Study of Single Agent Pembrolizumab (MK-3475) Versus Single Agent Chemotherapy for Metastatic Triple Negative Breast Cancer (MK-3475-119/KEYNOTE-119)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02555657
• Collaborator: (none)
• Enrollment: 622
• Arms: 2
• Actual Duration (Months): 60.9

Study Details

Study Description

Brief Summary

In this study, participants with metastatic triple negative breast cancer (mTNBC) will be randomly assigned to receive either single agent pembrolizumab or single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines, consisting of either capecitabine, eribulin, gemcitabine, or vinorelbine. The primary study hypothesis is that pembrolizumab extends overall survival compared to TPC.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Triple Negative Breast Cancer	Biological: pembrolizumab; Drug: capecitabine; Drug: eribulin; Drug: gemcitabine; Drug: vinorelbine	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 622 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Open-Label Phase III Study of Single Agent Pembrolizumab Versus Single Agent Chemotherapy Per Physician's Choice for Metastatic Triple Negative Breast Cancer (mTNBC) - (KEYNOTE-119)
• Actual Study Start Date: Oct 13, 2015
• Actual Primary Completion Date: Apr 11, 2019
• Actual Study Completion Date: Nov 10, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab Participants receive pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Qualified participants who receive first course of pembrolizumab but continue to experience disease progression may, at investigator's discretion, initiate a second course of pembrolizumab at 200 mg IV Q3W for up to 17 administrations (up to ~1 year).	Biological: pembrolizumab; Other Names: MK-3475 KEYTRUDA®
Active Comparator: Chemotherapy Participants receive capecitabine, eribulin, gemcitabine, or vinorelbine as TPC in accordance with local regulations and guidelines.	Drug: capecitabine; Other Names: XELODA® ; Drug: eribulin; Other Names: HALAVEN® ; Drug: gemcitabine; Other Names: GEMZAR® ; Drug: vinorelbine; Other Names: NAVELBINE®

Outcome Measures

Primary Outcome Measures

1. Overall Survival in Participants With Programmed Cell Death Ligand 1 (PD-L1) With Combined Positive Score (CPS) ≥10 [Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)]

   Overall survival (OS) was defined as the time from randomization to death due to any cause.

2. Overall Survival in Participants With PD-L1 CPS ≥1 [Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)]

   Overall survival (OS) was defined as the time from randomization to death due to any cause.

3. Overall Survival in All Participants [Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)]

   Overall survival (OS) was defined as the time from randomization to death due to any cause.

Secondary Outcome Measures

1. Overall Response Rate Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With PD-L1 CPS ≥10 [Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)]

   Overall Response Rate (ORR), based on a Blinded Independent Central Review (BICR) assessment per RECIST 1.1, was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions).

2. Overall Response Rate Per RECIST 1.1 in Participants With PD-L1 CPS ≥1 [Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)]

   Overall Response Rate (ORR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions).

3. Overall Response Rate Per RECIST 1.1 in All Participants [Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)]

   Overall Response Rate (ORR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions).

4. Progression-Free Survival Per RECIST 1.1 in Participants With PD-L1 CPS ≥10 [Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)]

   Progression-Free Survival (PFS), based on BICR assessment per RECIST 1.1, was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥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 ≥5 mm. The appearance of one or more new lesions was also considered PD.

5. Progression-Free Survival Per RECIST 1.1 in Participants With PD-L1 CPS ≥1 [Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)]

   Progression-Free Survival (PFS), based on BICR assessment per RECIST 1.1, was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥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 ≥5 mm. The appearance of one or more new lesions was also considered PD.

6. Progression-Free Survival Per RECIST 1.1 in All Participants [Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)]

   Progression-Free Survival (PFS), based on BICR assessment per RECIST 1.1, was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥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 ≥5 mm. The appearance of one or more new lesions was also considered PD.

7. Duration of Response Per RECIST 1.1 in Participants With PD-L1 CPS ≥10 Who Had a Confirmed Response [Up to approximately 36 months (from time of first documented evidence of CR or PR through Final Analysis database cutoff date of 11-April-2019)]

   For participants with PD-L1 CPS ≥10 who demonstrated a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, Duration of Response (DOR) was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR 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. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on BICR.

8. Duration of Response Per RECIST 1.1 in Participants With PD-L1 CPS ≥1 Who Had a Confirmed Response [Up to approximately 36 months (from time of first documented evidence of CR or PR through Final Analysis database cutoff date of 11-April-2019)]

   For participants with PD-L1 CPS ≥1 who demonstrated a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, Duration of Response (DOR) was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR 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. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on BICR.

9. Duration of Response Per RECIST 1.1 in All Participants Who Had a Confirmed Response [Up to approximately 36 months (from time of first documented evidence of CR or PR through Final Analysis database cutoff date of 11-April-2019)]

   For participants who demonstrated a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, Duration of Response (DOR) was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR 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. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on BICR.

10. Disease Control Rate Per RECIST 1.1 in Participants With PD-L1 CPS ≥10 [Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)]

    Disease Control Rate (DCR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease for at least 24 weeks (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.])

11. Disease Control Rate Per RECIST 1.1 in Participants With PD-L1 CPS ≥1 [Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)]

    Disease Control Rate (DCR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease for at least 24 weeks (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.])

12. Disease Control Rate Per RECIST 1.1 in All Participants [Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)]

    Disease Control Rate (DCR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease for at least 24 weeks (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.])

13. Number of Participants Who Experienced One or More Adverse Events [Up to approximately 60 months]

    An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.

14. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event [Up to approximately 60 months]

    An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Centrally confirmed Stage IV/M1 mTNBC

• Newly obtained tumor biopsy from metastatic site

• Central determination of programmed cell death ligand 1 (PD-L1) tumor status

• Received either one or two prior systemic treatments for metastatic breast cancer and have documented disease progression on or after the most recent therapy

• Previously treated with an anthracycline and/or taxane in the neoadjuvant/adjuvant or metastatic setting

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 10 days prior to study start

• Adequate organ function

Exclusion Criteria:

• Participation in another clinical trial within 4 weeks

• Monoclonal antibody (mAb) for direct anti-neoplastic treatment within 4 weeks

• Chemotherapy, targeted small molecule therapy, or radiation therapy within at least 2 weeks

• Active autoimmune disease that required systemic treatment in the past 2 years

• Diagnosed with immunodeficiency or receiving systemic steroid therapy or another form of immunosuppressive therapy within 7 days

• Known additional malignancy that required treatment or progressed in last 5 years

• Known active brain metastases and/or carcinomatous meningitis

• Prior therapy with an anti-programmed cell death (PD)-1, anti-PD-ligand-1 (anti-PD-L1), anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte associated protein 4 [CTLA-4], OX-40, CD137) or previously participated in any pembrolizumab (MK-3475) clinical studies

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 - Feb 19, 2018
• Statistical Analysis Plan - Apr 23, 2019

More Information

Additional Information:

• Merck Oncology Clinical Trial Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02555657
• Other Study ID Numbers: 3475-119; 2015-001020-27; 153082; MK-3475-119; KEYNOTE-119
• First Posted: Sep 21, 2015
• Last Update Posted: Dec 10, 2021
• Last Verified: Nov 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)
• Additional relevant MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms; Gemcitabine; Capecitabine; Pembrolizumab; Vinorelbine

Study Results

Participant Flow

Pre-assignment Detail	Per protocol, response/progression or adverse events during the second pembrolizumab course were not counted towards efficacy outcome measures or safety outcome measures respectively.

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Qualified participants who received first course of pembrolizumab but continued to experience disease progression may have, at investigator's discretion, initiated a second course of pembrolizumab at 200 mg IV Q3W for up to 17 administrations (up to ~1 year).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Period Title: Overall Study
STARTED	312	310
Treated	309	292
COMPLETED	0	0
NOT COMPLETED	312	310

Baseline Characteristics

Arm/Group Title	Pembrolizumab	Chemotherapy	Total
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Qualified participants who received first course of pembrolizumab but continued to experience disease progression may have, at investigator's discretion, initiated a second course of pembrolizumab at 200 mg IV Q3W for up to 17 administrations (up to ~1 year).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.	Total of all reporting groups
Overall Participants	312	310	622
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	51.4 (11.4)	52.6 (11.2)	52.0 (11.3)
Sex: Female, Male (Count of Participants)
Female	312 100%	308 99.4%	620 99.7%
Male	0 0%	2 0.6%	2 0.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	4 1.3%	4 1.3%	8 1.3%
Asian	87 27.9%	101 32.6%	188 30.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	13 4.2%	4 1.3%	17 2.7%
White	183 58.7%	180 58.1%	363 58.4%
More than one race	12 3.8%	12 3.9%	24 3.9%
Unknown or Not Reported	13 4.2%	9 2.9%	22 3.5%

Outcome Measures

1. Primary Outcome

Title	Overall Survival in Participants With Programmed Cell Death Ligand 1 (PD-L1) With Combined Positive Score (CPS) ≥10
Description	Overall survival (OS) was defined as the time from randomization to death due to any cause.
Time Frame	Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All participants with PD-L1 CPS ≥10 who were included in a treatment group at randomization

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	96	98
Median (95% Confidence Interval) [Months]	12.7	11.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0574
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Overall Survival in Participants With PD-L1 CPS ≥1
Description	Overall survival (OS) was defined as the time from randomization to death due to any cause.
Time Frame	Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All participants with PD-L1 CPS ≥1 who were included in a treatment group at randomization

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	203	202
Median (95% Confidence Interval) [Months]	10.7	10.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0728
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Overall Survival in All Participants
Description	Overall survival (OS) was defined as the time from randomization to death due to any cause.
Time Frame	Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All participants who were included in a treatment group at randomization

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	312	310
Median (95% Confidence Interval) [Months]	9.9	10.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3802
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Overall Response Rate Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With PD-L1 CPS ≥10
Description	Overall Response Rate (ORR), based on a Blinded Independent Central Review (BICR) assessment per RECIST 1.1, was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions).
Time Frame	Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All participants with PD-L1 CPS ≥10 who were included in a treatment group at randomization

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	96	98
Number (95% Confidence Interval) [Percentage of participants]	17.7 5.7%	9.2 3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0457
	Comments
	Method	Miettinen & Nurminen method
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	8.3
	Confidence Interval	(2-Sided) 95%; -1.4 to 18.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Overall Response Rate Per RECIST 1.1 in Participants With PD-L1 CPS ≥1
Description	Overall Response Rate (ORR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions).
Time Frame	Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All participants with PD-L1 CPS ≥1 who were included in a treatment group at randomization

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	203	202
Number (95% Confidence Interval) [Percentage of participants]	12.3 3.9%	9.4 3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1752
	Comments
	Method	Miettinen & Nurminen method
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	2.9
	Confidence Interval	(2-Sided) 95%; -3.3 to 9.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Overall Response Rate Per RECIST 1.1 in All Participants
Description	Overall Response Rate (ORR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions).
Time Frame	Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All participants who were included in a treatment group at randomization

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	312	310
Number (95% Confidence Interval) [Percentage of participants]	9.6 3.1%	10.6 3.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6629
	Comments
	Method	Miettinen & Nurminen method
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -5.9 to 3.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Progression-Free Survival Per RECIST 1.1 in Participants With PD-L1 CPS ≥10
Description	Progression-Free Survival (PFS), based on BICR assessment per RECIST 1.1, was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥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 ≥5 mm. The appearance of one or more new lesions was also considered PD.
Time Frame	Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All participants with PD-L1 CPS ≥10 who were included in a treatment group at randomization

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	96	98
Median (95% Confidence Interval) [Months]	2.1	3.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7936
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Progression-Free Survival Per RECIST 1.1 in Participants With PD-L1 CPS ≥1
Description	Progression-Free Survival (PFS), based on BICR assessment per RECIST 1.1, was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥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 ≥5 mm. The appearance of one or more new lesions was also considered PD.
Time Frame	Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All participants with PD-L1 CPS ≥1 who were included in a treatment group at randomization

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	203	202
Median (95% Confidence Interval) [Months]	2.1	3.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9964
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.35
	Confidence Interval	(2-Sided) 95%; 1.08 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Progression-Free Survival Per RECIST 1.1 in All Participants
Description	Progression-Free Survival (PFS), based on BICR assessment per RECIST 1.1, was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥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 ≥5 mm. The appearance of one or more new lesions was also considered PD.
Time Frame	Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All participants who were included in a treatment group at randomization

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	312	310
Median (95% Confidence Interval) [Months]	2.1	3.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.0000
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.60
	Confidence Interval	(2-Sided) 95%; 1.33 to 1.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Duration of Response Per RECIST 1.1 in Participants With PD-L1 CPS ≥10 Who Had a Confirmed Response
Description	For participants with PD-L1 CPS ≥10 who demonstrated a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, Duration of Response (DOR) was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR 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. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on BICR.
Time Frame	Up to approximately 36 months (from time of first documented evidence of CR or PR through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All randomized participants with PD-L1 CPS ≥10, whether or not they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	17	9
Median (Full Range) [Months]	NA	7.1

11. Secondary Outcome

Title	Duration of Response Per RECIST 1.1 in Participants With PD-L1 CPS ≥1 Who Had a Confirmed Response
Description	For participants with PD-L1 CPS ≥1 who demonstrated a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, Duration of Response (DOR) was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR 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. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on BICR.
Time Frame	Up to approximately 36 months (from time of first documented evidence of CR or PR through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All randomized participants with PD-L1 CPS ≥1, regardless of whether or not they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	25	19
Median (Full Range) [Months]	12.2	NA

12. Secondary Outcome

Title	Duration of Response Per RECIST 1.1 in All Participants Who Had a Confirmed Response
Description	For participants who demonstrated a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, Duration of Response (DOR) was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR 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. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on BICR.
Time Frame	Up to approximately 36 months (from time of first documented evidence of CR or PR through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All randomized participants, regardless of whether or not they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	30	33
Median (Full Range) [Months]	12.2	NA

13. Secondary Outcome

Title	Disease Control Rate Per RECIST 1.1 in Participants With PD-L1 CPS ≥10
Description	Disease Control Rate (DCR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease for at least 24 weeks (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.])
Time Frame	Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All participants with PD-L1 CPS ≥10 who were included in a treatment group at randomization

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	96	98
Number (95% Confidence Interval) [Percentage of participants]	19.8 6.3%	17.3 5.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3388
	Comments
	Method	Miettinen & Nurminen method
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; -8.7 to 13.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Disease Control Rate Per RECIST 1.1 in Participants With PD-L1 CPS ≥1
Description	Disease Control Rate (DCR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease for at least 24 weeks (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.])
Time Frame	Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All participants with PD-L1 CPS ≥1 who were included in a treatment group at randomization

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	203	202
Number (95% Confidence Interval) [Percentage of participants]	14.3 4.6%	15.8 5.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6701
	Comments
	Method	Miettinen & Nurminen method
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 95%; -8.6 to 5.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Disease Control Rate Per RECIST 1.1 in All Participants
Description	Disease Control Rate (DCR), based on BICR assessment per RECIST 1.1, was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or Stable Disease for at least 24 weeks (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.])
Time Frame	Up to approximately 36 months (through Final Analysis database cutoff date of 11-April-2019)

Outcome Measure Data

Analysis Population Description

All participants who were included in a treatment group at randomization

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	312	310
Number (95% Confidence Interval) [Percentage of participants]	12.2 3.9%	18.7 6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9877
	Comments
	Method	Miettinen & Nurminen method
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	-6.5
	Confidence Interval	(2-Sided) 95%; -12.2 to -0.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Number of Participants Who Experienced One or More Adverse Events
Description	An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
Time Frame	Up to approximately 60 months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study treatment

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	309	292
Count of Participants [Participants]	285 91.3%	281 90.6%

17. Secondary Outcome

Title	Number of Participants Who Discontinued Study Treatment Due to an Adverse Event
Description	An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
Time Frame	Up to approximately 60 months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study treatment

Arm/Group Title	Pembrolizumab	Chemotherapy
Arm/Group Description	Participants received pembrolizumab 200 mg IV every Q3W for up to 35 administrations (up to ~2 years).	Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines.
Measure Participants	309	292
Count of Participants [Participants]	14 4.5%	16 5.2%

Adverse Events

Time Frame	All-Cause Mortality and Adverse Events (including first and second courses): Up to approximately 60 months
Adverse Event Reporting Description	All-cause mortality table includes all randomized participants. Serious and other AEs include participants who received at least 1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" unrelated to drug were excluded as AEs. Participants who received a second course of pembrolizumab per protocol were monitored for all-cause mortality and AEs separately.
Arm/Group Title	Pembrolizumab First Course		Chemotherapy		Pembrolizumab Second Course
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W for up to 35 administrations (up to ~2 years).		Participants received capecitabine, eribulin, gemcitabine, or vinorelbine as TPC in accordance with local regulations and guidelines.		Qualified participants who received the first course of pembrolizumab 200 mg IV Q3W for up to 35 administrations (up to ~2 years), but experienced disease progression, initiated a second course of pembrolizumab at the investigator's discretion, at 200 mg IV Q3W for up to 17 administrations (up to ~1 year).
All Cause Mortality
	Pembrolizumab First Course		Chemotherapy		Pembrolizumab Second Course
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	283/312 (90.7%)		289/310 (93.2%)		0/8 (0%)
Serious Adverse Events
	Pembrolizumab First Course		Chemotherapy		Pembrolizumab Second Course
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	65/309 (21%)		60/292 (20.5%)		1/8 (12.5%)
Blood and lymphatic system disorders
Anaemia	2/309 (0.6%)	2	2/292 (0.7%)	2	0/8 (0%)	0
Febrile neutropenia	1/309 (0.3%)	1	5/292 (1.7%)	6	0/8 (0%)	0
Neutropenia	1/309 (0.3%)	1	4/292 (1.4%)	6	0/8 (0%)	0
Pancytopenia	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Thrombocytopenia	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Cardiac disorders
Cardiac arrest	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Cardio-respiratory arrest	2/309 (0.6%)	2	0/292 (0%)	0	0/8 (0%)	0
Cardiogenic shock	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Sinus tachycardia	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Endocrine disorders
Secondary adrenocortical insufficiency	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Colitis	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Constipation	1/309 (0.3%)	1	3/292 (1%)	3	0/8 (0%)	0
Diarrhoea	1/309 (0.3%)	1	2/292 (0.7%)	2	0/8 (0%)	0
Large intestine polyp	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Oesophageal achalasia	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Small intestinal perforation	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Vomiting	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
General disorders
Chest pain	0/309 (0%)	0	2/292 (0.7%)	2	0/8 (0%)	0
Death	0/309 (0%)	0	4/292 (1.4%)	4	0/8 (0%)	0
Fatigue	3/309 (1%)	3	0/292 (0%)	0	0/8 (0%)	0
Hyperthermia	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Influenza like illness	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Malaise	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Mucosal inflammation	0/309 (0%)	0	2/292 (0.7%)	2	0/8 (0%)	0
Oedema peripheral	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Pyrexia	4/309 (1.3%)	4	2/292 (0.7%)	2	0/8 (0%)	0
Hepatobiliary disorders
Cholangitis	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Cholecystitis	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Cholelithiasis	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Liver disorder	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Hepatotoxicity	0/309 (0%)	0	0/292 (0%)	0	1/8 (12.5%)	1
Infections and infestations
Bronchitis	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Cellulitis	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Device related infection	2/309 (0.6%)	2	1/292 (0.3%)	1	0/8 (0%)	0
Device related sepsis	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Enterococcal sepsis	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Erysipelas	1/309 (0.3%)	2	0/292 (0%)	0	0/8 (0%)	0
Gastroenteritis	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Herpes zoster	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Infectious pleural effusion	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Klebsiella infection	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Liver abscess	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Lower respiratory tract infection	1/309 (0.3%)	1	1/292 (0.3%)	1	0/8 (0%)	0
Mastitis	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Pharyngotonsillitis	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Pneumonia	6/309 (1.9%)	6	8/292 (2.7%)	8	0/8 (0%)	0
Pyelonephritis	1/309 (0.3%)	2	0/292 (0%)	0	0/8 (0%)	0
Respiratory tract infection	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Sepsis	2/309 (0.6%)	2	1/292 (0.3%)	1	0/8 (0%)	0
Staphylococcal bacteraemia	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Systemic candida	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Tonsillitis	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Upper respiratory tract infection	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Urinary tract infection	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Wound infection	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Injury, poisoning and procedural complications
Ankle fracture	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Femur fracture	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Post procedural complication	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Radiation associated pain	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Toxicity to various agents	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Investigations
Alanine aminotransferase increased	2/309 (0.6%)	2	0/292 (0%)	0	0/8 (0%)	0
Aspartate aminotransferase increased	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Blood corticotrophin abnormal	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Metabolism and nutrition disorders
Cachexia	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Decreased appetite	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Dehydration	0/309 (0%)	0	2/292 (0.7%)	2	0/8 (0%)	0
Diabetic ketoacidosis	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Hypercalcaemia	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Hyperglycaemia	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Hypocalcaemia	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Type 1 diabetes mellitus	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Back pain	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Flank pain	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Muscular weakness	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Myositis	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Rhabdomyolysis	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	3/309 (1%)	4	1/292 (0.3%)	1	0/8 (0%)	0
Infected neoplasm	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Inflammatory carcinoma of the breast	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Myelodysplastic syndrome	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Pelvic neoplasm	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Tumour associated fever	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Nervous system disorders
Brain oedema	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Headache	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Horner's syndrome	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Lethargy	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Neuralgia	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Neuropathy peripheral	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Post herpetic neuralgia	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Seizure	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Spinal cord compression	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Syncope	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Transient ischaemic attack	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Psychiatric disorders
Completed suicide	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Depression	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/309 (0%)	0	2/292 (0.7%)	2	0/8 (0%)	0
Tubulointerstitial nephritis	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Reproductive system and breast disorders
Breast pain	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Dyspnoea	3/309 (1%)	3	0/292 (0%)	0	0/8 (0%)	0
Haemothorax	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Interstitial lung disease	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Oropharyngeal pain	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Pleural effusion	8/309 (2.6%)	8	3/292 (1%)	3	0/8 (0%)	0
Pneumonitis	2/309 (0.6%)	2	0/292 (0%)	0	0/8 (0%)	0
Pneumothorax	0/309 (0%)	0	1/292 (0.3%)	1	0/8 (0%)	0
Pulmonary embolism	2/309 (0.6%)	2	2/292 (0.7%)	2	0/8 (0%)	0
Respiratory failure	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Skin and subcutaneous tissue disorders
Decubitus ulcer	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Rash maculo-papular	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Urticaria	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Vascular disorders
Circulatory collapse	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Deep vein thrombosis	1/309 (0.3%)	1	1/292 (0.3%)	1	0/8 (0%)	0
Jugular vein thrombosis	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Peripheral ischaemia	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Thrombosis	1/309 (0.3%)	1	0/292 (0%)	0	0/8 (0%)	0
Other (Not Including Serious) Adverse Events
	Pembrolizumab First Course		Chemotherapy		Pembrolizumab Second Course
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	259/309 (83.8%)		263/292 (90.1%)		4/8 (50%)
Blood and lymphatic system disorders
Anaemia	28/309 (9.1%)	31	46/292 (15.8%)	80	0/8 (0%)	0
Neutropenia	2/309 (0.6%)	2	61/292 (20.9%)	146	0/8 (0%)	0
Endocrine disorders
Hypothyroidism	25/309 (8.1%)	26	4/292 (1.4%)	4	0/8 (0%)	0
Gastrointestinal disorders
Abdominal pain	18/309 (5.8%)	18	15/292 (5.1%)	18	0/8 (0%)	0
Constipation	50/309 (16.2%)	56	51/292 (17.5%)	59	0/8 (0%)	0
Diarrhoea	29/309 (9.4%)	34	60/292 (20.5%)	83	1/8 (12.5%)	1
Nausea	50/309 (16.2%)	63	89/292 (30.5%)	117	0/8 (0%)	0
Stomatitis	6/309 (1.9%)	7	23/292 (7.9%)	24	0/8 (0%)	0
Vomiting	23/309 (7.4%)	30	33/292 (11.3%)	44	0/8 (0%)	0
General disorders
Asthenia	36/309 (11.7%)	40	38/292 (13%)	42	0/8 (0%)	0
Fatigue	55/309 (17.8%)	67	54/292 (18.5%)	61	1/8 (12.5%)	2
Malaise	9/309 (2.9%)	9	15/292 (5.1%)	17	0/8 (0%)	0
Mucosal inflammation	1/309 (0.3%)	1	22/292 (7.5%)	22	0/8 (0%)	0
Oedema peripheral	16/309 (5.2%)	17	14/292 (4.8%)	17	0/8 (0%)	0
Pyrexia	35/309 (11.3%)	46	34/292 (11.6%)	49	0/8 (0%)	0
Influenza like illness	3/309 (1%)	4	4/292 (1.4%)	4	1/8 (12.5%)	3
Infections and infestations
Nasopharyngitis	18/309 (5.8%)	22	14/292 (4.8%)	20	0/8 (0%)	0
Urinary tract infection	16/309 (5.2%)	18	20/292 (6.8%)	24	0/8 (0%)	0
Investigations
Alanine aminotransferase increased	22/309 (7.1%)	25	24/292 (8.2%)	43	1/8 (12.5%)	1
Aspartate aminotransferase increased	32/309 (10.4%)	39	28/292 (9.6%)	51	1/8 (12.5%)	1
Neutrophil count decreased	3/309 (1%)	8	44/292 (15.1%)	144	0/8 (0%)	0
Weight decreased	10/309 (3.2%)	10	16/292 (5.5%)	16	0/8 (0%)	0
White blood cell count decreased	5/309 (1.6%)	11	30/292 (10.3%)	103	0/8 (0%)	0
Blood bilirubin increased	3/309 (1%)	3	8/292 (2.7%)	9	1/8 (12.5%)	1
Metabolism and nutrition disorders
Decreased appetite	30/309 (9.7%)	31	38/292 (13%)	43	0/8 (0%)	0
Hyperglycaemia	12/309 (3.9%)	14	17/292 (5.8%)	21	0/8 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	37/309 (12%)	46	24/292 (8.2%)	28	1/8 (12.5%)	1
Back pain	22/309 (7.1%)	24	30/292 (10.3%)	33	0/8 (0%)	0
Pain in extremity	19/309 (6.1%)	20	24/292 (8.2%)	28	1/8 (12.5%)	1
Muscular weakness	4/309 (1.3%)	4	4/292 (1.4%)	4	1/8 (12.5%)	1
Musculoskeletal chest pain	11/309 (3.6%)	11	4/292 (1.4%)	4	1/8 (12.5%)	1
Nervous system disorders
Dizziness	14/309 (4.5%)	15	20/292 (6.8%)	21	0/8 (0%)	0
Headache	44/309 (14.2%)	61	34/292 (11.6%)	43	0/8 (0%)	0
Neuropathy peripheral	4/309 (1.3%)	4	26/292 (8.9%)	28	0/8 (0%)	0
Peripheral sensory neuropathy	6/309 (1.9%)	6	19/292 (6.5%)	20	0/8 (0%)	0
Psychiatric disorders
Insomnia	9/309 (2.9%)	9	17/292 (5.8%)	18	0/8 (0%)	0
Renal and urinary disorders
Leukocyturia	0/309 (0%)	0	0/292 (0%)	0	1/8 (12.5%)	1
Respiratory, thoracic and mediastinal disorders
Cough	53/309 (17.2%)	60	31/292 (10.6%)	33	0/8 (0%)	0
Dyspnoea	37/309 (12%)	41	32/292 (11%)	39	0/8 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	2/309 (0.6%)	2	43/292 (14.7%)	44	0/8 (0%)	0
Palmar-plantar erythrodysaesthesia syndrome	2/309 (0.6%)	2	36/292 (12.3%)	47	0/8 (0%)	0
Pruritus	35/309 (11.3%)	44	12/292 (4.1%)	12	0/8 (0%)	0
Rash	23/309 (7.4%)	25	13/292 (4.5%)	14	0/8 (0%)	0

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. Sponsor review can be expedited to meet publication timelines.