † 1	0/255 (0.00%)	0	2/266 (0.75%)	2	0/13 (0.00%)	0
Decreased appetite † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Dehydration † 1	2/255 (0.78%)	3	3/266 (1.13%)	3	0/13 (0.00%)	0
Electrolyte imbalance † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Fluid retention † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Hypercalcaemia † 1	2/255 (0.78%)	2	1/266 (0.38%)	1	0/13 (0.00%)	0
Hyponatraemia † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Type 1 diabetes mellitus † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Type 2 diabetes mellitus † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Vitamin B1 deficiency † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Gouty arthritis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Musculoskeletal pain † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Pathological fracture † 1	0/255 (0.00%)	0	2/266 (0.75%)	2	0/13 (0.00%)	0
Periostitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Tendonitis † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain † 1	3/255 (1.18%)	3	2/266 (0.75%)	3	0/13 (0.00%)	0
Lung neoplasm malignant † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Malignant neoplasm progression † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Malignant pleural effusion † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Metastases to central nervous system † 1	0/255 (0.00%)	0	1/266 (0.38%)	2	0/13 (0.00%)	0
Prostate cancer recurrent † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Squamous cell carcinoma † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Tumour associated fever † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Tumour pain † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Urethral cancer † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Nervous system disorders
Altered state of consciousness † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Cerebral haemorrhage † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Cerebral infarction † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Encephalopathy † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Posterior reversible encephalopathy syndrome † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Somnolence † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Syncope † 1	1/255 (0.39%)	1	1/266 (0.38%)	1	0/13 (0.00%)	0
Transient ischaemic attack † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Product Issues
Device dislocation † 1	0/255 (0.00%)	0	3/266 (1.13%)	3	0/13 (0.00%)	0
Device malfunction † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Device occlusion † 1	0/255 (0.00%)	0	0/266 (0.00%)	0	1/13 (7.69%)	2
Renal and urinary disorders
Acute kidney injury † 1	6/255 (2.35%)	6	5/266 (1.88%)	5	0/13 (0.00%)	0
Autoimmune nephritis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Azotaemia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Bladder neck obstruction † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Haematuria † 1	4/255 (1.57%)	5	6/266 (2.26%)	6	0/13 (0.00%)	0
Hydronephrosis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Nephritis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Prerenal failure † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Renal failure † 1	1/255 (0.39%)	1	2/266 (0.75%)	2	0/13 (0.00%)	0
Renal injury † 1	0/255 (0.00%)	0	1/266 (0.38%)	2	0/13 (0.00%)	0
Urinary retention † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Urinary tract obstruction † 1	1/255 (0.39%)	1	3/266 (1.13%)	3	0/13 (0.00%)	0
Reproductive system and breast disorders
Female genital tract fistula † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Pelvic fluid collection † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Pelvic pain † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease † 1	0/255 (0.00%)	0	2/266 (0.75%)	2	0/13 (0.00%)	0
Dyspnoea † 1	2/255 (0.78%)	2	3/266 (1.13%)	3	0/13 (0.00%)	0
Haemoptysis † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Interstitial lung disease † 1	0/255 (0.00%)	0	3/266 (1.13%)	4	0/13 (0.00%)	0
Pleurisy † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Pneumonitis † 1	0/255 (0.00%)	0	6/266 (2.26%)	7	1/13 (7.69%)	1
Pulmonary embolism † 1	1/255 (0.39%)	1	1/266 (0.38%)	1	0/13 (0.00%)	0
Pulmonary hypertension † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Skin and subcutaneous tissue disorders
Rash maculo-papular † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Vascular disorders
Deep vein thrombosis † 1	2/255 (0.78%)	2	2/266 (0.75%)	2	0/13 (0.00%)	0
Embolism † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Hypertension † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Hypotension † 1	1/255 (0.39%)	1	0/266 (0.00%)	0	0/13 (0.00%)	0
Hypovolaemic shock † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Iliac artery occlusion † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Superior vena cava syndrome † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Thrombosis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Vasoconstriction † 1	0/255 (0.00%)	0	1/266 (0.38%)	1	0/13 (0.00%)	0
Venous thrombosis limb † 1	0/255 (0.00%)	0	0/266 (0.00%)	0	1/13 (7.69%)	1
1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Control		Pembrolizumab		Control Switched Over to Pembrolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	237/255 (92.94%)		236/266 (88.72%)		11/13 (84.62%)
Blood and lymphatic system disorders
Anaemia † 1	86/255 (33.73%)	139	45/266 (16.92%)	61	1/13 (7.69%)	1
Neutropenia † 1	41/255 (16.08%)	74	0/266 (0.00%)	0	0/13 (0.00%)	0
Endocrine disorders
Hyperthyroidism † 1	0/255 (0.00%)	0	11/266 (4.14%)	11	1/13 (7.69%)	1
Hypothyroidism † 1	3/255 (1.18%)	3	21/266 (7.89%)	24	1/13 (7.69%)	1
Eye disorders
Cataract † 1	0/255 (0.00%)	0	5/266 (1.88%)	5	1/13 (7.69%)	1
Gastrointestinal disorders
Abdominal pain † 1	33/255 (12.94%)	40	32/266 (12.03%)	37	1/13 (7.69%)	1
Abdominal pain upper † 1	14/255 (5.49%)	16	9/266 (3.38%)	11	0/13 (0.00%)	0
Constipation † 1	79/255 (30.98%)	105	54/266 (20.30%)	63	2/13 (15.38%)	2
Diarrhoea † 1	47/255 (18.43%)	69	43/266 (16.17%)	72	1/13 (7.69%)	2
Nausea † 1	73/255 (28.63%)	100	56/266 (21.05%)	62	2/13 (15.38%)	2
Stomatitis † 1	23/255 (9.02%)	35	7/266 (2.63%)	8	0/13 (0.00%)	0
Vomiting † 1	34/255 (13.33%)	47	38/266 (14.29%)	47	0/13 (0.00%)	0
General disorders
Asthenia † 1	52/255 (20.39%)	67	33/266 (12.41%)	36	0/13 (0.00%)	0
Fatigue † 1	85/255 (33.33%)	107	66/266 (24.81%)	83	3/13 (23.08%)	3
Influenza like illness † 1	7/255 (2.75%)	8	10/266 (3.76%)	14	1/13 (7.69%)	2
Mucosal inflammation † 1	18/255 (7.06%)	24	6/266 (2.26%)	8	0/13 (0.00%)	0
Oedema peripheral † 1	39/255 (15.29%)	48	31/266 (11.65%)	36	0/13 (0.00%)	0
Pyrexia † 1	30/255 (11.76%)	38	36/266 (13.53%)	44	1/13 (7.69%)	1
Infections and infestations
Nasopharyngitis † 1	4/255 (1.57%)	4	15/266 (5.64%)	23	1/13 (7.69%)	1
Pharyngitis † 1	1/255 (0.39%)	1	1/266 (0.38%)	1	1/13 (7.69%)	2
Upper respiratory tract infection † 1	2/255 (0.78%)	2	10/266 (3.76%)	12	1/13 (7.69%)	1
Urinary tract infection † 1	27/255 (10.59%)	30	33/266 (12.41%)	45	2/13 (15.38%)	2
Injury, poisoning and procedural complications
Procedural pneumothorax † 1	0/255 (0.00%)	0	0/266 (0.00%)	0	1/13 (7.69%)	1
Investigations
Alanine aminotransferase increased † 1	4/255 (1.57%)	5	14/266 (5.26%)	15	0/13 (0.00%)	0
Aspartate aminotransferase increased † 1	3/255 (1.18%)	4	14/266 (5.26%)	15	0/13 (0.00%)	0
Blood alkaline phosphatase increased † 1	8/255 (3.14%)	8	9/266 (3.38%)	9	1/13 (7.69%)	1
Blood bilirubin increased † 1	2/255 (0.78%)	2	4/266 (1.50%)	4	1/13 (7.69%)	1
Blood creatinine increased † 1	13/255 (5.10%)	16	13/266 (4.89%)	22	2/13 (15.38%)	2
Neutrophil count decreased † 1	40/255 (15.69%)	73	1/266 (0.38%)	1	0/13 (0.00%)	0
Platelet count decreased † 1	8/255 (3.14%)	11	4/266 (1.50%)	4	1/13 (7.69%)	1
Weight decreased † 1	22/255 (8.63%)	23	25/266 (9.40%)	30	1/13 (7.69%)	1
White blood cell count decreased † 1	22/255 (8.63%)	41	1/266 (0.38%)	1	0/13 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	53/255 (20.78%)	65	57/266 (21.43%)	64	4/13 (30.77%)	4
Hypoalbuminaemia † 1	9/255 (3.53%)	9	9/266 (3.38%)	10	1/13 (7.69%)	1
Hypomagnesaemia † 1	4/255 (1.57%)	5	5/266 (1.88%)	6	1/13 (7.69%)	2
Hyponatraemia † 1	18/255 (7.06%)	21	16/266 (6.02%)	20	0/13 (0.00%)	0
Hypophosphataemia † 1	8/255 (3.14%)	16	5/266 (1.88%)	11	1/13 (7.69%)	2
Musculoskeletal and connective tissue disorders
Arthralgia † 1	31/255 (12.16%)	57	30/266 (11.28%)	35	1/13 (7.69%)	1
Back pain † 1	21/255 (8.24%)	22	40/266 (15.04%)	47	2/13 (15.38%)	2
Musculoskeletal pain † 1	9/255 (3.53%)	10	15/266 (5.64%)	16	1/13 (7.69%)	1
Myalgia † 1	17/255 (6.67%)	24	17/266 (6.39%)	20	1/13 (7.69%)	1
Pain in extremity † 1	27/255 (10.59%)	31	24/266 (9.02%)	28	0/13 (0.00%)	0
Synovitis † 1	0/255 (0.00%)	0	0/266 (0.00%)	0	1/13 (7.69%)	2
Nervous system disorders
Dizziness † 1	19/255 (7.45%)	26	19/266 (7.14%)	22	0/13 (0.00%)	0
Dysgeusia † 1	14/255 (5.49%)	16	7/266 (2.63%)	7	0/13 (0.00%)	0
Headache † 1	14/255 (5.49%)	18	14/266 (5.26%)	19	2/13 (15.38%)	2
Neuropathy peripheral † 1	31/255 (12.16%)	43	3/266 (1.13%)	3	0/13 (0.00%)	0
Paraesthesia † 1	4/255 (1.57%)	4	6/266 (2.26%)	9	1/13 (7.69%)	1
Peripheral sensory neuropathy † 1	28/255 (10.98%)	34	2/266 (0.75%)	3	0/13 (0.00%)	0
Psychiatric disorders
Confusional state † 1	2/255 (0.78%)	2	5/266 (1.88%)	6	1/13 (7.69%)	1
Delirium † 1	4/255 (1.57%)	5	3/266 (1.13%)	3	1/13 (7.69%)	1
Insomnia † 1	20/255 (7.84%)	20	19/266 (7.14%)	22	2/13 (15.38%)	2
Renal and urinary disorders
Haematuria † 1	17/255 (6.67%)	21	30/266 (11.28%)	43	1/13 (7.69%)	1
Respiratory, thoracic and mediastinal disorders
Cough † 1	18/255 (7.06%)	20	39/266 (14.66%)	51	3/13 (23.08%)	3
Dyspnoea † 1	23/255 (9.02%)	23	31/266 (11.65%)	38	0/13 (0.00%)	0
Dyspnoea exertional † 1	9/255 (3.53%)	11	5/266 (1.88%)	5	1/13 (7.69%)	1
Productive cough † 1	5/255 (1.96%)	5	8/266 (3.01%)	12	1/13 (7.69%)	1
Skin and subcutaneous tissue disorders
Alopecia † 1	100/255 (39.22%)	106	2/266 (0.75%)	2	0/13 (0.00%)	0
Dermatitis acneiform † 1	3/255 (1.18%)	3	4/266 (1.50%)	4	1/13 (7.69%)	1
Dermatitis allergic † 1	0/255 (0.00%)	0	0/266 (0.00%)	0	1/13 (7.69%)	1
Dry skin † 1	9/255 (3.53%)	9	17/266 (6.39%)	19	1/13 (7.69%)	1
Pruritus † 1	15/255 (5.88%)	17	66/266 (24.81%)	88	0/13 (0.00%)	0
Rash † 1	18/255 (7.06%)	19	32/266 (12.03%)	40	1/13 (7.69%)	1
Rash maculo-papular † 1	3/255 (1.18%)	5	7/266 (2.63%)	8	1/13 (7.69%)	1
Urticaria † 1	5/255 (1.96%)	5	6/266 (2.26%)	6	1/13 (7.69%)	1
Vascular disorders
Hypertension † 1	8/255 (3.14%)	8	14/266 (5.26%)	19	1/13 (7.69%)	1
1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results.

Results Point of Contact

• Name/Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.
• Phone: 1-800-672-6372
• EMail: ClinicalTrialsDisclosure@merck.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Cristescu R, Aurora-Garg D, Albright A, Xu L, Liu XQ, Loboda A, Lang L, Jin F, Rubin EH, Snyder A, Lunceford J. Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors. J Immunother Cancer. 2022 Jan;10(1):e003091. doi: 10.1136/jitc-2021-003091.

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.

Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. doi: 10.1093/annonc/mdz127.

Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. doi: 10.1200/JCO.2017.76.9562. Epub 2018 Mar 28.

Rassy EE, Bakouny Z, Aoun F, Haddad FG, Sleilaty G, Assi T, Kattan J. A network meta-analysis of the PD(L)-1 inhibitors in the salvage treatment of urothelial bladder cancer. Immunotherapy. 2018 Jun;10(8):657-663. doi: 10.2217/imt-2017-0190. Epub 2018 Mar 22.

Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. doi: 10.1056/NEJMoa1613683. Epub 2017 Feb 17.

Kim YS, Lee SI, Park SH, Park S, Hwang IG, Lee SC, Sun JM, Lee J, Lim HY. A Phase II Study of Weekly Docetaxel as Second-Line Chemotherapy in Patients With Metastatic Urothelial Carcinoma. Clin Genitourin Cancer. 2016 Feb;14(1):76-81. doi: 10.1016/j.clgc.2015.09.008. Epub 2015 Sep 25.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02256436
• Other Study ID Numbers: 3475-045; 2014-002009-40 ( EudraCT Number ); 152903 ( Registry Identifier: JAPIC-CTI ); MK-3475-045 ( Other Identifier: Merck Protocol Number )
• First Submitted: September 29, 2014
• First Posted: October 3, 2014
• Results First Submitted: June 12, 2017
• Results First Posted: August 31, 2017
• Last Update Posted: September 20, 2021