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

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02256436
• Collaborator: (none)
• Enrollment: 542
• Arms: 2
• Actual Duration (Months): 71.3

Study Details

Study Description

Brief Summary

Participants with metastatic or locally advanced/unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy will be randomly assigned to receive Investigator's choice of paclitaxel, docetaxel, or vinflunine (Control), or pembrolizumab. The primary study hypotheses are that pembrolizumab will prolong Overall Survival (OS) and Progression-free Survival (PFS) compared to paclitaxel, docetaxel, or vinflunine.

Condition or Disease	Intervention/Treatment	Phase
Urothelial Cancer	Biological: pembrolizumab; Drug: paclitaxel; Drug: vinflunine; Drug: docetaxel	Phase 3

Detailed Description

For the purposes of this study, participants with a programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) ≥10% were considered to have a strongly PD-L1 positive tumor status and participants with PD-L1 CPS ≥1% were considered to have a PD-L1 positive tumor status.

Effective with Amendment 15, eligible participants who are allocated to the Control arm (Investigator's Choice) and experience disease progression will be provided with the opportunity to switch over to receive pembrolizumab 200 mg one time every three weeks (Q3W) for up to two years of treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 542 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized Clinical Trial of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel or Vinflunine in Subjects With Recurrent or Progressive Metastatic Urothelial Cancer
• Actual Study Start Date: Oct 22, 2014
• Actual Primary Completion Date: Sep 7, 2016
• Actual Study Completion Date: Oct 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Control Participants receive 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 experience disease progression may be able to switch over to receive pembrolizumab 200 mg Q3W for up to 35 treatment administrations (up to approximately 2 years).	Drug: paclitaxel; IV infusion; Drug: vinflunine; IV infusion; Drug: docetaxel; IV infusion
Experimental: Pembrolizumab Participants receive pembrolizumab 200 mg IV on Day 1 Q3W. Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab 200 mg for up to 17 cycles (up to approximately 1 additional year).	Biological: pembrolizumab; IV infusion; Other Names: MK-3475 KEYTRUDA®

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - All Participants [Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)]

   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.

2. Overall Survival (OS) - All Participants [Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)]

   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.

3. PFS Per RECIST 1.1 - Participants With Programmed Cell Death-Ligand (PD-L1) Positive Tumors [Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)]

   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.

4. OS - Participants With PD-L1 Positive Tumors [Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)]

   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.

5. PFS Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors [Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)]

   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.

6. OS - Participants With Strongly PD-L1 Positive Tumors [Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)]

   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.

Secondary Outcome Measures

1. Number of Participants Who Experienced an Adverse Event (AE) [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

   An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. 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.

2. Number of Participants Who Discontinued Study Treatment Due to an AE [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

   An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. 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.

3. Objective Response Rate (ORR) Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

   ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: 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.

4. ORR Per RECIST 1.1 - Participants With PD-L1 Positive Tumors [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

   ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or a PR (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.

5. ORR Per RECIST 1.1 - All Participants [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

   ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or a PR (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.

6. PFS Per Modified RECIST (mRECIST) - Participants With Strongly PD-L1 Positive Tumors [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

   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.

7. PFS Per mRECIST - Participants With PD-L1 Positive Tumors [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

   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.

8. PFS Per mRECIST - All Participants [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

   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.

9. ORR Per mRECIST - Participants With Strongly PD-L1 Positive Tumors [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

   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.

10. ORR Per mRECIST - Participants With PD-L1 Positive Tumors [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

    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.

11. ORR Per mRECIST - All Participants [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

    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.

12. Duration of Response (DOR) Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

    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.

13. DOR Per RECIST 1.1 - Participants With PD-L1 Positive Tumors [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

    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.

14. DOR Per RECIST 1.1 - All Participants [Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Histologically- or cytologically-confirmed diagnosis of urothelial cancer of the renal pelvis, ureter, bladder, or urethra, that is transitional cell or mixed transitional/non-transitional (predominantly transitional) cell type

• Progression or recurrence of urothelial cancer following a first-line platinum-containing regimen (e.g cisplatin, carboplatin) for metastatic or inoperable locally advanced disease; or adjuvant platinum-based therapy following cystectomy for localized muscle-invasive urothelial cancer with recurrence/progression <=12 months following completion of therapy; or neoadjuvant platinum-containing therapy prior to cystectomy for localized muscle-invasive urothelial cancer with recurrence <=12 months following completion of therapy

• No more than 2 prior lines of systemic chemotherapy for metastatic urothelial cancer

• Able to provide tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated

• Measureable disease

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Adequate organ function

• Female participants of childbearing potential have a negative urine or serum pregnancy test; or are surgically sterile, or willing to use 2 acceptable methods of birth control, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine

• Male participants must be willing to use an adequate method of contraception starting with the first dose of study medication through 120 days after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine

Exclusion criteria:

• Urothelial cancer that is suitable for local therapy administered with curative intent

• Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to the first dose of trial medication

• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication

• Anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not recovered from adverse events due to agents administered more than 4 weeks earlier

• Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of study Day 1 or not recovered from adverse events due to a previously administered agent

• Prior therapy with all choices of active comparator

• Known additional malignancy that is progressing or requires active treatment with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cancer; or prostate cancer that was identified incidentally following cystoprostatectomy for bladder cancer that is Stage T2N0M0 or lower, Gleason score<= 6, or prostatic-specific antigen (PSA) undetectable

• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis

• Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents

• Active cardiac disease

• Evidence of interstitial lung disease or active non-infectious pneumonitis

• Active infection requiring systemic therapy

• History of severe hypersensitivity reaction to paclitaxel, docetaxel, or to other drugs formulated with polysorbate 80 or polyoxyethylated castor oil, or to vinflunine or other vinca alkaloids

• Requires ongoing therapy with a medication that is a strong inhibitor or inducer of the cytochrome 3A4 (CYP3A4) enzymes

• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine

• Prior therapy with an anti-programmed cell death 1 (PD-1) or anti-PD-Ligand 1 agent, or with an agent directed to another co-inhibitory T-cell receptor

• Human immunodeficiency virus (HIV)

• Active hepatitis B or hepatitis C

• Received a live virus vaccine within 30 days of planned start of trial treatment

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 13, 2017

More Information

Additional Information:

• Merck Oncology Clinical trials Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02256436
• Other Study ID Numbers: 3475-045; 2014-002009-40; 152903; MK-3475-045
• First Posted: Oct 3, 2014
• Last Update Posted: Sep 20, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Merck Sharp & Dohme LLC: Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1); Bladder cancer
• Additional relevant MeSH terms: Paclitaxel; Docetaxel; Pembrolizumab

Study Results

Participant Flow

Pre-assignment Detail	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

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 Participants	272	270	542
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	65.1 (9.2)	66.0 (10.2)	65.5 (9.7)
Sex: Female, Male (Count of 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).
Measure Participants	272	270
Median (95% Confidence Interval) [Months]	3.3	2.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Pembrolizumab
	Comments	PFS - All Participants
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	272	270
Median (95% Confidence Interval) [Months]	7.4 (5.1)	10.3 (37.8)

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	120	110
Median (95% Confidence Interval) [Months]	3.2	2.1

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	120	110
Median (95% Confidence Interval) [Months]	6.9	11.3

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	90	74
Median (95% Confidence Interval) [Months]	3.1	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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	90	74
Median (95% Confidence Interval) [Months]	5.2	8.0

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	255	266
Number [Participants]	250 91.9%	250 92.6%

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).
Measure Participants	255	266
Number [Participants]	36 13.2%	28 10.4%

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).
Measure Participants	90	74
Number (95% Confidence Interval) [Percentage of Participants]	6.7 2.5%	20.3 7.5%

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	120	110
Number (95% Confidence Interval) [Percentage of Participants]	8.3 3.1%	22.7 8.4%

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	272	270
Number (95% Confidence Interval) [Percentage of Participants]	11.0 4%	21.1 7.8%

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	90	74
Median (95% Confidence Interval) [Months]	3.3	2.1

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	120	110
Median (95% Confidence Interval) [Months]	3.3	2.1

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	272	270
Median (95% Confidence Interval) [Months]	3.4	2.2

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	90	74
Number (95% Confidence Interval) [Percentage of Participants]	7.8 2.9%	24.3 9%

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	120	110
Number (95% Confidence Interval) [Percentage of Participants]	9.2 3.4%	28.2 10.4%

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	272	270
Number (95% Confidence Interval) [Percentage of Participants]	11.4 4.2%	25.2 9.3%

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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).
Measure Participants	6	15
Median (95% Confidence Interval) [Months]	4.4	NA

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).
Measure Participants	10	25
Median (95% Confidence Interval) [Months]	NA	NA

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).
Measure Participants	30	57
Median (95% Confidence Interval) [Months]	4.4	NA

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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	230/272 (84.6%)		224/270 (83%)		9/13 (69.2%)
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 (40.8%)		107/266 (40.2%)		8/13 (61.5%)
Blood and lymphatic system disorders
Anaemia	7/255 (2.7%)	8	6/266 (2.3%)	7	0/13 (0%)	0
Anaemia of malignant disease	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Febrile neutropenia	16/255 (6.3%)	16	0/266 (0%)	0	0/13 (0%)	0
Leukopenia	2/255 (0.8%)	5	0/266 (0%)	0	0/13 (0%)	0
Nephrogenic anaemia	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Neutropenia	5/255 (2%)	5	0/266 (0%)	0	0/13 (0%)	0
Normocytic anaemia	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Pancytopenia	2/255 (0.8%)	2	0/266 (0%)	0	0/13 (0%)	0
Thrombocytopenia	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Cardiac disorders
Acute coronary syndrome	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Atrial fibrillation	2/255 (0.8%)	2	0/266 (0%)	0	0/13 (0%)	0
Atrial flutter	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Atrioventricular block	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Myocardial infarction	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Pericardial effusion	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Sinus tachycardia	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Endocrine disorders
Adrenal insufficiency	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Hypercalcaemia of malignancy	0/255 (0%)	0	2/266 (0.8%)	2	0/13 (0%)	0
Hyperthyroidism	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Hypophysitis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Gastrointestinal disorders
Abdominal pain	4/255 (1.6%)	4	1/266 (0.4%)	1	0/13 (0%)	0
Anal incontinence	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Colitis	0/255 (0%)	0	5/266 (1.9%)	5	1/13 (7.7%)	2
Constipation	7/255 (2.7%)	7	0/266 (0%)	0	0/13 (0%)	0
Diarrhoea	2/255 (0.8%)	2	3/266 (1.1%)	4	0/13 (0%)	0
Enteritis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Enterocolitis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Gastric ulcer	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Gastrointestinal haemorrhage	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Gastrointestinal perforation	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Ileus	3/255 (1.2%)	4	0/266 (0%)	0	0/13 (0%)	0
Ileus paralytic	2/255 (0.8%)	3	0/266 (0%)	0	0/13 (0%)	0
Intestinal obstruction	8/255 (3.1%)	8	0/266 (0%)	0	2/13 (15.4%)	2
Intestinal perforation	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Intestinal pseudo-obstruction	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Large intestinal obstruction	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Nausea	1/255 (0.4%)	1	1/266 (0.4%)	1	1/13 (7.7%)	1
Neutropenic colitis	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Retroperitoneal haemorrhage	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Small intestinal obstruction	1/255 (0.4%)	1	1/266 (0.4%)	1	0/13 (0%)	0
Stomatitis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Subileus	2/255 (0.8%)	3	0/266 (0%)	0	0/13 (0%)	0
Upper gastrointestinal haemorrhage	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Vomiting	1/255 (0.4%)	2	0/266 (0%)	0	1/13 (7.7%)	1
General disorders
Asthenia	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Death	5/255 (2%)	5	1/266 (0.4%)	1	0/13 (0%)	0
Fatigue	1/255 (0.4%)	1	2/266 (0.8%)	2	0/13 (0%)	0
General physical health deterioration	0/255 (0%)	0	3/266 (1.1%)	3	0/13 (0%)	0
Hyperthermia malignant	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Influenza like illness	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Malaise	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Mucosal inflammation	2/255 (0.8%)	2	0/266 (0%)	0	0/13 (0%)	0
Pain	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Pyrexia	5/255 (2%)	6	5/266 (1.9%)	5	2/13 (15.4%)	2
Hepatobiliary disorders
Hepatic pain	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Hyperbilirubinaemia	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Jaundice	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Infections and infestations
Abdominal abscess	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Anal abscess	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Atypical pneumonia	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Bacteraemia	0/255 (0%)	0	2/266 (0.8%)	2	0/13 (0%)	0
Bronchitis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Catheter site infection	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Cystitis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Device related sepsis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Diverticulitis	0/255 (0%)	0	0/266 (0%)	0	1/13 (7.7%)	1
Epididymitis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Fournier's gangrene	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Gastroenteritis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Gastroenteritis viral	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Infective exacerbation of chronic obstructive airways disease	1/255 (0.4%)	1	1/266 (0.4%)	2	0/13 (0%)	0
Influenza	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Lower respiratory tract infection	0/255 (0%)	0	2/266 (0.8%)	2	0/13 (0%)	0
Nasopharyngitis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Osteomyelitis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Pelvic infection	0/255 (0%)	0	1/266 (0.4%)	2	0/13 (0%)	0
Pneumocystis jirovecii infection	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Pneumonia	8/255 (3.1%)	9	11/266 (4.1%)	11	1/13 (7.7%)	1
Post procedural infection	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Psoas abscess	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Pyelonephritis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Respiratory tract infection	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Respiratory tract infection viral	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Sepsis	5/255 (2%)	6	0/266 (0%)	0	0/13 (0%)	0
Septic shock	1/255 (0.4%)	1	1/266 (0.4%)	1	0/13 (0%)	0
Tooth abscess	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Upper respiratory tract infection	1/255 (0.4%)	1	1/266 (0.4%)	1	0/13 (0%)	0
Urinary tract infection	12/255 (4.7%)	13	12/266 (4.5%)	16	0/13 (0%)	0
Urosepsis	1/255 (0.4%)	1	5/266 (1.9%)	5	0/13 (0%)	0
Vascular device infection	0/255 (0%)	0	1/266 (0.4%)	2	0/13 (0%)	0
Injury, poisoning and procedural complications
Craniocerebral injury	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Fall	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Hip fracture	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Incisional hernia	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Pelvic fracture	1/255 (0.4%)	1	1/266 (0.4%)	1	0/13 (0%)	0
Post procedural haemorrhage	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Procedural pain	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Stoma site haemorrhage	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Thoracic vertebral fracture	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Toxicity to various agents	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Wrist fracture	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Investigations
Alanine aminotransferase increased	0/255 (0%)	0	1/266 (0.4%)	1	1/13 (7.7%)	1
Aspartate aminotransferase increased	0/255 (0%)	0	1/266 (0.4%)	1	1/13 (7.7%)	1
Bacterial test positive	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Blood calcium increased	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Blood creatinine increased	2/255 (0.8%)	2	0/266 (0%)	0	0/13 (0%)	0
Lipase increased	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Neutrophil count decreased	2/255 (0.8%)	2	0/266 (0%)	0	0/13 (0%)	0
Platelet count decreased	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Transaminases increased	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Metabolism and nutrition disorders
Cachexia	0/255 (0%)	0	2/266 (0.8%)	2	0/13 (0%)	0
Decreased appetite	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Dehydration	2/255 (0.8%)	3	3/266 (1.1%)	3	0/13 (0%)	0
Electrolyte imbalance	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Fluid retention	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Hypercalcaemia	2/255 (0.8%)	2	1/266 (0.4%)	1	0/13 (0%)	0
Hyponatraemia	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Type 1 diabetes mellitus	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Type 2 diabetes mellitus	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Vitamin B1 deficiency	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Gouty arthritis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Musculoskeletal pain	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Pathological fracture	0/255 (0%)	0	2/266 (0.8%)	2	0/13 (0%)	0
Periostitis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Tendonitis	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	3/255 (1.2%)	3	2/266 (0.8%)	3	0/13 (0%)	0
Lung neoplasm malignant	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Malignant neoplasm progression	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Malignant pleural effusion	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Metastases to central nervous system	0/255 (0%)	0	1/266 (0.4%)	2	0/13 (0%)	0
Prostate cancer recurrent	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Squamous cell carcinoma	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Tumour associated fever	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Tumour pain	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Urethral cancer	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Nervous system disorders
Altered state of consciousness	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Cerebral haemorrhage	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Cerebral infarction	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Encephalopathy	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Posterior reversible encephalopathy syndrome	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Somnolence	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Syncope	1/255 (0.4%)	1	1/266 (0.4%)	1	0/13 (0%)	0
Transient ischaemic attack	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Product Issues
Device dislocation	0/255 (0%)	0	3/266 (1.1%)	3	0/13 (0%)	0
Device malfunction	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Device occlusion	0/255 (0%)	0	0/266 (0%)	0	1/13 (7.7%)	2
Renal and urinary disorders
Acute kidney injury	6/255 (2.4%)	6	5/266 (1.9%)	5	0/13 (0%)	0
Autoimmune nephritis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Azotaemia	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Bladder neck obstruction	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Haematuria	4/255 (1.6%)	5	6/266 (2.3%)	6	0/13 (0%)	0
Hydronephrosis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Nephritis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Prerenal failure	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Renal failure	1/255 (0.4%)	1	2/266 (0.8%)	2	0/13 (0%)	0
Renal injury	0/255 (0%)	0	1/266 (0.4%)	2	0/13 (0%)	0
Urinary retention	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Urinary tract obstruction	1/255 (0.4%)	1	3/266 (1.1%)	3	0/13 (0%)	0
Reproductive system and breast disorders
Female genital tract fistula	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Pelvic fluid collection	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Pelvic pain	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/255 (0%)	0	2/266 (0.8%)	2	0/13 (0%)	0
Dyspnoea	2/255 (0.8%)	2	3/266 (1.1%)	3	0/13 (0%)	0
Haemoptysis	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Interstitial lung disease	0/255 (0%)	0	3/266 (1.1%)	4	0/13 (0%)	0
Pleurisy	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Pneumonitis	0/255 (0%)	0	6/266 (2.3%)	7	1/13 (7.7%)	1
Pulmonary embolism	1/255 (0.4%)	1	1/266 (0.4%)	1	0/13 (0%)	0
Pulmonary hypertension	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Skin and subcutaneous tissue disorders
Rash maculo-papular	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Vascular disorders
Deep vein thrombosis	2/255 (0.8%)	2	2/266 (0.8%)	2	0/13 (0%)	0
Embolism	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Hypertension	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Hypotension	1/255 (0.4%)	1	0/266 (0%)	0	0/13 (0%)	0
Hypovolaemic shock	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Iliac artery occlusion	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Superior vena cava syndrome	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Thrombosis	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Vasoconstriction	0/255 (0%)	0	1/266 (0.4%)	1	0/13 (0%)	0
Venous thrombosis limb	0/255 (0%)	0	0/266 (0%)	0	1/13 (7.7%)	1
Other (Not Including Serious) Adverse Events
	Control		Pembrolizumab		Control Switched Over to Pembrolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	237/255 (92.9%)		236/266 (88.7%)		11/13 (84.6%)
Blood and lymphatic system disorders
Anaemia	86/255 (33.7%)	139	45/266 (16.9%)	61	1/13 (7.7%)	1
Neutropenia	41/255 (16.1%)	74	0/266 (0%)	0	0/13 (0%)	0
Endocrine disorders
Hyperthyroidism	0/255 (0%)	0	11/266 (4.1%)	11	1/13 (7.7%)	1
Hypothyroidism	3/255 (1.2%)	3	21/266 (7.9%)	24	1/13 (7.7%)	1
Eye disorders
Cataract	0/255 (0%)	0	5/266 (1.9%)	5	1/13 (7.7%)	1
Gastrointestinal disorders
Abdominal pain	33/255 (12.9%)	40	32/266 (12%)	37	1/13 (7.7%)	1
Abdominal pain upper	14/255 (5.5%)	16	9/266 (3.4%)	11	0/13 (0%)	0
Constipation	79/255 (31%)	105	54/266 (20.3%)	63	2/13 (15.4%)	2
Diarrhoea	47/255 (18.4%)	69	43/266 (16.2%)	72	1/13 (7.7%)	2
Nausea	73/255 (28.6%)	100	56/266 (21.1%)	62	2/13 (15.4%)	2
Stomatitis	23/255 (9%)	35	7/266 (2.6%)	8	0/13 (0%)	0
Vomiting	34/255 (13.3%)	47	38/266 (14.3%)	47	0/13 (0%)	0
General disorders
Asthenia	52/255 (20.4%)	67	33/266 (12.4%)	36	0/13 (0%)	0
Fatigue	85/255 (33.3%)	107	66/266 (24.8%)	83	3/13 (23.1%)	3
Influenza like illness	7/255 (2.7%)	8	10/266 (3.8%)	14	1/13 (7.7%)	2
Mucosal inflammation	18/255 (7.1%)	24	6/266 (2.3%)	8	0/13 (0%)	0
Oedema peripheral	39/255 (15.3%)	48	31/266 (11.7%)	36	0/13 (0%)	0
Pyrexia	30/255 (11.8%)	38	36/266 (13.5%)	44	1/13 (7.7%)	1
Infections and infestations
Nasopharyngitis	4/255 (1.6%)	4	15/266 (5.6%)	23	1/13 (7.7%)	1
Pharyngitis	1/255 (0.4%)	1	1/266 (0.4%)	1	1/13 (7.7%)	2
Upper respiratory tract infection	2/255 (0.8%)	2	10/266 (3.8%)	12	1/13 (7.7%)	1
Urinary tract infection	27/255 (10.6%)	30	33/266 (12.4%)	45	2/13 (15.4%)	2
Injury, poisoning and procedural complications
Procedural pneumothorax	0/255 (0%)	0	0/266 (0%)	0	1/13 (7.7%)	1
Investigations
Alanine aminotransferase increased	4/255 (1.6%)	5	14/266 (5.3%)	15	0/13 (0%)	0
Aspartate aminotransferase increased	3/255 (1.2%)	4	14/266 (5.3%)	15	0/13 (0%)	0
Blood alkaline phosphatase increased	8/255 (3.1%)	8	9/266 (3.4%)	9	1/13 (7.7%)	1
Blood bilirubin increased	2/255 (0.8%)	2	4/266 (1.5%)	4	1/13 (7.7%)	1
Blood creatinine increased	13/255 (5.1%)	16	13/266 (4.9%)	22	2/13 (15.4%)	2
Neutrophil count decreased	40/255 (15.7%)	73	1/266 (0.4%)	1	0/13 (0%)	0
Platelet count decreased	8/255 (3.1%)	11	4/266 (1.5%)	4	1/13 (7.7%)	1
Weight decreased	22/255 (8.6%)	23	25/266 (9.4%)	30	1/13 (7.7%)	1
White blood cell count decreased	22/255 (8.6%)	41	1/266 (0.4%)	1	0/13 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	53/255 (20.8%)	65	57/266 (21.4%)	64	4/13 (30.8%)	4
Hypoalbuminaemia	9/255 (3.5%)	9	9/266 (3.4%)	10	1/13 (7.7%)	1
Hypomagnesaemia	4/255 (1.6%)	5	5/266 (1.9%)	6	1/13 (7.7%)	2
Hyponatraemia	18/255 (7.1%)	21	16/266 (6%)	20	0/13 (0%)	0
Hypophosphataemia	8/255 (3.1%)	16	5/266 (1.9%)	11	1/13 (7.7%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	31/255 (12.2%)	57	30/266 (11.3%)	35	1/13 (7.7%)	1
Back pain	21/255 (8.2%)	22	40/266 (15%)	47	2/13 (15.4%)	2
Musculoskeletal pain	9/255 (3.5%)	10	15/266 (5.6%)	16	1/13 (7.7%)	1
Myalgia	17/255 (6.7%)	24	17/266 (6.4%)	20	1/13 (7.7%)	1
Pain in extremity	27/255 (10.6%)	31	24/266 (9%)	28	0/13 (0%)	0
Synovitis	0/255 (0%)	0	0/266 (0%)	0	1/13 (7.7%)	2
Nervous system disorders
Dizziness	19/255 (7.5%)	26	19/266 (7.1%)	22	0/13 (0%)	0
Dysgeusia	14/255 (5.5%)	16	7/266 (2.6%)	7	0/13 (0%)	0
Headache	14/255 (5.5%)	18	14/266 (5.3%)	19	2/13 (15.4%)	2
Neuropathy peripheral	31/255 (12.2%)	43	3/266 (1.1%)	3	0/13 (0%)	0
Paraesthesia	4/255 (1.6%)	4	6/266 (2.3%)	9	1/13 (7.7%)	1
Peripheral sensory neuropathy	28/255 (11%)	34	2/266 (0.8%)	3	0/13 (0%)	0
Psychiatric disorders
Confusional state	2/255 (0.8%)	2	5/266 (1.9%)	6	1/13 (7.7%)	1
Delirium	4/255 (1.6%)	5	3/266 (1.1%)	3	1/13 (7.7%)	1
Insomnia	20/255 (7.8%)	20	19/266 (7.1%)	22	2/13 (15.4%)	2
Renal and urinary disorders
Haematuria	17/255 (6.7%)	21	30/266 (11.3%)	43	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	18/255 (7.1%)	20	39/266 (14.7%)	51	3/13 (23.1%)	3
Dyspnoea	23/255 (9%)	23	31/266 (11.7%)	38	0/13 (0%)	0
Dyspnoea exertional	9/255 (3.5%)	11	5/266 (1.9%)	5	1/13 (7.7%)	1
Productive cough	5/255 (2%)	5	8/266 (3%)	12	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Alopecia	100/255 (39.2%)	106	2/266 (0.8%)	2	0/13 (0%)	0
Dermatitis acneiform	3/255 (1.2%)	3	4/266 (1.5%)	4	1/13 (7.7%)	1
Dermatitis allergic	0/255 (0%)	0	0/266 (0%)	0	1/13 (7.7%)	1
Dry skin	9/255 (3.5%)	9	17/266 (6.4%)	19	1/13 (7.7%)	1
Pruritus	15/255 (5.9%)	17	66/266 (24.8%)	88	0/13 (0%)	0
Rash	18/255 (7.1%)	19	32/266 (12%)	40	1/13 (7.7%)	1
Rash maculo-papular	3/255 (1.2%)	5	7/266 (2.6%)	8	1/13 (7.7%)	1
Urticaria	5/255 (2%)	5	6/266 (2.3%)	6	1/13 (7.7%)	1
Vascular disorders
Hypertension	8/255 (3.1%)	8	14/266 (5.3%)	19	1/13 (7.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.