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: November 6, 2020
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

• 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	This interim analysis of the results disclosure is based on data collected prior to the database cutoff date of 07-Sep-2016 (up to approximately 20 months of follow up from study start), at which time, 175 participants were ongoing in the study.

Arm/Group Title	Pembrolizumab	Active Comparator
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W).	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Period Title: Overall Study
Started	270	272
Treated	266	255
Completed	0	0
Not Completed	270	272
Reason Not Completed
Adverse Event	15	13
Death	137	158
Lost to Follow-up	1	1
Physician Decision	1	3
Protocol Violation	1	0
Withdrawal by Subject	7	30
Ongoing in Study	108	67

Baseline Characteristics

Arm/Group Title		Pembrolizumab	Active Comparator	Total
Arm/Group Description		Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.	Total of all reporting groups
Overall Number of Baseline Participants		270	272	542
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	270 participants	272 participants	542 participants
		66.0 (10.2)	65.1 (9.2)	65.5 (9.7)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	270 participants	272 participants	542 participants
	Female	70 25.9%	70 25.7%	140 25.8%
	Male	200 74.1%	202 74.3%	402 74.2%

Outcome Measures

1. 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 database cutoff date of 07-Sep-2016.
Time Frame	Through database cutoff 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	270	272
Median (95% Confidence Interval); Unit of Measure: Months
	10.3; (8.0 to 11.8)	7.4; (6.1 to 8.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Active Comparator
	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]

2. 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 radiologist review in all participants up through the database cutoff date of 07-Sep-2016.
Time Frame	Through database cutoff 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	270	272
Median (95% Confidence Interval); Unit of Measure: Months
	2.1; (2.0 to 2.2)	3.3; (2.3 to 3.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Active Comparator
	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]

3. 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 programmed cell death-ligand 1 (PD-L1) combined proportion score (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 database cutoff date of 07-Sep-2016.
Time Frame	Through database cutoff 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	74	90
Median (95% Confidence Interval); Unit of Measure: Months
	8.0; (5.0 to 12.3)	5.2; (4.0 to 7.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Active Comparator
	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]

4. 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 blinded independent radiologist review in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) up through the database cutoff date of 07-Sep-2016.
Time Frame	Through database cutoff 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	74	90
Median (95% Confidence Interval); Unit of Measure: Months
	2.1; (1.9 to 2.1)	3.1; (2.2 to 3.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Active Comparator
	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]

5. 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 database cutoff date of 07-Sep-2016.
Time Frame	Through database cutoff 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	110	120
Median (95% Confidence Interval); Unit of Measure: Months
	11.3; (7.7 to 16.0)	6.9; (4.7 to 8.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Active Comparator
	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]

6. Primary Outcome

Title	PFS Per RECIST 1.1 - 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 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 blinded independent radiologist review in all participants who had PD-L1 positive tumors (CPS ≥1%) up through the database cutoff date of 07-Sep-2016.
Time Frame	Through database cutoff 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	110	120
Median (95% Confidence Interval); Unit of Measure: Months
	2.1; (2.0 to 2.4)	3.2; (2.2 to 3.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Active Comparator
	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]

7. Secondary Outcome

Title	Objective Response Rate (ORR) Per RECIST 1.1 - All Participants
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 blinded independent radiologist review in all participants up through the database cutoff date of 07-Sep-2016.
Time Frame	Through database cutoff 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	270	272
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	21.1; (16.4 to 26.5)	11.4; (7.9 to 15.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Active Comparator
	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	0.00106
	Comments	One-sided p-value for testing H0: difference in %=0; H1: difference in %>0
	Method	Miettinen & Nurminene 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	9.6
	Confidence Interval	(2-Sided) 95%; 3.5 to 15.9
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	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 blinded independent radiologist review in participants with strongly PD-L1 positive tumors (CPS ≥10%) up through the database cutoff date of 07-Sep-2016.
Time Frame	Through database cutoff 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	74	90
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	21.6; (12.9 to 32.7)	6.7; (2.5 to 13.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Active Comparator
	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	0.00020
	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	19.3
	Confidence Interval	(2-Sided) 95%; 8.6 to 31.7
	Estimation Comments	[Not Specified]

9. 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 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 blinded independent radiologist review in participants with PD-L1 positive tumors (CPS ≥1%) up through the database cutoff date of 07-Sep-2016.
Time Frame	Through database cutoff 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	110	120
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	23.6; (16.1 to 32.7)	8.3; (4.1 to 14.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Active Comparator
	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	0.00022
	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	16.9
	Confidence Interval	(2-Sided) 95%; 7.7 to 27.0
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	PFS Per Modified RECIST - 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 modified (immune-related [ir]) RECIST, progressive disease (irPD) was defined as: increase in tumor burden ≥25% relative to minimum recorded tumor burden confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented. PFS per modified RECIST was assessed by blinded independent radiologist review in all randomized participants up through the database cutoff date of 07-Sep-2016.
Time Frame	Through database cutoff 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	270	272
Median (95% Confidence Interval); Unit of Measure: Months
	2.2; (2.1 to 3.4)	3.5; (3.1 to 4.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Active Comparator
	Comments	PFS per Modified RECIST - All Participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.16411
	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%; 0.74 to 1.11
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	ORR Per Modified RECIST - All Participants
Description	ORR per modified RECIST was defined as the percentage of participants in the analysis population who had a Complete Response (irCR: complete disappearance of all lesions [and no new lesions] confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented) or a Partial Response (irPR: decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation). ORR per modified RECIST was assessed by blinded independent radiologist review in all participants up through the database cutoff date of 07-Sep-2016.
Time Frame	Through database cutoff 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	270	272
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	25.2; (20.1 to 30.8)	11.8; (8.2 to 16.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Active Comparator
	Comments	All 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	13.4
	Confidence Interval	(2-Sided) 95%; 7.0 to 19.9
	Estimation Comments	[Not Specified]

12. Secondary Outcome

Title	Number of Participants Who Experienced an Adverse Event (AE)
Description	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study 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 assessed.
Time Frame	Up to approximately 23 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	266	255
Measure Type: Number; Unit of Measure: Participants
	248	250

13. Secondary Outcome

Title	Number of Participants Who Discontinued Study Treatment Due to an AE
Description	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who discontinued study treatment due to an AE was assessed.
Time Frame	Up to approximately 20 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	266	255
Measure Type: Number; Unit of Measure: Participants
	22	32

14. Secondary Outcome

Title	Response Duration Per RECIST 1.1 - All Participants
Description	For participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, response duration was defined as the time from first documented evidence of CR or PR until disease progression or death. Response duration for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Response duration was assessed in all participants based on independent radiologist review and was analyzed using the Kaplan-Meier method.
Time Frame	Through database cutoff date of 07-Sep-2016 (Up to approximately 20 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	57	31
Median (Full Range); Unit of Measure: Months
	NA [1]; (1.6 to NA)	4.3; (1.4 to 15.4)

[1]

NA=Not reached

15. Secondary Outcome

Title	Response Duration 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, response duration was defined as the time from first documented evidence of CR or PR until disease progression or death. Response duration for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Response duration was assessed in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) based on independent radiologist review and was analyzed using the Kaplan-Meier method.
Time Frame	Through database cutoff 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	16	6
Median (Full Range); Unit of Measure: Months
	NA [1]; (1.6 to NA)	4.4; (1.5 to 10.8)

[1]

NA=Not reached

16. Secondary Outcome

Title	Response Duration 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, response duration was defined as the time from first documented evidence of CR or PR until disease progression or death. Response duration for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Response duration was assessed in all participants who had PD-L1 positive tumors (CPS ≥1%) based on independent radiologist review and was analyzed using the Kaplan-Meier method.
Time Frame	Through database cutoff 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	Pembrolizumab	Active Comparator
Arm/Group Description:	Participants received pembrolizumab 200 mg IV on Day 1 Q3W.	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.
Overall Number of Participants Analyzed	26	10
Median (Full Range); Unit of Measure: Months
	NA [1]; (1.6 to NA)	NA [1]; (1.5 to NA)

[1]

NA=Not reached

Adverse Events

Time Frame	Nonserious AEs: Up to 30 days after last dose of study treatment (Up to approximately 21 months) Serious AEs: Up to 90 days after last dose of study treatment (Up to approximately 23 months)
Adverse Event Reporting Description	The safety 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	Active Comparator		Pembrolizumab
Arm/Group Description	Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV on Day 1 Q3W.		Participants received pembrolizumab 200 mg IV on Day 1 Q3W.
All-Cause Mortality
	Active Comparator		Pembrolizumab
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Active Comparator		Pembrolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	104/255 (40.78%)		104/266 (39.10%)
Blood and lymphatic system disorders
Anaemia † 1	8/255 (3.14%)	9	7/266 (2.63%)	8
Anaemia of malignant disease † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Febrile neutropenia † 1	15/255 (5.88%)	15	0/266 (0.00%)	0
Leukopenia † 1	2/255 (0.78%)	5	0/266 (0.00%)	0
Nephrogenic anaemia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Neutropenia † 1	5/255 (1.96%)	5	0/266 (0.00%)	0
Normochromic normocytic anaemia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Pancytopenia † 1	2/255 (0.78%)	2	0/266 (0.00%)	0
Thrombocytopenia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Cardiac disorders
Acute coronary syndrome † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Atrial fibrillation † 1	2/255 (0.78%)	2	0/266 (0.00%)	0
Atrial flutter † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Atrioventricular block † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Myocardial infarction † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Pericardial effusion † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Sinus tachycardia † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Endocrine disorders
Adrenal insufficiency † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Hypercalcaemia of malignancy † 1	0/255 (0.00%)	0	2/266 (0.75%)	2
Hyperthyroidism † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Gastrointestinal disorders
Abdominal pain † 1	4/255 (1.57%)	4	2/266 (0.75%)	2
Anal incontinence † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Colitis † 1	0/255 (0.00%)	0	4/266 (1.50%)	4
Colonic pseudo-obstruction † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Constipation † 1	7/255 (2.75%)	7	0/266 (0.00%)	0
Diarrhoea † 1	2/255 (0.78%)	2	3/266 (1.13%)	4
Enterocolitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Enterocutaneous fistula † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Gastrointestinal haemorrhage † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Gastrointestinal perforation † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Ileus † 1	3/255 (1.18%)	4	0/266 (0.00%)	0
Ileus paralytic † 1	2/255 (0.78%)	3	0/266 (0.00%)	0
Intestinal obstruction † 1	8/255 (3.14%)	8	0/266 (0.00%)	0
Large intestinal obstruction † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Nausea † 1	1/255 (0.39%)	1	1/266 (0.38%)	1
Neutropenic colitis † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Small intestinal obstruction † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Subileus † 1	2/255 (0.78%)	3	0/266 (0.00%)	0
Upper gastrointestinal haemorrhage † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Vomiting † 1	1/255 (0.39%)	2	1/266 (0.38%)	1
General disorders
Asthenia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Death † 1	4/255 (1.57%)	4	1/266 (0.38%)	1
Fatigue † 1	1/255 (0.39%)	1	2/266 (0.75%)	2
General physical health deterioration † 1	0/255 (0.00%)	0	3/266 (1.13%)	3
Hyperthermia malignant † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Influenza like illness † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Malaise † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Mucosal inflammation † 1	2/255 (0.78%)	2	0/266 (0.00%)	0
Pyrexia † 1	5/255 (1.96%)	5	5/266 (1.88%)	5
Hepatobiliary disorders
Hepatic pain † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Hyperbilirubinaemia † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Jaundice † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Infections and infestations
Abdominal abscess † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Anal abscess † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Atypical pneumonia † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Bacteraemia † 1	0/255 (0.00%)	0	2/266 (0.75%)	2
Catheter site infection † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Cystitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Device related infection † 1	0/255 (0.00%)	0	1/266 (0.38%)	2
Device related sepsis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Gastroenteritis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Gastroenteritis viral † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Infective exacerbation of chronic obstructive airways disease † 1	1/255 (0.39%)	1	1/266 (0.38%)	2
Influenza † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Lower respiratory tract infection † 1	0/255 (0.00%)	0	2/266 (0.75%)	2
Lung infection † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Nasopharyngitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Necrotising fasciitis † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Osteomyelitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Pelvic infection † 1	0/255 (0.00%)	0	1/266 (0.38%)	2
Pneumocystis jirovecii infection † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Pneumonia † 1	8/255 (3.14%)	9	9/266 (3.38%)	9
Post procedural infection † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Psoas abscess † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Pyelonephritis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Respiratory tract infection † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Respiratory tract infection viral † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Sepsis † 1	5/255 (1.96%)	6	0/266 (0.00%)	0
Septic shock † 1	1/255 (0.39%)	1	1/266 (0.38%)	1
Tooth abscess † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Upper respiratory tract infection † 1	1/255 (0.39%)	1	1/266 (0.38%)	1
Urinary tract infection † 1	12/255 (4.71%)	13	12/266 (4.51%)	15
Urosepsis † 1	1/255 (0.39%)	1	4/266 (1.50%)	5
Injury, poisoning and procedural complications
Craniocerebral injury † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Fall † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Hip fracture † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Incisional hernia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Pelvic fracture † 1	1/255 (0.39%)	1	1/266 (0.38%)	1
Post procedural haemorrhage † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Procedural pain † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Stoma site haemorrhage † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Thoracic vertebral fracture † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Toxicity to various agents † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Wrist fracture † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Investigations
Alanine aminotransferase increased † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Aspartate aminotransferase increased † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Bacterial test positive † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Blood calcium increased † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Blood creatinine increased † 1	2/255 (0.78%)	2	0/266 (0.00%)	0
Neutrophil count decreased † 1	3/255 (1.18%)	3	0/266 (0.00%)	0
Platelet count decreased † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Transaminases increased † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Metabolism and nutrition disorders
Cachexia † 1	0/255 (0.00%)	0	2/266 (0.75%)	2
Decreased appetite † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Dehydration † 1	2/255 (0.78%)	3	3/266 (1.13%)	3
Electrolyte imbalance † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Fluid retention † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Hypercalcaemia † 1	2/255 (0.78%)	2	0/266 (0.00%)	0
Hyponatraemia † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Type 2 diabetes mellitus † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Vitamin B1 deficiency † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Bone pain † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Gouty arthritis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Pain in extremity † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Pathological fracture † 1	0/255 (0.00%)	0	2/266 (0.75%)	2
Periostitis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Tendonitis † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain † 1	3/255 (1.18%)	3	4/266 (1.50%)	5
Lung neoplasm malignant † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Malignant neoplasm progression † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Malignant pleural effusion † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Metastases to central nervous system † 1	0/255 (0.00%)	0	1/266 (0.38%)	2
Tumour haemorrhage † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Tumour pain † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Urethral cancer † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Nervous system disorders
Cerebral infarction † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Encephalopathy † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Posterior reversible encephalopathy syndrome † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Somnolence † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Syncope † 1	1/255 (0.39%)	1	1/266 (0.38%)	1
Transient ischaemic attack † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Product Issues
Device dislocation † 1	0/255 (0.00%)	0	3/266 (1.13%)	3
Device malfunction † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Renal and urinary disorders
Acute kidney injury † 1	6/255 (2.35%)	6	4/266 (1.50%)	4
Autoimmune nephritis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Azotaemia † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Bladder neck obstruction † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Haematuria † 1	5/255 (1.96%)	6	5/266 (1.88%)	5
Hydronephrosis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Nephritis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Prerenal failure † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Renal failure † 1	1/255 (0.39%)	1	2/266 (0.75%)	2
Renal injury † 1	0/255 (0.00%)	0	1/266 (0.38%)	2
Urinary fistula † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Urinary retention † 1	2/255 (0.78%)	2	0/266 (0.00%)	0
Urinary tract obstruction † 1	1/255 (0.39%)	1	3/266 (1.13%)	3
Reproductive system and breast disorders
Female genital tract fistula † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Pelvic fluid collection † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Pelvic pain † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Prostatic obstruction † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease † 1	0/255 (0.00%)	0	2/266 (0.75%)	2
Dyspnoea † 1	2/255 (0.78%)	2	3/266 (1.13%)	3
Haemoptysis † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Interstitial lung disease † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Pleurisy † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Pneumonitis † 1	0/255 (0.00%)	0	6/266 (2.26%)	7
Pulmonary embolism † 1	1/255 (0.39%)	1	1/266 (0.38%)	1
Pulmonary hypertension † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Skin and subcutaneous tissue disorders
Rash maculo-papular † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Vascular disorders
Deep vein thrombosis † 1	2/255 (0.78%)	2	2/266 (0.75%)	2
Embolism † 1	1/255 (0.39%)	1	0/266 (0.00%)	0
Hypertension † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Hypovolaemic shock † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
Thrombosis † 1	0/255 (0.00%)	0	1/266 (0.38%)	1
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 19.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Active Comparator		Pembrolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	233/255 (91.37%)		223/266 (83.83%)
Blood and lymphatic system disorders
Anaemia † 1	84/255 (32.94%)	132	43/266 (16.17%)	59
Neutropenia † 1	39/255 (15.29%)	70	0/266 (0.00%)	0
Endocrine disorders
Hypothyroidism † 1	3/255 (1.18%)	3	17/266 (6.39%)	18
Gastrointestinal disorders
Abdominal pain † 1	31/255 (12.16%)	38	32/266 (12.03%)	36
Abdominal pain upper † 1	14/255 (5.49%)	16	9/266 (3.38%)	11
Constipation † 1	79/255 (30.98%)	105	50/266 (18.80%)	59
Diarrhoea † 1	46/255 (18.04%)	68	42/266 (15.79%)	66
Nausea † 1	73/255 (28.63%)	100	55/266 (20.68%)	60
Stomatitis † 1	22/255 (8.63%)	34	6/266 (2.26%)	7
Vomiting † 1	34/255 (13.33%)	47	38/266 (14.29%)	47
General disorders
Asthenia † 1	52/255 (20.39%)	67	30/266 (11.28%)	32
Fatigue † 1	85/255 (33.33%)	107	67/266 (25.19%)	83
Mucosal inflammation † 1	18/255 (7.06%)	24	5/266 (1.88%)	7
Oedema peripheral † 1	40/255 (15.69%)	48	26/266 (9.77%)	28
Pyrexia † 1	29/255 (11.37%)	37	34/266 (12.78%)	42
Infections and infestations
Urinary tract infection † 1	25/255 (9.80%)	28	30/266 (11.28%)	39
Investigations
Blood creatinine increased † 1	13/255 (5.10%)	16	13/266 (4.89%)	19
Neutrophil count decreased † 1	36/255 (14.12%)	69	1/266 (0.38%)	1
Weight decreased † 1	21/255 (8.24%)	22	24/266 (9.02%)	28
White blood cell count decreased † 1	20/255 (7.84%)	38	1/266 (0.38%)	1
Metabolism and nutrition disorders
Decreased appetite † 1	52/255 (20.39%)	64	56/266 (21.05%)	61
Hyponatraemia † 1	18/255 (7.06%)	21	14/266 (5.26%)	16
Musculoskeletal and connective tissue disorders
Arthralgia † 1	30/255 (11.76%)	55	24/266 (9.02%)	26
Back pain † 1	21/255 (8.24%)	22	37/266 (13.91%)	44
Myalgia † 1	17/255 (6.67%)	24	14/266 (5.26%)	14
Pain in extremity † 1	27/255 (10.59%)	31	21/266 (7.89%)	25
Nervous system disorders
Dizziness † 1	19/255 (7.45%)	26	15/266 (5.64%)	18
Dysgeusia † 1	18/255 (7.06%)	21	7/266 (2.63%)	7
Headache † 1	13/255 (5.10%)	17	13/266 (4.89%)	17
Neuropathy peripheral † 1	31/255 (12.16%)	43	1/266 (0.38%)	1
Peripheral sensory neuropathy † 1	28/255 (10.98%)	34	2/266 (0.75%)	3
Psychiatric disorders
Insomnia † 1	19/255 (7.45%)	19	16/266 (6.02%)	20
Renal and urinary disorders
Haematuria † 1	17/255 (6.67%)	20	27/266 (10.15%)	38
Respiratory, thoracic and mediastinal disorders
Cough † 1	18/255 (7.06%)	20	38/266 (14.29%)	47
Dyspnoea † 1	22/255 (8.63%)	22	30/266 (11.28%)	35
Skin and subcutaneous tissue disorders
Alopecia † 1	99/255 (38.82%)	105	2/266 (0.75%)	2
Dry skin † 1	9/255 (3.53%)	9	14/266 (5.26%)	16
Pruritus † 1	14/255 (5.49%)	16	62/266 (23.31%)	78
Rash † 1	16/255 (6.27%)	17	29/266 (10.90%)	34
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 19.0

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):

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 Corp.
• 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: November 6, 2020