Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Participants With Advanced Melanoma (MK-3475-002/P08719/KEYNOTE-002)

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Completed

CT.gov ID

NCT01704287

Collaborator

(none)

540

Enrollment

Arms

74.3

Actual Duration (Months)

Study Details

Study Description

Brief Summary

This study was conducted to compare survival using pembrolizumab (SCH 900475, MK-3475) or standard chemotherapy in participants with advanced melanoma (MEL) who had progressed after prior therapy.

Initial Treatment Period:

Participants were initially randomized to receive either low-dose (2 mg/kg) pembrolizumab, higher dose (10 mg/kg) pembrolizumab or Investigator-choice chemotherapy (ICC). The four standard chemotherapy choices were: carboplatin + paclitaxel, paclitaxel alone, dacarbazine, or temozolomide. The randomization to either pembrolizumab or ICC was conducted in an open-label fashion.

The starting pembrolizumab dose was initially blinded to Investigators and participants until Amendment 03. With Amendment 03, all ongoing pembrolizumab participants were to be treated with open label, fixed dose pembrolizumab 200 mg, instead of a weight-based dosing of pembrolizumab.

Switch-to-Pembrolizumab Treatment Period:

Participants who were initially randomized to receive ICC and experienced progressive disease (PD) may have been eligible to switch to receiving pembrolizumab provided they met protocol-specified requirements for switching. Qualified participants were re-randomized to receive either pembrolizumab 2 mg/kg or pembrolizumab 10 mg/kg in a double-blind fashion. Participants who qualified to switch to pembrolizumab must have completed a washout period of ≥28 days from last dose of chemotherapy before receiving pembrolizumab. With Amendment 03, all switched-to-pembrolizumab participants were to be treated with open-label, fixed dose pembrolizumab 200 mg instead of a weight-based dosing of pembrolizumab.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Biological: Pembrolizumab Drug: Carboplatin Drug: Paclitaxel Drug: Dacarbazine Drug: Temozolomide	Phase 2

Detailed Description

Two interim and one final statistical analyses were planned for and conducted during this study:

Interim Analysis 1 (futility analysis),
Interim Analysis 2 (~18 months into study): database cutoff date 12-May-2014, and
Final Analysis (~36 months into study): database cutoff date 16-Nov-2015. The End of Trial Analysis for the study was conducted at ~75 months into the study: database cutoff date 31-Jan-2019.

Study Design

Study Type:

Interventional

Actual Enrollment :

540 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

Randomized, Phase II Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Patients With Advanced Melanoma (KEYNOTE 002)

Actual Study Start Date :

Nov 20, 2012

Actual Primary Completion Date :

Nov 16, 2015

Actual Study Completion Date :

Jan 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab 2 mg/kg Participants were initially randomized to receive pembrolizumab 2 mg/kg intravenously (IV) once every 3 weeks (Q3W). With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Biological: Pembrolizumab IV infusion Other Names: SCH 900475 MK-3475 KEYTRUDA®
Experimental: Pembrolizumab 10 mg/kg Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Biological: Pembrolizumab IV infusion Other Names: SCH 900475 MK-3475 KEYTRUDA®
Active Comparator: Investigator-Choice Chemotherapy (ICC) Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Drug: Carboplatin Carboplatin per institutional standard Other Names: PARAPLATIN® Drug: Paclitaxel Paclitaxel per institutional standard Other Names: TAXOL® Drug: Dacarbazine Dacarbazine per institutional standard Other Names: DTIC Drug: Temozolomide Temozolomide per institutional standard Other Names: TEMODAR®
Experimental: ICC→Pembrolizumab 2 mg/kg Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Biological: Pembrolizumab IV infusion Other Names: SCH 900475 MK-3475 KEYTRUDA® Drug: Carboplatin Carboplatin per institutional standard Other Names: PARAPLATIN® Drug: Paclitaxel Paclitaxel per institutional standard Other Names: TAXOL® Drug: Dacarbazine Dacarbazine per institutional standard Other Names: DTIC Drug: Temozolomide Temozolomide per institutional standard Other Names: TEMODAR®
Experimental: ICC→Pembrolizumab 10 mg/kg Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Biological: Pembrolizumab IV infusion Other Names: SCH 900475 MK-3475 KEYTRUDA® Drug: Carboplatin Carboplatin per institutional standard Other Names: PARAPLATIN® Drug: Paclitaxel Paclitaxel per institutional standard Other Names: TAXOL® Drug: Dacarbazine Dacarbazine per institutional standard Other Names: DTIC Drug: Temozolomide Temozolomide per institutional standard Other Names: TEMODAR®

Outcome Measures

Primary Outcome Measures

Progression-free Survival (PFS) - Initial Treatment Period [Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)]
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1), PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Analysis of PFS was based on an integrated radiology and oncology (IRO) assessment and was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median PFS based on the product limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for PFS.
Interim Overall Survival (OS) - Initial Treatment Period [Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)]
OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the interim analysis for OS.
Final Overall Survival (OS) - Initial Treatment Period [Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)]
OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for OS.

Secondary Outcome Measures

Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period [Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)]
OS was defined as the time from randomization to death due to any cause. Participants with an Allred Proportion Score (APS) ≥2 (membranous staining in ≥1% of cells for PD-L1) were considered to be PD-L1 Positive and participants with an APS of 0 or 1 were considered to be PD-L1 Negative. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data by PD-L1 tumor expression status is presented.
Overall Response Rate (ORR) - Initial Treatment Period [Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)]
ORR was defined as the percentage of participants 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) as assessed using RECIST 1.1. Analysis of ORR was not planned or conducted for the switch-to-pembrolizumab treatment groups. The percentage of participants who experienced a CR or PR is presented. This was the final analysis for ORR.
Best Overall Response (BOR) - Initial Treatment Period [Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)]
BOR was assessed by independent radiology review using RECIST 1.1 and was recorded from randomization until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. BOR for the Initial Treatment Period was based on IRO. BOR for participants during the Initial Treatment Period is presented.
Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period [Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)]
The BOR was assessed using RECIST 1.1 and was recorded from the start of the second line of study drug (pembrolizumab) until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For the switch-to-pembrolizumab treatment groups, BOR was based on independent review committee (IRC) assessment. The BOR for switched-to pembrolizumab treatment groups is presented.
Duration of Response (DOR) - Initial Treatment Period [Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)]
For participants who demonstrated a confirmed response (Complete Response [CR]: disappearance of all target lesions or Partial Response [PR]: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression 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. DOR analysis was based on IRO assessment. Analysis of DOR was not planned or analyzed for the switch-to-pembrolizumab treatment groups. Median DOR for participants who demonstrated a confirmed response is presented.
Number of Participants Who Experienced an Adverse Event (AE) - Overall Study [Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)]
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study drug, was also an AE. Participants were included in the treatment group in which an AE was experienced. The number of participants who experienced at least one AE is presented.
Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study [Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)]
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of study drug, was also an AE. The number of participants who discontinued study drug due to an AE is presented.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed diagnosis of unresectable Stage III or metastatic MEL not amenable to local therapy
Participants must be refractory to ipilimumab
Participants with BRAF gene mutant melanoma must have had a prior treatment regimen that included vemurafenib, dabrafenib, or an approved BRAF gene and/or mitogen-activated protein kinase (MEK) protein inhibitor
Must consent to allow correlative studies; must provide a newly obtained tissue/biopsy specimen (or specimen obtained within 60 days of consenting)
Radiographically measurable disease
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria:

Chemotherapy, radiation therapy, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or not recovered from the AEs due to cancer therapies administered more than 4 weeks earlier
Disease progression within 24 weeks of last dose of ipilimumab
Participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug
Expected to require any other form of systemic or localized antineoplastic therapy while on study
Chronic systemic steroid therapy within 2 weeks before the planned date for first dose randomized treatment or on any other form of immunosuppressive medication
Known history of any other than the current malignancy excepting adequately treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, breast cancer, or other in situ cancers
Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
Active autoimmune disease or a history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents
Prior treatment with any other anti-programmed cell death (PD) agent
Active infection requiring systemic therapy
Known history of Human Immunodeficiency Virus (HIV)
Active Hepatitis B or Hepatitis C
Regular user (including recreational use of) illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol)
Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study through 120 days after last dose of study drug

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)

None provided.

More Information

Additional Information:

Merck Oncology Clinical Trials Information

Publications

Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. doi: 10.1016/S1470-2045(15)00083-2. Epub 2015 Jun 23.

Responsible Party:

Merck Sharp & Dohme LLC

ClinicalTrials.gov Identifier:

NCT01704287

Other Study ID Numbers:

P08719
MK-3475-002
2012-003030-17
KEYNOTE-002
P08719

First Posted:

Oct 11, 2012

Last Update Posted:

May 18, 2020

Last Verified:

Apr 1, 2020

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:

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:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail	This end of trial analysis is based on a trial closure database cutoff date of 31-Jan-2019.

Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)	ICC→Pembrolizumab 2 mg/kg	ICC→Pembrolizumab 10 mg/kg
Arm/Group Description	Participants were initially randomized to receive pembrolizumab 2 mg/kg intravenously (IV) once every 3 weeks (Q3W). With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Period Title: Initial Treatment Period
STARTED	180	181	179	0	0
Treated	178	179	171	0	0
COMPLETED	33	47	6	0	0
NOT COMPLETED	147	134	173	0	0
Period Title: Initial Treatment Period
STARTED	0	0	0	53	45
COMPLETED	0	0	0	15	7
NOT COMPLETED	0	0	0	38	38

Baseline Characteristics

Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)	Total
Arm/Group Description	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Total of all reporting groups
Overall Participants	180	181	179	540
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.5 (14.9)	60.1 (13.3)	60.5 (12.7)	60.1 (13.6)
Sex: Female, Male (Count of Participants)
Female	76 42.2%	72 39.8%	65 36.3%	213 39.4%
Male	104 57.8%	109 60.2%	114 63.7%	327 60.6%
Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status (Count of Participants)
PD-L1 Positive	99 55%	97 53.6%	98 54.7%	294 54.4%
PD-L1 Negative	48 26.7%	46 25.4%	40 22.3%	134 24.8%
Unknown	33 18.3%	38 21%	41 22.9%	112 20.7%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) - Initial Treatment Period
Description	PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1), PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Analysis of PFS was based on an integrated radiology and oncology (IRO) assessment and was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median PFS based on the product limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for PFS.
Time Frame	Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)

Outcome Measure Data

Analysis Population Description
The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.

Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Measure Participants	180	181	179
Median (95% Confidence Interval) [Months]	2.9	3.0	2.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	Cox regression model with treatment as covariate stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1); lactate dehydrogenase (LDH) levels (normal vs. elevated LDH levels [≥110% Upper Limit of Normal (ULN)]); & BRAF mutational status (mutant vs. wild-type)

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	One-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95% 0.46 to 0.73
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 2 mg/kg Denominator=ICC

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	One-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95% 0.37 to 0.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=ICC

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)

Statistical Test of Hypothesis	p-Value	0.1247
	Comments	Two-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95% 0.66 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg

2. Primary Outcome

Title	Interim Overall Survival (OS) - Initial Treatment Period
Description	OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the interim analysis for OS.
Time Frame	Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)

Outcome Measure Data

Analysis Population Description
The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.

Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Measure Participants	180	181	179
Median (95% Confidence Interval) [Months]	13.4	14.7	11.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.1173
	Comments	One-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95% 0.67 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 2 mg/kg Denominator=ICC

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0106
	Comments	One-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95% 0.57 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=ICC

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.2905
	Comments	Two-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95% 0.67 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg

3. Primary Outcome

Title	Final Overall Survival (OS) - Initial Treatment Period
Description	OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for OS.
Time Frame	Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)

Outcome Measure Data

Analysis Population Description
The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.

Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Measure Participants	180	181	179
Median (95% Confidence Interval) [Months]	13.4	14.7	11.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.1146
	Comments	One-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95% 0.68 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 2 mg/kg Denominator=ICC

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0023
	Comments	One-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95% 0.55 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=ICC

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.1490
	Comments	Two-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95% 0.66 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg

4. Secondary Outcome

Title	Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period
Description	OS was defined as the time from randomization to death due to any cause. Participants with an Allred Proportion Score (APS) ≥2 (membranous staining in ≥1% of cells for PD-L1) were considered to be PD-L1 Positive and participants with an APS of 0 or 1 were considered to be PD-L1 Negative. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data by PD-L1 tumor expression status is presented.
Time Frame	Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)

Outcome Measure Data

Analysis Population Description
The analysis population consisted of all randomized participants who had a PD-L1 tumor expression status assessment. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.

Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Measure Participants	180	181	179
PD-L1 Positive	15.0	17.5	12.1
PD-L1 Negative	10.5	13.4	9.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	PD-L1-Positive Participants

Statistical Test of Hypothesis	p-Value	0.3113
	Comments	One-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95% 0.66 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 2 mg/kg Denominator=ICC

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	PD-L1 Positive Participants

Statistical Test of Hypothesis	p-Value	0.0208
	Comments	One-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95% 0.50 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=ICC

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	PD-L1 Positive Participants

Statistical Test of Hypothesis	p-Value	0.0496
	Comments	Two-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95% 0.50 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	PD-L1 Negative Participants

Statistical Test of Hypothesis	p-Value	0.6043
	Comments	One-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95% 0.65 to 1.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 2 mg/kg Denominator=ICC

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 10 mg/kg, Investigator-Choice Chemotherapy (ICC)
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	PD-L1 Negative Participants

Statistical Test of Hypothesis	p-Value	0.0335
	Comments	One-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95% 0.37 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=ICC

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg
	Comments	Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [≥110% ULN]); & BRAF mutational status (mutant vs. wild-type)
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	PD-L1 Negative Participants

Statistical Test of Hypothesis	p-Value	0.1504
	Comments	Two-sided p-value based on stratified log rank test
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95% 0.44 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg

5. Secondary Outcome

Title	Overall Response Rate (ORR) - Initial Treatment Period
Description	ORR was defined as the percentage of participants 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) as assessed using RECIST 1.1. Analysis of ORR was not planned or conducted for the switch-to-pembrolizumab treatment groups. The percentage of participants who experienced a CR or PR is presented. This was the final analysis for ORR.
Time Frame	Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)

Outcome Measure Data

Analysis Population Description
The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.

Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Measure Participants	180	181	179
Number (95% Confidence Interval) [Percentage of Participants]	22.2 12.3%	27.6 15.2%	4.5 2.5%

6. Secondary Outcome

Title	Best Overall Response (BOR) - Initial Treatment Period
Description	BOR was assessed by independent radiology review using RECIST 1.1 and was recorded from randomization until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. BOR for the Initial Treatment Period was based on IRO. BOR for participants during the Initial Treatment Period is presented.
Time Frame	Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)

Outcome Measure Data

Analysis Population Description
The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.

Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Measure Participants	180	181	179
Complete Response	3.3 1.8%	7.2 4%	0.0 0%
Partial Response	18.9 10.5%	20.4 11.3%	4.5 2.5%
Stable Disease	16.7 9.3%	14.9 8.2%	19.0 10.6%
Progressive Disease	46.7 25.9%	47.5 26.2%	61.5 34.4%
Not Evaluable	13.3 7.4%	9.9 5.5%	15.1 8.4%
No Disease	0.6 0.3%	0.0 0%	0.0 0%
No Assessment	0.6 0.3%	0.0 0%	0.0 0%

7. Secondary Outcome

Title	Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period
Description	The BOR was assessed using RECIST 1.1 and was recorded from the start of the second line of study drug (pembrolizumab) until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For the switch-to-pembrolizumab treatment groups, BOR was based on independent review committee (IRC) assessment. The BOR for switched-to pembrolizumab treatment groups is presented.
Time Frame	Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)

Outcome Measure Data

Analysis Population Description
The analysis population consisted of all randomized participants in ICC who switched to receiving pembrolizumab. Participants were included in the treatment group to which they were re-randomized (switched) for this efficacy analysis.

Arm/Group Title	ICC→Pembrolizumab 2 mg/kg	ICC→Pembrolizumab 10 mg/kg
Arm/Group Description	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Measure Participants	53	45
Complete Response	1.9 1.1%	4.4 2.4%
Partial Response	17.0 9.4%	13.3 7.3%
Stable Disease	15.1 8.4%	11.1 6.1%
Progressive Disease	54.7 30.4%	55.6 30.7%
Not Evaluable	11.3 6.3%	13.3 7.3%
No Assessment	0.0 0%	2.2 1.2%

8. Secondary Outcome

Title	Duration of Response (DOR) - Initial Treatment Period
Description	For participants who demonstrated a confirmed response (Complete Response [CR]: disappearance of all target lesions or Partial Response [PR]: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression 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. DOR analysis was based on IRO assessment. Analysis of DOR was not planned or analyzed for the switch-to-pembrolizumab treatment groups. Median DOR for participants who demonstrated a confirmed response is presented.
Time Frame	Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)

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. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.

Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	Investigator-Choice Chemotherapy (ICC)
Arm/Group Description	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
Measure Participants	40	50	8
Median (Full Range) [Months]	22.8	NA	6.8

9. Secondary Outcome

Title	Number of Participants Who Experienced an Adverse Event (AE) - Overall Study
Description	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study drug, was also an AE. Participants were included in the treatment group in which an AE was experienced. The number of participants who experienced at least one AE is presented.
Time Frame	Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)

Outcome Measure Data

Analysis Population Description
The analysis population consisted of all participants who received at least one dose of study drug.

Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	ICC Only	ICC→Pembrolizumab 2 mg/kg	ICC→Pembrolizumab 10 mg/kg	ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)	ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
Arm/Group Description	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). This treatment group included the participants who remained on ICC through the database cutoff date. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Measure Participants	178	179	73	53	45	53	45
Count of Participants [Participants]	172 95.6%	179 98.9%	71 39.7%	52 9.6%	45 NaN	53 NaN	41 NaN

10. Secondary Outcome

Title	Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study
Description	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of study drug, was also an AE. The number of participants who discontinued study drug due to an AE is presented.
Time Frame	Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)

Outcome Measure Data

Analysis Population Description
The analysis population consisted of all participants who received at least one dose of study drug.

Arm/Group Title	Pembrolizumab 2 mg/kg	Pembrolizumab 10 mg/kg	ICC Only	ICC→Pembrolizumab 2 mg/kg	ICC→Pembrolizumab 10 mg/kg	ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)	ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
Arm/Group Description	Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants were randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). This treatment group included the participants who remained on ICC through the database cutoff date. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)	Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
Measure Participants	178	179	73	53	45	53	45
Count of Participants [Participants]	29 16.1%	33 18.2%	13 7.3%	1 0.2%	1 NaN	4 NaN	4 NaN

Adverse Events

	Investigator-Choice Chemotherapy (ICC) Only		ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab)		Pembrolizumab 2 mg/kg		Pembrolizumab 10 mg/kg		ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
Time Frame	Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
Adverse Event Reporting Description	Safety Population: All participants who received ≥1 dose of study drug. Per protocol, disease progression of cancer under study was not considered an AE unless considered related to study drug. Therefore, Medical Dictionary for Regulatory Activities (MedDRA) preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.

Arm/Group Title	Investigator-Choice Chemotherapy (ICC) Only		ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab)		Pembrolizumab 2 mg/kg		Pembrolizumab 10 mg/kg		ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
Arm/Group Description	Participants received 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). This treatment group included the participants who remained on ICC through the final analysis. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)		Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)		Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)		Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)		Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)		Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)		Participants who were initiall randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/73 (97.3%)		0/53 (0%)		0/45 (0%)		139/178 (78.1%)		129/179 (72.1%)		35/53 (66%)		37/45 (82.2%)
Serious Adverse Events
	Investigator-Choice Chemotherapy (ICC) Only		ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab)		Pembrolizumab 2 mg/kg		Pembrolizumab 10 mg/kg		ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/73 (45.2%)		15/53 (28.3%)		9/45 (20%)		91/178 (51.1%)		78/179 (43.6%)		18/53 (34%)		18/45 (40%)
Blood and lymphatic system disorders
Anaemia	3/73 (4.1%)	3	1/53 (1.9%)	1	0/45 (0%)	0	7/178 (3.9%)	7	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Febrile neutropenia	2/73 (2.7%)	2	1/53 (1.9%)	1	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Leukopenia	1/73 (1.4%)	2	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Neutropenia	1/73 (1.4%)	2	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Thrombocytopenia	2/73 (2.7%)	2	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Cardiac disorders
Atrial fibrillation	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Atrioventricular block complete	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Cardiac failure	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Cardiac ventricular disorder	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Cardiogenic shock	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Myocardial infarction	0/73 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Pericardial effusion	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Ear and labyrinth disorders
Vertigo positional	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Endocrine disorders
Adrenal insufficiency	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Addison's disease	0/73 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Adrenocortical insufficiency acute	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Hyperparathyroidism	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Hypophysitis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Hypopituitarism	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	2/179 (1.1%)	2	0/53 (0%)	0	0/45 (0%)	0
Secondary adrenocortical insufficiency	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Inappropriate antidiuretic hormone secretion	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Eye disorders
Eye movement disorder	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Iritis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Gastrointestinal disorders
Colitis	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	1/179 (0.6%)	1	0/53 (0%)	0	1/45 (2.2%)	1
Diarrhoea	0/73 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1	1/178 (0.6%)	1	4/179 (2.2%)	4	1/53 (1.9%)	1	1/45 (2.2%)	1
Dysphagia	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Pancreatitis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	1/179 (0.6%)	2	1/53 (1.9%)	1	0/45 (0%)	0
Rectal haemorrhage	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Small intestinal obstruction	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	1/45 (2.2%)	1
Abdominal pain	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	4/179 (2.2%)	4	0/53 (0%)	0	0/45 (0%)	0
Ascites	0/73 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Autoimmune colitis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Constipation	0/73 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0	2/178 (1.1%)	2	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Diverticular perforation	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Diverticulum	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Gastric disorder	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Gastrointestinal disorder	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Gastrointestinal pain	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Haematemesis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Haematochezia	0/73 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Ileus	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	2/179 (1.1%)	2	0/53 (0%)	0	0/45 (0%)	0
Intestinal obstruction	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Intussusception	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Large intestinal ulcer	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Large intestine perforation	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Malabsorption	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Nausea	3/73 (4.1%)	3	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Small intestinal perforation	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Upper gastrointestinal haemorrhage	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Vomiting	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	2/178 (1.1%)	2	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Gastritis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Lower gastrointestinal haemorrhage	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	2/45 (4.4%)	2
Gastrointestinal haemorrhage	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
General disorders
Generalised oedema	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	3/178 (1.7%)	3	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Asthenia	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Chest pain	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	2/178 (1.1%)	2	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Cyst	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Death	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	2/178 (1.1%)	2	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Fatigue	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Gait disturbance	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
General physical health deterioration	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	6/179 (3.4%)	6	0/53 (0%)	0	0/45 (0%)	0
Infusion site extravasation	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Malaise	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Oedema	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Pyrexia	1/73 (1.4%)	1	0/53 (0%)	0	1/45 (2.2%)	1	3/178 (1.7%)	4	4/179 (2.2%)	5	0/53 (0%)	0	0/45 (0%)	0
Hepatobiliary disorders
Autoimmune hepatitis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Cholangitis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Cholecystitis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	3/178 (1.7%)	3	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Hepatic failure	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Hepatic necrosis	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Hyperbilirubinaemia	0/73 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Bile duct obstruction	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Immune system disorders
Anaphylactic reaction	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Hypersensitivity	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Cytokine release syndrome	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Infections and infestations
Clostridium difficile colitis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Diverticulitis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	2	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Pneumonia	3/73 (4.1%)	3	0/53 (0%)	0	2/45 (4.4%)	2	2/178 (1.1%)	2	3/179 (1.7%)	5	3/53 (5.7%)	3	1/45 (2.2%)	1
Sepsis	2/73 (2.7%)	2	1/53 (1.9%)	1	0/45 (0%)	0	1/178 (0.6%)	1	1/179 (0.6%)	1	0/53 (0%)	0	1/45 (2.2%)	1
Wound infection	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Appendicitis perforated	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Bacteraemia	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Bronchitis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	2/178 (1.1%)	2	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Candida infection	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Cellulitis	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Cellulitis streptococcal	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Enterocolitis infectious	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Erysipelas	1/73 (1.4%)	1	1/53 (1.9%)	1	0/45 (0%)	0	2/178 (1.1%)	2	2/179 (1.1%)	2	0/53 (0%)	0	0/45 (0%)	0
Gastroenteritis viral	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Herpes zoster	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Infected cyst	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Infection	2/73 (2.7%)	2	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Infectious pleural effusion	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	2	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Influenza	0/73 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Mastitis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Osteomyelitis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Pelvic abscess	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Respiratory syncytial virus infection	0/73 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Salmonellosis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Septic shock	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Skin infection	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	2/178 (1.1%)	2	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Soft tissue infection	0/73 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Streptococcal sepsis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Urinary tract infection	2/73 (2.7%)	2	0/53 (0%)	0	0/45 (0%)	0	2/178 (1.1%)	2	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Viral infection	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Viral rash	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Viral upper respiratory tract infection	0/73 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Abdominal abscess	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Lung infection	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Postoperative wound infection	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Urosepsis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Injury, poisoning and procedural complications
Fall	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Femur fracture	0/73 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Fracture displacement	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Hip fracture	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Limb injury	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Lower limb fracture	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Radiation necrosis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Rib fracture	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Spinal fracture	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Traumatic intracranial haemorrhage	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Accidental overdose	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Investigations
Alanine aminotransferase increased	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Aspartate aminotransferase increased	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Hepatic enzyme increased	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Neutrophil count decreased	1/73 (1.4%)	2	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Platelet count decreased	2/73 (2.7%)	2	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
White blood cell count decreased	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Metabolism and nutrition disorders
Cachexia	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Dehydration	1/73 (1.4%)	1	1/53 (1.9%)	1	0/45 (0%)	0	4/178 (2.2%)	4	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Diabetic metabolic decompensation	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Hypercalcaemia	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Hypocalcaemia	0/73 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Hyponatraemia	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	3/179 (1.7%)	3	0/53 (0%)	0	0/45 (0%)	0
Hyperglycaemia	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Type 1 diabetes mellitus	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	2/179 (1.1%)	2	0/53 (0%)	0	1/45 (2.2%)	1
Pain in extremity	0/73 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Back pain	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	2/179 (1.1%)	2	0/53 (0%)	0	0/45 (0%)	0
Groin pain	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Musculoskeletal pain	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Neck pain	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Osteoarthritis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Osteolysis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Spondylolisthesis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Cervical spine stenosis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intracranial tumour haemorrhage	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Metastases to central nervous system	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	3/178 (1.7%)	3	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Tumour pain	0/73 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1	1/178 (0.6%)	1	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Basal cell carcinoma	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	2/178 (1.1%)	3	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Cancer pain	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Colon cancer metastatic	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Intestinal metastasis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Invasive ductal breast carcinoma	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Metastases to lymph nodes	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Metastases to meninges	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Metastasis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Oncologic complication	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Prostate cancer	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Rectal cancer	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Small cell carcinoma	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Squamous cell carcinoma	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Squamous cell carcinoma of skin	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	1/179 (0.6%)	3	0/53 (0%)	0	0/45 (0%)	0
Tumour haemorrhage	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Nervous system disorders
Dizziness	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	1/53 (1.9%)	1	0/45 (0%)	0
Hemiparesis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	1/45 (2.2%)	1
Seizure	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	1/53 (1.9%)	1	2/45 (4.4%)	2
Syncope	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	2/178 (1.1%)	2	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Aphasia	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Ataxia	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Brain oedema	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Cerebrovascular accident	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Encephalopathy	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Epilepsy	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	2/178 (1.1%)	2	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Haemorrhage intracranial	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Hemiplegia	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Lumbar radiculopathy	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Meningitis noninfective	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Myasthenic syndrome	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Myoclonus	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Neuropathy peripheral	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Paraesthesia	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Partial seizures	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	2/178 (1.1%)	2	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Presyncope	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Sciatica	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Spinal cord compression	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Transient ischaemic attack	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Peripheral motor neuropathy	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Product Issues
Device dislocation	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Psychiatric disorders
Confusional state	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	2/178 (1.1%)	2	3/179 (1.7%)	3	1/53 (1.9%)	1	0/45 (0%)	0
Delirium	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Mental status changes	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/73 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0	1/178 (0.6%)	1	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Hydronephrosis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Postrenal failure	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Renal failure	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	2	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Tubulointerstitial nephritis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Urinary tract obstruction	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Renal impairment	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Reproductive system and breast disorders
Pelvic pain	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/73 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0	2/178 (1.1%)	2	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Dyspnoea	3/73 (4.1%)	3	0/53 (0%)	0	1/45 (2.2%)	1	2/178 (1.1%)	2	5/179 (2.8%)	5	1/53 (1.9%)	1	0/45 (0%)	0
Pleural effusion	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	1/179 (0.6%)	1	0/53 (0%)	0	1/45 (2.2%)	1
Pulmonary embolism	2/73 (2.7%)	2	2/53 (3.8%)	2	0/45 (0%)	0	2/178 (1.1%)	2	1/179 (0.6%)	1	1/53 (1.9%)	1	0/45 (0%)	0
Cough	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Dyspnoea exertional	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Epistaxis	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Haemoptysis	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	2	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Hypoxia	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Interstitial lung disease	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Laryngeal inflammation	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Pneumonia aspiration	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Pneumonitis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	3/179 (1.7%)	3	0/53 (0%)	0	0/45 (0%)	0
Pneumothorax	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Pulmonary thrombosis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Acute respiratory failure	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Alveolitis allergic	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Skin and subcutaneous tissue disorders
Lichenoid keratosis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Rash maculo-papular	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Skin mass	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Stevens-Johnson syndrome	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Purpura	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Vascular disorders
Hypotension	0/73 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0
Circulatory collapse	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Deep vein thrombosis	0/73 (0%)	0	1/53 (1.9%)	1	0/45 (0%)	0	1/178 (0.6%)	1	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Lymphoedema	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Orthostatic hypotension	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Phlebitis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Poor venous access	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	1/178 (0.6%)	1	0/179 (0%)	0	0/53 (0%)	0	0/45 (0%)	0
Venous thrombosis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	1/179 (0.6%)	1	0/53 (0%)	0	0/45 (0%)	0
Thrombosis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1
Other (Not Including Serious) Adverse Events
	Investigator-Choice Chemotherapy (ICC) Only		ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab)		Pembrolizumab 2 mg/kg		Pembrolizumab 10 mg/kg		ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)		ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/73 (90.4%)		52/53 (98.1%)		44/45 (97.8%)		158/178 (88.8%)		176/179 (98.3%)		48/53 (90.6%)		36/45 (80%)
Blood and lymphatic system disorders
Anaemia	21/73 (28.8%)	26	15/53 (28.3%)	25	10/45 (22.2%)	10	30/178 (16.9%)	43	26/179 (14.5%)	31	12/53 (22.6%)	13	8/45 (17.8%)	21
Leukopenia	8/73 (11%)	8	3/53 (5.7%)	6	4/45 (8.9%)	7	0/178 (0%)	0	2/179 (1.1%)	3	0/53 (0%)	0	0/45 (0%)	0
Neutropenia	2/73 (2.7%)	2	7/53 (13.2%)	14	5/45 (11.1%)	8	1/178 (0.6%)	1	2/179 (1.1%)	4	0/53 (0%)	0	0/45 (0%)	0
Thrombocytopenia	9/73 (12.3%)	12	7/53 (13.2%)	10	2/45 (4.4%)	2	3/178 (1.7%)	5	3/179 (1.7%)	5	0/53 (0%)	0	0/45 (0%)	0
Cardiac disorders
Tachycardia	4/73 (5.5%)	4	2/53 (3.8%)	3	0/45 (0%)	0	3/178 (1.7%)	4	7/179 (3.9%)	7	0/53 (0%)	0	0/45 (0%)	0
Ear and labyrinth disorders
Vertigo	3/73 (4.1%)	3	1/53 (1.9%)	1	0/45 (0%)	0	4/178 (2.2%)	8	10/179 (5.6%)	11	0/53 (0%)	0	0/45 (0%)	0
Endocrine disorders
Hypothyroidism	0/73 (0%)	0	0/53 (0%)	0	1/45 (2.2%)	1	16/178 (9%)	17	15/179 (8.4%)	16	4/53 (7.5%)	4	3/45 (6.7%)	3
Eye disorders
Dry eye	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	3/53 (5.7%)	3	0/45 (0%)	0
Gastrointestinal disorders
Abdominal pain	8/73 (11%)	10	1/53 (1.9%)	2	4/45 (8.9%)	4	28/178 (15.7%)	38	27/179 (15.1%)	33	7/53 (13.2%)	7	2/45 (4.4%)	3
Constipation	16/73 (21.9%)	19	12/53 (22.6%)	17	8/45 (17.8%)	10	40/178 (22.5%)	47	42/179 (23.5%)	57	12/53 (22.6%)	14	6/45 (13.3%)	6
Diarrhoea	13/73 (17.8%)	20	11/53 (20.8%)	17	11/45 (24.4%)	17	40/178 (22.5%)	52	41/179 (22.9%)	67	16/53 (30.2%)	23	9/45 (20%)	22
Dyspepsia	2/73 (2.7%)	2	2/53 (3.8%)	3	3/45 (6.7%)	3	3/178 (1.7%)	3	4/179 (2.2%)	5	4/53 (7.5%)	4	2/45 (4.4%)	2
Nausea	23/73 (31.5%)	30	29/53 (54.7%)	44	19/45 (42.2%)	23	44/178 (24.7%)	74	49/179 (27.4%)	56	12/53 (22.6%)	12	10/45 (22.2%)	17
Vomiting	17/73 (23.3%)	22	10/53 (18.9%)	14	13/45 (28.9%)	14	19/178 (10.7%)	26	38/179 (21.2%)	58	6/53 (11.3%)	7	2/45 (4.4%)	2
Abdominal distension	1/73 (1.4%)	1	3/53 (5.7%)	3	0/45 (0%)	0	11/178 (6.2%)	13	9/179 (5%)	10	0/53 (0%)	0	0/45 (0%)	0
Abdominal pain upper	2/73 (2.7%)	2	0/53 (0%)	0	2/45 (4.4%)	2	6/178 (3.4%)	6	12/179 (6.7%)	12	0/53 (0%)	0	0/45 (0%)	0
Dry mouth	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	9/178 (5.1%)	11	7/179 (3.9%)	10	0/53 (0%)	0	0/45 (0%)	0
Dysphagia	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	3/53 (5.7%)	4	0/45 (0%)	0
General disorders
Asthenia	10/73 (13.7%)	11	4/53 (7.5%)	4	2/45 (4.4%)	2	19/178 (10.7%)	25	20/179 (11.2%)	44	2/53 (3.8%)	2	3/45 (6.7%)	3
Fatigue	28/73 (38.4%)	34	27/53 (50.9%)	36	26/45 (57.8%)	33	74/178 (41.6%)	106	91/179 (50.8%)	117	15/53 (28.3%)	17	16/45 (35.6%)	24
Influenza like illness	1/73 (1.4%)	2	1/53 (1.9%)	1	1/45 (2.2%)	1	9/178 (5.1%)	13	14/179 (7.8%)	17	4/53 (7.5%)	4	3/45 (6.7%)	6
Oedema peripheral	4/73 (5.5%)	4	5/53 (9.4%)	5	1/45 (2.2%)	1	17/178 (9.6%)	19	21/179 (11.7%)	24	6/53 (11.3%)	7	2/45 (4.4%)	2
Pain	0/73 (0%)	0	4/53 (7.5%)	5	1/45 (2.2%)	1	6/178 (3.4%)	7	7/179 (3.9%)	7	3/53 (5.7%)	3	0/45 (0%)	0
Pyrexia	7/73 (9.6%)	7	5/53 (9.4%)	7	5/45 (11.1%)	6	23/178 (12.9%)	33	30/179 (16.8%)	43	3/53 (5.7%)	4	8/45 (17.8%)	8
Chest pain	3/73 (4.1%)	3	3/53 (5.7%)	4	1/45 (2.2%)	1	7/178 (3.9%)	8	11/179 (6.1%)	15	0/53 (0%)	0	0/45 (0%)	0
Chills	0/73 (0%)	0	3/53 (5.7%)	3	5/45 (11.1%)	5	10/178 (5.6%)	11	11/179 (6.1%)	13	0/53 (0%)	0	0/45 (0%)	0
Malaise	0/73 (0%)	0	3/53 (5.7%)	3	0/45 (0%)	0	7/178 (3.9%)	9	2/179 (1.1%)	2	0/53 (0%)	0	0/45 (0%)	0
Infections and infestations
Nasopharyngitis	2/73 (2.7%)	2	4/53 (7.5%)	4	1/45 (2.2%)	1	10/178 (5.6%)	11	20/179 (11.2%)	36	4/53 (7.5%)	9	0/45 (0%)	0
Upper respiratory tract infection	1/73 (1.4%)	1	1/53 (1.9%)	2	2/45 (4.4%)	2	8/178 (4.5%)	12	18/179 (10.1%)	25	5/53 (9.4%)	6	3/45 (6.7%)	3
Urinary tract infection	5/73 (6.8%)	5	2/53 (3.8%)	2	2/45 (4.4%)	2	17/178 (9.6%)	19	17/179 (9.5%)	23	8/53 (15.1%)	8	2/45 (4.4%)	2
Oral herpes	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	3/53 (5.7%)	3	1/45 (2.2%)	1
Investigations
Alanine aminotransferase increased	0/73 (0%)	0	2/53 (3.8%)	2	3/45 (6.7%)	4	9/178 (5.1%)	10	13/179 (7.3%)	18	3/53 (5.7%)	4	2/45 (4.4%)	4
Aspartate aminotransferase increased	0/73 (0%)	0	1/53 (1.9%)	2	1/45 (2.2%)	1	11/178 (6.2%)	11	14/179 (7.8%)	17	3/53 (5.7%)	4	1/45 (2.2%)	1
Blood alkaline phosphatase increased	2/73 (2.7%)	2	1/53 (1.9%)	1	2/45 (4.4%)	2	12/178 (6.7%)	13	10/179 (5.6%)	16	4/53 (7.5%)	4	2/45 (4.4%)	2
Weight decreased	1/73 (1.4%)	1	4/53 (7.5%)	5	3/45 (6.7%)	3	12/178 (6.7%)	12	17/179 (9.5%)	17	4/53 (7.5%)	5	1/45 (2.2%)	1
Blood bilirubin increased	1/73 (1.4%)	1	3/53 (5.7%)	3	0/45 (0%)	0	6/178 (3.4%)	11	2/179 (1.1%)	5	0/53 (0%)	0	0/45 (0%)	0
Blood cholesterol increased	0/73 (0%)	0	2/53 (3.8%)	2	3/45 (6.7%)	3	5/178 (2.8%)	9	7/179 (3.9%)	14	0/53 (0%)	0	0/45 (0%)	0
Lymphocyte count decreased	4/73 (5.5%)	4	3/53 (5.7%)	4	2/45 (4.4%)	2	6/178 (3.4%)	17	7/179 (3.9%)	8	0/53 (0%)	0	0/45 (0%)	0
Neutrophil count decreased	3/73 (4.1%)	3	3/53 (5.7%)	4	4/45 (8.9%)	5	2/178 (1.1%)	10	1/179 (0.6%)	5	0/53 (0%)	0	0/45 (0%)	0
Platelet count decreased	5/73 (6.8%)	7	4/53 (7.5%)	9	5/45 (11.1%)	8	2/178 (1.1%)	9	5/179 (2.8%)	9	0/53 (0%)	0	0/45 (0%)	0
White blood cell count decreased	5/73 (6.8%)	6	3/53 (5.7%)	3	3/45 (6.7%)	3	4/178 (2.2%)	12	3/179 (1.7%)	3	0/53 (0%)	0	0/45 (0%)	0
Blood creatinine increased	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	3/53 (5.7%)	7	2/45 (4.4%)	2
Lipase increased	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	3/53 (5.7%)	3	1/45 (2.2%)	1
Metabolism and nutrition disorders
Decreased appetite	20/73 (27.4%)	21	8/53 (15.1%)	10	11/45 (24.4%)	12	36/178 (20.2%)	43	51/179 (28.5%)	55	9/53 (17%)	9	8/45 (17.8%)	8
Hyperglycaemia	2/73 (2.7%)	2	5/53 (9.4%)	9	3/45 (6.7%)	3	12/178 (6.7%)	21	11/179 (6.1%)	21	3/53 (5.7%)	7	1/45 (2.2%)	3
Hypokalaemia	3/73 (4.1%)	3	4/53 (7.5%)	5	3/45 (6.7%)	3	9/178 (5.1%)	9	8/179 (4.5%)	10	4/53 (7.5%)	7	3/45 (6.7%)	3
Hyponatraemia	4/73 (5.5%)	6	3/53 (5.7%)	3	2/45 (4.4%)	3	19/178 (10.7%)	28	10/179 (5.6%)	11	6/53 (11.3%)	11	3/45 (6.7%)	4
Dehydration	2/73 (2.7%)	3	3/53 (5.7%)	7	3/45 (6.7%)	4	7/178 (3.9%)	15	6/179 (3.4%)	7	0/53 (0%)	0	0/45 (0%)	0
Hypertriglyceridaemia	0/73 (0%)	0	4/53 (7.5%)	5	5/45 (11.1%)	7	7/178 (3.9%)	18	10/179 (5.6%)	25	0/53 (0%)	0	0/45 (0%)	0
Hypoalbuminaemia	5/73 (6.8%)	5	3/53 (5.7%)	4	2/45 (4.4%)	2	5/178 (2.8%)	6	12/179 (6.7%)	13	0/53 (0%)	0	0/45 (0%)	0
Hyperkalaemia	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	4/53 (7.5%)	4	0/45 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	5/73 (6.8%)	6	6/53 (11.3%)	7	7/45 (15.6%)	9	36/178 (20.2%)	52	24/179 (13.4%)	37	9/53 (17%)	13	8/45 (17.8%)	9
Back pain	8/73 (11%)	10	5/53 (9.4%)	5	6/45 (13.3%)	6	24/178 (13.5%)	31	21/179 (11.7%)	27	3/53 (5.7%)	3	2/45 (4.4%)	2
Musculoskeletal pain	3/73 (4.1%)	3	4/53 (7.5%)	4	1/45 (2.2%)	1	18/178 (10.1%)	20	15/179 (8.4%)	15	4/53 (7.5%)	5	2/45 (4.4%)	2
Myalgia	3/73 (4.1%)	3	4/53 (7.5%)	4	4/45 (8.9%)	7	19/178 (10.7%)	23	14/179 (7.8%)	15	3/53 (5.7%)	3	3/45 (6.7%)	3
Pain in extremity	2/73 (2.7%)	2	6/53 (11.3%)	6	5/45 (11.1%)	5	18/178 (10.1%)	25	19/179 (10.6%)	25	4/53 (7.5%)	4	1/45 (2.2%)	4
Bone pain	1/73 (1.4%)	1	2/53 (3.8%)	10	3/45 (6.7%)	3	2/178 (1.1%)	2	8/179 (4.5%)	8	0/53 (0%)	0	0/45 (0%)	0
Muscular weakness	3/73 (4.1%)	3	5/53 (9.4%)	6	2/45 (4.4%)	3	5/178 (2.8%)	5	9/179 (5%)	11	0/53 (0%)	0	0/45 (0%)	0
Muscle spasms	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	1/53 (1.9%)	1	3/45 (6.7%)	6
Neck pain	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	5/53 (9.4%)	5	1/45 (2.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	4/73 (5.5%)	4	4/53 (7.5%)	4	3/45 (6.7%)	3	2/178 (1.1%)	2	8/179 (4.5%)	8	0/53 (0%)	0	0/45 (0%)	0
Melanocytic naevus	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	3/53 (5.7%)	5	0/45 (0%)	0
Nervous system disorders
Dizziness	9/73 (12.3%)	9	4/53 (7.5%)	4	3/45 (6.7%)	3	19/178 (10.7%)	25	18/179 (10.1%)	27	3/53 (5.7%)	4	7/45 (15.6%)	7
Headache	8/73 (11%)	8	9/53 (17%)	11	7/45 (15.6%)	10	21/178 (11.8%)	33	30/179 (16.8%)	45	8/53 (15.1%)	11	6/45 (13.3%)	10
Dysgeusia	2/73 (2.7%)	2	5/53 (9.4%)	5	4/45 (8.9%)	4	3/178 (1.7%)	3	2/179 (1.1%)	2	0/53 (0%)	0	0/45 (0%)	0
Neuropathy peripheral	6/73 (8.2%)	6	7/53 (13.2%)	7	5/45 (11.1%)	7	4/178 (2.2%)	4	3/179 (1.7%)	3	0/53 (0%)	0	0/45 (0%)	0
Paraesthesia	3/73 (4.1%)	3	5/53 (9.4%)	6	3/45 (6.7%)	3	4/178 (2.2%)	4	4/179 (2.2%)	4	0/53 (0%)	0	0/45 (0%)	0
Peripheral sensory neuropathy	1/73 (1.4%)	1	2/53 (3.8%)	2	3/45 (6.7%)	3	1/178 (0.6%)	1	2/179 (1.1%)	2	0/53 (0%)	0	0/45 (0%)	0
Tremor	0/73 (0%)	0	1/53 (1.9%)	1	3/45 (6.7%)	3	3/178 (1.7%)	3	5/179 (2.8%)	5	0/53 (0%)	0	0/45 (0%)	0
Psychiatric disorders
Anxiety	4/73 (5.5%)	6	4/53 (7.5%)	4	1/45 (2.2%)	1	10/178 (5.6%)	10	8/179 (4.5%)	8	3/53 (5.7%)	3	1/45 (2.2%)	1
Insomnia	8/73 (11%)	8	2/53 (3.8%)	2	3/45 (6.7%)	3	9/178 (5.1%)	10	11/179 (6.1%)	12	3/53 (5.7%)	3	1/45 (2.2%)	1
Depression	4/73 (5.5%)	4	4/53 (7.5%)	4	1/45 (2.2%)	1	7/178 (3.9%)	7	12/179 (6.7%)	13	0/53 (0%)	0	0/45 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	9/73 (12.3%)	9	13/53 (24.5%)	13	6/45 (13.3%)	8	37/178 (20.8%)	50	42/179 (23.5%)	50	7/53 (13.2%)	7	5/45 (11.1%)	6
Dyspnoea	9/73 (12.3%)	10	10/53 (18.9%)	10	1/45 (2.2%)	1	18/178 (10.1%)	20	29/179 (16.2%)	33	7/53 (13.2%)	7	4/45 (8.9%)	4
Pleural effusion	4/73 (5.5%)	4	1/53 (1.9%)	1	0/45 (0%)	0	3/178 (1.7%)	3	3/179 (1.7%)	3	4/53 (7.5%)	4	1/45 (2.2%)	1
Skin and subcutaneous tissue disorders
Night sweats	2/73 (2.7%)	2	4/53 (7.5%)	5	3/45 (6.7%)	4	4/178 (2.2%)	4	10/179 (5.6%)	11	1/53 (1.9%)	1	4/45 (8.9%)	4
Pruritus	5/73 (6.8%)	6	4/53 (7.5%)	4	6/45 (13.3%)	6	49/178 (27.5%)	77	57/179 (31.8%)	74	6/53 (11.3%)	7	5/45 (11.1%)	5
Rash	6/73 (8.2%)	7	4/53 (7.5%)	5	3/45 (6.7%)	3	29/178 (16.3%)	38	33/179 (18.4%)	49	11/53 (20.8%)	15	7/45 (15.6%)	9
Rash maculo-papular	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	10/178 (5.6%)	11	18/179 (10.1%)	23	3/53 (5.7%)	4	1/45 (2.2%)	1
Alopecia	10/73 (13.7%)	10	15/53 (28.3%)	18	11/45 (24.4%)	11	7/178 (3.9%)	8	2/179 (1.1%)	4	0/53 (0%)	0	0/45 (0%)	0
Dry skin	4/73 (5.5%)	4	1/53 (1.9%)	1	0/45 (0%)	0	18/178 (10.1%)	24	18/179 (10.1%)	18	0/53 (0%)	0	0/45 (0%)	0
Erythema	2/73 (2.7%)	2	2/53 (3.8%)	2	1/45 (2.2%)	2	10/178 (5.6%)	12	7/179 (3.9%)	8	0/53 (0%)	0	0/45 (0%)	0
Vitiligo	0/73 (0%)	0	2/53 (3.8%)	2	1/45 (2.2%)	1	14/178 (7.9%)	19	16/179 (8.9%)	19	0/53 (0%)	0	0/45 (0%)	0
Vascular disorders
Hypotension	1/73 (1.4%)	1	0/53 (0%)	0	0/45 (0%)	0	5/178 (2.8%)	7	11/179 (6.1%)	11	2/53 (3.8%)	2	3/45 (6.7%)	5
Hypertension	1/73 (1.4%)	1	2/53 (3.8%)	2	1/45 (2.2%)	1	2/178 (1.1%)	2	9/179 (5%)	9	0/53 (0%)	0	0/45 (0%)	0
Deep vein thrombosis	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	3/53 (5.7%)	3	0/45 (0%)	0
Lymphoedema	0/73 (0%)	0	0/53 (0%)	0	0/45 (0%)	0	0/178 (0%)	0	0/179 (0%)	0	3/53 (5.7%)	3	1/45 (2.2%)	1

Limitations/Caveats

[Not Specified]

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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 study 60 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission. Sponsor review can be expedited to meet publication timelines.

Results Point of Contact

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

Responsible Party:

Merck Sharp & Dohme LLC

ClinicalTrials.gov Identifier:

NCT01704287

Other Study ID Numbers:

P08719
MK-3475-002
2012-003030-17
KEYNOTE-002
P08719

First Posted:

Oct 11, 2012

Last Update Posted:

May 18, 2020

Last Verified:

Apr 1, 2020

Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Participants With Advanced Melanoma (MK-3475-002/P08719/KEYNOTE-002)

Study Details

Study Description

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Initial Treatment Period:

Switch-to-Pembrolizumab Treatment Period:

Detailed Description

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Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

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Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

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Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Statistical Analysis 5

Statistical Analysis 6

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

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